Aung Kyaw Oo

McKee’s
Pathology
of the Skin
Commissioning Editor: William R. Schmitt
Development Editors: Louise Cook & Rachael Harrison
Editorial Assistant: Kirsten Lowson
Project Manager: Nancy Arnott
Design: Kirsteen Wright
Illustration Manager: Merlyn Harvey
Marketing Manager (USA): Tracie Pasker
 

Fourth Edition

McKee’s
Pathology
of the Skin
with Clinical Correlations
Volume 1

Eduardo Calonje MD, DipRCPath Alexander Lazar MD, PhD

Director of Dermatopathology Associate Professor
Department of Dermatopathology Departments of Pathology and Dermatology
St John's Institute of Dermatology Sections of Dermatopathology and Sarcoma Pathology
St Thomas' Hospital Faculty, Sarcoma Research Center and Graduate School
London, UK of Biomedical Science
The University of Texas M.D. Anderson Cancer Center
Thomas Brenn MD, PhD, FRCPath Houston, Texas, USA
Consultant Dermatopathologist and Honorary Senior
Lecturer Editor-in-Chief
Department of Pathology
Western General Hospital and The University
Phillip H McKee MD, FRCPath
Formerly Associate Professor of Pathology and
of Edinburgh
Director, Division of Dermatopathology
Edinburgh, UK
Department of Surgical Pathology
Brigham and Women's Hospital and Harvard Medical
School
Boston, MA, USA

For additional online references and video content visit expertconsult.com

SAUNDERS an imprint of Elsevier Limited

© 2012, Elsevier Limited All rights reserved.

First edition 1989

Second edition 1996
Third edition 2005
Fourth edition 2012

The right of Eduardo Calonje, Thomas Brenn, Alexander Lazar and Phillip H McKee to be identified as author
of this work has been asserted by them in accordance with the Copyright, Designs and Patents Act 1988. No
part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
including photocopying, recording, or any information storage and retrieval system, without permission in
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Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the
individual contributions contained in it are protected under copyright by the Publisher (other than as may be
noted herein).

Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any
information, methods, compounds, or experiments described herein. In using such information or methods they
should be mindful of their own safety and the safety of others, including parties for whom they have a professional
responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most current
information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered,
to verify the recommended dose or formula, the method and duration of administration, and contraindications.
It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make
diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate
safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability
for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or
from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

British Library Cataloguing in Publication Data

McKee's Pathology of the Skin. – 4th ed.

1. Skin–Diseases. 2. Skin–Histopathology.
I. Pathology of the skin II. Calonje, Eduardo. III. McKee,
Phillip H. Pathology of the skin.
616.5'07-dc22
ISBN-13: 978 1 4160 5649 2

Printed in China
Last digit is the print number: 9  8  7  6  5  4  3  2  1
 Contents

List of Contributors vii

Preface to the fourth edition  x
Acknowledgements xi
Dedications xii
Glossary xiii

Volume 1

  1 The structure and function of skin  1 11 Diseases of the oral mucosa  362
John A. McGrath Sook-Bin Woo

  2 Specialized techniques in dermatopathology  32 12 Diseases of the anogenital skin  437

Pratistadevi A. Ramdial, Boris C. Bastian, John Goodlad, Eduardo Calonje, Sallie Neill, Chris Bunker,
John K. McGrath and Alexander Lazar Nick Francis, Alcides Chaux and Antonio C Cubilla

  3 Disorders of keratinization  46 13 Degenerative and metabolic diseases  520

Dieter Metze Nooshin Brinster and Eduardo Calonje

  4 Inherited and autoimmune subepidermal blistering 14 Cutaneous adverse reactions to drugs  590
diseases  99 Nooshin Brinster
  5 Acantholytic disorders  151
15 Neutrophilic and eosinophilic
  6 Spongiotic, psoriasiform and pustular dermatoses  631
dermatoses  180
16 Vascular diseases  658
  7 Lichenoid and interface dermatitis  219
17 Idiopathic connective tissue
Wei-Lien Wang and Alexander Lazar disorders  711
Bostjan Luzar and Eduardo Calonje
  8 Superficial and deep perivascular inflammatory
dermatoses  259
18 Infectious diseases of the skin  760
  9 Granulomatous, necrobiotic and perforating Wayne Grayson
dermatoses  281
10 Inflammatory diseases of the subcutaneous fat  326
Bostjan Luzar and Eduardo Calonje

Volume 2

19 Human immunodeficiency virus (HIV) 22 Diseases of the hair  967

and acquired immunodeficiency Rodrigo Restrepo and Eduardo Calonje
syndrome (AIDS)-associated cutaneous
diseases  896 23 Diseases of the nails  1051
Pratistadevi K. Ramdial and Wayne Grayson Josette Andre, Ursula Sass and Anne Theunis

20 Disorders of pigmentation  912 24 Tumors of the surface epithelium  1076

21 Diseases of collagen and elastic tissue  935 25 Melanocytic nevi  1150
Wei-Lien Wang and Alexander Lazar Bostjan Luzar, Boris C. Bastian and Eduardo Calonje
vi Contents

26 Melanoma  1221 30 Cutaneous metastases and Paget's disease

Boris C. Bastian and Alexander Lazar
27 Tumors of the conjunctiva  1268
Jacob Péer and Shahar Frenkel
28 Sentinel lymph node biopsies  1296
Alistair J. Cochran
29 Cutaneous lymphoproliferative
diseases and related
disorders  1311
John Goodlad and Eduardo Calonje
of the skin  1421
Doina Ivan, Alexander Lazar and Eduardo Calonje
31 Tumors of the hair follicle  1445
32 Tumors and related lesions of the sebaceous
glands  1488
33 Tumors of the sweat glands  1508
34 Cutaneous cysts  1571
35 Connective tissue tumors  1588

Index  I1
 Chapter

List of Contributors

Josette André, MD Alistair J. Cochran, MD

Head of the Dermatology and Dermatopathology Department. Distinguished Professor of Pathology and Laboratory
CHU Saint-Pierre - CHU Brugmann Medicine and Surgery
Hôpital Universitaire des Enfants Reine Fabiola Department of Pathology and Laboratory Medicine
Université Libre de Bruxelles David Geffen School of Medicine at UCLA
Brussels, Belgium Los Angeles, CA, USA
Ch 23: Diseases of the nails with Ursula Sass and Anne Ch 28: Sentinel node biopsies
Theunis

Boris C. Bastian, MD Antonio C. Cubilla, MD

Instituto de Patología e Investigación
Chairman, Department of Pathology
Asuncion, Paraguay
The James Ewing Alumni Chair
Ch 12: Diseases of the anogenital skin with Eduardo
Member, Human Oncology and Pathogenesis Program
Calonje, Sallie Neill, Chris Bunker, Nick Francis and Alcides
Memorial Sloan-Kettering Cancer Center
Chaux
Professor of Pathology
Weill Cornell Medical College
New York, NY, USA Nick Francis, FRCPath
Ch 2: Specialized techniques in dermatopathology with
Consultant Histopathologist
Pratistadevi K Ramdial, John Goodlad, John A. McGrath and
Imperial College Healthcare NHS trust
Alexander Lazar
Honorary Senior Lecturer
Ch 25: Melanocytic nevi with Eduardo Calonje
Imperial College Faculty of Medicine
Ch 26: Melanoma with Alexander Lazar
London, UK
Ch 12: Diseases of the anogenital skin with Eduardo
Nooshin K. Brinster, MD Calonje, Sallie Neill, Chris Bunker, Alcides Chaux, Antonio C
Assistant Professor Cubilla
Department of Pathology and Dermatology
Director of Dermatopathology
VCU Medical Center Shahar Frenkel, MD, PhD
Richmond, VA, USA Ocular Oncologist and Ophthalmic Pathologist
Ch 13: Degenerative and metabolic diseases Specialized Ocular Oncology Service
Ch 14: Cutaneous adverse reactions to drugs Ophthalmic Pathology Laboratory
Jerusalem, Israel
Chris Bunker, MA, MD, FRCP Lecturer in Ophthalmology
Department of Ophthalmology
Consultant Dermatologist
Hadassah – Hebrew University Medical Center
University College and Chelsea and Westminster Hospitals
Jerusalem, Israel
London;
Ch 27: Tumors of the conjunctiva with Jacob Pe'er
Professor of Dermatology
University College London
London, UK John Goodlad, MD, FRCPath
Ch 12: Diseases of the anogenital skin with Eduardo Calonje,
Consultant Haematopathologist and Honorary
Sallie Neill, Nick Francis, Alcides Chaux, Antonio C Cubilla
Senior Lecturer
Department of Pathology
Alcides Chaux, MD Western General Hospital and University of Edinburgh
GU Research Fellow, Edinburgh, UK
Department of Pathology Ch 2: Specialized techniques in dermatopathology with
Johns Hopkins University School of Medicine Pratistadevi K Ramdial, Boris C. Bastian, John A. McGrath and
Baltimore, MD, USA Alexander Lazar
Ch 12: Diseases of the anogenital skin with Eduardo Calonje, Ch 29 Cutaneous lymphoproliferative diseases and related
Sallie Neill, Chris Bunker, Nick Francis, and Antonio C Cubilla disorders with Eduardo Calonje
viii List of Contributors

Wayne Grayson, MBChB, PhD, FCPath(SA) Sallie Neill, MB ChB, FRCP

Consultant Anatomical Pathologist and Dermatopathologist Consultant Dermatologist
AMPATH National Laboratories; Guys and St Thomas' NHS Trust
Honorary Associate Professor London, UK
School of Pathology Ch 12: Diseases of the anogenital skin with Eduardo Calonje,
University of the Witwatersrand, Johannesburg Chris Bunker, Nick Francis, Alcides Chaux, Antonio C Cubilla
Johannesburg, South Africa
Ch 18: Infectious diseases of the skin
Ch 19: Human immunodeficiency virus (HIV) and Jacob Pe'er, MD
acquired immunodeficiency syndrome Professor and Chairman
(AIDS)-associated cutaneous diseases with Department of Ophthalmology
Pratistadevi K Ramdial Jonas Friedenwald Professor of Ophthalmic Research
Hadassah – Hebrew University Medical Center
Jerusalem, Israel
Doina Ivan, MD Ch 27: Tumors of the conjunctiva with Shahar Frenkel
Assistant Professor
Departments of Pathology and Dermatology
Section of Dermatopathology Pratistadevi K. Ramdial, MBChB, FCPath(SA)
The University of Texas M.D. Anderson Cancer Center Professor and Head
Houston, TX, USA Department of Anatomical Pathology
Ch 30: Cutaneous metastases and Paget's disease Nelson R. Mandela School of Medicine
of the skin with Alexander Lazar and Eduardo Calonje University of Kwazulu-Natal and the National Health
Laboratory Service
Durban, South Africa
Boštjan Luzar, MD, PhD Ch 2: Specialized techniques in dermatopathology with
Professor of Pathology Boris C. Bastian, John Goodlad, John A. McGrath and
Consultant Pathologist Alexander Lazar
Institute of Pathology Ch 19: Human immunodeficiency virus (HIV) and acquired
Medical Faculty University of Ljubljana immunodeficiency syndrome (AIDS)-associated cutaneous
Ljubljana, Slovenia diseases with Wayne Grayson
Ch 10: Inflammatory diseases of the subcutaneous fat with
Eduardo Calonje
Ch 17: Idiopathic connective tissue disorders with Eduardo Rodrigo Restrepo, MD
Calonje Director, Dermatopathology Fellowship Program
Universidad CES;
Professor of Dermatopathology
John A. McGrath, MD, FRCP Universidad Pontificia Bolivariana;
Professor of Molecular Pathology Director, Laboratory of Pathology
St John's Institute of Dermatology Clinica Medellin
King's College London Medellin, Colombia
Guy's Hospital Ch 22: Diseases of the hair with Eduardo Calonje
London, UK
Ch 1: The structure and function of skin
Ch 2: Specialized techniques in dermatopathology with Ursula Sass, MD
Pratistadevi K Ramdial, Boris C. Bastian, John Goodlad and Assistant Professor
Alexander Lazar Dermatology and Dermatopathology Department
CHU Saint-Pierre
Université Libre de Bruxelles
Dieter Metze, MD Brussels, Belgium
Professor of Dermatology Ch 23: Diseases of the nails with Josette André and Anne
Director, Dermatopathology Unit Theunis
Department of Dermatology
University Hospital Münster
Münster, Germany
Ch 3: Disorders of keratinization
 List of Contributors ix

Anne Theunis, MD Sook-Bin Woo, DMD, MMSc

Assistant Professor Associate Professor
Dermatopathology and Pathology Department Department of Oral Medicine, Infection and Immunity
CHU Saint-Pierre and Institut Bordet Harvard School of Dental Medicine, Boston, MA, USA;
Université Libre de Bruxelles Attending Dentist and Consultant Pathologist
Brussels, Belgium Brigham and Women's Hospital
Ch 23: Diseases of the nails with Josette André and Ursula Boston, MA, USA
Sass Co-Director
Center for Oral Pathology Strata Pathology Services Inc.
Wei-Lien Wang, MD Lexington, MA, USA
Assistant Professor Ch 11: Diseases of the oral mucosa
Department of Pathology
Sections of Dermatopathology and Sarcoma Pathology
The University of Texas M.D. Anderson Cancer Center
Houston, TX, USA
Ch 7: Lichenoid and interface dermatoses with Alexander
Lazar
Ch 21: Diseases of collagen and elastic tissue with Alexander
Lazar
 Preface to the fourth edition
It is hard to believe that sometime in 1988, when I was just starting my
training in dermatopathology, I met Phillip McKee at a course on soft tissue
tumors organized in London by an unforgettable teacher, Dr Chris Fletcher.
When Phillip heard about my interest in dermatopathology he said to me
“I am writing a textbook in dermatopathology and you must buy it”. So I
did, little suspecting that I was going to become heavily involved in the third
edition and the main editor to the fourth edition with the invaluable help
of Thomas Brenn and Alex Lazar. During the 1980s immunohistochemistry
was a relatively new diagnostic technique becoming in this age an invaluable
ancillary tool that has been instrumental in research and in diagnostic pathol-
ogy. During the same period molecular biology was being developed as a
powerful research mechanism in pathology, becoming an additional and cru-
cial aid in diagnosis in the fields of hematopathology and soft tissue tumors in
the 1990s. Furthermore, some of these developments in the latter fields have
allowed an understanding of many aspects of the pathogenesis of neoplasia,
and this has led to the ever expanding use of targeted therapy in the 21st cen-
tury. These advances have had an important impact in dermatopathology, and
more exciting developments have followed in research, diagnosis and under-
standing of the pathogenesis of neoplastic processes that are of particular
importance in the skin, particularly melanocytic neoplasms. This is ongoing
work with many questions still unanswered and although with great limita-
tions particularly in the field of diagnosis, it has nonetheless allowed immense
understanding of pathogenesis and the development of some targeted thera-
pies for melanoma some with very promising although limited results.
In this edition we have invited a number of experts to contribute in their
areas of expertise realizing that it is very difficult if not impossible for a hand-
ful of people to cover such an extensive area as dermatopathology. We have
tried to include as much material as possible encompassing most of what is
new in the literature but realize that inevitably this cannot be achieved to
complete satisfaction. The third edition of this book was received with great
enthusiasm by many people all over the world and we hope to have fulfilled
the task and answered their criticisms in this new edition.
Eduardo Calonje
The fourth edition has been a huge undertaking and taken an immense amount
of time and energy. I would first like to congratulate Eduardo Calonje for doing
a wonderful job against a background of a heavy daily workload and lecture
commitment. I decided that having left hospital practice and been in charge of
the book for three editions, that it was high time for new blood to take over
control of the new edition while I became overall editor-in-chief. I have known
Eduardo since the early 1980's during which time he has become more than just
a close friend; both Gracie and I regard him as one of the family. He is a superb
dermatopathologist (without question Europe's leading light) and I had every
confidence that he would produce a wonderful new edition of Pathology of the
Skin. Needless to say he has gone beyond my greatest expectation and produced
a truly magnificent fourth edition. Words cannot express my gratitude.
Thomas Brenn and Alex Lazar are also both very close friends and also
regarded by me as members of the family. They both took on much greater
responsibilities in the fourth edition than in the third edition and have done
a wonderful job. I am deeply indebted to them. Similar to Eduardo this was
accomplished in a background of both a heavy routine workload and research
commitment.
When planning a new edition, it has been my practice to try to make the
new edition as different as possible from the preceding one to ensure that
people who buy the book get true value for money. To this end, a number
of new chapters have been added including, specialized techniques in der-
matopathology, sentinel lymph node biopsy pathology, the pathology of
HIV/AIDS and tumors of the conjunctiva. The oral pathology chapter has
been expanded to include tumors of the salivary glands. We have taken
on a large number of very experienced excellent new authors to bring per-
sonal experience to many of the more difficult topics and this has certainly
paid dividends. Much progress has been achieved in our understanding of
the pathogenesis of disease and this is reflected in the new text with up-to-
date scientific data. I am deeply indebted to all of our new contributors.
The Fourth edition is certainly a very different book than the first edition
which I wrote for fun almost single handedly as an atlas with integrated
text.
In order to increase valuable space for the increased figures, enlarged text and
new chapters, it was decided to make the references an online only component
of the book. This has allowed us to considerably expand the text and increase
the number of figures in the book, a large proportion of which are new.
I am also heavily indebted to my two friends in the publishing world -
Louise Cook and Bill Schmitt. I have been associated with Louise for more
years than I choose to remember and she has always proven to be a pillar of
support particularly during the numerous episodes of stress that are inevi-
table in a task of this magnitude. I thank her for always being there when
help was necessary. I met Bill when I moved to the United States and he has
also become a great friend in addition to being the senior Elsevier represen-
tative overseeing the progress of the book. Similar to Louise he has had to
put up with much from me and has always steered the project with a steady
hand during all of its crises which have been innumerable. Producing the
Fourth edition would have been an even harder task without their input.
More recently I have worked with Nancy Arnott in Edinburgh. She has been
the senior editor of the project and most certainly done a wonderful job. The
editors and contributors owe her an awful lot.
Lastly and most importantly, I owe so much as always to Gracie. She has
had to put up with me for the past 4 years while working on the new edition.
This has been no mean feat. She has let my ill temper and moods of depres-
sion and anxiety wash over her and in her own thoughtful quiet way made
the seemingly impossible possible. I would never have been able to complete
this task without her loyalty, support and love.
Phillip H. McKee
 Acknowledgements
Working for so many years on a book of this proportion, especially when the
task is something that has to be done as a “hobby” after formal work hours,
represents a daunting task. I often wondered in times of despair whether the
job was ever going to be finished. It has finally been completed and I would
not have been able to achieve this without the invaluable help of many peo-
ple. They not only gave me emotional support but often went out of their
way to help me with the many details necessary to finalize the numerous
tasks that this job entailed. My wife Claudia has always given me her unwav-
ering support no matter how trying the challenge ahead. My children Mateo
and Isabella have given me their patience and understanding. Numerous col-
leagues, many of them visiting fellows from many different countries, have
made my life easy in millions of ways and I cannot thank them enough for
their patience, hard work and mainly for being wonderful human beings sup-
porting me in what for many reasons were the darkest days of my life. I espe-
cially want to show my appreciation to Drs Maiko Tanaka, Anoud Zidan,
Vicki Howard, Viky Damaskou, Thomas Brenn, Bostjan Luzar, Ravi Ratnavel,
Rathi Ramakrishnan and Gregory Spiegel (who sadly died last year).
EC
The path of life is often determined by the people we encounter. There are
many ways in which certain individuals touch our hearts, steer us in the right
direction and help us achieve goals which would have been unattainable oth-
erwise. Words aren't ever enough to really show one's true appreciation for
the generosity, support and motivation received over the years.
My wonderful, loving parents, Sonja and Walter, have always been there
for me and supported my every move. My wife and daughter, Anne and Yaëlle,
have had a terrible time dealing with my tempers throughout the writing of
this book. They have always stood by my side and saved a smile for me for
which I am ever so grateful. My professional life could have gone very wrong
indeed had it not been for the kindness and gracious support from these truly
unique mentors and teachers Uta Francke, Heinz Furthmayr, Ramzi Cotran
and Christopher Fletcher. Finally, there is so much I owe to these two won-
derful individuals who have become very close friends, Phillip McKee and
Eduardo Calonje.
TB
Academic life is a complex web of mentors, colleagues and students. I have
been lucky to have worked with a number of fine mentors and colleagues
who strongly influenced my thinking in pathology in general and/or in der-
matopathology specifically: Chris Fletcher, Scott Granter, George Murphy,
Ramzi Cotran (deceased), Chris Crum, Bill Welch, Rob Odze, Jon Aster,
Felix Brown (deceased), Jason Hornick, John Iafrate, Marcus Bosenberg,
Jonathan Fletcher, Marty Mihm, Lyn Duncan, Steve Tahan, Steve Lyle, Victor
Prieto, Harry Evans, Sharon Weiss, Bogdan Czerniak, Frasier Symmans,
Ken Aldape, Russell Broaddus, Greg Fuller, Mike Davies, Jon Reed, John
Goldblum, David Berman, Vinay Kumar, Marc Ladanyi, Matt van de Rijn,
Brian Rubin, Jesse McKenney, Steve Billings, Howard Gerber, Ron Rapini,
Julia Bridge, Paula dal Cin, Andre Oliveira, Pancras Hogendoorn, Paulo Dei
Tos, Andrew Folpe, Judith Bovee, Lola Lopez-Terrada, Cristina Antonescu,
along with numerous others I have encountered either directly or through
their writing and lecturing. This extended list testifies not only to my good
fortune in meeting so many wonderful people, but also the generosity of
academic pathologists as a group. I have many other friends in pathology
and medicine who shall have to remain nameless due to space constraints,
but this line hails that brilliant group. The other authors and editors of
this present work have been a joy to work with and I have benefited much
from these interactions. The Dermatopathology Section at my institution
has a delightful combination of great people and fascinating diagnostic
material. My former Chairman of Pathology, Janet Bruner, was enthusi-
astic and supportive of this project from our first conversation regarding
it. Another group of colleagues including Ralph Pollock, Dina Lev and the
entire Sarcoma Research Center have done more than their share to help
me balance the demands of clinical work, research, grants, papers and this
book. The talented staff at Elsevier provided invaluable support through-
out this project. Last, but certainly not least, I am indebted to my trainees.
On a daily basis, they remind me of the marvels of what we do, ask difficult
and challenging questions, prompt re-examination of assumptions, expose
biases, and force clarity and reproducibility in diagnostic criteria; may we
all retain these characteristics of motivated students throughout our career.
For all of this, I am humbled and grateful.
AL
 Dedications

To my wife Claudia who always gives without expecting anything in return.

To my children Mateo and Isabella and to the memory of my parents Julio
and Alicia both of whom passed away while this edition was in production.
EC

To Anne, Yaelle, Sanja and Walter.

TB

I am assured that my two beautiful children, Elliott and Abigail, have no

memories that predate me working on this book. I hope that this example of
what fascination with a subject, continued application to a task, and working
as a disciplined team can accomplish will be a small, but meaningful substi-
tution for the time designated to this endeavor. My wife, Victoria, has been
ever supportive in every way despite having an extremely busy and demand-
ing career in law as has been my mother-in-law Sara. My parents, Joe and
Glenda, always allowed me the freedom to pursue my own interests and the
encouragement and support to accomplish them, a wonderful gift I hope to
pass on to my children as well.
AL

This new edition is dedicated to my wife and best friend Gracie with all my
love
PHM
 Glossary
5-ARD 5-a-reductase
AA alopecia areata
ACE angiotensin converting enzyme
[inhibitor]
AgNORS argyrophilic nucleolar organizer regions
AHNMD associated clonal hematological
non-mast cell lineage disease
AIDS acquired immunodeficiency syndrome
AILD angioimmunoblastic lymphadenopathy
with dysproteinemia
ALA aminolevulinic acid
ALK anaplastic lymphoma kinase
ALK1 activin-like receptor kinase 1
ALM acral lentiginous melanoma
AN acanthosis nigricans
ANA antinuclear antibodies
ANCA antineutrophil cytoplasmic antibodies
API2 apoptosis inhibitor-2
ARC AIDS-related complex
ATF1 activating transcription factor 1
ATLL adult T-cell leukemia/lymphoma
BANS back, arm, neck and scalp [sites]
BB mid borderline leprosy
BCC basal cell carcinoma
BCG bacille Calmette–Guérin
B-FGF basic fibroblast growth factor
BIDS brittle sulfur-deficient hair, intellectual
impairment, decreased fertility and
short stature
BL borderline lepromatous leprosy
BLAISE Blaschko linear acquired inflammatory
skin eruption
BMP bone morphogenetic protein
BP bullous pemphigoid
BPA bullous pemphigoid antigen
BSAP B-cell-specific activator protein
BSLE bullous systemic lupus erythematosus
BT borderline tuberculoid leprosy
C3NeF C3 nephritic factor
CAD chronic actinic dermatitis
cAMP cyclic adenosine 3'-5'- monophosphate
c-ANCA cytoplasmic-antineutrophil cytoplasmic
antibodies
CDC Centers for Disease Control and
Prevention
CEA carcinoembryonic antigen
CGRP calcitonin-gene-related polypeptide
CHILD congenital hemidysplasia with
ichthyosiform nevus and limb defects
[syndrome]
CK cytokeratin
CLA cutaneous lymphocyte antigen
CLL chronic lymphocytic leukemia
CMG capillary morphogenesis protein
CNS central nervous system
CP cicatricial pemphigoid (mucous membrane
pemphigoid)
CRASP complement regulator-acquiring surface
protein
CREST calcinosis, Raynaud’s phenomenon,
esophageal dysfunction, sclerodactyly,
telangiectasis [syndrome]
CTCL cutaneous T-cell lymphoma
dcSSc diffuse cutaneous systemic sclerosis
DDEB dominant dystrophic epidermolysis
bullosa
DEB dystrophic epidermolysis bullosa
DH dermatitis herpetiformis
DIC disseminated intravascular coagulation
DIMF direct immunofluorescence
DLE discoid lupus erythematosus
DNCB dinitrochlorobenzene
DSAP disseminated superficial actinic
porokeratosis
Dsc desmocollin
dsDNA double-stranded DNA
Dsg desmoglein
DSP disseminated superficial porokeratosis
EB epidermolysis bullosa
EBA epidermolysis bullosa acquisita
EBS epidermolysis bullosa simplex
EBS-DM epidermolysis bullosa simplex,
Dowling–Meara
EBS-K epidermolysis bullosa simplex, Koebner
EBS-MD epidermolysis bullosa simplex with
muscular dystrophy
EBS-WC epidermolysis bullosa simplex,
Weber–Cockayne
EBV Epstein–Barr virus
ECE endothelin-converting enzyme
ECM extracellular membrane
EDS Ehlers–Danlos syndrome
EGFR endothelial growth factor receptor
ELAM endothelial leukocyte adhesion
molecule
ELISA enzyme-linked immunosorbent assay
EM electron microscopy
EMA epithelial membrane antigen
ENA extractable nuclear antigen
ENL erythema nodosum leprosum
EPPER eosinophilic, polymorphic and
pruritic eruption associated with
radiotherapy
EPPK epidermolytic palmoplantar
keratoderma
EPS extracellular polysaccharide substance
ESR erythrocyte sedimentation rate
ETA exfoliative toxin A
ETB exfoliative toxin B
EV epidermodysplasia verruciformis
EWSR1 Ewing’s sarcoma [proto-oncogene]
FACE facial Afro-Caribbean childhood
eruption
FADS fetal akinesia deformation sequence
FAMMM familial atypical multiple mole
melanoma [syndrome]
FAP familial adenomatous polyposis
FAPA fever, aphthous stomatitis, pharyngitis,
adenitis [syndrome]
FHIT fragile histidine triad
FIGURE facial idiopathic granulomata with
regressive evolution
FISH fluorescent in situ hybridization
GA granuloma annulare
GABEB generalized atrophic benign
epidermolysis bullosa
GCDFP gross cystic disease fluid protein
G-CSF granulocyte-colony stimulating
factor
GFAP glial fibrillary acidic protein
GM-CSF granulocyte–macrophage colony
stimulating factor
GSE gluten-sensitive enteropathy
GVHD graft-versus-host disease
HA hyperandrogenism
HAART highly active antiretroviral therapy
HAIR-AN hyperandrogenism–insulin resistance–
acanthosis nigricans [syndrome]
HBV hepatitis B virus
HDL high density lipoprotein
HF hemorrhagic fever
HG herpes gestationis
HHV human herpesvirus
HIT heparin-induced thrombocytopenia
[syndrome]
HIV human immunodeficiency virus
HLA human leukocyte antigen
HMFG human milk fat globulin
HNPCC hereditary non-polyposis colorectal
carcinoma [syndrome]
HPF (hpf) high power fields
HPL hyperlipoproteinemia
HPV human papillomavirus
HRF histamine-releasing factor
HSP heat shock protein
HSV herpes simplex virus
HTLV human T-cell lymphotropic virus
hTR telomerase RNA
HUS hemolytic uremic syndrome
IBIDS ichthyosis and BIDS (see BIDS above)
ICAM intercellular adhesion molecule
ICH indeterminate cell histiocytosis
IDL intermediate density lipoproteins
IEN intraepidermal neutrophilic [IgA
dermatosis variant]
IFAP ichthyosis follicularis–alopecia–
photophobia [syndrome]; intermediate
filament associated protein
IFN interferon
Ig immunoglobulin
IIMF indirect immunofluorescence
xiv Glossary
ILVEN inflammatory linear verrucous
epidermal nevus
IMF immunofluorescence
IP inducible protein; immunoprecipitation
IR insulin resistance
ISSVD International Society for the Study of
Vulvovaginal Disease
JEB junctional epidermolysis bullosa
JEB-H junctional epidermolysis bullosa,
Herlitz
JEB-nH junctional epidermolysis bullosa,
non-Herlitz
JEB-PA junctional epidermolysis bullosa with
pyloric atresia
KID keratitis–ichthyosis–deafness
[syndrome]
KOH potassium hydroxide
KPAF keratosis pilaris atrophicans facei
L&H cells lymphocytic and/or histiocytic
Reed–Sternberg cell variants
LAD linear IgA disease
LATS long-acting thyroid stimulator
LCA leukocyte common antigen
LCH Langerhans’ cell histiocytosis
lcSSc limited cutaneous systemic sclerosis
LDL low density lipoprotein
LE lupus erythematosus
LFA lymphocyte function-associated
antigen
LH–RH luteinizing hormone–releasing hormone
LL lamina lucida; lepromatous leprosy
LP lichen planus
LPP lichen planus pemphigoides
LS lichen sclerosus
LYVE lymphatic vessel endothelial
[hyaluronan receptor]
MAC membrane attack complex
MAI M. avium intracellulare
MALT mucosa-associated lymphoid tissue
MART-1 melanoma antigen recognized by
T-cells 1
MBP myelin basic protein
MC1R melanocortin-1 receptor
MCGN mesangiocapillary glomerulonephritis
MCP molecule chemoattractant protein
M-CSF macrophage colony stimulating factor
MCTD mixed connective tissue disease
MDR multidrug resistance gene
Mel-CAM melanoma cell adhesion molecule
MEN multiple endocrine neoplasia
[syndrome]
MFH malignant fibrous histiocytoma
MGS/ melanoma growth stimulatory
GRO activity
MHC major histocompatibility complex
miH minor histocompatibility complex
MITF microphthalmia transcription factor
MMP matrix metalloproteinase
MMR mismatch repair
MSA muscle-specific actin
MSI microsatellite instability
NADH nicotine adenine dinucleotide, reduced
nDNA native [double-stranded] DNA
NEMO nuclear factor [NF]-kappaB gene
modulator
NF necrotizing fasciitis
NFI neurofibromatosis type I
NFII neurofibromatosis type II
NFP neurofilament protein
NIH National Institutes of Health
NISH non-isotopic in situ hybridization
NK natural killer
NL necrobiosis lipoidica
NRAMP1 natural resistance-associated
macrophage protein 1
NSAIDs non-steroidal anti-inflammatory drugs
NSE neuron-specific enolase
OL-EDA- osteopetrosis, lymphedema,
ID anhidrotic ectodermal dysplasia,
immunodeficiency [syndrome]
ORF open reading frame
PAIN perianal intraepithelial neoplasia
p-ANCA perinuclear-antineutrophil cytoplasmic
antibodies
PAPA pyogenic sterile arthritis, pyoderma
gangrenosum and acne [syndrome]
PAS periodic acid–Schiff
PBG porphobilinogen
PCNA proliferating cell nuclear antigen
PCR polymerase chain reaction
PDGFβ platelet-derived growth factor b
PECAM platelet endothelial cell adhesion
molecule
PEComa perivascular epithelioid cell tumor
PGL phenolic glycolipid
PGP protein gene product
PGWG purely granulomatous Wegener’s
granulomatosis
PI protease inhibitor
PIBIDS photosensitivity and IBIDS (see IBIDS
above)
PILA papillary intralymphatic
angioendothelioma
PLEVA pityriasis lichenoides et varioliformis acuta
PNET primitive neuroectodermal tumor
POEMS polyneuropathy, organomegaly,
endocrinopathy, M-protein and skin
changes [syndrome]
PPD purified protein derivative
PPDL pure and primitive diffuse leprosy
PPK palmoplantar keratoderma
pRB retinoblastoma protein
PSS progressive systemic sclerosis
PTEN phosphatase and tensin homolog
PUPPP pruritic urticarial papules and plaques
of pregnancy
PUVA psoralen plus ultraviolet light of
A [long] wavelength
r IL-2 recombinant interleukin 2
RBC red blood cell
RDEB recessive dystrophic epidermolysis
bullosa
RDEB-HS recessive dystrophic epidermolysis
bullosa, Hallopeau–Siemens
RDEB- recessive dystrophic
nHS epidermolysis bullosa, non-Hallopeau–
Siemens
RER rough endoplasmic reticulum
RNP ribonucleoprotein
RT-PCR reverse transcription polymerase chain
reaction
SA syphilitic alopecia
SA1 slowly adapting type-1
[mechanoreceptor]
SALE summertime actinic lichenoid eruption
SALT skin-associated lymphoid tissue
SAPHO synovitis, acne, pustulosis, hyperostosis,
osteitis [syndrome]
SCC squamous cell carcinoma
SCH squamous cell hyperplasia
SCID severe combined immunodeficiency
SCLE subacute cutaneous lupus
erythematosus
scRNP small cytoplasmic ribonuclear protein
SEA staphylococcal enterotoxin A
SEB staphylococcal enterotoxin B
Shh Sonic Hedgehog
SIBIDS osteosclerosis and IBIDS (see IBIDS
above)
SIL squamous intraepithelial lesion
SLE systemic lupus erythematosus
SLL small lymphocytic lymphoma
SMA smooth muscle actin
snRNP small nuclear ribonuclear protein
SPD subcorneal pustular dermatosis
SPRRs small proline rich proteins/cornifins
SPTL subcutaneous panniculitis-like T-cell
lymphoma
SRP signal recognition particle
ssDNA single-stranded DNA
SSSS staphylococcal scalded skin syndrome
STD sexually transmitted disease
sub-LD sub-lamina densa
TCR T-cell receptor
TEN toxic epidermal necrolysis
TFIIH transcription/DNA repair factor IIH
TGF transforming growth factor
thio- triethylene thiophosphoramide
TEPA
TIMP tissue inhibitor of metalloproteinase
TNF tumor necrosis factor
TORCH toxoplasmosis, other infections, rubella,
cytomegalovirus and herpes simplex
[syndrome]
TRAPS tumor necrosis factor receptor-
associated periodic syndrome
TSST toxic shock syndrome toxin
TT tuberculoid leprosy
tTA tetracycline transactivator [transcription
factor]
TTF-1 thyroid-transcription factor 1
tTG tissue transglutaminase
TTP thrombotic thrombocytopenic
purpura
UPS undifferentiated pleomorphic sarcoma
URO uroporphyrinogen
URO-D uroporphyrinogen decarboxylase
URR upstream regulatory region
UV ultraviolet
UVA ultraviolet A
UVB ultraviolet B
UVL ultraviolet light
VCAM vascular cell adhesion molecule
VEGF vascular endothelial growth factor
VEGFR vascular endothelial growth factor receptor
VIN vulval intraepithelial neoplasia
VIP vasoactive intestinal peptide
VLDL very low density lipoprotein
VZV varicella-zoster virus
wrfr wrinkle free [mouse model]
XP xeroderma pigmentosum
 The structure and function
See
www.expertconsult.com
for references and
additional material
of skin
Properties of skin  1 Melanocytes  10
Normal epidermal histology  1 Merkel cells  12
Regional variations in skin anatomy  2 Intercellular junctions  13
Skin development  2 Pilosebaceous units  15
Keratinocyte biology  5 Eccrine glands  17
Epidermal stem cells  6 Apocrine glands  19
Skin barrier  8 Dermal–epidermal junction  21
Skin immunity  9 Dermal collagen  22
Skin is a double-layered membrane covering the exterior of the body and
consists of a stratified cellular epidermis and an underlying dermis of con-
nective tissue. In adults, the skin weighs over 5 kg and covers a surface area
approaching 2 m2. The epidermis is mainly composed of keratinocytes and is
typically 0.05–0.1 mm in thickness. The dermis contains collagen, elastic tis-
sue and ground substance and is of variable thickness, from 0.5 mm on the
eyelid or scrotum to more than 5 mm on the back (Fig. 1.1).
The dermis is subdivided into a more superficial component (the papillary
dermis) which is bounded inferiorly by the superficial vascular plexus and an
underlying much thicker reticular dermis. Below the dermis is a layer of sub-
cutaneous fat which is separated from the rest of the body by a vestigial layer
of striated muscle.
Properties of skin
A key role of skin is to provide a mechanical barrier against the external
environment. The cornified cell envelope and the stratum corneum restrict
water loss from the skin while keratinocyte-derived endogenous antibiot-
ics (defensins and cathelicidins) provide an innate immune defense against
bacteria, viruses and fungi. The epidermis also contains a network of about
2 × 109 Langerhans cells which serve as sentinel cells whose prime function
is to survey the epidermal environment and to initiate immune responses
against microbial threats. Melanin, which is mostly found in basal keratino-
cytes, provides some protection against DNA damage from ultraviolet radia-
tion. An important function of skin is thermoregulation. Vasodilatation or
­vasoconstriction of the blood vessels in the deep or superficial plexuses helps
regulate heat loss. Eccrine sweat glands are found at all skin sites and are
present in densities of 100–600/cm2; they play a role in heat control and
aspects of metabolism. Secretions from apocrine sweat glands contribute to
body odor. Skin lubrication and waterproofing is provided by sebum secreted
from sebaceous glands. Subcutaneous fat has important roles in cushioning
trauma as well as providing insulation and a calorie reserve. Fat also has an
endocrine function and contributes to tissue remodeling and phagocytosis.
Nails provide protection to the ends of the fingers and toes as well as being
important in pinching and prising objects. Hair may have important social
and psychological value. Skin also has a key function in synthesizing various
metabolic products, such as vitamin D.
Chapter
John A. McGrath
1
Dermal elastic tissue  24
Ground substance  26
Fibroblast biology  26
Cutaneous blood vessels and
lymphatics  27
Nervous system of the skin  28
Subcutaneous fat  30
Normal epidermal histology
Although the basic structure is relatively constant at various skin sites, there
are often clear differences which enable one to determine the site of origin.
The epidermis consists of four clearly defined layers or strata:
• Basal cell layer (stratum basale)
• Prickle cell layer (stratum spinosum)
• Granular cell layer (stratum granulosum)
• Keratin layer (stratum corneum)
An eosinophilic acellular layer known as the stratum lucidum is sometimes
seen in skin from the palms and soles (Fig. 1.2).
Basal cells are cuboidal or columnar with a large nucleus typically con-
taining a conspicuous nucleolus. Small numbers of mitoses may be evident.
Clear cells are also present in the basal layer of the epidermis; these repre-
sent melanocytes. Cells with clear cytoplasm seen in the stratum spinosum
represent Langerhans cells. Very occasional Merkel cells may also be present
but these are not easily identified in hematoxylin and eosin stained sections.
Histologically, prickle cells are polygonal in outline, have abundant eosino-
philic cytoplasm and oval vesicular nuclei, often with conspicuous nucleoli.
Keratohyalin granules typify the granular cell layer (Fig. 1.3). Further matu-
ration leads to loss of nuclei and flattening of the keratinocytes to form the
plates of the keratin layer (stratum corneum). Adjacent cells are united at
their free borders by intercellular bridges (prickles), which are most clearly
identifiable in the prickle cell layer and in disease states of the skin where
there is marked intercellular edema (spongiosis) (Fig. 1.4).
Toker cells represent an additional clear cell population, which may be
found in nipple epidermis of both sexes in up to 10% of the population.1 The
cells are large, polygonal or oval and have abundant pale staining or clear
cytoplasm with vesicular nuclei often containing prominent, albeit small,
nucleoli. The cytoplasm is mucicarmine and PAS negative.1 The cells may be
distributed singly but more often they are found as small clusters, not uncom-
monly forming single layered ductules.1 They are located along the basal layer
of the epidermis or suprabasally and are also sometimes seen within the epi-
thelium of the terminal lactiferous duct.
Toker cells are of particular importance as they may be mistaken by the
unwary as Paget cells. They are thought to be the source of mammary Paget's
disease in those exceptional cases where an underlying ductal carcinoma is
2 The structure and function of skin

Fig. 1.1
Skin from forearm: there is a fairly thin epidermis. Compare the thickness of the Fig. 1.4
dermis with that from the back (see Fig. 1.5). Spongiosis: the
intercellular bridges
(prickles) are stretched
and more visible in this
biopsy from a patient with
acute eczema.

absent.2 Toker cells express CK7, AE1, CAM 5.2, epithelial membrane anti-
gen (EMA), cerbB2, estrogen and progesterone receptors.3,4 They do not
express p53 or CD138. Carcinoembryonic antigen (CEA) may also be present
albeit weakly.4 Paget's cells by way of contrast are often negative for estrogen
and progesterone receptors and are p53 and CD138 positive.4

Regional variations in skin anatomy

There are two main kinds of human skin: glabrous skin (nonhairy skin)
and hair-bearing skin. Glabrous skin is found on the palms and soles. It
has a grooved surface with alternating ridges and sulci giving rise to the
dermatoglyphics (fingerprints). Glabrous skin has a compact, thick stratum
­corneum, and contains encapsulated sense organs within the dermis but no
hair follicles or sebaceous glands. In contrast, hair-bearing skin has both
Fig. 1.2
Skin from palm: note the eosinophilic stratum lucidum clearly separating the
hair follicles and sebaceous glands but lacks encapsulated sense organs.
granular cell layer from the overlying stratum corneum. Hair follicle size, structure and density can vary between different body
sites. For example, the scalp has large hair follicles that may extend into
subcutaneous fat whereas the forehead has only small vellus hair-producing
follicles although sebaceous glands are large. The number of hair follicles
does not alter until middle life but there is a changing balance between vel-
lus and terminal hairs throughout life. In hair-bearing sites, such as the
axilla, there are apocrine glands in addition to the eccrine sweat glands.
Sebaceous glands are active in the newborn, and from puberty onwards,
and the relative activity modifies the composition of the skin surface lipids.
The structure of the dermal–epidermal junction also shows regional vari-
ations in the number of hemidesmosomal-anchoring filament complexes
(more in the leg than the arm). In the dermis, the arrangement and size
of elastic fibers ­varies from very large fibers in perianal skin to almost no
fibers in the scrotum. Marked variation in the cutaneous blood supply is
found between areas of distensible skin such as the eyelid and more rigid
areas such as the fingertips.
Regional variation in skin structure is illustrated in Figures 1.5–1.20.

Skin development
Two major embryological elements juxtapose to form skin. These comprise
Fig. 1.3 the prospective epidermis that originates from a surface area of the early
Skin from palm: there is a conspicuous granular cell layer. ­gastrula, and the prospective mesoderm that comes into contact with the

Fig. 1.5
Skin from the lower
back: at this site the
dermis is very thick
and is characterized by
broad parallel fascicles of
collagen.
Fig. 1.6
Skin of the nose: there are conspicuous sebaceous glands: at this site, they often
drain directly onto the skin surface. These appearances should not be confused
with that of sebaceous hyperplasia.
inner surface of the epidermis during gastrulation. The mesoderm generates
the dermis and is involved in the differentiation of epidermal structures such
as hair follicles.1 Melanocytes are derived from the neural crest. After gastru-
lation, there is a single layer of neuroectoderm on the embryo surface: this
layer will go on to form the nervous system or the skin epithelium, depend-
ing on the molecular signals (e.g., fibroblast growth factors or bone mor-
phogenic proteins) it receives.2 The embryonic epidermis consists of a single
layer of multipotent epithelial cells which is covered by a special layer known
as periderm that is unique to mammals. Periderm provides some protection
to the newly forming skin as well as exchange of material with the amniotic
fluid. The embryonic dermis is at first very cellular and at 6–14 weeks three
types of cell are present: stellate cells, phagocytic macrophages and granule-
­secretory cells, either melanoblasts or mast cells (Fig. 1.21). From weeks
Skin development 3
Fig. 1.7
Skin from the sole of the foot: this is typified by a thickened stratum corneum
and prominent epidermal ridge pattern. The dermis is relatively dense at this site.
Similar features are seen on the palms and ventral aspects of the fingers and toes.
Fig. 1.8
Skin from the scalp: there are numerous terminal hair follicles with many of the
bulbs in the subcutaneous fat.
14  to 21, fibroblasts are numerous and active, and perineural cells, pericytes,
melanoblasts, Merkel cells and mast cells can be individually identified. Hair
follicles and nails are evident at 9 weeks. Sweat glands are also noted at 9
weeks on the palms and the soles.3 Sweat glands at other sites and sebaceous
glands appear at 15 weeks. Touch pads become recognizable on the fingers
and toes by the sixth week and development is maximal by the 15th week.
The earliest development of hair occurs at about 9 weeks in the regions of the
eyebrow, upper lip and chin. Sebaceous glands first appear as hemispherical
protuberances on the posterior surfaces of the hair pegs and become differ-
entiated at 13–15 weeks. Langerhans cells are derived from the monocyte–
macrophage–histiocyte lineage and enter the epidermis at about 12 weeks.
Merkel cells appear in the glabrous skin of the fingertips, lip, gingiva and
nail bed, and in several other regions, around 16 weeks. Although some cells
of the dermis may migrate from the dermatome (venterolateral part of the
somite) and take part in the formation of the skin, most of the dermis is
formed by ­mesenchymal cells that migrate from other mesodermal areas.4
These ­mesenchymal cells give rise to the whole range of blood and ­connective
4 The structure and function of skin

Fig. 1.9 Fig. 1.11 Fig. 1.12

Skin from axilla: apocrine glands as seen at the Skin from the outer aspect of the lip: note the Mucosal aspect of lip: at this site the squamous
bottom of the field are typical for this site. keratinizing stratified squamous epithelium and epithelium does not normally keratinize. Minor salivary
skeletal muscle fibers. glands as shown in this field are not uncommonly present.

Fig. 1.13
Mucosal aspect of lip:
close-up view of the
salivary gland shown in
Figure 1.12.

Fig. 1.10
Skin of areola: there are abundant smooth muscle
fibers: lactiferous ducts may also sometimes be
present (not shown).

Fig. 1.14
Mucosal aspect of lip:
the cytoplasm of the
keratinocytes is often rich
in glycogen.
 Keratinocyte biology 5

A B

Fig. 1.15 Fig. 1.16

Skin from the ear: note the vellus hairs, and a fairly (A, B) Vulval vestibule: at this site the stratum corneum is absent and there is no granular cell layer. The
thin dermis overlying the auricular cartilage. suprabasal keratinocytes have clear cytoplasm due to abundant glycogen and revealed by the periodic ­
acid-Schiff reaction.

Fig. 1.17 Fig. 1.18

Variation of skin: sample of skin from the forearm of a 92-year-old female. Note the Stasis change: skin from the lower leg. Although abnormal, the presence of
epidermal thinning and dermal atrophy. stasis change characterized in this example by papillary dermal lobular capillary
proliferation is a very common feature at this site.

tissue cells, including the fibroblasts and mast cells of the dermis and the fat
cells of the subcutis. In the second month, the dermis and subcutis are not
discernible as distinct skin layers but collagen fibers are evident in the dermis
by the end of the third month. Later, the papillary and reticular layers become
established and, at the fifth month, the connective tissue sheaths are formed
around the hair follicles. Elastic fibers are first detectable at 22 weeks.
Keratinocyte biology
The cytoskeleton of all mammalian cells, including epidermal keratinocytes,
comprises actin containing microfilaments ≈7 nm in diameter, tubulin contain-
ing microtubules 20–25 nm in diameter, and filaments of intermediate size,
7–10 nm in diameter, known as intermediate filaments. There are six types
of intermediate filaments of which keratins are the filaments in keratinocytes
(Figs 1.22, 1.23). The human genome possesses 54 functional keratin genes
located in two compact gene clusters, as well as many nonfunctional pseudo-
genes, scattered around the genome.1 Keratin genes are very specific in their
expression patterns. Each one of the many highly specialized epithelial tissues
has its own profile of keratins. Hair and nails express modified keratins con-
taining large amounts of cysteine which forms numerous chemical cross-links
to further strengthen the cytoskeleton. The genes encoding the keratins fall
into two gene families: type I (basic) and type II (acidic) and there is coex-
pression of particular acidic–basic pairs in a cell- and tissue-­specific manner.
Keratin heterodimers are assembled into protofibrils and ­protofilaments by
6 The structure and function of skin

Fig. 1.21
A (A, B)Development of
normal human fetal skin:
(A) at 7 week's gestation,
the epidermis is only
two cell layers thick but
the dermis appears very
cellular; (B) at 19 weeks
gestation the skin has
an outer layer specific
to mammals known as
periderm. This contains
surface blebs which are
Fig. 1.19 full of glycogen (G). Also
Stasis change: high-power present is a hair peg
view. (H). This downgrowth
of the epidermis is the
first histologic step in
B generating a hair follicle.
Bar = 25 μm.

Fig. 1.20
Variation of normal skin: in dark-skinned races, the presence of intense basal cell
melanin pigmentation is a normal histological finding.
Fig. 1.22
Cytoskeleton of a keratinocyte: the major intermediate filament of a keratinocyte is
keratin, highlighted in green.
an antiparallel stagger of some complexity. Simple epithelia are characterized
by the keratin pair K8/K18, and the stratified squamous epithelia by K5/K14.
Suprabasally, keratins K1/K10 are characteristic of epidermal differentiation
genetic disorder of keratin to be described was epidermolysis bullosa sim-
(Fig. 1.24). K15 is expressed in some interfollicular basal keratinocytes as
plex, which involves mutations in the genes encoding K5 or K14 (Fig. 1.25).
well as keratinocytes within the hair-follicle bulge region at the site of pluri-
About half of the keratin genes are expressed in the hair follicle, and muta-
potential stem cells. K9 and K2e expression is site restricted in skin: K9 to
tions in these genes may underlie cases of monilethrix as well as hair and nail
palmoplantar epidermis and K2e to superficial interfollicular epidermis.
ectodermal dysplasias.5
Apart from their structural properties, keratins may also have direct roles
in cell signaling, the stress response and apoptosis.2 In epidermal hyperprolif-
eration, as in wound healing and psoriasis, expression of suprabasal keratins Epidermal stem cells
K6/K16/K17 is rapidly induced.
Currently, 21 of the 54 known keratin genes have been linked to ­monogenic To maintain, repair and regenerate itself, the skin contains stem cells which
genetic disorders, and some have been implicated in more complex traits, reside in the bulge area of hair follicles, the basal layer of interfollicular epi-
such as idiopathic liver disease or inflammatory bowel disease.3,4 The first dermis and the base of sebaceous glands (Fig. 1.26).1 Stem cells are able to

Fig. 1.23
Mid-prickle cell layer of normal epidermis: the abundant keratin filaments
(tonofibrils) form a distinct interlacing lattice within the cytoplasm of keratinocytes.
Fig. 1.24
Normal skin: suprabasal keratinocytes preferentially express keratins 1 and 10 as
shown in this picture. Anti-Keratin1 antibody courtesy of I.M. Leigh, MD, Royal
London Hospital Trust, London, UK.
self-renew as well as give rise to differentiating cells.2 It is not clear, however,
whether every basal keratinocyte or only a proportion of cells is a stem cell.3
Two possible hypotheses have emerged. One theory divides basal keratino-
cytes into epidermal proliferation units, which comprise one self-renewing
stem cell and about 10 tightly packed transient amplifying cells, each of which
is capable of dividing several times and then exiting the basal layer to undergo
terminal differentiation.4 This unit gives rise to a column of larger and flat-
ter cells that culminates in a single hexagonal surface. The process of divi-
sion of basal cells in this model is viewed as a symmetrical process in which
equal daughter cells are generated with the basal cells progressively reducing
their adhesiveness to the underlying epidermal basement membrane, delami-
nating and committing to terminal differentiation. The alternative theory is
that some basal cells (perhaps up to 70% of cells) can undergo asymmetrical
cell division, shifting their spindle orientation from lateral to perpendicular.5
Asymmetrical cell divisions provide a means of maintaining one proliferative
daughter while the other daughter cell is committed to terminal differentia-
tion. Asymmetrical cell divisions, therefore, can bypass the need for transient
amplifying cells.
Epidermal stem cells 7
Fig. 1.25
Clinicopathological consequences of mutations in the keratin 14 gene: (left) typical
appearances of Dowling-Meara epidermolysis bullosa simplex which results from
heterozygous missense mutations in the KRT14 gene; (right) ultrastructurally, there
is keratin filament disruption and clumping as well as a plane of blistering just above
the dermal–epidermal (DE) junction.
Epidermis
Epidermal Sebocyte
stem cells stem cells
Sebaceous gland
Bulge stem cells
Hair shaft
Outer root sheath
Inner root sheath
Dermal papilla
Fig. 1.26
Diagrammatic representation of the location of stem cells in human skin: stem cells
are located within the bulge area of hair follicles (where the arrector pili muscle
attaches) as well as in the basal keratinocyte layer in the interfollicular epidermis
and at the base of sebaceous glands. Stem cells from the bulge area are capable of
regenerating all parts of the pilosebaceous unit and interfollicular skin.
Hair follicle stem cells are found in the bulge regions below the sebaceous
glands. These stem cells are slow cycling and express the cell surface mol-
ecules CD34 and VdR as well as the transcription factors TCF3, Sox9, Lhx2
and NFATc1 (Fig. 1.27). The bulge area stem cells generate cells of the outer
root sheath, which drive the highly proliferative matrix cells next to the mes-
enchymal papillae. After proliferating, matrix cells differentiate to form the
hair channel, the inner root sheath and the hair shaft. Hair follicle stem cells
8 The structure and function of skin

Markers of interfollicular stem cells

α6 integrin
β1 integrin
p63

Markers of hair follicle bulge stem cells

DNA label retention
CD34
NFATc1
Vitamin D receptor
TCF3
Fox9
Lhx2
Fig. 1.27
Markers of sebocyte stem cells
Molecular markers of stem cells in the
Blimp 1 skin.

can also differentiate into sebocytes and interfollicular epidermis. Despite this
multipotency, however, the follicle stem cells only function in pilosebaceous
unit homeostasis and do not contribute to interfollicular epidermis unless the Fig. 1.28
Granular cell layer: note the keratohyalin and membrane coating granules (arrowed).
skin is wounded.6
Stem cells are also found in the base of sebaceous glands: the progeny of
these cells differentiate into lipid-filled sebocytes. Apart from stem cells in
the hair follicles, sebaceous glands and interfollicular epidermis, other cells the cell membrane. They fuse with the plasma membrane, dispersing their
in the dermis and subcutis may have stem cells properties. These include cells contents into the intercellular space. Polar lipids from the lamellar granules
that have been termed skin-derived precursors (SKPs), which can differentiate are remodeled into neutral lipids in the intercellular space between corneo-
into both neural and mesodermal progeny.7 In addition, a subset of dermal cytes, thereby contributing to the barrier.
fibroblasts can have adipogenic, osteogenic, chondrogenic, neurogenic and Within the granular layer of the epidermis, the main keratinocyte pro-
hepatogenic differentiation potential.8 teins are keratin and filaggrin, which together contribute approximately
80–90% of the mass of the epidermis and are ultrastructurally represented
by the keratohyalin granules (Fig. 1.29). Filaggrin is initially synthesized as
Skin barrier profilaggrin, a ≈500-kDa highly phosphorylated, histidine-rich polypeptide.
During the post-translational processing of profilaggrin, the individual filag-
A major function of the epidermis is to form a barrier against the external grin polypeptides, each ≈35 kD, are proteolytically released. These are then
environment. To achieve this, terminal differentiation of keratinocytes results dephosphorylated, a process that assists keratin filament aggregation and
in formation of the cornified cell envelope. This physical barrier is rendered explains the origin of the name ‘filaggrin’ (filament aggregating ­protein) (Fig.
highly insoluble by the formation of glutamyl-lysyl isodipeptide bonds between 1.30). Typically, there are 10 highly homologous filaggrin units, although the
envelope proteins, catalyzed by transglutaminases.1 Several different proteins number of filaggrin repeat units is variable and genetically determined, with
contribute to construction of the cornified cell envelope, including involucrin,
and the family of small proline-rich proteins (SPR1) including cornifin or
SPR1 and pancornulins. Other envelope proteins include SKALP/elafin and
keratolinin/cystatin. Some precursors of the cornified envelope are delivered
by granules: small, smooth, sulfur-rich L granules contain the cysteine-rich
protein loricrin, and accumulate in the stratum granulosum.2 Loricrin is the
major component of the cornified envelope. Profilaggrin in F granules may
make a minor contribution to the envelope. Membrane-associated proteins
that contribute to the cornified envelope include the plakin family members,
periplakin, envoplakin, epiplakin, desmoplakin as well as plectin. Formation
of the cornified cell envelope is triggered by a rise in intracellular calcium
levels.3 This leads to cross-link formation between plakins and involucrin
catalyzed by transglutaminases. Other desmosomal proteins are then also
cross-linked, forming a scaffold along the entire inner surface of the plasma
membrane. Ceramides from the secreted contents of lamellar bodies are then
esterified onto glutamine residues of the scaffold proteins. The cornified cell
envelope is reinforced by the addition of a variable amount of SPRs, repe-
tin, trichohyalin, cystostatin α, elafin and LEP/XP-5 (skin-specific protein).
Although most desmosomal components are degraded, keratin intermediate
filaments (mostly K1, K10 and K2e) may be cross-linked to desmoplakin and
envoplakin remnants.
In the upper stratum spinosum and stratum granulosum lipid is synthe-
sized and packaged into lamellated membrane-bound organelles known as
membrane-coating granules, lamellar granules or Odland bodies (Fig. 1.28).4
They are found adjacent to the cell membrane with alternating thick and Fig. 1.29
thin dense lines separated by lighter lamellae of equal width, consistent with Stratum corneum:
packing of flattened discs within a membrane boundary. These granules con- keratohyalin granules are
tain phospholipids, glycolipids and free sterols and move towards the plasma present just beneath the
membrane as the cells move through the granular layer where they cluster at keratin lamellae.
 Skin immunity 9

Epidermal barrier: Keratohyalin granules composed of profilaggrin Micro-organisms

mechanical strength;
prevent water loss;
restrict allergen penetration External allergens
Stratum corneum
Stratum Filaggrin deaminated Fig. 1.32
corneum and degraded Innate immunity in the
Granular layer
Granular skin: the physical barrier is
layer complemented by an innate
Upper spinous layer immune response that
targets bacteria, viruses
Spinous Inflammatory cells and fungi and prevents
layer them from invading the
Constitutive anti-microbial peptides (psoriasin) skin. These peptides
include constitutive and
Inducible anti-microbial peptides
(β-defensins, RNASE7, LL-37) inducible substances
against a broad range of
Basal layer Pro-inflammatory cytokines (IL-1, TNFα, etc) organisms.

Dermal-
epidermal
junction Profilaggrin cleaved into Keratinocyte Langerhans cell
10-12 filaggrin peptides Melanocyte
Fig. 1.30
Function of filaggrin in human skin: this is the major component of keratohyalin
granules. In the granular layer profilaggrin is cleaved into filaggrin peptides
subsequent deamination and degradation provides the skin with mechanical
strength and restricts transepidermal water loss. Filaggrin also prevents allergen
penetration. In the absence of filaggrin, for example caused by common mutations
in the filaggrin gene, external allergens may penetrate the epidermis and encounter
Langerhans cells. This may lead to the development of atopic dermatitis as well as
other atopic manifestations and systemic allergies.
duplications of filaggrin repeat units 8 and/or 10 in some individuals. Fewer
filaggrin repeats leads to dryer skin. Loss-of-function mutations in filaggrin
are very common, occurring in up to 10% of the European population. These
mutations lead to reduced or absent keratohyalin granules, and are the cause
of ichthyosis vulgaris as well as constituting a major risk factor for atopic
dermatitis (Fig. 1.31).5
Skin immunity
Skin possesses both innate and adaptive immune responses to defend against
microbial pathogens and thereby prevent infection. One of the primary mech-
anisms is the synthesis, expression and release of antimicrobial peptides (Fig.
1.32).1 There are more than 20 antimicrobial peptides in the skin, includ-
ing cathelicidins, β-defensins, substance P, RANTES, RNase 2, 3, and 7, and
S100A7. Many of these peptides have antimicrobial action against bacteria,
viruses, and fungi. In the stratum corneum there is an effective chemical bar-
rier maintained by the expression of S100A7 (psoriasin).2 This antimicro-
bial substance is very effective at killing Escherichia coli. Subjacent to this
in the skin there is another class of antimicrobial peptides, such as RNASE7,
which is effective against a broad spectrum of microorganisms, especially
enterococci.3 Below this in the living layers of the skin are other antimicro-
bial peptides including the β-defensins.4 The antimicrobial activity of most
peptides occurs as a result of unique structural characteristics that enable
them to disrupt the microbial cell membrane while leaving human cell mem-
branes intact. The antimicrobial peptides can have immunostimulatory and
immunomodulatory capacities as well as being chemotactic for distinct sub-
populations of leukocytes and other inflammatory cells.5 Some peptides have
additional roles in signaling host responses through chemotactic, angiogenic,
growth factor and immunosuppressive activity. These peptides are known as
alarmins.6 Alarmins may also stimulate parts of the host defense system, such
as barrier repair and recruitment of inflammatory cells.
Skin immunity is also provided by a distinct population of antigen present-
ing cells in the epidermis known as Langerhans cells (Fig. 1.33). These are
­dendritic cells that were first described by Langerhans, who demonstrated their
existence in human epidermis by staining with gold chloride. Without stimula-
tion, Langerhans cells exhibit a unique motion termed ‘Dendrite Surveillance
Extension And Retraction Cycling Habitude (dSEARCH)’.7 This is charac-
terized by rhythmic extension and retraction of dendritic processes between
intercellular spaces. When exposed to antigen, there is greater dSEARCH
motion and also direct cell-to-cell contact between adjacent Langerhans
cells which function as intraepidermal macrophages, phagocytosing antigens
among keratinocytes. Langerhans cells then leave the epidermis and migrate
via lymphatics to regional lymph nodes. In the paracortical region of lymph
nodes the Langerhans cell expresses protein on its surface to present to a T
lymphocyte that can then undergo clonal proliferation. Langerhans cells, in
combination with macrophages and dermal dendrocytes, represent the skin's
mononuclear phagocyte system.8 By electron microscopy, Langerhans cells
have a lobulated nucleus, a relatively clear cytoplasm and well-developed
endoplasmic reticulum, Golgi complex and lysosomes. They also possess
characteristic granules which are rod or racquet-shaped (Fig. 1.34). These
‘Birbeck’ granules represent subdomains of the endosomal recycling compart-
ment and form at sites where the protein Langerin accumulates.
Besides antigen detection and the processing role by epidermal Langerhans
cells, cutaneous immune surveillance is also carried out in the dermis by an
array of macrophages, T cells and dendritic cells. These immune sentinel and
effector cells can provide rapid and efficient immunologic back-up to restore
tissue homeostasis if the epidermis is breached. The dermis contains a very

May cause Are the cause of Are a major risk factor Are associated with atopic
hyperlinearity of the palms ichthyosis vulgaris for atopic dermatitis dermatitis persisting into adulthood

Occur in up to 10% Loss-of function Are a major risk factor for

of the population
Are not associated with
psoriasis or non-atopic asthma
mutations in the FLG gene
Can modify clinical Are implicated in development
expression of other diseases of systemic allergies
asthma with atopic dermatitis
Are associated with increased
severity of atopic asthma
Fig. 1.31
Functional consequences of
loss-of-function mutations in the
filaggrin gene, which can affect up to
10% of the people in some populations.
10 The structure and function of skin

large number of resident T cells. Indeed, there are approximately 2 × 1010

resident T cells, which is twice the number of T cells in the circulating blood.
Dermal dendritic cells may also have potent antigen-presenting capacities
or the potential to develop into CD1a-positive and Langerin-positive cells.
Dermal immune sentinels are capable of acquiring an antigen-presenting
mode, a migratory mode or a tissue resident phagocytic mode.9

Fig. 1.33
Langerhans cells express S-100 protein: note the conspicuous dendritic processes.
Melanocytes
Melanocytes are pigment-producing cells and are found in the skin, inner ear,
choroid and iris of the eye. In skin, melanocytes are located in the basal keratino-
cyte layer. The ratio of melanocytes to basal cells ranges from approximately 1:4
on the cheek to 1:10 on the limbs. They appear as vacuolated cells in hematoxylin
and eosin stained sections (Fig. 1.35). Ultrastructurally, melanocytes have pale
cytoplasm and are devoid of tonofilaments and ­desmosomes (Fig. 1.36). They are
easily recognized by their specific cytoplasmic organelles (melanosomes) which
are derived from the smooth endoplasmic reticulum. Melanosomes are believed
to represent a specialized variant of lysosome (Fig. 1.37). The function of mel-
anocytes is the production of melanin, a ­pigment that varies in color from yel-
low to brown or black and accounts for the various skin colors within and

Fig. 1.34
(A, B) Langerhans cell:
(A) note the characteristic
lobulated nucleus. Dendritic
processes are evident,
(B) typical rod forms with
the characteristic trilaminar
A B
structure.

Fig. 1.35
(A, B) Normal epidermis:
melanocytes are seen
along the basal layer of the
epidermis. The cytoplasmic
vacuolation is a fixation
artifact; (B) melanocytes
can be highlighted
with S100-protein
immunohistochemistry.
A Note the dendritic
B
processes.
 Melanocytes 11

Melanin is transferred from melanocytes in melanosomes to neighboring

Fig. 1.36
Normal melanocyte: it has abundant pale cytoplasm and scattered solitary
melanosomes. Note the absence of tonofibrils and desmosomes.
keratinocytes in the epidermis and into the growing shaft in hair follicles and
can be identified by silver techniques such as the Masson-Fontana reaction
(Fig. 1.38). Transport occurs along the dendritic processes of the melanocytes
and the melanosomes are engulfed as membrane-bound (lysosomal) single
or compound melanosomes by a group of adjacent largely basally located
keratinocytes (epidermal melanin unit) where they are typically seen in an
umbrella-like distribution over the outer aspect of the nucleus (Fig. 1.39).
A compound melanosome typically contains from three to six single melano-
somes. In heavily pigmented skin and dark hair, melanosomes remain solitary
and are longer than those seen in melanogenesis in paler races. Other cells
that may contain compound melanosomes include macrophages (melano-
phages), melanoma cells and, occasionally, Langerhans cells, the other type of
epidermal dendritic cell. Macromelanosomes (giant melanosomes) measure
several microns in diameter and therefore are readily visible in hematoxylin
and eosin stained sections (Fig. 1.40). They may be encountered in normal
skin, in lentigines, dysplastic nevi, Spitz nevi, in the café-au-lait macules of
neurofibromatosis and in albinism. A key protein involved in melanosome
assembly is NCKX5, encoded by the gene SLC24A5.4 Loss of expression of
this gene in mice results in marked changes in skin color with loss of pigment.

Fig. 1.38
Normal epidermis: this section of black skin has been stained by the Masson–
Fontana reaction for melanin. Note the heavy pigmentation, which is present in
Fig. 1.37 both melanocytes and keratinocytes.
Melanosome: note the typical striated internal structure.

among races. Melanin protects the mitotically active basal epidermal cells from
the injurious effects of ultraviolet light, which accounts for individuals with
less pigmentation (fair-haired and light-skinned) having a much greater risk of
sunburn and developing cutaneous malignancies (squamous cell and basal cell
carcinomas, and melanoma). The mechanism involves absorbing or scatter-
ing ultraviolet radiation and/or its photoproducts. Other functions of melanin
include control of vitamin D3 synthesis and local thermoregulation.
In skin and hair, two forms of melanin pigment are produced; eumelanin
and pheomelanin. Eumelanin is a brown or black pigment and is synthe-
sized from tyrosine; it is particularly found in dark-colored races, whereas,
pheomelanin has a yellow-red color and is synthesized from tyrosine and
cysteine; it predominates in Caucasian skin.
Melanocytes also possess melanocyte-specific receptors including melano-
cortin-1 (MC1R) and melatonin receptors.1 The activation or the inhibition
of melanocyte-specific receptors can augment normal melanocyte function,
skin color, and photoprotection. Moreover, receptor polymorphisms are
known to underlie red hair phenotypes.2 Hair graying reflects abnormalities
in melanocyte signaling. Notably, Notch transcription factor signaling in mel- Fig. 1.39
anocytes is essential for the maintenance of proper hair pigmentation, includ- Melanin pigment: actinically damaged skin. Note that the melanin pigment is
ing ­regeneration of the melanocyte population during hair follicle cycling.3 located in a ‘cap’ overlying the keratinocyte nuclei.
12 The structure and function of skin

Fig. 1.41
Merkel cells: separated human epidermis showing a striking linear arrangement
Fig. 1.40 (troma-1 antibody). By courtesy of J.P. Lacour, MD, and J.P. Ortonne, MD, University
Macromelanosomes: of Nice, France.
note the large spherical
melanosomes in the
cytoplasm of the
melanocytes.

Mature melanosomes of eumelanin are ellipsoidal in shape, while pheomela-

nin-producing melanosomes are spherical.

Merkel cells
Merkel cells are postmitotic cells scattered throughout the epidermis of ver-
tebrates and constitute 0.2–0.5% of epidermal cells.1 Merkel cells represent
part of the affector limb in cutaneous slowly adapting type-1 (SA1) mechano-
receptors and are therefore particularly concerned with touch sensation. They
are located amongst basal keratinocytes and are mainly found in hairy skin,
tactile areas of glabrous skin, taste buds, the anal canal, labial ­epithelium
and eccrine sweat glands. In glabrous skin, the density of Merkel cells is ≈50
per mm2. Sun-exposed skin may contain twice as many Merkel cells as non-
sun-exposed skin.2 Numerous Merkel cells can be found in actinic keratoses.3
Merkel cells cannot be recognized in conventional hematoxylin and eosin
stained sections. Rather, immunocytochemistry, particularly using antikeratin
antibodies, or electron microscopy, is necessary for their identification (Figs
1.41 and 1.42).
Ultrastructurally, Merkel cells appear oval with a long axis of ≈15 μm ori-
entated parallel to the basement membrane (Fig. 1.43). They also have a large
bilobed nucleus and clear cytoplasm which reflects a relative scarcity of intra-
cellular organelles. Merkel cells contain numerous neurosecretory granules,
each 50 nm to 160 nm across; these are found opposing the junctions with
the sensory nerve ending (Fig. 1.44). Merkel cells contain keratin filaments,
particularly keratin filament types 8, 18, 19, and 20, which are characteris-
tic of simple epithelium and fetal epidermis. Immunocytochemically, Merkel
cells also express neuropeptides including synaptophysin, vasoactive intes-
tinal peptide (VIP) and calcitonin gene-related polypeptide (CGRP).4,5 They
contain neuron-specific proteins including neuron-specific enolase (NSE) and
protein gene product (PGP) 9.5.6 In addition, Merkel cells express desmo-
somal proteins, membranous neural cell adhesion molecule and nerve growth
factor receptor.7–9 Merkel cells show a positive uranaffin reaction.10 Merkel
cells form close connections with sensory nerve endings and secrete or express
a number of these peptides.11 The close contact between Merkel cells and
nerve fibers represents a Merkel cell–neurite complex, but there is no clear
evidence of synaptic transmission, although numerous vesicles can be identi-
fied in neurons apposed to Merkel cells.12
Fig. 1.42
Merkel cell: positive labeling for CAM 5.2 identifies Merkel cells in this obliquely
sectioned epidermal ridge.
Human skin contains an extensive neural network that contains cholin-
ergic and adrenergic nerves and myelinated and unmyelinated sensory fibers.
Moreover, the skin also contains several transducers involved in the percep-
tion of touch, pressure, and vibration, including Ruffini organs surrounding
hair follicles, Meissner's corpuscles, Vater–Pacini corpuscles located in the
deep layer of the dermis, and nerve endings which pass through the epider-
mal basement membrane. Some of these contain Merkel cells which form the
Merkel cell–neurite complex, while others are free nerve endings. The cell
bodies for all these neurons reside in the dorsal root ganglion. The Merkel
cell–neurite complexes are thought to serve as mechanoreceptors and to be
responsible for the sensation of touch. They are clustered near unmyelinated
sensory nerve endings, where they group and form ‘touch spots’ at the bottom
of rete ridges. These complexes are also known as hair discs, touch domes,
touch corpuscles, or Iggo discs. The complex is innervated by a single, slowly
adapting type 1 nerve fiber. In hairy skin, Merkel cells also cluster in the
rete ridges and in the outer root sheath of the hair follicle where the arrector
pili muscles attach. The function of Merkel cells in hair follicles is unclear,
although they may be involved in the induction of new anagen cycles.
There are two hypotheses for the origin of Merkel cells: one possibility is
that they differentiate from epidermal keratinocyte-like cells and the other
 Intercellular junctions 13

Intercellular junctions
Desmosomes are the major intercellular adhesion complexes in the epider-
mis. They anchor keratin intermediate filaments to the cell membrane and
link adjacent keratinocytes (Fig. 1.45). Desmosomes are found in the epider-
mis, myocardium, meninges and cortex of lymph nodes. Ultrastructurally,
desmosomes contain plaques of electron-dense material running along
the cytoplasm parallel to the junctional region, in which three bands can
be distinguished: an electron-dense band next to the plasma membrane, a
less dense band, and then a fibrillar area (Fig. 1.46).1 Identical components
are present on opposing cells which are separated by an intercellular space
of 30 nm within which there is an electron-dense midline. There are three
main protein components of desmosomes in the epidermis: the desmosomal
cadherins, the armadillo family of nuclear and junctional proteins, and the
plakins (Fig. 1.47).2 The transmembranous cadherins comprise mostly het-
erophilic ­associations of desmogleins and desmocollins. There are four main
­epidermis-specific desmogleins (Dsg1–4) and three desmocollins (Dsc1–3).
These show differentiation-specific expression. For example, Dsg1 and Dsc1

Fig. 1.43
Merkel cell: a heavily
granulated Merkel
cell is present in the
midfield. This is located
immediately adjacent to a
small nerve fiber.

Fig. 1.45
Mid-prickle cell layer of normal epidermis: there are complex interdigitations
between adjacent cell membranes with numerous desmosomal junctions.

Fig. 1.44
Merkel cell granules: they are membrane bound and measure approximately
150 nm in diameter. By courtesy of A.S. Breathnach, MD (1977) Electron
microscopy of cutaneous nerves and receptors. Journal of Investigative
Dermatology 69, 8–26. Blackwell Publishing Inc., USA.

is that they arise from stem cells of neural crest origin that migrated during
embryogenesis, in similar fashion to melanocytes.13 Merkel cell hyperplasia is
a common histological finding and may accompany keratinocyte hyperpro-
liferation as well as being frequently seen in adnexal tumors such as nevus
sebaceus, trichoblastomas, trichoepitheliomas, and nodular hidradenomas.14
Merkel cell hyperplasia is associated with hyperplasia of nerve endings that
occurs in neurofibromas, neurilemomas, nodular prurigo, or neurodermati-
tis. It is not clear whether Merkel cell carcinoma originates from Merkel cells Fig. 1.46
or their precursors but the latter may be more likely given that many dermal Mid-prickle cell layer of normal epidermis showing the stratified nature of the
Merkel cell carcinomas do not connect with the epidermis. desmosome.
14 The structure and function of skin

Autosomal dominant Autosomal recessive

Ectodermal dysplasia -
Plakophilin 1
Skin fragility syndrome

Arrhythmogenic right Arrhythmogenic right

Plakophilin 2
ventricular cardiomyopathy ventricular cardiomyopathy

Woolly hair, keratoderma, Woolly hair, keratoderma,

cardiomyopathy +/- cardiomyopathy

Arrhythmogenic right
Desmoplakin
ventricular cardiomyopathy

Striate palmoplantar Lethal acantholytic

keratoderma epidermolysis bullosa

Arrhythmogenic right
Plakoglobin Naxos disease
Desmoglein Plakoglobin Desmoplakin ventricular cardiomyopathy

Desmocollin Plakophilin Keratin Striate palmoplantar

Desmoglein 1
keratoderma
Fig. 1.47
Protein composition of a desmosome junction between adjacent keratinocytes. The Arrhythmogenic right Arrhythmogenic right
Desmoglein 2
keratin filament network of two keratinocytes is linked by a series of desmosomal ventricular cardiomyopathy ventricular cardiomyopathy
plaque proteins and transmembranous molecules to create a structural and
signaling bridge between the cells. Localized recessive
Desmoglein 4
hypotrichosis

Recessive monilethrix
are found predominantly in the superficial layers of the epidermis whereas
Hypotrichosis with
Dsg3 and Dsc3 show greater expression in basal keratinocytes. The intra- Desmocollin 3
scalp vesicles
cellular parts of the cadherins interact with the keratin filament network
Arrhythmogenic right
via the desmosomal plaque proteins, mainly desmoplakin, plakoglobin and Desmocollin 2
ventricular cardiomyopathy
plakophilin.1
Clues to the biologic function of these desmosomal components have arisen Hypotrichosis simplex Corneodesmosin
from various inherited and acquired human diseases.3,4 Naturally occurring
Fig. 1.48
human mutations have been reported in ten different desmosome genes with
Genetic disorders of desmosomes: autosomal dominant or autosomal recessive
variable skin, hair and heart abnormalities and several desmosomal proteins mutations in ten different structural components of desmosomes may give rise to
serve as autoantigens in immunobullous blistering skin diseases such as pem- specific diseases that can affect skin, hair or heart or combinations thereof.
phigus (Figs 1.48 and 1.49).5 Antibodies to multiple desmosomal proteins
may develop in diseases such as paraneoplastic pemphigus through the phe-
nomenon of epitope spreading.6 Cleavage of the extracellular domain of Dsg1 Immunobullous diseases
has also been demonstrated as the basis of staphylococcal scalded skin syn-
drome and bullous impetigo.7 Desmoglein 3 Pemphigus vulgaris
Adherens junctions are recognized ultrastructurally as electron-dense trans-
Pemphigus foliaceus
membrane structures, with two opposing membranes separated by approxi- Desmoglein 1
mately 20 nm, that form links with the actin skeleton.8 They are 0.2–0.5 μm Endemic pemphigus
in diameter and can be found as isolated cell junctions or in association with Desmocollin 3 Atypical pemphigus
tight junctions and desmosomes. Adherens junctions are expressed early in
skin development and contribute to epithelial assembly, adhesion, barrier for- Atypical pemphigus
Desmocollin 1
mation, cell motility and changes in cell shape. They may also spatially co-
IgA pemphigus
ordinate signaling molecules and polarity cues as well as serving as docking (sub-corneal type)
sites for vesicle release. Adherens junctions contain two basic adhesive units:
the nectin-afadin complex and the classical cadherin complex.9,10 The nectins Fig. 1.49
form a structural link to the actin cytoskeleton via afadin (also known as Immunobullous diseases of desmosomes: intraepidermal blistering can arise
AF-6) and may be important in the initial formation of adherens junctions. through autoantibody disruption of four separate desmosomal proteins which leads
The cadherins form a complex with the catenins (α-, β-, and p120 catenin) to different clinical variants of pemphigus.
and help mediate adhesion and signaling. Cell signaling via β-catenin can acti-
vate several pathways linked to morphogenesis and cell fate determination. connexons (homotypic or heterotypic) to form a gap junction. To date, 13
Inherited gene mutations of the adherens junction proteins plakoglobin different human connexins have been described. The formation and stabil-
and P-cadherin have been reported. Plakoglobin mutations result in Naxos ity of gap junctions can be regulated by protein kinase C, Src kinase, cal-
disease (woolly hair, keratoderma, cardiomyopathy).3 P-cadherin mutations cium concentration, calmodulin, adenosine 3′,5′-cyclic monophosphate
underlie autosomal recessive hypotrichosis with juvenile macular dystrophy (cAMP) and local pH.14 The connexins are classified into three groups (α,
as well as ectodermal dysplasia-ectrodactyly-macular dystrophy (EEM) syn- β and γ) according to their gene structure, overall gene homology and spe-
drome, in which there is hypotrichosis, macular degeneration, hypodontia cific sequence motifs.15 Apart from the connexins, vertebrates also contain
and limb defects, including ectrodactyly, syndactyly and camptodactyly.11,12 another class of gap junction proteins, the pannexins, which are related to the
Gap junctions represent clusters of intercellular channels, known as innexins found in nonchordate animals. The function of gap junctions is to
­connexons, which form connections between the cytoplasm of adjacent allow sharing of low molecular mass metabolites (<1000 Da) and exchange of
­keratinocytes (and other cells).13 Formation of a connexon involves ­assembly ions between neighboring cells. Gap junction communication is essential for
of six connexin subunits within the Golgi network. This complex is then cell ­synchronization, differentiation, cell growth and metabolic coordination
transported to the plasma membrane where connexons associate with other of avascular organs, including epidermis.14
 Pilosebaceous units 15

Deafness with unusual Deafness with e­ ndocuticle, exocuticle and ‘a’ layer.1 Around the cuticle is the inner root
hyperkeratosis and oral erosions Clouston-like phenotype sheath (IRS), which is composed of three distinct layers of cells that undergo
keratinization: the IRS cuticle, the Huxley layer and the outermost Henle
Hystrix-like-ichthyosis Palmoplantar keratoderma layer.2 Differentiation in the IRS involves the development of trichohyalin
deafness syndrome with deafness granules, with 8–10 nm filaments orientated in the direction of hair growth.
Keratitis-ichthyosis - The IRS moves up the follicle, forming a support for the hair fiber, and
26 Bart-Pumphrey syndrome degenerates above the sebaceous gland. The outermost layer is the outer root
deafness syndrome
sheath (ORS), which is continuous with the epidermis and expresses epithe-
Non-syndromic deafness Vohwinkel’s syndrome lial keratins, K5/K14, K1/K10 and K6/K16 in the upper ORS and K5/K14/
Non-syndromic deafness 30 Clouston’s syndrome K17 in the deeper ORS.
Normal growth of the hair fiber is 300–400 μm/day. Hair growth is gener-
Erythro-keratoderma ated by the high rate of proliferation of progenitor cells in the follicle bulb.
30.3
variabilis
There are three phases of cyclical hair growth: anagen, when growth occurs;
Peripheral neuropathy and Erythro-keratoderma catagen, a regressing phase; and telogen, a resting phase. The follicle re-enters
31 anagen, and the old hair is replaced by a new one.
hearing impairment variabilis
Immediately above the basal layer in the hair bulb, cells undergo a sec-
Non-syndromic deafness Charcot-Marie ondary pathway of ‘trichocyte’ or hair differentiation, and express a fur-
32
tooth disease (X-linked) ther complex group of keratins, the hard keratins.2 Two families of hair
Atrial fibrillation 40 keratins, types I and II, are present in mammals, which have distinctive
Non-syndromic deafness 43 Oculodentodigital dysplasia amino- and carboxy-terminals with high levels of cysteine residues but
lack the extended glycine residues of epidermal keratins. The proteins dif-
Zonular pulverulent
46
fer from epithelial keratins in position on two-dimensional gels but form
cataract-3 acidic and basic groups. There are four major proteins in each family and
Zonular pulverulent
50 several minor proteins, Ha 1–4 and Hb 1–4. Recent cloning of the hair ker-
cataract -1
atin genes, which cluster on chromosomes 12 and 17, has shown an even
Fig. 1.50 greater number of hair keratin genes, HaKRT1–6 (including 3.1 and 3.2)
Genetic disorders of connexins: nine different human connexin molecules are and HbKRT1–6.
associated with different inherited diseases. Mutations in the four low molecular Mutations in hair keratin genes have been found to cause autosomal domi-
weight connexins shown at the top of the diagram are associated with a spectrum nant forms of the human disease monilethrix. More common hair variants,
of skin pathology, as highlighted.
such as curly hair, may be explained by dynamic changes during hair growth.3
Curvature of curly hair is programmed from the very basal area of the follicle
and the bending process is linked to a lack of axial symmetry in the lower
Inherited abnormalities in genes encoding four different connexins (Cx26, part of the bulb, affecting the connective tissue sheath, ORS, IRS and the hair
30, 30.3 and 31) have been detected in several forms of keratoderma and/or shaft cuticle.
hearing loss (Fig. 1.50). Nondermatologic disorders can also arise from muta- Sebaceous glands usually develop as lateral protrusions from the outer
tions in some higher molecular weight connexins (Cx32, 40, 43, 46 and 50). root sheath of hair follicles, but at certain sites, such as the eyelids, lips, are-
Tight junctions contribute to skin barrier integrity and maintaining cell olae, nipples and labia minora, they appear to arise independently and drain
polarity, although in simple epithelia they are major regulators of perme- directly onto the skin's surface (Figs 1.51 and 1.52). They are widespread in
ability.8 An important function is to regulate the paracellular flux of water- distribution, being found everywhere on the body except on the palms and
­soluble molecules between adjacent cells.16 The main structural proteins of soles. They are particularly abundant on the face and scalp, in the midline
tight junctions are the claudins, of which there are approximately 24 sub- of the back and about the perineum, and are concentrated around the ori-
types, as well as the IgG-like family of junctional adhesion molecules (JAMs) fices of the body (Fig. 1.53). Those of the eyelid are known as the glands
and the occludin group of proteins. The principal claudins in the epidermis
are claudin 1 and 4. These transmembranous proteins can bind to the intrac-
ellular zonula occudens proteins ZO-1, ZO-2, ZO-3 which interact with the
actin cytoskeleton.8,17
Clinically, abnormalities in tight junction proteins can result in skin, kid-
ney, ear and liver disease. Inherited gene mutations in claudin 1 have been
reported in one pedigree with diffuse ichthyosis, hypotrichosis, scarring
­alopecia and sclerosing cholangitis.18

Pilosebaceous units
There are four classes of pilosebaceous unit: terminal on the scalp and beard;
apopilosebaceous in axilla and groin; vellus on the majority of skin; and
sebaceous on the chest, back and face. The dermal papilla is located at the
base of the hair follicle and is associated with a rich extracellular matrix.
Around the papilla are germinative (matrix) cells that have a very high rate
of division, and give rise to spindle-shaped central cortex cells of the hair
fiber, and the single outer layer of flattened overlapping cuticle cells. A cen-
tral medulla is seen in some hairs, with regularly stacked condensed cells
interspersed with air spaces or low-density cores. The cortical cells are filled
with keratin intermediate filaments orientated along the long axis of the Fig. 1.51
cell, interspersed with a dense interfilamentous protein matrix. The cuticu- Sebaceous glands: on the inner aspect of the labia these appear as tiny yellow
lar cells are morphologically distinct, with flattened outward-facing cells, papules (Fordyce spots). By courtesy of S.M. Neill, MD, Institute of Dermatology,
with three layers inside the cuticle of condensed, flattened protein granules: London, UK.
16 The structure and function of skin

Fig. 1.52 Fig. 1.54

Normal vulva: sebaceous glands are conspicuous, but arise independently of a hair Nose: multiple sebaceous glands are evident.
follicle and open directly onto the surface epithelium.

Fig. 1.55
Sebaceous lobule: germinative cells are basophilic and flattened. With maturation
the cells acquire their characteristic ‘bubbly’ cytoplasm.
Fig. 1.53
Nose: sebaceous glands are particularly numerous at this site.

of Zeis and the meibomian glands. Sebaceous glands within the areolae are
known as Montgomery's tubercles. The largest sebaceous glands are associ-
ated with small vellus hairs in specialized pilosebaceous units known as seba-
ceous f­ ollicles (facial pores).
Sebaceous glands consist of several lipid-containing lobules, usually con-
nected to a hair follicle (Fig. 1.54). Each lobule is composed of an outer
layer of small cuboidal or flattened basophilic germinative cells, from which
arises the inner zone of lipid-laden vacuolated cells with characteristic cren-
ated nuclei (Fig. 1.55). The secretions drain into the sebaceous duct, which
joins the hair follicle at the level of the infundibulum (Fig. 1.56). The duct is
lined by keratinizing stratified squamous epithelium and is continuous with
the external root sheath. The glands are holocrine because their secretions
depend on complete degeneration of the acini, with release of all the cells'
lipid contents to become sebum.
Immunohistochemically, the sebaceous cells label strongly for EMA but
they do not express CEA or low molecular weight keratin (CAM 5.2) or
S-100 protein (Fig. 1.57). Ultrastructurally, the mature sebaceous gland
shows gradual accumulation of variably sized, nonmembrane-bound, lipid Fig. 1.56
inclusions in differentiating cells. Numerous mitochondria, ribosomes and Sebaceous duct: this is lined by keratinizing stratified squamous epithelium; it is
membrane-bound vesicles may also be evident. As the cells mature before continuous with the external root sheath.
 Eccrine glands 17

Histologically, eccrine sweat glands are divided into four subunits: a highly
vascularized coiled secretory gland, a coiled dermal duct, a straight dermal
duct, and a coiled intraepidermal duct (the acrosyringium) (Fig. 1.59). The
secretory coil is located in the lower dermis, and the duct extends through
the dermis and opens directly onto the skin surface (Figs 1.60, 1.61). The
active sweat glands are present most densely on the sole, forehead and palm,
somewhat less on the back of the hand, still less on the lumber region, and
the lateral and extensor surfaces of the extremities, and least on the trunk
and the flexor and medial surfaces of the extremities. The uncoiled dimen-
sion of the secretory portion of the gland is approximately 30–50 μm in diam-
eter and 2–5 mm in length. The size of the adult secretory coil ranges 1–8 ×
10−3 mm3. The secretory component lies in the lower reaches of the reticular

Fig. 1.57
Sebaceous gland: the epithelial cells normally strongly express EMA.

Fig. 1.58
Sebaceous gland: in this field from the center of a sebaceous lobule, the cytoplasm
is completely distended with lipid droplets. Germinative cells are evident in the ­
right-lower quadrant.

their disintegration, the lipid droplets completely fill the cytoplasm and com-
press the centrally located nucleus (Fig. 1.58).
The secretion of sebaceous glands is sebum, an exceedingly compli-
cated lipid mixture that includes triglycerides (57%), wax esters (26%) and
squalene (12%). Its function includes waterproofing, control of epidermal
water loss, and a protective function, inhibiting the growth of fungi and bac-
teria. Secreted sebum undergoes significant changes due to the presence of
Propionibacterium acnes (triglyceride hydrolysis) within the pilosebaceous Fig. 1.59
Eccrine gland: (A) palmar
canal and Staphylococcus epidermidis (cholesterol ester formation) on the
skin showing numerous
perifollicular skin. Skin surface lipid is composed of a mixture of sebum and eccrine glands located in
epidermal lipids. the deep reticular dermis
and subcutaneous fat,
(B) the secretory unit is in
Eccrine glands the lower field. Sections
through the coiled duct
Human sweat glands are generally divided into two types: eccrine and apo- are evident in the upper
crine.1 The eccrine gland is the primary gland responsible for thermoregula- field. The epithelium of
tory sweating in humans.2 Eccrine sweat glands are distributed over nearly the duct is more darkly
the entire body surface. The number of sweat glands in humans varies greatly, B stained than that of the
ranging from 1.6 to 4.0 million. glandular component.
18 The structure and function of skin

(see below). Sometimes the secretory lobules show striking clear cell change
due to glycogen accumulation (Fig. 1.62). The myoepithelial cells contract
in response to cholinergic stimuli. They have spindled cell morphology and
are distributed in a spiral, parallel array along the long axis of the secretory
tubule. On the basis of their expression of keratin filaments, they appear to
be of ectodermal rather than mesenchymal derivation. They do not label for
vimentin. Myoepithelial cells therefore develop from the epithelial cells of the
tip of the secretory coil and not, as might be expected, from adjacent mesen-
chymal cells. The dermal duct components consist of a double layer of cuboi-
dal basophilic cells. The duct is not merely a conduit, but has a biologically
active function, modifying the composition of eccrine secretion and, particu-
larly, the reabsorption of water. The intraepidermal portion of the sweat duct
opens directly onto the surface of the skin. A myoepithelial layer is absent.
The secretory unit is strongly labeled by CAM 5.2 (both cytoplasmic and
membranous) and Ber-EP4 and there is luminal accentuation (Fig. 1.63). The
ductal component is completely negative. EMA can be detected along the
luminal aspect of the secretory unit and outlining the intercellular canaliculi.
It is also present around the luminal border of the duct, and is often present
in large quantities within the lumen. CEA is present in a similar distribution
to EMA although secretory labeling tends to be rather focal and somewhat
weaker while the ductal lumen is more strongly outlined. The ­myoepithelial

Fig. 1.60
Eccrine gland: high-power
view of eccrine straight
duct.

Fig. 1.62
Eccrine gland: excessive glycogen has resulted in vacuolated epithelium.

Fig. 1.61
Eccrine gland: most
superficially, the duct
coils through the stratum
corneum.

dermis or around the interface between the dermis and subcutaneous fat and
is surrounded by a thick basement membrane and loose connective tissue
often rich in mucin. It embodies an outer discontinuous layer of contractile
myoepithelial cells and an inner layer of secretory cells comprising two cell
types: large clear pyramidal cells, which appear to be responsible for water
secretion, and smaller, darkly staining mucopolysaccharide-containing cells
(probably secreting a glycoprotein), which are much less commonly seen. Fig. 1.63
Between adjacent cells are canaliculi, which open into the lumen of the tubule Eccrine gland: immunohistochemistry.

cells can be identified by antibodies to S-100 protein, desmin and smooth
muscle actin. The eccrine glands show strong activity for the enzymes
­amylophosphorylase, leucine aminopeptidase, succinic dehydrogenase and
cytochrome oxidase.3 Weak or no activity is seen for NADH ­diaphorase,
esterase and acid phosphatase.
With electron microscopy, the serous cells are characterized by abundant
intracytoplasmic glycogen granules and numerous mitochondria (Figs 1.64,
1.65). Adjacent cell membranes, which show marked interdigitations, may
separate to form microvilli-lined intercellular canaliculi. The mucous cells
contain numerous electron-dense lipid droplets and lysozymes. Myoepithelial
cells are present at the periphery of the secretory coil within the eccrine basal
lamina (lamina densa) and contain abundant myofilaments with characteris-
tic dense bodies. The sweat duct lumen is bordered by conspicuous microvilli
(Fig. 1.66). The cytoplasm contains numerous clear vesicles. Tonofilaments
are characteristically orientated in a circumferential manner deep to the
plasma membrane, the so-called cuticle of light microscopy. This is particu-
larly well developed in the acrosyringium.
Human perspiration is classified into two types: insensible perspiration
and active sweating. Insensible perspiration involves water loss from the
Fig. 1.64
Eccrine gland: low-power electron micrograph showing the lumen in the upper-right
quadrant, granular mucous-secreting cells and serous cells.
A B
Fig. 1.65
Eccrine gland: (left) high-power view of clear cell showing conspicuous
mitochondria and numerous electron-dense glycogen granules, (right) high-power
view of secretory granules in a dark cell.
Apocrine glands 19
A B
Fig. 1.66
Eccrine gland: (A) lumen of the eccrine dermal duct lined by conspicuous microvilli,
(B) high-power view of eccrine dermal duct showing microvilli and circumferentially
orientated tonofilaments.
respiratory passages, the skin, and gaseous exchanges in the lungs. Heat,
exercise and carbon dioxide can all induce active sweating in human beings.
Active sweating may be classified into two types: thermal and mental/emo-
tional. Thermal sweating plays an important role in keeping the body's tem-
perature constant and involves the whole body surface.4 The secretory nerve
fibers innervated in human sweat glands are sympathetic, which appear to be
cholinergic in character as sweating is produced by pilocarpine and stopped
by atropine.5 Vasoactive intestinal peptide (VIP) coexisting in the cholinergic
nerve fibers has been suggested as a candidate neurotransmitter that may con-
trol the blood circulation of the sweat glands. Acetylcholine is the primary
neurotransmitter released from cholinergic sudomotor nerves and binds to
muscarinic receptors on the eccrine sweat gland, although sweating can also
occur via exogenous administration of α- or β-adrenergic agonists. The ini-
tial fluid released from the secretory cells is isotonic and similar to plasma
although it is devoid of proteins. As the fluid travels up the duct towards the
surface of the skin, sodium and chloride are reabsorbed, resulting in sweat
on the surface being hypotonic relative to plasma.6 When the rate of sweat
production increases, however, for example during exercise, ion reabsorption
mechanisms can be overwhelmed due to the large quantity of sweat secreted
into the duct, resulting in higher ion losses. The sodium content in sweat on
the skin's surface, therefore, is greatly influenced by sweat rate.
Apocrine glands
Apart from eccrine glands, the skin also contains apocrine sweat glands.1,2
Apocrine glands have a low secretory output, and hence no significant role in
thermoregulation. Apocrine glands are found predominantly in the anogeni-
tal and axillary regions, but are also located in the external auditory meatus
(ceruminous glands), the eyelid (Moll's gland), and within the areola. They
are derived from the epidermis, and develop as an outgrowth of the follicu-
lar epithelium. They first appear during the fourth to fifth month of gesta-
tion. Their function in humans is unknown, but in other mammals they are
responsible for scent production and have importance in sexual attraction.
As with sebaceous glands, they are smaller in childhood, becoming larger and
functionally active at puberty. The secretions of the ceruminous glands are
believed to lubricate, clean and protect the external ear from bacterial and
fungal infections.
Apocrine glands include two distinct components: a complex secretory
element situated in the lower reticular dermis or subcutaneous fat, and
a tubular duct linking the gland with the pilosebaceous follicle at a site
above the sebaceous duct. Microscopically, the secretory portion comprises
an outer discontinuous layer of myoepithelial cells and an inner layer of
20 The structure and function of skin

­cuboidal to columnar eosinophilic cells (Figs 1.67, 1.68). Although a histo-

logical artifact, secretory droplets, which appear to be pinched off from the
superficial aspect of the columnar cells (decapitation secretion), can be seen
on light microscopy. The duct portion is formed by a double layer of cuboi-
dal epithelium. It is morphologically indistinguishable from the eccrine
duct. The inner layer of the secretory portion contains a single columnar
secretory cell type containing numerous large dense granules located at the
apical aspect, which contribute to the lipid-rich secretion produced. The
inner layer is also surrounded by a fenestrated layer of myoepithelial cells
but the lumen may be larger in diameter than that present in eccrine tissue
The apocrine excretory duct does not have any known reabsorptive func-
tion and consists of a double layer of cuboidal cells that merge distally with
the epithelium of the hair follicle, resulting in emptying of the secretion into
the hair follicle.
Immunohistochemically, the secretory unit shows very strong labeling
with the antibody CAM 5.2 (both cytoplasmic and membranous), and there
is luminal accentuation. The apocrine duct is negative (Fig. 1.69). EMA labels
the cytoplasm of the secretory cells, and is accentuated along the luminal
border. It is also present along the luminal aspect of the apocrine duct. With
CEA, there is faint, focal staining of the secretory epithelium. The luminal Fig. 1.69
Apocrine gland: immunohistochemistry (CAM 5.2 and EMA).

aspect of the duct is strongly outlined. Cytoplasmic granules express epider-

Fig. 1.67
Apocrine gland: this specimen from normal axillary skin shows apocrine secretory
lobules in the subcutaneous fat. Ducts are present in the upper right of the field.
mal growth factor. The myoepithelial cells of the secretory unit are reactive
for S-100 protein and smooth muscle actin (Fig. 1.70). The apocrine secre-
tory epithelium strongly expresses the enzymes NADH diaphorase, esterase,
acid phosphatase and β-glucuronidase. There is weak or absent reactivity for
amylophosphorylase, leucine aminopeptidase, succinic dehydrogenase and
cytochrome oxidase. The apocrine gland also can be stained with cationic
colloidal gold at pH 2.0.3
Ultrastructure of the apocrine reveals cuboidal to columnar secretory cells
containing numerous osmiophilic secretory vacuoles. Mitochondria are pres-
ent in large numbers. While some show obvious double cristae, others are so
electron dense that the internal structure is obscured. The Golgi is conspicu-
ous. The luminal border is lined by prominent microvilli (Fig. 1.71).
The mechanism of apocrine secretion and control of apocrine glands is
uncertain, but there is adrenergic sympathetic innervation, and secretion is
provoked by external stimuli such as excitement or fear. The unpleasant odor
of apocrine secretion, which is odorless in itself, is due to breakdown prod-
ucts produced by cutaneous bacterial flora.
A third type of intermediate sweat gland, the apo-eccrine gland, has
also been described in axillary skin but its existence is not universally
accepted.

Fig. 1.68
Apocrine gland: lobules are lined by tall columnar cells with intensely eosinophilic Fig. 1.70
cytoplasm. ‘Decapitation secretion’ is conspicuous. Apocrine gland: immunohistochemistry (S-100 protein and SMA).
 Dermal–epidermal junction 21

Basal keratinocyte

Keratin filaments

Hemidesmosomal inner plaque

Hemidesmosomal outer plaque

Cell membrane
Sub-basal dense plate
Lamina lucida
Anchoring filaments

Lamina densa

Anchoring fibrils
Fig. 1.71
Apocrine gland: close-up view showing microvilli and decapitation secretion.
Papillary dermis

Dermal–epidermal junction Fig. 1.73

Schematic representation of a hemidesmosome-anchoring filament-anchoring
The interface between the lower part of epidermis and the top layer of dermis
fibril complex at the dermal–epidermal junction. A continuum of adhesive proteins
consists of a complex network of interacting macromolecules that form the extends from the keratin tonofilaments within basal keratinocytes through to
cutaneous basement membrane zone (BMZ) (Figs 1.72, Fig. 1.73).1 Many of dermal collagen. This complex represents the main adhesion unit at the dermal–
these components are glycoproteins and thus the BMZ can be recognized his- epidermal junction.
tologically as staining positive with PAS staining (Fig. 1.74). Ultrastructural
examination of the BMZ by transmission electron microscopy shows two
layers with different optical densities (Fig. 1.75).2 The upper layer, the lam-
ina lucida, is a low electron density region of 30–40 nm in breadth which is
directly subjacent to the plasma membranes of basal keratinocytes. Below the
lamina lucida is the lamina densa, an electron-dense region, 30–50 nm across,
which interacts with the extracellular matrix of the upper dermis. Within
the cutaneous BMZ distinct adhesion complexes are evident. Extending from

Keratins
5 & 14

Plectin
230-kDa
BP Ag

α6β4
integrin Type XVII Fig. 1.74
collagen The basement membrane region stains strongly with periodic acid-Schiff.
Laminin-332

Type IV inside the basal keratinocytes, through the lamina lucida and lamina densa,
collagen and into the superficial dermis are ultrastructurally recognizable attachment
structures. The components of these adhesion units are the hemidesmosomes,
anchoring filaments and anchoring fibrils.3 The importance of these struc-
Type VII tural complexes in securing adhesion of the epidermis to the underlying der-
collagen mis is highlighted by both inherited and acquired subepidermal blistering skin
diseases (Figs 1.76, Fig. 1.77). The precise role of individual proteins in adhe-
sion is demonstrated by the group of inherited skin blistering diseases, epi-
dermolysis bullosa, in which components in the hemidesmosomal structures,
Fig. 1.72 anchoring filaments, or anchoring fibrils are genetically defective or absent.4
The macromolecular components of the dermal–epidermal junction centered on This leads to fragility at the dermal–epidermal junction as a result of minor
a hemidesmosome-anchoring filament-anchoring fibril complex. Protein–protein trauma.
interactions between these molecules secure adhesion between the epidermis and The hemidesmosomes extend from the intracellular compartment of the
the subjacent dermis. basal keratinocytes to the cell membrane adjacent to the lamina lucida in
22 The structure and function of skin

Keratins
5 & 14
Bullous
pemphigoid
Bullous Plectin
pemphigoid-like 230-kDa
BP Ag Mucous
membrane
Bullous α6β4 pemphigoid
pemphigoid-like integrin Type XVII
Mucous
collagen Laminin-332 membrane
pemphigoid

Fig. 1.75
Transmission electron microscopy of the dermal–epidermal junction. Bar = 200 nm.
EB acquisita Type VII
Bullous SLE collagen

Keratins
EB simplex
5 & 14 Fig. 1.77
Recessive Acquired disorders of hemidesmosomal proteins. Autoantibodies directed against
EB simplex EB simplex components of the hemidesmosome-anchoring filament-anchoring fibril complex
EB simplex with give rise to specific subepidermal autoimmune blistering diseases.
Plectin
muscular dystrophy 230-kDa
BP Ag
EB simplex with Non-Herlitz
pyloric atresia junctional EB ­structure of laminins contains both globular and rodlike segments which con-
α6β4 tribute to interactions with other extracellular matrix molecules, as well as
integrin Type XVII
Herlitz & cell attachment and spreading, and cellular differentiation. The critical role
Junctional EB with collagen of laminin 332 in providing integrity to the cutaneous BMZ is evident from
Laminin-332 non-Herlitz
pyloric atresia
junctional EB findings that mutations in any of the three polypeptide subunits (the α3, β3,
or γ2 chains) can result in junctional forms of epidermolysis bullosa.
The major component of the lamina densa is type IV collagen, which in
skin is mainly composed of the α1 and α2 chains.7 Type IV collagen is assem-
bled to form a complex hexagonal arrangement which allows high flexibility
Dominant and to the BMZ and facilitates interactions with other collagenous and noncollag-
Type VII
recessive
collagen enous proteins (Fig. 1.79). Other BMZ components at the dermal–­epidermal
dystrophic EB
junction include the glycoprotein nidogen (previously known as entactin)
which interacts with type IV collagen either alone or as part of a laminin-
nidogen complex. Also present are the heparan sulfate proteoglycans, which
are highly negatively charged and hydrophilic and capable of interacting with
Fig. 1.76 a number of basement membrane components and thus contribute to the
Genetic disorders of hemidesmosomal proteins. Mutations in components of the architectural organization of the BMZ.8
hemidesmosome-anchoring filament-anchoring fibril network give rise to specific
Anchoring fibrils are ultrastructurally recognizable fibrillar structures
variants of epidermolysis bullosa (EB).
which extend from the lower part of lamina densa to the upper reticular der-
mis. The main component of anchoring fibrils is type VII collagen (Fig. 1.80).9
Individual type VII collagen molecules are ≈450 nm long and by complexing
the upper portion of the dermal–epidermal basement membrane. The inner
as antiparallel dimmers and aggregating laterally, they forms loops which are
plaques of hemidesmosomes serve as attachment sites for keratin filaments
traversed by interstitial dermal collagens (types I, III and V) to adhere the
while the outer plaques associate with anchoring filaments that traverse the
BMZ to the underlying dermis.10 Type VII collagen is synthesized by both
lamina lucida. Subjacent to the hemidesmosomal outer plaques in the lamina
dermal fibroblasts and epidermal keratinocytes. Also inserting into the lam-
lucida are the sub-basal dense plates which contribute to the structural orga-
ina densa at the dermal–epidermal junction are elastic microfibrils, contain-
nization of the attachment complex. Intracellular hemidesmosomal proteins
ing proteins such as fibrillin. Fibrillin-containing microfibrils may exist as a
include the 230-kD bullous pemphigoid antigen 1 and the 500-kD plectin
fibrillar mantle surrounding an elastin core or be found independently as elas-
protein. Transmembranous hemidesmosomal proteins comprise the 180-kD
tin-free microfibrils. The latter, located beneath the lamina densa, are known
bullous pemphigoid antigen (also known as type XVII collagen), and the α6
as the dermal microfibril bundles (Fig. 1.81)
and β4 integrin molecules.5 The hemidesmosomes are associated with anchor-
ing filaments in the lamina lucida, thread-like structures 3–4 nm in diameter
that span the lamina lucida to the lamina densa. Dermal collagen
Located at the lamina lucida–lamina densa interface are the laminins.
The major laminin within the cutaneous BMZ is laminin 332, previously The major extracellular matrix component in the dermis is collagen.
known as laminin 5 (Fig. 1.78). In addition, laminin 111 (laminin 1), laminin Currently, 29 distinct collagens have been identified in vertebrate tissues
311 (laminin 6), laminin 321 (laminin 7) and laminin 511 (laminin 10) are and each is designated a Roman numeral in the chronological order of its
also integral components of the dermal–epidermal junction.6 The cruciform ­discovery. At least eight different collagens are found in human skin. All collagen
 Dermal collagen 23

α3

β3 γ2

Fig. 1.78
Laminin-332 is a major
adhesion protein at the dermal–
epidermal junction: (A) the
protein is composed of three
polypeptide chains: α3, β3, and
γ2; (B) Laminin-322 identified by
B immunofluorescence in a sample
A
of split skin.

­molecules ­consist of three subunit polypeptides which can either be iden-

tical in homotrimers or can consist of two or even three genetically differ-
ent polypeptides in heterotrimeric molecules. Since the different subunits
are all distinct gene products, there are well over 40 different genes in the
human genome that encode the different subunit polypeptides.1 Collagens
demonstrate considerable tissue specificity and are synthesized by a number
of different cell types, including dermal fibroblasts, keratinocytes, vascular
endothelial cells, and smooth muscle cells. A characteristic feature of col-
lagen is the presence of hydroxyproline and hydroxylysine residues, amino
acids that are post-translationally synthesized by hydroxylation of proline
and lysine residues, respectively. These hydroxylation reactions take place in
the rough endoplasmic reticulum by prolyl and lysyl hydroxylases, respec-
tively, enzymes that require ascorbic acid, molecular oxygen and ferrous iron
as cofactors. The hydroxylation of prolyl residues is necessary for stabili-
zation of the triple-helical conformation at physiologic temperatures, and
hydroxylysyl residues are required for formation of stable covalent cross-
links. In the rough endoplasmic reticulum, trimeric molecules are formed
and following the prolyl hydroxylation reactions, triple helices are generated
which are then secreted through Golgi vesicles into the extracellular space.
Here, parts of the noncollagenous peptide extensions are cleaved by specific
proteases, and the collagen molecules undergo supramolecular organization.
To acquire fibrillar strength, the fibers are then covalently linked together by
specific intra- and intermolecular cross-links. The most common forms of
cross-links in type I collagen are derived from lysine and hydroxylysine resi-
dues, and in some collagens there are also cysteine-derived disulfide bonds.

Fig. 1.80
Normal skin: the anchoring fibrils are composed predominantly of type VII collagen
as shown in this immunogold electron microscopic preparation.

On the basis of their fiber architecture in tissues, collagens can be divided

into different classes. Types I, II, III, V and IX align into large fibrils and
are designated as fibril-forming collagens. Type IV is arranged in an inter-
lacing network within the basement membranes, while type VI is a distinct
microfibril-forming collagen and type VII collagen forms anchoring fibrils.
FACIT collagens (fibril-associated collagens with interrupted triple-heli-
ces), include types IX, XII, XIV, XIX, XX, and XXI.2 Many of the FACIT
­collagens ­associate with larger collagen fibers and act as molecular bridges
stabilizing the organization of the extracellular matrices.
Fig. 1.79 Type I collagen, the most abundant form of collagen, is the predomi-
Basement membrane: basement membrane staining with type IV collagen. nant collagen in human dermis, accounting for approximately 80% of total
24 The structure and function of skin

Fig. 1.82
Normal skin of forearm:
Fig. 1.81 in the papillary dermis
Normal skin: this view the collagen fibers are
shows a well-formed fine and sometimes have
dermal microfibril bundle a vertical orientation.
(arrowed). Masson's trichrome.

c­ ollagen. Type I collagen associates with type III collagen to form broad,
extracellular fibers in the dermis. Mutations in the type I and III collagens or
in their processing enzymes can result in connective tissue abnormalities seen
in different forms of the Ehlers-Danlos syndrome, and mutations in the type
I collagen gene lead to osteogenesis imperfecta.3
Type III collagen accounts for about 10% of the total collagen in adult der-
mis, although it is the predominant dermal collagen in the fetus. It predomi-
nates in vascular connective tissues, the gastrointestinal tract, and the uterus,
and mutations in the type III collagen gene occur in the vascular type of the
Ehlers-Danlos syndrome.
Type V collagen is present in most connective tissues, including the der-
mis, where it represents less than 5% of the total collagen. Type V collagen is
located on the surface of large collagen fibers in the dermis, and its function
is to regulate their lateral growth. A lack of type V collagen leads to vari-
able collagen fiber diameters and an irregular fiber contour in cross-section.
Such fibers are seen in autosomal dominant forms of Ehlers-Danlos syndrome
associated with mutations in the type V collagen gene.
Mature collagen fibers are relatively inert and can exist in tissues under
normal physiologic conditions for long periods. However, there is some
continuous turnover of collagen that involves a number of enzymes of Fig. 1.83
the matrix metalloproteinases (MMP) family. These proteinase families Normal skin of back: broad bundles of collagen typify the reticular dermis.
include the collagenases, gelatinases, stromelysins, matrilysins, and the Masson's trichrome.
membrane-type MMPs.4 The MMPs are synthesized and secreted as inert
proenzymes which become activated proteolytically by removal of the
approximately 64 nm (Fig. 1.84). The cross-striations are seen because of
propeptide. The MMPs are zinc metalloenzymes and require calcium for
the longitudinal overlap of individual collagen molecules, which occurs dur-
their activity. The MMPs also have specific small molecular weight pep-
ing assembly of the mature fibril. Fibrous long-spacing collagen is a vari-
tide inhibitors, known as tissue inhibitors of metalloproteinases (TIMPs).
ant with a periodicity of 90–120 nm (Fig. 1.85). It is characteristically seen
These proteins stoichiometrically complex with MMPs to prevent colla-
in peripheral nerve and central nervous system tumors. Collagen bundles
gen degradation. In normal human skin, a number of MMPs are syn-
exhibit anisotropy and are therefore birefringent when viewed with polar-
thesized and secreted by fibroblasts and keratinocytes. The expression of
ized light (Fig. 1.86).
these enzymes is enhanced in various pathologic states, including inva-
sion and metastasis of cutaneous malignancies, as well as during dermal
wound healing. Dermal elastic tissue
Within the papillary dermis, collagen fibers are fine and often verti-
cally orientated whereas reticular dermal collagen consists of broad, thick The elastic fiber network provides resilience and elasticity to the skin.1 Elastic
bundles generally arranged parallel to the surface epithelium (Figs 1.82, fibers are a relatively minor component in normal sun-protected adult skin, com-
1.83). When longitudinal sections of collagen are examined by transmis- prising less than 2–4% of the total dry weight of the dermis. The ­configuration
sion electron microscopy they show cross-striations with a periodicity of of elastic fibers in the reticular dermis consists of horizontally orientated fibers
 Dermal elastic tissue 25

Fig. 1.84
Collagen: it is characterized by cross-striations with a periodicity of 64 nm.
which interconnect (Fig. 1.87).2 Extending from these into the papillary ­dermis
is a network of vertical extensions of relatively fine fibrils which consist either
of bundles of microfibrils (oxytalan fibers) or of small amounts of cross-linked
elastin (elaunin fibers) (Fig. 1.88).3 Elastic fibers have two principal compo-
nents: elastin, which is a connective tissue protein that forms the core of the
mature fibers, and the elastin-associated microfibrils which consist of a family
of proteins. Examination by transmission electron microscopy reveals an elas-
tin core that makes up over 90% of the elastic fiber and which is surrounded
by more electron-dense microfibrillar structures (Fig. 1.89).
Elastin is initially synthesized as a precursor polypeptide, tropoelastin,
which consists of approximately 700 amino acids with a molecular mass of
≈70 kD.4 The amino acid composition of tropoelastin is similar to collagen in
that about one-third of the total amino residues consist of glycine but the pri-
mary sequence is different, with domains rich in glycine, valine, and proline,
alternating with lysine- and alanine-rich sequences: a characteristic sequence
motif is the presence of two lysine residues separated by two or three alanine
residues. The lysine residues in tropoelastin are critical for the formation of
covalent cross-links between desmosine and its isomer, ­isodesmosine, which
appear to be unique to elastin. The first step in formation of these elastin-
specific cross-links is oxidative deamination of three lysine residues to form

Fig. 1.85 Fig. 1.87

Fibrous long-spacing collagen: compare with the adjacent conventional collagen Reticular dermis: the elastic fibers are long and fairly thick and tend to run parallel to
fibers. There is a very different periodicity. the surface epithelium.

Fig. 1.86 Fig. 1.88

Collagen of the reticular dermis: note the birefringence when viewed with polarized Papillary dermis: the elastic fibers are delicate and orientated perpendicular to the
light. Masson's trichrome. epithelial surface. Weigert–van Gieson stain.
26 The structure and function of skin
Fig. 1.89
Elastic fiber: this consists of microfibrils embedded in an electron-dense matrix
called elastin.
aldehydes, known as allysines. These aldehydes, with additional lysine, fuse
to form a stable desmosine compound which covalently links two of the tro-
poelastin polypeptides. Addition of desmosines to other parts of the molecule
progressively converts tropoelastin molecules into an insoluble fiber struc-
ture. The oxidative deamination of lysyl residues to corresponding aldehydes
is catalyzed by a group of enzymes, lysyl oxidases, which require copper for
their activity. Thus, copper deficiency can lead to reduced lysyl oxydase activ-
ity and synthesis of elastic fibers that are not stabilized by sufficient amounts
of desmosines. In such a situation, the individual tropoelastin polypeptides
remain soluble and susceptible to non-specific proteolysis, and the elastin-rich
tissues are fragile. The metabolic turnover of elastin is slow, but is increased
in some forms of cutis laxa and cutaneous aging. Elastic fibers are degraded
by elastases and metalloelastases.
The elastin-associated microfibrils consist of tubular structures of ≈10–
12 nm in diameter. These proteins include fibrillin, the latent transforming
growth factor-β binding family of proteins, and the fibulins. Other compo-
nents comprise the families of microfibril-associated glycoproteins and micro-
fibril-associated proteins (MFAP), the emilins and certain lysyl oxidases. The
importance of the fibrillin is illustrated by mutations resulting in Marfan
syndrome with skeletal abnormalities, aortic dilatation, subluxation of the
ocular lens, and cutaneous hyperextensibility.5 Likewise, the significance of
certain fibulins is evident from mutations resulting in cutis laxa, manifesting
with loose and sagging skin and loss of elastic recoil.
Ground substance
Proteoglycans form a number of subfamilies defined by a core protein to which
polymers of unbranched disaccharide units, glycosaminoglycans (GAGs), are
linked.1 The core proteins can be intracellular, reside on the cell surface, or
be part of the extracellular matrix and the GAGs are highly charged polyan-
ionic molecules that vary greatly in size. For example, dermal fibroblasts can
synthesize versican which consists of a core protein with attachment sites for
12 to 15 GAG side chains. The GAGs in versican are primarily chondroitin
sulfate or dermatan sulfate, but versican can also bind hyaluronic acid, result-
ing in formation of large aggregates. Proteoglycan/GAG complexes have mul-
tiple functions. For example, the proteoglycans containing heparan sulfate
and dermatan sulfate have the ability to bind extracellular matrix compo-
nents, including various collagens.2 In addition, these proteoglycans bind
several growth factors, cytokines, cell adhesion molecules, and growth fac-
tor binding proteins, thereby influencing the bioactivity of these molecules.
They can also serve as antiproteases. In addition to binding to a number
of extracellular molecules, proteoglycans also play a role in the adhesion of
cells to the extracellular matrix. For example, syndecan-4, which is selectively
Fig. 1.90
Ground substance: an eccrine gland from the sole of the foot shows an abundance
of glycosaminoglycans.
enriched in dermal fibroblasts, facilitates the adherence of cells in conjunc-
tion with other extracellular matrix binding molecules, such as the integrins.3
Proteoglycans also interact with other extracellular matrix molecules besides
collagen; notably, chondroitin sulfate and dermatan sulfate bind fibronectin
and laminin. The largest extracellular GAG, hyaluronic acid, plays an impor-
tant role in providing physical and chemical properties to the skin, mediated
in part by its hydrophilicity and viscosity in dilute solutions. Of particular
note, hyaluronic acid has an expansive water-binding capacity, providing
hydration to normal skin. Indeed, water makes up ≈60% of the weight of
normal human skin in vivo. Other properties attributed to large proteogly-
cans complexes, such as those formed with the versican or basement mem-
brane proteoglycans, include their ability to serve as ionic filters, regulate salt
and water balance, and provide an elastic cushion.1
Except when present in very large amounts, ground substance cannot be
easily detected by routine hematoxylin and eosin staining (Fig. 1.90). Cationic
dyes, such as Alcian blue at appropriate pH and electrolyte concentration, are
usually necessary for its demonstration.
Fibroblast biology
The main cell responsible for the synthesis of collagens, elastic tissue and
proteoglycan/glycosaminoglycan macromolecules in the dermis is the fibro-
blast.1 In the mid-dermis of postnatal skin, the number of fibroblasts ranges
from 2100 to 4100 per mm3, and the cells have a limited replicative capacity
ranging from 50–100 cell divisions. Fibroblasts also play a significant role
in epithelial–mesenchymal interactions, secreting various growth factors and
cytokines that have a direct effect on epidermal proliferation, differentiation
and formation of extracellular matrix. The term fibroblast refers to a fully
differentiated, biosynthetically active cell, while the term fibrocyte refers to
an inactive cell.
Myofibroblasts are a specialized form of fibroblast found in granulation
tissue and are involved in wound contraction. They are functionally distinct
from other fibroblasts with ultrastructural, biochemical and physical fea-
tures of smooth muscle cells. Moreover, myofibroblasts are characterized
by the presence of intracellular bundles of α smooth muscle actin, which is
the actin isoform expressed by smooth muscle cells. Currently it is thought
that the evolution of myofibroblasts involves a preceding form known as
the protomyofibroblast, although the latter do not always become the fully
differentiated myofibroblast. In contrast to myofibroblasts, protomyofibro-
blasts have stress fibers but no α smooth muscle actin filaments. A bio-
synthetically active fibroblast has an abundant cytoplasm, well-developed
rough endoplasmic reticulum, and prominent ribosomes attached to the
membrane surfaces.

Fibroblasts from different anatomical sites all have similar morphology
but fibroblasts in different sites have their own gene-expression profiles and
characteristic phenotypes, synthesizing extracellular matrix proteins and
cytokines in a site-specific manner.2
Dermal fibroblasts have numerous functions, not only in synthesizing and
depositing extracellular matrix components, but also in proliferation and migra-
tion in response to chemotactic, mitogenic and modulatory cytokines, and also
autocrine and paracrine interactions. Autocrine activity includes the trans-
forming growth factor (TGF)-β-induced synthesis and secretion of connective
tissue growth factor which promotes collagen synthesis as well as fibroblast
proliferation. Paracrine activity affects keratinocyte growth and differentiation,
specifically through fibroblast secretion of keratinocyte growth factor (KGF),
granulocyte-macrophage colony-stimulating factor, interleukin (IL)-6 and fibro-
blast growth factor (FGF)-10. Fibroblasts also contribute to basement membrane
formation partly by producing type IV collagen, type VII collagen, laminins and
nidogen, but also through the secretion of cytokines, such as TGF-β, that stimu-
late keratinocytes to produce basement membrane components.
Neovascularization and lymphangiogenesis are also important processes for
the maintenance of normal skin homeostasis and wound healing, for which
fibroblasts have an important paracrine role. Members of the vascular endothe-
lial growth factor (VEGF) family include VEGF-A, -B, -C, and -D, which are
produced by normal human fibroblasts and are important in regulating vascu-
lar and lymphatic endothelial cell proliferation through specific receptors.
There is, however, considerable heterogeneity within fibroblast popula-
tions. For example, fibroblasts isolated from the papillary dermis compared
to the reticular dermis have higher rate of synthesis of type III collagen and
there can be as much as 30-fold differences in the level of fibronectin expres-
sion within individual cells. Fibroblasts from the papillary dermis appear
smaller, grow faster and have a longer replicative lifespan.3 When co-cultured
with keratinocytes, papillary dermal fibroblasts produce a more differentiated
and organized epidermis with complete formation of the dermal–epidermal
junction. Papillary dermal fibroblasts also produce more granulocyte–mac-
rophage colony-stimulating factor (GM-CSF) and relatively less keratinocyte
growth factor (KGF) than reticular dermal fibroblasts. In addition, there are
differences in the synthesis of some extracellular matrix components, such
as decorin. While fibroblasts demonstrate certain variability in their gene
expression profiles they are considered fully differentiated cells with relatively
little plasticity. Recent observations, however, suggest that fibroblasts can be
induced to become pluripotent stem cells (iPS), essentially indistinguishable
from the embryonic stem cells, by transduction of cultured fibroblasts with
four transcription factors, Oct4, Sox2, Klf4, and c-myc.4
Cutaneous blood vessels and lymphatics
The skin receives a rich blood supply from perforating vessels within the skele-
tal muscle and subcutaneous fat.1 Most of the blood flow is directed toward the
more metabolically active constituents of the skin, namely the epidermis, hair
papillae and the adnexal structures. While the dermal papillae are richly vascu-
larized, no capillaries actually enter the epidermis, which receives its nutrition
by diffusion. The subcutaneous vessels give rise to two vascular plexuses linked
by intercommunicating vessels: the deep vascular plexus lies in the region of the
interface between the dermis and subcutaneous fat, and the superficial vascu-
lar plexus lies in the superficial aspects of the reticular dermis and supplies the
papillary dermis with a candelabra-like capillary loop system (Fig. 1.91). Each
loop consists of an ascending arterial limb and a descending venous limb. The
vessels of the dermal papillae comprise terminal arterioles, arterial and venous
capillaries, and postcapillary venules, with the last predominating. Within the
deep vascular plexus are small muscular arteries, which give rise to the arteri-
oles that supply the superficial vascular plexus (Fig. 1.92).
The histology of these plexuses is similar, the difference being one of size
rather than structure (arterioles have a diameter of less than 0.3 mm).2 From
the lumen outwards the arteriole consists of a very thin intima resting against a
conspicuous internal elastic lamina. Next to this is the media, consisting of two
layers of smooth muscle, which constitutes the bulk of the vessel. The adven-
titia surrounding the media is composed of loose connective tissue. In small
muscular arteries (but not arterioles), the adventitia often contains elastic fibers
Cutaneous blood vessels and lymphatics 27
Epidermis
Papillary dermis
Superficial
vascular plexus
Reticular dermis
Deep
vascular plexus
Subcutaneous fat Fig. 1.91
Relationship of the
superficial and deep
vascular plexuses.
constituting the external elastic lamina. Small arterioles have an endothelium
surrounded by a single layer of smooth muscle. Capillaries consist of a single
layer of endothelial cells, but may have adjacent pericytes, which have less
well-developed dense bodies and fewer filaments than smooth muscle cells.
Endothelial cells and pericytes form tight junctions. Venous capillaries have
numerous pericytes and a multilayered basement membrane in contrast to
arterial vessels where the basement membrane is solitary and homogeneous.
Each dermal papilla is supplied by a single capillary loop. Endothelial cells
contain vimentin filaments, Weibel-Palade bodies measuring approximately
0.1 × 3.0 μm (containing factor VIII) and numerous pinocytotic vesicles (Figs
1.93, 1.94). Postcapillary venules are larger, but have the same basic struc-
ture as capillaries. Their wall is devoid of smooth muscle. The small muscu-
lar venules into which the postcapillary venules drain have an intima made
up of flattened endothelial cells surrounded by a smooth muscle layer one or
two cells thick. They are therefore similar to small arterioles, but with much
wider lumina. Veins are composed of an endothelium surrounded by a muscle
coat several layers thick. Typically, an internal elastic lamina is poorly repre-
sented. There is usually a thick connective tissue adventitia, but elastic fibers
are absent; only very large muscular veins have elastic tissue (Fig. 1.95).
Also present in the dermis are veil cells, which surround all the microves-
sels and separate them from the adjacent connective tissue. Veil cells are long,
thin cells with an attenuated cytoplasm, and they more closely resemble fibro-
blasts than pericytes. They do not have a basement membrane investment and
are located outside the vessel wall.
The capillary loop in the dermal papilla has an ascending arterial compo-
nent and an intrapapillary segment, which is characterized by a hairpin turn
and a descending venous capillary segment. Capillary loops run perpendicular
to the skin surface, except in the nail where they have a parallel orientation.
The dermis is richly supplied with arteriovenous anastomoses. Specialized
shunts (glomus bodies), found primarily in the dermis of the fingertips, con-
sist of an arterial segment (Sucquet-Hoyer canal), which connects directly
to the venous limb (Fig. 1.96). The canal is surrounded by several layers of
modified smooth muscle cells (glomus cells) with a particularly rich nerve
supply. Glomus bodies function as sphincters, allowing the capillaries of the
superficial dermis to be bypassed, therefore increasing the venous return from
the extremities.
Cutaneous blood flow (under hypothalamic control) is of extreme impor-
tance in thermoregulation. Mediated by the autonomic nervous system, heat
loss can be increased or decreased by varying the blood flow to the superficial
vascular plexuses. If the environmental temperature exceeds that of the body,
then the blood flow to the papillary dermis increases. A concomitant increase
in eccrine sweat gland secretion, evaporation of which cools the outer parts
of the body, lowers the temperature of the circulating blood and maintains a
stable core temperature. Temperature control therefore depends on a delicate
interplay between both vascular and sweat gland functions.
28 The structure and function of skin
A B
Fig. 1.93
Normal dermal capillary: note the lining of endothelial cells surrounded by a pericyte
cell process and adjacent basal lamina. The lumen contains erythrocytes (E).
The dermis also contains an extensive lymphatic system, which is closely
associated with the vascular plexuses.3 Although largely disregarded except
for their role in tumor spread, lymphatics are of major importance in
removing the debris of daily wear and tear including fluid, cells and macro-
molecules (Fig. 1.97). They also represent the primary disposal mechanism
for contaminating microorganisms. Lymphatics have been shown to supply
the major route for epidermal Langerhans cells to reach the regional lymph
node following antigen stimulation. Under normal circumstances these deli-
cate vessels are collapsed and are difficult to detect. They are supported by
delicate elastic tissue scaffolding and consist of a large thin-walled collapsed
vessel lined by attenuated endothelium and characterized by the presence of
multiple valves. Their presence is much more obvious in obstructive situ-
ations (e.g., lymphedema or due to the presence of metastases). Dermal
lymphatics are loosely aggregated into a superficial and deep plexus, which
drain into muscularized lymphatic trunks.4 In the lower limbs the lymphatic
Fig. 1.92
Small muscular artery from the deep vascular plexus from
the lower leg of an elderly man with endarteritis (intimal
thickening): note the thick muscle coat and conspicuous
internal elastic lamina, the latter accentuated by the
Weigert–van Gieson reaction. (A) Hematoxylin and eosin;
(B) Weigert–van Gieson.
trunks are very thick and muscular and can be confused with an artery
(Fig. 1.98). The absence of an internal elastic lamina readily allows their
distinction. Vascular endothelial cells may be identified by the monoclo-
nal antibody CD31 or by an anti-von Willebrand factor antibody. Vascular
endothelial growth factor receptor 3 (VEGFR-3) has not lived up to its
promise to be a useful lymphatic endothelial cell marker.5,6 Lymphatic vessel
endothelial hyaluronan receptor 1 (LYVE-1), Prox-1 and podoplanin may
be more useful.7
Nervous system of the skin
The skin may be innervated with around one million afferent nerve fibers.
Most terminate in the face and extremities; relatively few supply the back.
The cutaneous nerves contain axons with cell bodies in the dorsal root gan-
glia. Their diameters range from 0.2 to 20.0 μm. The main nerve trunks enter-
ing the subdermal fatty tissue each divide into smaller bundles. Groups of
myelinated fibers fan out in a horizontal plane to form a branching network
from which fibers ascend, usually accompanying blood vessels, to form a
web of interlacing nerves in the superficial dermis. The cutaneous nerves sup-
ply the skin appendages and form prominent plexuses around the hair bulbs
and the papillary dermis. The afferent receptors consist of free nerve endings,
nerve endings in relation to hair, and encapsulated nerve endings. Free nerve
endings, of both myelinated and nonmyelinated types and with a low conduc-
tion speed, are mainly responsible for the appreciation of temperature, itch
and pain. Hair follicles are supplied by an intricate network of myelinated
fibers, some of which ramify as free nerve endings in the periadnexal fibrous
tissue sheath, while others enter the epidermis to terminate as expansions
in intimate association with Merkel cells in the external root sheath. The
hair disc is a complex structure consisting of basally situated Merkel cells
and an associated myelinated peripheral nerve fiber. Despite the name, it has
an inconstant association with hair follicles. Hair discs are slowly adapting
mechanoreceptors. Throughout their course the axons of cutaneous nerves
are enveloped in Schwann cells but, as they track peripherally, an increas-
ing number lack myelin sheaths. Most end in the dermis; some penetrate the
basement membrane, but do not travel far into the epidermis.
Sensory endings are of two main kinds: corpuscular, which embrace non-
nervous elements; and ‘free’, which do not. Corpuscular endings can, in turn,
be subdivided into encapsulated receptors, of which a range occurs in the
 Nervous system of the skin 29

A B

Fig. 1.94
(A) Small dermal arteriole: the lumen is compressed to a narrow slitlike space; (B) high-power view of typical Weibel–Palade bodies. These are characteristic of blood vessel
endothelium.

A B

Fig. 1.95
Companion vein to Figure 1.92: note the wide diameter of the lumen in comparison to the relatively thin muscle coat. There is a little elastic tissue but no discernible internal
elastic lamina. (A) Hematoxylin and eosin; (B) Weigert–van Gieson.

dermis, and nonencapsulated, exemplified by Merkel's ‘touch spot’, which
is epidermal.
The most striking of the encapsulated receptors is the Pacinian corpuscle.
It is an ovoid structure about 1 mm in length, which is lamellated in cross-
section like an onion, and is innervated by a myelinated sensory axon, which
loses its sheath as it traverses the core (Fig. 1.99). Pacinian corpuscles are
responsible for the appreciation of deep pressure and vibration and are found
predominantly in the subcutaneous fat of the palms and soles, dorsal surfaces
of the digits, around the genitalia, and in ligaments and joint capsules.
The Golgi-Mazzoni corpuscle found in the subcutaneous tissue of the
human finger is similarly laminate but of much simpler organization. Another
classical receptor is the Krause end bulb, an encapsulated swelling on myeli-
nated fibers situated in the superficial layers of the dermis.
Meissner's corpuscles are characteristic of the papillary ridges of glabrous
skin in primates. They have a thick, lamellated capsule, 20–40 μm in diameter
and up to 150 μm long (Fig. 1.100).1 Meissner's corpuscles are involved in the
appreciation of touch sensation (rapidly adapting mechanoreceptors) and are
found predominantly in the dermal papillae of the hands and feet, the lips,
and on the front of the forearm. They comprise a perineural-derived lamel-
lated capsule surrounding a core of cells and nerve fibers, and are supplied by
myelinated and nonmyelinated nerve fibers. They make intimate contact with
the basal keratinocytes. Meissner's corpuscles have a multiple nerve supply
and each nerve may also supply multiple corpuscles. Of somewhat different
structure are the terminals first described by Ruffini in human digits, in which
several expanded endings branch from a single, myelinated afferent fiber. The
endings are directly related to collagen fibrils. ‘Free nerve-endings’, which
30 The structure and function of skin

Fig. 1.96 Fig. 1.99

Glomus body: note the arterial and venous limbs connected by a vascular channel Pacinian corpuscle: note the characteristic lamellar internal structure.
rich in glomus cells.

Fig. 1.97
Lymphatics: these exceedingly thin-walled channels are normally not visible in the
dermis. They become readily apparent, however, when obstructed, as in this patient
with lymphedema.

Fig. 1.100
Meissner's corpuscle within a dermal papilla: with hematoxylin and eosin staining it
appears as perpendicularly orientated lamellae of Schwann cells.

appear to be derived from nonmyelinated fibers, occur in the superficial der-

mis and in the overlying epidermis.2 Those in the dermis are arranged in a
tuftlike manner and have thus been designated penicillate nerve endings.

Fig. 1.98
Skin of lower leg: muscular lymphatic trunks can be readily mistaken for arteries.
An internal elastic lamina is characteristically absent.
Subcutaneous fat
Fat is a major component of the human body. In nonobese males, 10–12% of
body weight is fat, while in females the figure is 15–20%. Eighty per cent of fat
is under the skin; the rest surrounds internal organs. Fat comprises white and
brown adipose tissue, the latter being more common in infants and children
and is characterized by different mitochondrial properties and increased heat
production.1 Historically, fat has been thought to provide insulation, mechani-
cal cushioning and an energy store but recent data suggest that it also has an
 Subcutaneous fat 31

endocrine function, communicating with the brain via secreted molecules such ­ ediastinum. The brown coloration is due to the high cytochrome con-
m
as leptin to alter energy turnover in the body.2 Adipocytes also have important tent. The brown fat cytoplasm contains numerous, somewhat pleomorphic,
signaling roles in osteogenesis and angiogenesis. Indeed, multipotent stem cells mitochondria. Endoplasmic reticulum and a Golgi apparatus are not usually
have been identified in human fat which are capable of developing into adi- visible. The adipocytes have a bubbly appearance with the nucleus located
pocytes, osteoblasts, myoblasts and chondroblasts. Biological clues to genes, towards the center of the cell (Fig. 1.103).
proteins, hormones and other molecules that influence fat deposition and
distribution are gradually being realized, from both research on rare inher-
ited disorders (such as the lipodystrophies or obesity syndromes) as well as
­population studies on more common forms of obesity.3
The subcutaneous fat is divided into lobules by vascular fibrous septa, and
its cells are characterized by the presence of a large single globule of lipid,
which compresses the cytoplasm and nucleus against the plasma membrane
(Fig. 1.101). The adipocyte is large, measuring up to 100 μm in diameter. The
cytoplasm contains numerous mitochondria. Smooth endoplasmic reticulum
is prominent and a Golgi is often conspicuous. Processing for routine histo-
logical preparation dissolves the lipid, but the use of special stains on fro-
zen sections will reveal its presence (Fig. 1.102). The subcutaneous fat may
­contain large numbers of mast cells.
Deposits of brown fat may be seen in the newborn and occasionally
in adults, particularly in the interscapular region, the back, thorax and

Fig. 1.102
Adult fat in frozen section stained by the Sudan IV technique.

Fig. 1.101
The lipid contents of fat cells are dissolved during processing using conventional
(paraffin-embedding) techniques. The cells therefore appear empty and have Fig. 1.103
peripheral compressed nuclei. Typical brown fat showing pink granular cytoplasm.
Chapter
Specialized techniques in
2 dermatopathology
Pratistadevi K. Ramdial, Boris C. Bastian, John Goodlad, John A. McGrath and
Alexander Lazar
See
www.expertconsult.com
for references and
additional material

Specimen fixation, grossing/put-through, Immunofluorescence  35 Polymerase chain reaction (PCR)  43

processing, embedding and
sectioning  32
Routine and ‘special’ stains  33
Immunohistochemical techniques  34
Immunohistochemical techniques and
trouble shooting  34
Electron microscopy  37
Diagnosis of inherited skin diseases  37
Molecular techniques  39
Chromosomal karyotyping  39
Allelic imbalance  39
Fluorescence in situ hybridization (FISH)  39
Comparative genomic hybridization (CGH)  42
Diagnosis of lymphomas  43
PCR analysis of cutaneous lymphoid infiltrates  44
TCR gene rearrangement in cutaneous
lymphoproliferations  44
IG gene rearrangement in cutaneous
lymphoproliferations  45

Specimen fixation, grossing/ put-through,
processing, embedding and sectioning
The aim of fixation in dermatopathology is to maintain clear and consistent
morphological features and to preserve tissue in an optimal state suitable for
a range of staining and ancillary histopathological techniques.1,2 Most fixa-
tion methods employed during tissue processing depend on chemical fixa-
tion of tissue in liquid fixatives.3 Tissue fixation may also be accomplished
by physical (heat, microwave, freeze-drying and freeze substitution) and/or
chemical (coagulant and cross-linking) methods.4 The most commonly used
fixative is 10% neutral-buffered formalin solution. The quality of fixation is
affected by:
• the size of the specimen,
• duration and temperature of fixation,
• pH,
• concentration,
• osmolality,
• ionic composition of fixatives and additives contained in the fixative.5
Formalin fixation occurs at an approximate rate of 1 mm per hour.4,6,7
The volume of the fixative should be at least 10 times the volume of the
specimen.7 Large specimens, such as tumors, may require sectioning into
5-mm thick slices, covering with fixative soaked gauze or cloth and fixation
overnight.5,7
Diagnostic dermatological biopsies may be:
• small incisional (shave, core, punch),
• excisional specimens.8
Prior to put-through, excisional specimens that require an appraisal of
margins should be inked. If localization sutures have been inserted by sur-
geons then four-quadrant, four-color painting or two-color painted halves
(Fig. 2.1) may be appropriate. Shave biopsies are used to sample or remove
lesions, and if of appropriate size, may be divided into sections, bisected or
trisected and embedded on edge. Edge embedding is critical in a shave exci-
sion of a lesion such as a small melanoma so that the width and depth of
invasion can then be quantified.8,9 The main purpose of core or punch biop-
sies, which generally measure 2–8 mm in diameter, is to sample large lesions.
Biopsies larger than 4 mm in size should be bisected eccentrically and the
specimens embedded with the cut surfaces down. The eccentric sectioning
ensures that the lesion is not missed. Biopsies less than 4 mm are put through
in toto.9,10
Tissue processing refers to a series of steps that effect the removal of
extractable water from biopsies to ensure sections of optimal diagnostic qual-
ity.9 These include fixation, dehydration, clearing, infiltration and embedding
in a support matrix. Use of manual and automated tissue processing achieves
this goal, including:
• carousel-type processors,
• self-contained vacuum tissue processors,
• microwave tissue processing.
In most laboratories, overnight processing runs are the norm. 9
However, microwave-assisted tissue processing facilitates shorter pro-
cessing times of one to two hours. Dehydrating reagents promote the
removal of unbound water and aqueous fixatives from the tissue.
Clearing reagents serve as an intermediary between the dehydrating and
infiltrating solutions, being miscible with both. Paraffin is the most pop-
ular infiltration and embedding medium, being suitable for the major-
ity of routine and special stains. The important principle to be adhered
to during embedding of skin biopsies is that the orientation of the skin
sample should offer the least resistance to the blade during microtomy.
Skin biopsies are usually cut in a plane at right angles to the epidermis
so that the epidermal surface is sectioned last, minimizing its compres-
sion and distortion.
Suboptimally processed tissue may result in incomplete tissue sections and
expansion or disintegration of sections in the water bath. Incorrectly embed-
ded tissue may result in poorly orientated incomplete sections. Faulty micro-
tome mechanisms, loose, dull or damaged blades and inaccurate clearance
angles may be the causes for:
• thick and thin sections,
• folds (Fig. 2.2),
• holes (Fig. 2.3),
• scores (Fig. 2.4),
• chatter.10
The presence of calcified areas and suture in skin tissue and nicks in the
blade may result in chatter or splitting of sections at right angles to the knife
edge.
 Routine and ‘special’ stains 33

A B C D

Fig. 2.1
Gross representation of basal cell carcinoma: (A) with two-color painting of the
inferior surface (B). A 2-mm thick gross sections demonstrating the black and
blue painting at put through (C) and in paraffin blocks (D). By courtesy of Dr. J.
Deonarain, Department of Anatomical Pathology, National Health Laboratory
Service, Durban, South Africa.

Fig. 2.3
Technical artifact: holes in
tissue sections because
tissue sections were cut
too thin.

Fig. 2.2
Technical artifact: folds in tissue sections because of poor water bath floating
technique.

Routine and ‘special’ stains

With the advent of immunohistochemistry, special stains are less commonly
employed, but can still play an important role in highlighting certain tissue
characteristics or for detection of infectious organisms.
Diagnostic sections are usually stained with hematoxylin and eosin (H&E),
the most widely used routine stain.1 The hematoxylin component stains the
nuclei blue-black and the eosin stains the cytoplasmic compartment and con-
nective tissue in variable shades and intensity of pink, orange and red. The
periodic acid-Schiff (PAS) technique is used widely to demonstrate: Fig. 2.4
Technical artifact: score
• glycogen, in tissue section because
• starch, of a damaged microtome
• sialomucin, blade.
• neutral mucin,
• basement membranes,
• α1-antitrypsin, charides are not. Mucicarmine demonstrates acidic epithelial mucins.2 It is
• reticulin, useful for the diagnosis of adenocarcinomas and the mucoid C. neoformans
• Russell bodies of plasma cells, capsule. Alcian blue highlights acidic mucopolysaccharides, staining the muci-
• fungi.2 nous components of dermal mucinoses, granuloma annulare, scleredema of
The PAS technique is therefore employed to demonstrate basement mem- Bushke, lupus erythematosus and metastatic adenocarcinomas. Alcian blue
brane thickening in lupus erythematosus, porphyria cutanea tarda and in demonstrates heterogeneity of staining that is pH based: sialomucins are
some tumors. Glycogen is digested by diastase, while neutral mucopolysac- demonstrated at pH 2.5 and sulfamucins at pH 1.0.3
34 Specialized techniques in dermatopathology

Table 2.1
The more commonly used histochemical stains
Stain Component Outcome
A. Routine
Hematoxylin- Cells, connective Nuclei: blue
eosin tissue Cytoplasm: pink/red
Extracellular matrix:
red/pink
B. Carbohydrates &
glycoconjugates
Periodic acid-Schiff Neutral mucins, glycogen Magenta
PAS-diastase Glycogen, Resistant to
proteoglycans, HA diastase
resistant sialomucin digestion
Alcian blue, pH 2.5 Labile sialomucin Blue
Alcian blue, pH 1.0 Sulfomucin, resistant Blue
sialomucin
Mucicarmine Sialomucin, sulfomucin Pink
Colloidal iron Sialomucin, sulfomucin Blue
Fig. 2.5 HA, proteoglycans
Special stains: Warthin-Starry silver stain demonstrating Donovan bodies. High iron diamine Proteoglycans, Blue
sulfomucin
Toluidine blue Sulfomucin Blue
Hyaluronidase HA Sensitive to HA
While colloidal iron, initially described by Hale for the identification of
acid mucopolysaccharides, is as sensitive as Alcian blue for this purpose, C. Connective tissue
its specificity and selectivity are debatable and background staining may be fibers
problematic.4 However, reduction of pH of the colloidal iron solution and Masson trichrome Collagen Blue or green
Muscle, nerve Red
inclusion of acetic acid washes may reduce this artifact.3–5 The high iron
Verhöeff-van Gieson Elastic fibers Black
diamine stain, in contrast to colloidal iron, stains highly acidic sulfamu- Pinkus acid orcein Elastic Dark brown
cins but does not stain sialomucins or hyaluronic acid.5–7 Connective tissue Silver nitrate Reticulum fibers Black
stains highlight collagen, elastic and reticulin fibers. The trichrome stain, a
D. Infective stains
combination of three dyes, is employed for the differential demonstration
Ziehl Neelsen Acid fast bacilli Red
of muscle, collagen fibers, fibrin and erythrocytes.8 Elastic fibers may stain
Fite-Faraco (weakly) acid fast bacilli Red
with eosin, phloxine, Congo red and PAS stains but are demonstrated well Periodic acid-Schiff Fungi, parasites Magenta
with the Verhöeff method in the diagnosis of scleroderma, anetoderma and Mucicarmine Cryptococcus sp Red
pseudoxanthoma elasticum. Silver stains are useful to demonstrate reticulin Giemsa Leishmania sp, Red
fibers, melanin and the identification of infective agents. While methenamine Donovan bodies Metachromatically
silver and Gomori Grocott methenamine silver stains highlight fungi and purple
bacteria, Warthin-Starry, Dieterle and Steiner silver stains are particularly Methenamine silver Fungi, bacteria Black
useful in the demonstration of spirochetes, B. henselae and Donovan bodies Grocott Fungi Black
(Fig. 2.5). Masson-Fontana silver staining is pivotal to the staining of the methenamine
silver
cell wall of C. neoformans, especially in the identification of capsule-deficient
Warthin Starry silver Spirochetes, bacteria Black
C. neoformans. The role of the more commonly used special stains is sum-
Dieterle and Spirochetes, bacteria Black
marized in Table 2.1. Steiner silver
E. Other
Immunohistochemical techniques Perl's potassium Hemosiderin Blue
ferrocyanide
Since the first practical application of antibodies using the peroxidase labeled Oil red O Lipids Red
antibody method on paraffin-embedded tissues in 1968, immunohistochemis- Scarlet Red Lipids Red
Von Kossa Phosphate (often as Black
try (IHC) has emerged as a powerful supplementary investigation to histomor-
calcium phosphate) Black
phologic assessment.1–3 IHC has widespread dermatopathologic diagnostic,
Alizarin red S Calcium Orange-Red
prognostic, therapeutic and pathogenetic applications, not only in a range of Alkaline Congo Red Amyloid Apple green
neoplastic (Table 2.2), immunobullous and infective disease, but also in the birefringence
distinction between reactive and neoplastic disorders.4–14 Immunohistologic Chloro-acetate Myeloid series Red granules
techniques can be performed manually or in automated platforms. While esterase
automation allows enhanced quality and reproducibility of staining, detailed,
exact IHC protocols are critical in the many laboratories that still perform Key: HA, hyaluronic acid

manual IHC, to achieve optimal, reproducible results.

Immunohistochemical techniques and
trouble shooting
In many centers, IHC is now the most commonly utilized ancillary test for
clinical tissue samples.
Historically, the introduction of enzymes as labels in IHC overcame dif-
ficulties associated with immunofluorescence, including the inability to
assess histomorphology with the latter.1 The peroxidase-antiperoxidase
(PAP) technique, was replaced by alkaline phosphatase-antialkaline phos-
phatase (APAAP) techniques and avidin-biotin labeling.1,2 Although the
­streptavidin-biotin labeling system gained popularity, the endogenous biotin-
associated background staining under certain circumstances has resulted in
increasing use of labeled polymer-based detection systems, suitable for man-
ual and automated IHC platforms (Fig. 2.6).3
The direct conjugation of the primary antibody to the label formed the
principle of the initial, traditional direct technique, in which the labeled

Table 2.2
Some diagnostic immunohistochemical applications for cutaneous tumors4–13
Stain Application
Epidermal and appendageal neoplasms
AE1/AE3 Pan-keratin. Confirms epithelial lineage
CAM 5.2 CKs 8,18. Confirm epithelial lineage. Useful to confirm
glandular neoplasms
MNF 116 CKs 5, 6, 8, 17, 19. Useful in diagnosis of SCC with
single cell infiltration
BerEP4 Positive in BCC. Negative in SCC.
CK 7 Confirmation of mammary and extra-mammary Paget's
disease
p63 Distinguish primary cutaneous spindle SCC from
mesenchymal spindle cell tumors & primary
cutaneous adnexal from metastatic adenocarcinomas
CD10 Trichoepithelioma: positive in stroma and papillae,
negative in epithelium. BCC: positive in epithelium,
negative in stroma.
bcl2 Positive in BCC, negative in SCC.
Vascular proliferations
CD31 High specificity and good sensitivity for endothelial tumors
CD34 High sensitivity but low specificity for endothelial tumors
Fli-1 Nuclear staining of endothelial tumors
GLUT 1 Positive in endothelial cells of all juvenile hemangiomas.
Usually negative in congenital hemangiomas
(rapidly involuting congenital hemangioma and non-
involuting congenital hemangioma)
Melanocytic tumors
S-100 protein Most widely used melanocytic marker. It is highly sensitive
but not as specific as other melanocytic markers
HMB 45 Good specificity but relatively low sensitivity.Tends to
be negative in spindle cell melanoma. Also positive in
PEComa.
Melan A/Mart 1 Similar specificity to HMB45. Tends to be negative in
spindle cell melanomas.
Ki-67 Higher proliferation index in melanoma (13–35%)
than in nevi (<5%). Useful in the evaluation of some
melanocytic tumors, mainly nevoid melanoma
Neuroectodermal and neural tumors
S-100 protein Positive in neuroectodermal, neuronal, nerve sheath,
chondroid tumors, some sweat gland tumors and
myoepithelioma
NSE Merkel cell carcinoma
CK 20 Merkel cell carcinoma
Neurofilament Merkel cell carcinoma
Chromogranin Merkel cell carcinoma
Synaptophysin Merkel cell carcinoma
TTF1 Negative in most Merkel cell carcinoma
Myogenic/myofibroblastic differentiation
MSA Tumors of muscle origin
Desmin Tumors of muscle origin (smooth muscle and skeletal
muscle, rarely and focally in myofibroblastic tumors)
Myogenin Positive in rhabdomyosarcoma
SMA Positive in smooth muscle tumors, glomus tumor,
myopericytoma, dermatomyofibroma
BCC, basal cell carcinoma; SCC, squamous cell carcinoma; SMA, anti-smooth muscle
actin; MSA, muscle specific actin; CK, cytokeratin.
a­ ntibody reacted directly with the tissue antigen.1 In the two-step indirect
technique, labeled secondary antibody directed against the immunoglobulin
of the animal in which the primary antibody was raised was used to visual-
ize an unlabeled primary antibody.4 The labeled streptavidin-biotin (LSAB)
method is a three-step technique. An unconjugated primary monoclonal
or polyclonal antibody, attached to the tissue antigen forms the first layer,
­creating an antigen-antibody complex. The second layer is formed by a bioti-
nylated secondary antibody raised against the same species of the primary
Immunofluorescence 35
animal.1 The secondary antibody binds to the primary antibody with the
biotinylated end being available for binding to a third layer. This layer may
bind either to enzyme-labeled streptavidin or to a complex of enzyme-labeled
biotin and streptavidin. The enzyme may be horseradish peroxidase or alka-
line phosphatase. An appropriate chromogen is used for detection. In the per-
oxidase method, peroxidase-oriented chromogens such as diaminobenzidine
or 3-amino-9 ethylcarbazole are appropriate. Indole reagents (red), naphthol
fast red (red) or NBT / BCIP (blue) are the chromogens used in the alkaline
phosphatase-streptavidin method.1,4
The presence of endogenous biotin and resultant background staining led
to the introduction of the increasingly popular polymer-based immunohis-
tochemical methods. In the new direct Enhanced Polymer One Step (EPOS)
technique, approximately 70 enzyme molecules and 10 primary antibodies
are conjugated to a dextran ‘backbone’. While the entire IHC procedure is
completed in one step, the method is limited to highly select manufacturer-
specific primary antibodies. Other newer polymer detection systems with a
dextran backbone to which multiple enzyme molecules may attach are avail-
able for manual and automated IHC. These quick, reliable and reproducible
techniques are also characterized by greater sensitivity. Single-, dual-, and
triple-color staining with different chromogens is possible.1,2,4,5
Background staining is a common difficulty that has multiple predispos-
ing causes.6 While monoclonal antibodies reduce non-specific background
staining, not only must antibody concentrates and prediluted preparations be
optimized for usage at the correct dilution in different laboratories (Figs
2.7 and 2.8), diluent pH is also critical in ensuring the absence of antibody
degeneration and resultant background staining. Avidin-biotin detection sys-
tems and horseradish peroxidase systems may require biotin blocking and
endogenous peroxidase quenching steps to decrease unnecessary background
staining. Polymer-based detection systems can effectively eliminate biotin-
induced false-positive staining. While antigen retrieval techniques are criti-
cal for antigen unmasking, optimal results require control of the pH and
temperature of retrieval solutions and controlled enzymatic digestion (Fig.
2.9).7–10 The latter causes excessive background staining when sections are
exposed to increased digestion time, inappropriate high temperature and
inadequate rinsing, causing protein diffusion into or deposition in skin sec-
tions and b­ ackground staining.
Chromogen entrapment, precipitation and contaminants may lead to false-
positive interpretation of an IHC test. Depletion of peroxidase or alkaline
phosphatase chromogenic activity, a consequence of the breakdown of chro-
mogens because of the sensitivity to light and heat, results in a background
blush. A  similar effect is seen when there is inadequate chromogen rinsing
or prolonged chromogen time. Filtering of the chromogen is effective in pre-
venting chromogen precipitation. Chatter, tears, folds and wrinkles and poor
adhesion of sections to slides causes entrapment and suboptimal rinsing of
chromogen (Fig. 2.10). Skin sections with a thick stratum corneum, dermal
calcification, or sclerosis may be prone to these artifacts, requiring meticulous
microtomy to prevent its occurrence. The handling of water baths, tissue sec-
tions and slides with ungloved hands may cause contamination of sections
with squames.1
False-negative immunostaining may also compromise IHC interpreta-
tion. Incomplete deparaffinization causes suboptimal or incomplete staining
because of incomplete tissue penetration by the antibody. Overdigestion of
tissue sections by proteolytic enzymes can destroy the tissue sections with
attendant loss of antigen for antibody binding. Other causes of false-negative
immunostaining include:
• incorrect temperature of reagents, including retrieval solutions,
• expired antibodies,
• inappropriate dilutions,
• suboptimal storage of antibodies .1,3
Immunofluorescence
Immunofluorescent techniques have the potential to define antigen-antibody
interactions at a subcellular level.1 This interaction requires the irreversible
binding of a readily identifiable label for its recognition.1,2 Fluorochromes
such as rhodamine or fluorescein are labels that can absorb radiation in the
36 Specialized techniques in dermatopathology

P Antigen

Biotin
B
P Peroxidase
P B B P

P B P Primary
P
Antibody

Secondary
Antibody
P
Secondary Antibody on
a polymer backbone Fig. 2.6
Immunohistochemical techniques:
(A) direct, (B) indirect (C)
streptavidin biotin (D) polymer
chain. By courtesy of Dr. J.
Ag Ag Ag Ag Ag Deonarain, Department of
Direct method Indirect method Avidin-biotin method Polymer chain two step direct method Anatomical Pathology, National
Health Laboratory Service, Durban,
A B C D South Africa.

Fig. 2.7 Fig. 2.9

Technical artifact: poor tissue fixation resulting in incomplete sections, Technical artifact p53 stain: wrinkling and background staining of tissue sections
fragmentation and suboptimal AE1/AE3 stained section. because of erroneously high temperature heat-assisted microwave antigen retrieval
exposure of sections in EDTA buffer (pH 8.0).

Fig. 2.8 Fig. 2.10

Technical artifact: suboptimal antibody concentration of CD3 antibody resulting in Technical artifact: HHV8 stained sections demonstrating chromogen entrapment in
background staining. stratum corneum.
 Diagnosis of inherited skin diseases 37

form of ultraviolet or visible light.1–5 Direct and indirect immunofluorescence
(IMF) techniques demonstrate a range of tissue antigens of dermatopatho-
logic importance, including the diagnosis of infectious and autoimmune blis-
tering disorders.3 In the direct IMF technique, antibody is conjugated directly
with a fluorochrome and is used to detect an antigen in a tissue section using
ultraviolet light microscopy.1–3 In the indirect IMF technique, patient serum
(containing the antibodies) interacts with a tissue section containing the anti-
gen. Antibody to a human immunoglobulin, conjugated to a fluorochrome, is
applied thereafter.1–7 The successful demonstration of the antigen requires the
antigen to remain sufficiently insoluble in situ. Skin biopsies for direct immu-
nofluorescence can be transported fresh on saline-soaked gauze in a container
on ice, or in a transport medium such as Michel medium.8 The transport
medium must be maintained at a pH of 7.0 to 7.2.1,3,5 The main uses for IMF
in dermatopathology are in the interpretation of the autoimmune blistering
diseases, lupus erythematosus, and vasculitis.6,7 In general, immunofluores-
cence has the following advantages over immunohistochemistry:
• more sensitive detection of antigen.
• use of special fixation that preserves ‘difficult’ antigens.
between the dermatopathologist and molecular laboratory is absolutely criti-
cal for efficient use of molecular techniques.
Analysis of the inherited skin blistering disorder known collectively as epi-
dermolysis bullosa (EB) discussed in detail in Chapter 4 demonstrates the
complex, multifaceted approach to diagnosis required in such cases. EB has
been shown to result from mutations in genes encoding at least 11 different
structural proteins at or close to the dermal–epidermal junction (Fig. 2.11).1
Clinically, the different types of EB are characterized by widely differing
prognoses, from death in early infancy to blistering that may become milder
in later life.2 The clinical presentation in neonates, however, can be confusing
to dermatologists and pediatricians because of the overlapping features (Fig.
2.12). In these circumstances, skin biopsy, usually a superficial shave biopsy
since the key region is the dermal–epidermal junction, can provide critical
Keratins
5 & 14
EB simplex

Electron microscopy EB simplex

with muscular Plectin
Electron microscopy is less utilized than in the past. Immunohistochemical 230-kDa
dystrophy
BP Ag
approaches are preferred in those instances where they are a reasonable
Non-Herlitz
substitute. junctional EB
Junctional
Transmission electron microscopy offers better resolution than light α6β4
EB with Type XVII
microscopy.1 To optimize this, tissue has to be embedded in extremely rigid integrin Herlitz &
pyloric atresia collagen
material to allow sectioning at 80 nm. In most circumstances, hydrophobic Laminin-332 non-Herlitz
epoxy resins are preferred. When a specimen is removed for ultrastructural junctional EB
examination, it must be fixed in a suitable fixative immediately. The volume
of the fixative should be 10 times the sample size. The final specimen size is
1 mm2.1 Fixation is affected by:
• pH,
Dominant and
• osmolarity, recessive
Type VII
• ionic composition of buffer, dystrophic EB
collagen
• fixative concentration,
• temperature,
• duration of fixation.
Primary fixation in an aldehyde, usually gluteraldehyde, and secondary
Fig. 2.11
fixation in osmium tetroxide are standard procedures. Advances in immu-
Basement membrane region: protein components at the dermal–epidermal junction
nohistochemistry have decreased the dependence on electron microscopy for and the subtypes of EB that result from mutations in the genes encoding these
ultrastructural confirmation of cell lineage. Notwithstanding, dermatologic proteins.
ultrastructural investigations are important in the diagnosis of:
• undifferentiated tumors,
• immunobullous disease,
• cerebral autosomal dominant arteriopathy with subcortical infarcts and
leucoencephalopathy (CADSIL),
• amyloidosis,
• metabolic storage diseases.2–7
Intercellular junctions, Weibel-Palade bodies, melanosomes, and premelano-
somes may help in the diagnosis of carcinomas, endothelial tumors, and mel-
anocytic tumors, respectively.3 In CADSIL, extracellular, electron-dense granular B
material is present in an indentation in vascular smooth muscle cells.5,6 Amyloid
is identifiable as randomly arranged, extracellular, nonbranching fibrils of inde-
terminate length and 7–10 nm diameter.7 Transmission electron microscopy
remains a valuable tool in the ongoing evaluation of the structure of normal and
pathological human cell and tissue components and infective agents.8–10

Diagnosis of inherited skin diseases

An efficient approach to genetic testing often relies on initial traditional his-
tologic characterization of skin biopsies.
Recent advances in molecular genetics and gene sequencing have led to
many inherited skin diseases being diagnosed or confirmed by clinical molec-
ular biologists rather than dermatopathologists. Analysis of skin biopsies still
remains vital for the accurate diagnosis of several genodermatoses, and often
provides a guide for subsequent molecular analyses. Examination of the skin
biopsy informs the selection of additional molecular testing. Communication
A C
Fig. 2.12
Epidermolysis bullosa: clinical appearances of neonates with different forms of
inherited EB. All three cases have similar blisters and erosions but their respective
prognoses differ considerably; (A) Severe, generalized recessive dystrophic EB; (B)
Dowling-Meara EB simplex; (C) Herlitz junctional EB. Skin biopsy is fundamental to
establishing the subtype of severe forms of EB.
38 Specialized techniques in dermatopathology
Fig. 2.13
Optimal skin biopsy for diagnosing EB: following local anesthesia, the normal-
appearing skin is gently rubbed, and then a superficial shave biopsy is taken. The
skin sample can then be subdivided for immunolabeling of frozen sections as well
as being processed for transmission electron microscopy.
diagnostic and prognostic information. Typically, nonblistered skin from any
body site is sampled. Just before the biopsy is taken, the skin is rubbed gently
in an attempt to induce fresh microsplits at the dermal–epidermal junction, to
facilitate the microscopic subtyping of EB (Fig. 2.13).
The most informative investigation is immunolabeling of the der-
mal–epidermal junction using a panel of basement membrane anti-
bodies. Skin biopsies can be transported in Michel's medium to a
diagnostic laboratory at ambient temperature: this fixative is extremely
useful since basement membrane zone immunoreactivity is main-
tained for at least 6 months. 3 For the immunolabeling, frozen skin
sections are used rather than formalin-fixed paraffin-embedded mate-
rial because the antigenic epitopes of several transmembranous pro-
teins may be lost in routine skin processing. The basement membrane
Fig. 2.14
Antigen mapping to diagnose the subtype of inherited EB: this picture shows
immunolabeling of rubbed skin from an individual with EB (case illustrated in
Fig. 2.12a) with an anti-type IV collagen antibody. Rubbing the skin induces microsplits
at the dermal–epidermal junction (asterisk). The type IV collagen reactivity maps to the
roof of the dermal–epidermal junction (arrows). This indicates a sub-lamina densa plane
of cleavage and establishes a diagnosis of dystrophic EB. (Bar = 25 μm.)
A B
Fig. 2.15
Specific antibody probes to subtype inherited EB: (A) immunostaining of normal
control skin with an antibody to type VII collagen shows bright linear labeling at the
dermal–epidermal junction; (B) in contrast, the complete absence of labeling in skin
from an individual with EB (case illustrated in Fig. 2.12a) indicates a diagnosis of severe,
generalized recessive dystrophic EB. (Bar = 50 μm.)
antibodies can be used either to determine the level of cleavage in the
skin (antigen mapping) or to see if there is a reduction or absence of
immunostaining for a particular antigen.4 Figure 2.14 , for example,
demonstrates labeling using an antibody against type IV collagen in skin
from the neonate illustrated in Figure 2.12a . In this example, labeling
maps to the roof of the split. This indicates that the lamina densa is in
the blister roof and that there is a sublamina densa plane of blister for-
mation. These findings support a diagnosis of dystrophic EB. This diag-
nosis can be refined by immunolabeling with an antibody to type VII
collagen, as shown in ( Fig. 2.15 ). In normal skin there is bright, linear
labeling at the dermal–epidermal junction; however, in the skin from the
neonate shown in Figure 2.12a , there is a complete absence of type VII
collagen immunoreactivity. All other antibodies show normal ­reactivity
Fig. 2.16
Transmission electron microscopy of skin in Dowling-Meara EB simplex (case
illustrated in Fig. 2.12b): within the basal keratinocyte cytoplasm the keratin
filaments are condensed and form clumps and there is cytolysis that occurs just
above the dermal–epidermal junction. (Bar = 1 μm.)
 Molecular techniques 39

at the dermal–epidermal junction. These findings therefore establish a

diagnosis of severe, generalized recessive dystrophic EB. Reduced or Molecular techniques
absent immunolabeling with specific basement membrane antibodies is
an extremely useful and rapid means of diagnosing recessive forms of Chromosomal karyotyping
EB. For example, skin from the neonate shown in Figure 2.12c demon-
This technique can be used as an initial screen to demonstrate gross chromo-
strated a lack of reactivity against laminin-332 but normal immunos-
somal aberrations associated with certain tumors. Most skin tumors are small
taining for all other antibodies. These findings establish a diagnosis of
and thus tissue is generally not set aside for karyotype analysis.
Herlitz junctional EB.
Chromosomal karyotyping is the historical gold standard for detecting
The development of a panel of basement membrane antibodies, most of
chromosomal aberrations in neoplastic tissue (Fig. 2.17). Fresh tumor tissue is
which are commercially available, has led to decreased emphasis on transmis-
required to grow the cells and the cytogenetic preparations and interpretation
sion electron microscopy as a diagnostic tool in EB.5 Ultrastructural analysis,
require skilled personnel. Nonetheless, this technique provides an open, unbi-
however, can be useful in confirming the plane of cleavage and in establish-
ased look at all of the chromosomes of a particular tumor. Total chromosomal
ing the diagnosis of certain dominant forms of EB. Skin from the neonate
gains and losses and also translocations between chromosomes can be demon-
illustrated in Figure 2.12b, for example, shows normal intensity basement
strated. Some of these chromosomal translocations are virtually diagnostic of
membrane zone reactivity for all diagnostic probes but transmission electron
certain tumors, particularly soft tissue and hematopoietic tumors.1 Other chro-
microscopy (Fig. 2.16) identifies discrete clumps of tonofilament and basal
mosomal changes can be suggestive of certain tumor types. While most trans-
keratinocyte cytolysis, characteristic of the Dowling-Meara variant of EB
locations are now confirmed by the other molecular methods described below,
simplex. For recessive forms of EB, however, immunolabeling of basement
traditional chromosomal karyotyping retains a role as an initial examination
membrane proteins has become the most important diagnostic approach.6,7
of the chromosomal complement of a neoplasm and an important tool for dis-
Reduced or absent staining for a particular protein provides a rapid diagnosis
covery of new chromosomal aberrations.2 Indeed, over time, the discovery of
as well as a means of identifying the encoding gene (or genes) in which the
chromosomal translocations within specific tumor types is proportional to the
underlying pathogenic mutations are present. Thus the skin biopsy findings,
number of cases karyotyped.3 Additional methodologies discussed below such
both histologic and immunohistochemical, provide a direct guide to molecu-
as spectral karyotyping (SKY) or multiplexed fluorescence in situ hybridiza-
lar screening tests, most of which are PCR-based, as discussed below. This
tion (mFISH) can aid in the interpretation of complex karyotypes.
molecular information can then be used for genetic counseling, carrier screen-
ing, and DNA-based prenatal testing, if indicated.
While the details of the initial analysis change in the diagnostic work-
Allelic imbalance
up of various inherited skin diseases, in many cases, preliminary histologic Gains or losses of specific regions of DNA, often containing particular genes
and other testing is performed in an attempt to determine which molecular of interest, can provide diagnostic insight.
diagnostic test is most relevant. This is important, as such testing is difficult An allele is a variant of a particular genetic locus or region of DNA such
and expensive and thus selection of which gene to examine is important for as a gene. Detection of allelic imbalance or loss of heterozygosity (LOH) is a
­efficient diagnostic work-up. method that can detect the presence of deletions or gains of specific alleles in

Fig. 2.17
Genetics of clear cell sarcoma: (A) this complicated karyotype shows derivative chromosomes 12 (blue box) and 22 (orange box). While recurrent translocation-associated
karyotypes are initially simple, they can become more complex with tumor progression. (B) The mechanism of chromosomal translocation involves breaks in chromosomes
12 and 22 that recombine to produce novel derivative chromosomes 12 and 22. The active fusion gene (EWSR1-ATF1) is produced on der(22). The fusion genes can be
produced by a variety of breakpoints within the introns of the involved genes making multiple exon combinations (C). This complicates the design of PCR-based detection
methods, as does substitution of the CREB1 gene for ATF1 on occasion.
40 Specialized techniques in dermatopathology

paraffin-embedded material.4 This usually corresponds to regions of a particu-

lar gene(s) of interest. For this approach, PCR is used to amplify small genomic
fragments that carry common polymorphisms and thus have a high likelihood
of being present in two different variants (alleles) in an individual. Ideally, these
variants are of different size so that they can easily be detected on an electro-
phoretic gel; DNA sequencing can be used if this is not possible. Only if two
different alleles in the normal tissue of a patient are present is this technique
informative. Imbalance (loss of one allele) is implied if one detects only one
of the alleles in the tumor tissue. More detailed analysis can distinguish those
which are true losses. Sites of recurrent losses are typically areas that harbor
tumor suppressor genes. This method can detect losses that would not be dem-
onstrated in a traditional chromosomal karyotype analysis and can be readily
adapted to formalin-fixed, paraffin-embedded (FFPE) tissue. The limitations of
LOH analysis include that it is sensitive to contamination by normal (stromal)
cells that can make it difficult to decide whether an allele is lost. Another draw-
back is its inability to determine whether the imbalance is caused by the loss of
one marker or by a copy number increase of the other marker.

Fluorescence in situ hybridization (FISH)

FISH uses specific probes to determine the number of copies of a specific
region of DNA that are present or whether a particular locus has been rear-
ranged as part of a chromosomal translocation.
FISH utilizes fluorescently labeled probes that are complementary to and
thus specifically hybridize a specific region of genomic DNA, allowing it to
be visualized.5,6 The labeled probe and the target genomic DNA, which can be
metaphase spreads, interphase nuclei (Fig. 2.18), or nuclei in ­formalin-fixed,
paraffin-embedded tissue sections (Fig. 2.19), are denatured and brought
into contact for several hours to days. Given appropriate hybridization con- Fig. 2.18
ditions, the labeled probes will anneal with the corresponding sequence Four-color FISH to two interface nuclei and metaphase chromosomes: the upper
portion shows two interface nuclei with the hybridization signals for the four
in the target DNA. This is easiest if probes are targeted to chromosomal
colors detectable as discrete spots. In the metaphase spread underneath, the
regions that are rich in repetitive sequences such as the centromeres. In these
hybridization signals can be seen to map to chromosome 6p (purple), 6 centromere
regions the probe can hybridize multiple times, resulting in hybridization (light blue), 6q (yellow), and chromosome 11q13 (green).
signals that are large and easy to detect. However, these regions typically do
not contain any functional genes, and while increases in chromosome copy
number can be recognized, no direct information on the copy number of a
specific cancer gene or locus can be obtained. Human cancers, including
melanoma, frequently have aberrations that involve only fragments of the
chromosome. The detection of these types of aberrations requires probes
targeted to unique, i.e., non-repetitive, sequences of DNA. Unique sequence
probes give smaller hybridization signals and can be more difficult to detect.
However, by using larger probe sizes of 100–300 kb, detection of unique
sequences is possible in paraffin sections (see Fig. 2.17). The advantage of
FISH is that it can detect cells with aberrations in the presence of signifi-
cant numbers of normal cells, provided that the neoplastic cells can be mor-
phologically identified in the hybridized section. Combinations of FISH and
immunofluorescence have been developed to assist in the identification of
the target cell population, but the compromises that have to be made to
accommodate antigen preservation by maintaining acceptable hybridization
Fig. 2.19
efficiency restrict its application for routine use in paraffin-embedded tissue. FISH to tissue sections of a melanoma (left panel) and nevus (right panel): the
Detection of heterozygous deletions is more difficult with FISH in tissue sec- panels show 400-fold magnifications of two nests of melanocytes with the nuclei
tions, because truncation of nuclei in tissue sections cut at normal thickness stained in blue. The green probe for chromosome 11q13 shows amplification in the
results in random loss of hybridization signals. Similarly, increased ploidy of melanoma as evident by a marked copy number increase compared to the purple
the neoplastic tumor cell population can simulate a gain of the target locus. signals representing chromosome 6p. By contrast, the melanocytes of the nevus in
These problems can be compensated by simultaneously hybridizing multiple, the right panel do not show significant differences for these two loci.
differentially labeled, probes to several loci in the genome and by analyzing a
larger number of cells. Comparing a probed locus to a centromeric probe on the flanking probes are fluorescently labeled in two different colors such as
the same chromosome in an alternate color can also compensate for cell ane- green and red, and when they are in close proximity in an intact chromo-
uploidy. A common example of this technique is comparison of the hybrid- some, the spectral overlap leads to two yellow signals, one for each normal
ization signals for the HER2 locus on 17q with centromere 17. This allows chromosome. In a cell with a rearrangement of a gene such as EWSR1 at
one to detect and distinguish both increased copy number of chromosome 22q12 in clear cell sarcoma, nuclei are seen with one intact chromosome 22
17 and specific amplification of the HER2 locus. with EWSR1 producing a yellow signal. In addition, the centromeric probe is
FISH using probes that flank a potential breakpoint associated with a chro- retained on the derivative (rearranged) 22 chromosome while the telomeric
mosomal translocation can be used to demonstrate rearrangement of that probe is transferred to the recipient chromosome (12 in the case of clear cell
locus (Fig. 2.20). This can be diagnostically helpful in certain hematopoi- sarcoma) leading to separate red and green signals in the nucleus. This method
etic malignancies with recurrent translocations, e.g., large cell anaplastic lym- only indicates that a locus is rearranged, not the identity of the chromosomal
phoma and some soft tissue tumors that can involve the skin.7,8 In this method, partner and gene. Thus caution must be used in interpretation as different
 Molecular techniques 41

der(22) d(22)
22 22
d(12)
12 R
der(12) 22
Y Y

Probe Y G
22
R
R
EWSR1 ATF1
Active breakpoint
ATF1 I

Probes Probe
G Y G
Y Y G
R EWSR1 ATF1 EWSR1 G
(q12) Silent breakpoint
R Y

A B

Fig. 2.20
Break-apart fluorescent in situ hybridization (FISH) technique: the 12;22 translocation associated with clear cell sarcoma is depicted; (A) when the EWSR1 locus is intact, the
probes hybridize to the centromeric (red) and telomeric (green) regions flanking the gene. The spectral overlap of the two signals in juxtaposition produce a yellow signal.
Thus in cell lacking rearrangement of this locus, two yellow signals are present, representing the two copies of chromosome 22 lacking rearrangement (right); (B) When
rearrangement occurs, such as the balanced translocation with chromosome 12 depicted here, the centromeric probe (red) is retained by the derivative chromosome
22 while the green probe is transferred to the derivative chromosome 12. Thus in the nuclei one yellow signal indicates the intact chromosome 22 while the derivative 12
and 22 chromosomes segregate freely as single green and red signals, respectively (right).

Desmoplastic small
round cell tumor

WT1 NR4A3(TEC) Extraskeletal myxoid

11p13 9q22 chondrosarcoma

Myxoid CHOP/DDIT3 EWSR1

posarcoma 12q13 22q12

Angiomatoid
ATF1 ETS family Ewing
fibrous / PNET
12q13 FLI1 11q24 sarcoma
histiocytoma
ERG 21q22
FUS/TLS
FEV 2q36
Clear cell sarcoma 16p11 Acute myeloid leukemia
(EWSR1-ATF1) CREB1
ETV1 7p22 Fig. 2.21
ETV4 17q12 (FUS-ERG) Multiple translocations involve EWSR1 and the
(EWSR1-CREB1) 2q32
ZSG 22q12 Ewing homologous gene, FUS: both EWSR1 and FUS
(FUS-ATF1) CREB3L2 / PNET
7q33 sarcoma can often substitute for one another and both are
involved in balanced translocations with multiple
CREB3L1 genes resulting in a variety of neoplasms. Since
11p11 FISH only indicates that a single locus, such as
EWSR1, is re-arranged and nothing about the fusion
partner, results must be interpreted carefully within
the clinical and morphologic context of a tested
Low grade
case. Sometimes techniques such as RT-PCR must
fibromyxoid sarcoma
be used to verify the fusion partner.

translocations seen in different ­neoplasms can be associated with the same

probed locus. For instance, EWSR1 is rearranged in clear cell sarcoma, Ewing
sarcoma, extraskeletal myxoid chondrosarcoma, angiomatoid fibrous histio-
cytoma, and some cases of myxoid liposarcoma (Fig. 2.21). Careful correla-
tion with the clinical and histologic features can help avoid confusion in these
situations.
The disadvantage of FISH is that it can only look at a few loci at a time,
and that analysis is time-consuming because signals in a large number of
nuclei have to be counted. The latter restriction has been partially overcome
by the development of computer-based counting algorithms.9
In situ hybridization can also employ chromogenic probes such that
light microscopy can be used to visualize signals (termed CISH). This
method is useful for detecting amplification of a genetic locus and tech-
nically can be utilized in a break-apart probe strategy to detect trans-
locations, but in practice this latter application can be very difficult to
42 Specialized techniques in dermatopathology

interpret. Probably the most common use for CISH is in direct detection
of nucleic acids associated with infections in cells such as human papil-
lomavirus (HPV) or Epstein-Barr virus. In HPV, this technique can be use
to type the virus and determine whether it is high risk (e.g., 16 and 18)
or low risk (6 and 11). In this application, ISH is used to demonstrate the
presence of viral DNA that is not present in a cell until infection occurs.
Modifications of this technique can be used to detect messenger RNA in
tissue sections as well.
In situ hybridization, fluorescent or chromogenic, is best used to
demonstrate:
• amplification of a specific gene,
• rearrangement of a specific gene,
• presence of ‘foreign’ (infection-related) DNA or RNA.

Comparative genomic hybridization (CGH)

Comparative genomic hybridization can be used to demonstrate gains and
losses of DNA through the entire genome of a tumor sample. While this is
mainly a research tool at this time, its application has lead to important dis-
coveries that have been translated into focused genetic tests.
CGH demonstrates for the entire genome:
• regions of chromosomal loss (often containing tumor suppressor genes),
• regions of chromosomal gains (often containing oncogenes),
• overall patterns of gains and losses (rather than just a few focused
regions).
As originally described, CGH detects and maps DNA sequence copy num- Fig. 2.22
ber variation throughout the entire genome onto a cytogenetic map supplied Comparative genomic hybridization (CGH) on a metaphase chromosome spread
by metaphase chromosomes (Fig. 2.22).10 CGH can be regarded as a varia- (upper panels) and a microarray (lower panels): the regions of the chromosomes
tion of FISH in which the entire genome of a sample such as DNA from a skin (upper panel) that appear red are affected by deletions, whereas the regions that
tumor is used as a hybridization probe. The tumor is freed from contaminat- appear green are affected by gains or amplifications (bright green). Yellow indicates
ing normal cells by manual dissection, the DNA extracted, and labeled with a an area with normal DNA complement-no gain or loss. The lower panel on the right
fluorochrome (green, for example). In addition, a reference probe of normal shows a DNA microarray with approximately 2500 targets printed as triplicates
genomic DNA from a healthy donor is labeled with a different fluorochrome spots. Triplets that appear green indicate gains whereas those that appear red
indicate loss. The array targets are not printed in order of their genomic position
(red, for example). Equal amounts of the green- and red-labeled DNA are
which can help control for technical variations. The precise genomic location of
mixed and hybridized onto a substrate, which represents the entire human the DNA copy number changes detected by the measurement only becomes
genome. Originally, these were metaphase spreads of normal human chro- apparent after plotting the average ratios of red to green fluorescence intensities
mosomes prepared from lymphocytes of a healthy donor that represented a corresponding to their genomic position as illustrated in Figure 2.23
cytogenetic map. More recently, this substrate has been replaced by manu-
factured microarrays composed of nucleotide probes that are printed at high
density on a solid surface.11 Depending on the number and lengths of these
nucleotide probes, the entire genome can be represented on an array. By using
smaller probes, higher resolution of genetic gains and losses can be achieved.
During the hybridization, the red- and green-labeled DNA populations com-
pete for binding to corresponding regional microarray targets. For each
array target (or region of a chromosome in the original protocol) the ratio
of red and green fluorescence intensity ratio is determined. A ratio of 1 indi-
cates a balanced situation at this locus, i.e., no gain or loss in the tumor (see
Fig. 2.23). In the presence of deletions in the tumor genome, less green probe
will be available to hybridize to the corresponding targets, which will result
in a decreased green to red fluorescence intensity ratio (< 1). In the presence
Fig. 2.23
of increased copies, the corresponding targets still show a green to red fluo-
DNA copy number changes as detected by array CGH of an acral melanoma: the
rescence intensity ratio greater than 1. The ratio of red and green fluores- graph shows the log2 of the ratio of the fluorescence intensity ratios of tumor
cence intensity can be used to quantify the copy number change. A ratio of to reference DNA plotted according to their genomic position on the x-axis. The
1 indicates normal copy number, a ratio < 1 indicates a loss, and a ratio > 1 numbers at the top and at the bottom indicate the chromosomes. A log2 ratio of
indicates a gain. Gains with a high ratio that only affect portions of a chro- zero corresponds to normal copy number. As can be seen, multiple contiguous
mosomal arm are called amplifications. They arise from multiple independent chromosomal regions showed losses and gains. The arrow corresponds to an
events (chromosomal breakage and fusions) that accumulate under positive amplification of chromosome 11q13 interval containing the gene that encodes
selection, typically because the genomic region present in the amplicon con- cyclin D1.
tained an oncogene, i.e., a gene that provided a growth advantage to the
tumor cells with increased copies of the gene. analysis of solid tumors. Compared to conventional cytogenetic analysis,
The full experimental protocol for CGH is slightly more complex than CGH does not require culture of cells for karyotypic analysis, which brings
outlined above. A third, unlabeled DNA population is needed to ascertain the major advantage that CGH can be performed on archival tissue. It is
that repetitive regions that are scattered throughout the genome do not cross- important to note that the DNA copy number measurement obtained with
hybridize and interfere with the measurement. This blocking DNA is highly CGH represents an average of the entire cell population from which the DNA
enriched for repetitive regions and suppresses unwanted cross-hybridization was extracted. For this reason, only the copy number alterations present in
between repetitive regions in the labeled DNA populations and the chro- a substantial portion of the cells are detected by the method. Depending on
mosomes which serve as substrate. CGH has revolutionized the cytogenetic the type of aberration – amplifications can be detected most easily – the copy

number change needs to be present in about 30% to 50% of the cells in
order to be identifiable. Alterations affecting only a minority of cells remain
undetected. A further limitation is that CGH only detects genomic aberra-
tions that result in DNA copy number changes. Balanced translocations and
point mutations are not detected. Copy number neutral rearrangements that
arise through chromosomal recombination and LOH (see above) are also not
detectable by CGH. More recent implementations that use oligonucleotides
to determine single nucleotide polymorphisms (SNPs) allow the genome-wide
simultaneous assessment of DNA copy number and LOH in unfixed tumor
tissue.12,13 However, these methods are still being optimized to allow broad
applicability to routinely fixed tissue.
Polymerase chain reaction (PCR)
In the diagnostic setting, PCR is used primarily to acquire sufficient DNA for
analysis by sequencing or other methods, primarily to demonstrate a muta-
tion or other genetic change or the presence of a specific gene or messenger
RNA.
PCR is an extremely flexible technique and can be adapted to:
• detect mutations (base pair substitutions, insertions and deletions) in
genes,
• demonstrate novel fusion transcripts (gene fusions),
• demonstrate clonality,
• demonstrate loss of heterozygosity (loss of one allele),
• detect DNA or RNA associated with infectious organisms,
• detect the levels of expression of messenger RNA.
The ability to specifically amplify and detect any segment of DNA in the
human genome has opened many diagnostic doors. In this technique, a pair
of short sequences of DNA (called primers) that hybridize to two sequences
of genomic DNA (or RNA reverse transcribed to DNA) are designed to
amplify a specific region of DNA. Using a DNA polymerase that is stable
at high temperatures, a series of annealing, extending, and melting/denatur-
ing cycles amplifies the DNA between the two probes. This technique can be
used on nucleic acids extracted from formalin-fixed, paraffin-embedded tis-
sue, although probes must be designed to amplify shorter segments of DNA
since the starting material has been cross-linked and fragmented from the
formalin treatment. A variety of techniques based on PCR can be used to
amplify DNA and then determine its sequence. Direct sequencing of genomic
DNA allows detection of point mutations in cancer, such as BRAF or NRAS
in melanoma.14 Generally, one can detect a mutation in 1 in 5 cells with this
technique. More sensitive techniques such as pyrosequencing can reduce this
to 1 in 10 or 20 cells by analysis for a precise mutation. Finally, allele-­specific
PCR can be used to detect a known point mutation in as little as 1 in 50
or 100 cells. This technique has applications such as detecting KIT D816V
mutation in mastocytosis in skin where the neoplastic cells may be sparse
relative to the surrounding normal tissue.15 Insertions and deletions in genes
can also be detected, usually by Sanger sequencing.8
Reverse transcribing RNA to DNA can allow specific detection of fusion
genes produced by chromosomal translocations such as seen in clear cell
sarcoma or dermatofibrosarcoma protuberans.16,17 This technique is partic-
ularly valuable as there is no amplification product in the absence of tumor
as the translocations are not seen in normal tissue or other tumors (see
Fig. 2.24). Because the two genes involved in a translocation event may
have breaks at multiple introns (the noncoding region of DNA between the
protein encoding exon segments), multiple primer pairs may be necessary to
detect all of the possible translocation types. Also, since multiple genes can
be involved, for instance clear cell sarcoma can contain either an EWSR1-
ATF1 or EWSR1-CREB1 fusion, additional primer sets will be required for
detection of these as well (see Fig. 17.11c).18,19 In hematopoietic malignan-
cies, detection of fusion transcripts can be used to detect minimal residual
disease in the peripheral blood or marrow to measure tumor DNA as a sur-
rogate of tumor load to assess response to therapy or allow early detection
of recurrence. This approach may be applied to solid tumors in the future.
PCR can be used to detect normal genes as well. An instance of this in der-
matopathology was the attempt to detect melanocyte-specific RNA (reverse
transcribed to DNA) in sentinel lymph nodes that might have been missed by
histology and immunohistochemical screening.20–22 Ultimately, this technique
Diagnosis of lymphomas 43
Primer Primer Primer Primer
EWSR1 ATF1
EWSR1 / ATF1 Fusion
No Amplification Amplification
1 2
Type 2
EWSR1-ATF1
fusion amplicon
Fig. 2.24
Use of reverse transcription-polymerase chain reaction (RT-PCR) to detect fusion
transcripts: this technique uses reverse transcription to convert RNA to cDNA that
can then be amplified by PCR. This step is necessary as the breakpoints in the
usually large intronic regions of genomic DNA within a gene are essentially random,
making it extremely difficult to amplify such large regions to identify the breakpoints
using genomic DNA as the template. When the gene is transcribed to RNA, the
introns are removed during splicing and introns are directly juxtaposed
(Fig. 2.11c) allowing more ready detection of the novel juxtaposition of exons from
two different genes. When primers are designed for the exons of each of the two
genes involved in a translocation, amplification only occurs of the cDNA of the fusion
transcript as these introns would not be adjacent in normal tissue. This product
will have a specific size and can be detected on a gel, but direct DNA sequencing
or other methods should be used to confirm its identity. Amplification of normal
housekeeping gene transcripts are used to ensure the quality of the cDNA.
was not valuable, at least in part because of the presence of nodal nevi which
would also be detected by this technique. While widely used in the research
arena, other diagnostic approaches based on detection of gene expression will
likely evolve with time.
It is often advantageous to have multiple methodologies for detecting vari-
ous molecular defects, as they are used in different situations and provide
slightly different information. Figure 2.25 depicts this for the translocation
present in clear cell sarcoma.
Diagnosis of lymphomas
The diagnosis and subclassification of lymphomas has transformed dramati-
cally in the last three decades. Prior to this, the classifications in general use
were based purely on the morphological features of the neoplastic lympho-
cytes.1,2 However, modern classification systems also utilize all available immu-
nophenotypic, genetic, and clinical information to group cases together for
the purposes of treatment and prognostication.3–7 Immunohistochemical and
molecular techniques therefore form an integral part of the diagnostic process,
and are routinely employed in the assessment of suspect cutaneous lymphop-
roliferations in order to discriminate reactive from neoplastic processes, and
to subclassify the latter once identified. A battery of antibodies and molecular
techniques are now available to the practicing pathologist. 8–14
This section focuses specifically on amplications of the polymerase chain
reaction (PCR) to diagnostic hematopathology, the molecular technique in
most common usage, for the detection of antigen receptor gene rearrange-
ment. The relevant immunophenotypic and genetic features of specific
lymphoma subtypes are detailed in Chapter 29. In addition, FISH-based tech-
niques can also be used to demonstrate translocation associated primarily
with B-cell lymphomas.
44 Specialized techniques in dermatopathology

Fig. 2.25
Multiple modalities for detection of recurrent translocations. Traditional karyotypes use metaphase chromosomes spreads to detect translocations and other structural
genetic aberrations using banding (staining) techniques. FISH uses less condensed interphase chromosomes to detect rearrangements or amplifications. RT-PCR can detect
the precise exons involved in a fusion RNA transcript. Each is a valid method for demonstrating chromosomal translocations, but each has applicability to different sample
types and provides different information.

PCR analysis of cutaneous lymphoid

infiltrates
The diagnosis of cutaneous lymphoma relies on a constellation of morpho-
logic, immunophenotypic, and clinical features, and may be difficult, par- * *
ticularly in the early stages. Molecular genetic findings are increasingly
incorporated into the diagnostic process. Often, their role is confirmatory,
demonstrating clonality in a lesion already thought to be lymphomatous on
the basis of pathological findings. However, in a significant proportion of
cases, a definitive diagnosis cannot be reached with certainty on the basis of
histology and immunophenotype. In such instances, the results of molecular
clonality studies may provide sufficient additional information for a diagno-
* *
sis to be assigned and/or to guide patient management. However, PCR analy-
sis of skin biopsies is subject to the same limitations and pitfalls as described
above. Therefore, the results of such studies must always be interpreted with
caution and only following close discussions between the pathologist, molec-
ular biologist, and clinician.

TCR gene rearrangement in cutaneous

lymphoproliferations
Unlike the testing of solid tumors, PCR-based testing of lymphoid infiltrates
can take advantage of TCR receptor gene rearrangements to establish clonal-
ity, although this does not always equate to malignancy.
Clonality studies may be useful in identifying the early stages of myco-
sis fungoides or other cutaneous T-cell lymphomas. Dominant clones can
be demonstrated in the early lesions of mycosis fungoides and in cases of
cutaneous T-cell lymphoma which could not otherwise be identified using
conventional morphology (Fig. 2.26).1–6 They have also been said to facil-
itate discrimination between mycosis fungoides and inflammatory derma-
toses, and simulators of mycosis fungoides such as actinic reticuloid.3–8 PCR
is also useful in identifying the underlying disease in erythroderma when it is
due to cutaneous T-cell lymphoma, rather than inflammatory processes such
as eczema, contact dermatitis, drug reactions, pityriasis rubra pilaris, pso-
A B
riasis, and pemphigus foliaceus.5,9–12 In addition, there are certain variants
and malignant mimics of cutaneous T-cell lymphoma, in which absence of a Fig. 2.26
clonal TCR gene rearrangement helps confirm the diagnosis. These include Mycosis fungoides: TCR gene rearrangement (photo of gel). Red astrixes indicate
extranodal NK/T-cell lymphoma of nasal type, CD4+/CD56+ hematodermic dominant clonal T-cell gene rearrangement shown as discrete bands rather than a
neoplasm and leukemia cutis. smear demonstrating numerous clones and non-rearranged receptors.
 Diagnosis of lymphomas 45

However, clonality does not always equate with a diagnosis of malignant

lymphoma. Monoclonal TCR gene rearrangements have been demonstrated Constant Variable Disulphide Heavy Light
domain domain chain chain
in otherwise typically benign dermatoses. These include: bonds

• discoid lupus erythematosus,

• lichen planus,
• lichen sclerosus.13–15
Bona fide T-cell clones may also be found in examples of cutaneous T-cell
pseudolymphoma, particularly those associated with reversible hypersensitivity
drug reactions, and in some instances the same clone has been demonstrated
in biopsies from the same patient taken at different sites.15–19 There is also a
group of disorders which generally run a benign clinical course, but can be
associated with progression to cutaneous T-cell lymphoma, usually mycosis
fungoides but occasionally cutaneous anaplastic large cell lymphoma or some
other form of cutaneous T-cell lymphoma. These include:
• pigmented purpuric dermatosis,
• pityriasis lichenoides chronica,
• pityriasis lichenoides et varioliformis acuta, Fig. 2.27
Structure of Ig. The two
• lymphomatoid papulosis.20–34 epitope binding sites are
A variable, but often high, incidence of monoclonality is found when series of formed primarily by the
these conditions are analyzed by PCR for the TCRG and/or TCRB gene, and the two variable domains.
same clone is usually found in follow-up biopsies when lymphoma ensues.18,25,32–39
Another similar group comprises cutaneous T-cell lymphoproliferative dis- cases using PCR techniques designed to detect IG gene rearrangements as part
orders that are currently thought to represent very indolent or prelymphoma- of the routine diagnostic work-up (Figs 2.27 and 2.28).1–4 However, even
tous forms of recognized subtypes of cutaneous T-cell lymphomas including: using BIOMED-2 protocols, there may be a significant false-negative rate.
• large plaque parapsoriasis,15,19,40 This is particularly the case if the only primers used are for the framework
• idiopathic follicular mucinosis,15,41 regions on the IG heavy chain gene, one study detecting clonality in only 67%
• syringolymphoid hyperplasia with alopecia,42–44 of primary cutaneous B-cell lymphomas.4 This is likely to be due to the rela-
• hypopigmented mycosis fungoides.45 tively high proportion of lymphomas of germinal center, or postgerminal cen-
These are thought to be related to variants of mycosis fungoides. Idiopathic ter origin encountered in the skin, since these are associated with high levels
erythroderma has similarities to Sezary syndrome46 and atypical lymphocytic of somatic hypermutation. Detection levels increase when assays targeting IG
lobular panniculitis to subcutaneous panniculitis-like T-cell lymphoma.47,48 light chains, including the Kde, are introduced.2
These entities are typically monoclonal and share many characteristics with Clonality assays are not a reliable way of differentiating B-cutaneous lym-
the lymphomas to which they are putatively related. However, they lack full phoid hyperplasia from cutaneous B-cell lymphoma. Monoclonal immuno-
morphologic and/or phenotypic evidence of lymphoma, and although most globulin gene rearrangements have been demonstrated in lesions designated
run a recalcitrant course resistant to topical therapy, and some progress to B-cutaneous hyperplasia (or synonyms thereof), even when less sensitive
overt malignant lymphoma, most have an innocuous clinical outcome. Southern blotting techniques have been used.5–9 However, in series quoting
It has been proposed that the following be encompassed under the rubric high levels of monoclonal B-CLH, relatively few cases progress to overt lym-
of ‘cutaneous T-cell lymphoid dyscrasia’49: phoma.5,7,8 These lesions may therefore be analogous to the cutaneous T-cell
• idiopathic pigmented purpuric dermatosis, dyscrasias described above, in that they may run a protracted but ultimately
• pityriasis lichenoides, benign clinical course, only rarely progressing to overt malignancy.
• large plaque parapsoriasis,
• idiopathic follicular mucinosis,
• syringolymphoid hyperplasia with alopecia,
• hypopigmented mycosis fungoides,
• idiopathic clonal erythroderma,
• atypical lymphocytic lobular panniculitis.
The concept is similar to that of monoclonal gammopathy of uncertain sig-
nificance, already well established for plasma cell dyscrasias.46 ‘Cutaneous T-cell
lymphoid dyscrasia’ is used to convey the limited but real malignant potential
of these monoclonal and oligoclonal lymphoproliferations, and is preferred by
the authors to terms such as ‘premycotic’, because evolution to overt cutaneous
T-cell lymphoma is uncommon. It is hypothesized that T-cell clones develop as
a result of chronic antigenic stimulation. Acquisition of genetic abnormalities
by an expanded clone results in an ability for autonomous growth. This is ini-
tially held in check by the host immune cells, and only when these are overcome
does the fully malignant clone emerge. Entities that occasionally harbor clonal
populations of T cells, but have no malignant potential (such as drug-induced
pseudolymphoma), are excluded from this category.

IG gene rearrangement in cutaneous

lymphoproliferations
Fig. 2.28
A number of variant gene rearrangements often involve the promoters of
B-cell lymphoma: Ig gene rearrangement
immunoglobulin genes to drive the expression of oncogene critical to lym- (photo of gel). The upper bands arrowed in
phomagenesis. The current World Health Organization (WHO) classification lanes two and three indicate non-rearranged
scheme relies on these molecular results for precise classification. IG with the astrix in lane two indicates a
The clonal nature of cutaneous B-cell infiltrates in both primary and sec- polyclonal IG population. The lower band in
ondary cutaneous B-cell lymphomas can be confirmed in a high percentage of lane three shows a dominant IG clone.
Chapter

3 Disorders of keratinization
Dieter Metze
See
www.expertconsult.com
for references and
additional material

Ichthyosis  46 Lichen spinulosus  66 Marginal papular acrokeratoderma  82

Ichthyosis vulgaris  46
X-linked recessive ichthyosis  49
Syndromes with steroid sulfatase
deficiency  50
Multiple sulfatase deficiency  50
Refsum syndrome  50
Autosomal recessive lamellar ichthyoses  51
Harlequin ichthyosis  54
Autosomal dominant lamellar ichthyosis  55
Congenital bullous ichthyosiform
erythroderma  55
Ichthyosis bullosa of Siemens  58
Linear epidermolytic epidermal nevus  59
Epidermolytic acanthoma  59
Focal epidermolytic hyperkeratosis  60
Peeling skin syndrome  60
Ichthyosis hystrix Curth-Macklin  60
Congenital reticular ichthyosiform
erythroderma  61
Comèl-Netherton's syndrome  61
Sjögren-Larsson syndrome  63
Conradi-Hünermann-Happle syndrome  65
Other congenital ichthyotic
syndromes  65
Follicular ichthyosis  66
Ichthyosis follicularis with alopecia and
photophobia  66
Phrynoderma  67 Huriez syndrome  82
Keratosis pilaris  67 Vohwinkel's syndrome  83
Keratosis pilaris atrophicans  68 Loricrin keratoderma  84
Clouston's syndrome  84
Acquired ichthyosis-like conditions  69
Olmsted syndrome  85
Pityriasis rotunda  70
Papillon-Lefèvre syndrome  86
Erythrokeratodermas  71 Naxos syndrome  87
Erythrokeratoderma variabilis  71 McGrath syndrome  87
Progressive symmetric erythrokeratodermia  73 Pachyonychia congenita type I  88
Keratitis-ichthyosis-deafness Pachyonychia congenita type II  88
syndrome  73 Tyrosinemia type II  89
Hystrix-like ichthyosis with deafness  74 Carvajal Huerta syndrome  89
Howell-Evans syndrome  90
Palmoplantar keratoderma  75 Schöpf-Schulz-Passarge syndrome  91
Keratosis palmoplantaris diffusa
Vörner-Unna-Thost  76 Acquired palmoplantar keratoderma and
Epidermolytic hyperkeratosis with polycyclic internal malignancy  91
psoriasiform plaques  77 Keratoderma climactericum  91
Diffuse nonepidermolytic palmoplantar Clavus  91
keratoderma  77 Callus  91
Progressive palmoplantar keratoderma  78 Acrokeratosis verruciformis of Hopf  91
Keratolytic winter erythema  78 Porokeratosis  92
Mal de Meleda  79 Hyperkeratosis lenticularis perstans  95
Keratosis palmoplantaris areata Granular parakeratosis  96
et striata  80 Circumscribed palmar or plantar
Keratosis palmoplantaris nummularis  80 hypokeratosis  96
Punctate palmoplantar keratoderma  81
Keratosis punctata of the palmar creases  81

• Congenital ichthyoses present with collodion membrane or ichthyosiform

Ichthyosis
The term ichthyosis (Gr. ichthys, fish) is applied to a number of heterogenous
genetic disorders characterized by permanent and generalized abnormal kera-
tinization.1,2 The clinical features range from mild involvement, often passed
off as ‘dry skin’ (xerosis), through to severe widespread scaly lesions causing
much discomfort and social embarrassment (Fig. 3.1). The scales are often
shed as clusters rather than as single cells as is the norm.1 The pathogenesis of
the ichthyoses is very complex but ultimately depends upon two distinct final
common pathways: one relates to retention of corneocytes (e.g., ichthyosis
vulgaris, recessive X-linked ichthyosis), the other involves epidermal hyper-
proliferation (e.g., congenital ichthyosiform erythroderma, bullous ichthyo-
sis, Sjögren-Larsson syndrome and Refsum's disease).3
Ichthyotic skin disorders are classified into the following groups3a
(Tables 3.1, 3.2):
• Noncongenital ichthyoses develop 4 weeks after birth and spare flexures,
palms and soles.
erythroderma at birth or manifest within 4 weeks.
• Variants in which the skin lesions are but one facet of a more sinister
systemic illness (syndromic ichthyosis).
The development of a diffuse ichthyosis-like scaling during life should not
be confused with ichthyotic skin disorders. These acquired ichthyosis-like
(ichthyosiform) skin conditions can be caused by different underlying dis-
eases (see below). 4
Ichthyosis vulgaris
Clinical features
This relatively common disorder (incidence of 1:250 to 1:1000 births) has
an autosomal dominant mode of inheritance.1,2 It may present initially as
keratosis pilaris (follicular hyperkeratosis) on the arms, buttocks and thighs.
The disease is usually fairly mild and becomes apparent within the first few
months or years of life. It affects the sexes equally and presents as dryness
 Ichthyosis 47

Fig. 3.1
(A, B) Severe generalized ichthyosis: this was an
A B incidental finding at postmortem. Ichthyosis can be very
disfiguring and a considerable social disadvantage.

Table 3.1
Non-congenital ichthyoses
Isolated (nonsyndromic
ichthyosis)
Autosomal dominant ichthyosis
vulgaris
Recessive X-linked ichthyosis
With associated symptoms
(syndromic ichthyosis)
Syndromes with steroid sulfatase
deficiency
Multiple sulfatase deficiency
Refsum's disease
those on the face and scalp. The rims of the ears are often scaly.3 There is sea-
sonal variation, with improvement of the condition in the summer months,
particularly in humid climates.2 The palms and soles show increased palmar
and plantar markings in contradistinction to sex-linked ichthyosis and may
also show mild hyperkeratosis.3 An association with keratosis punctata of
the palms and soles has also been documented.4 Chapping of the hands and
feet can be a problem.5 There is no evidence of hair, nail, or teeth involve-
ment. There is an increased incidence of atopic disorders.5 Serum lipids are
normal.3

Table 3.2 Pathogenesis and histological features

Congenital ichthyoses Ichthyosis vulgaris is characterized by deficiency of profilaggrin, a major con-
stituent of the keratohyalin granules.6,7 Flaky tail mice, which represent an ani-
Isolated (nonsyndromic With associated symptoms
mal model of ichthyosis vulgaris, produce defective profilaggrin with resultant
ichthyosis) (syndromic ichthyosis)
absence of filaggrin.8 Ultrastructurally, the keratohyalin granules are reduced,
Autosomal recessive lamellar Comèl-Netherton's syndrome
spongy or crumbly and associated with decreased amounts of filaggrin.9 The
ichthyoses (nonbullous congenital Sjögren-Larsson syndrome
clinical severity of ichthyosis vulgaris correlates with the reduction of keratohy-
ichthyosiform erythroderma)
alin granules, which reflects a defective epidermal synthesis of filaggrin. Using
Harlequin ichthyosis Conradi-Hünermann-Happle fluorescein-labeled filaggrin antibodies demonstrates the severity of the defect
syndrome (chondrodysplasia (H. Traupe and V. Oji, unpublished observation). Filaggrin aggregates keratin
puncta type 2)
intermediate filaments in the lower stratum corneum and is subsequently prote-
Autosomal dominant lamellar Ichthyosis prematurity syndrome olyzed to form free amino acids including urocanic and pyrrolidone carboxylic
ichthyosis acids critical as water-binding compounds in the stratum corneum.
Bullous congenital ichthyosiform Gaucher syndrome, Type 2 Linkage analysis of the epidermal differentiation complex on chromosome
erythroderma Dorfman-Chanarin syndrome 1q21 has identified mutations in the gene encoding filaggrin. Parents with one
Ichthyosis bullosa of Siemens Trichothiodystrophy heterozygous filaggrin mutation may be asymptomatic, whereas affected off-
spring with two mutations often show classic ichthyosis vulgaris.10 Since the
Peeling skin syndrome Ichthyosis follicularis with atrichia filaggrin gene is a major susceptibility gene for atopic dermatitis, ­mutations
ichthyosis hystrix Curth-Macklin and photophobia
have also been shown in atopic dermatitis.11
Congenital reticular ichthyosiform Ichthyosis vulgaris is characterized by mild to moderate orthohyperkera-
erythroderma tosis associated with a hyperplastic, atrophic or normal epidermis. The key
feature is a thin or absent granular cell layer (Fig. 3.3).12,13 Regional vari-
ation in the thickness and/or presence of the granular cell layer may be a
(xerosis) and slight to moderate fine scaling, particularly involving the exten- ­feature and therefore it is best to take the biopsy from a site of maximal scal-
sor surfaces of arms and legs and characteristically sparing the flexures (Fig. ing. The lesions of keratosis pilaris show dilated follicles containing large
3.2). The light-gray scales vary in quality from thick adherent shiny plates keratin plugs. In the upper dermis a mild perivascular lymphocytic infiltrate
to simply dusty accumulations which, when scratched, leave a mark just as may be present. When ichthyosis vulgaris is associated with atopic dermatitis,
when one touches a dusty surface. The truncal lesions tend to be thicker than ­parakeratosis and other signs of a spongiotic dermatitis can be found.
48 Disorders of keratinization

Differential diagnosis
The histologic differential diagnosis includes other diseases character-
ized by orthohyperkeratosis and a reduced or absent stratum granulosum
(Table 3.3)

Table 3.3
Histologic patterns in ichthyotic skin disorders

Orthohyperkeratosis & stratum granulosum reduced or absent

Fig. 3.2
Ichthyosis vulgaris:
abdominal involvement
is most noticeable in this
patient. Sparing of the
flexures is characteristic
of this variant of
ichthyosis. By courtesy
of W.A.D. Griffiths, MD,
Institute of Dermatology,
London, UK.
A Differential diagnosis:
B Annular epidermolytic ichthyosis
Fig. 3.3
(A, B) Ichthyosis vulgaris: there is hyperkeratosis. The granular cell layer is absent.
Ichthyosis vulgaris (w/o atopic dermatitis)
Acquired ichthyosis-like condition
Refsum syndrome
Dorfman syndrome
Trichothiodystrophy syndrome
Conradi-Hünermann-Happle syndrome
Orthohyperkeratosis & stratum granulosum well developed
XR-ichthyosis
AR-lamellar ichthyosis
Harlequin ichthyosis
Acquired ichthyosis-like condition
(Lichen simplex chonicus)
Hyperkeratosis with ortho- and parakeratosis and stratum granulosum
prominent
AD-lamellar ichthyosis
Sjögren-Larsson syndrome
Harlequin ichthyosis
Inflammatory skin disease
Epidermolytic hyperkeratosis
Bullous ichthyotic erythroderma Brocq
Annular epidermolytic ichthyosis
Ichthyosis bullosa Siemens
Epidermal nevi
Epidermolytic acanthoma/leukoplakia
Epidermolytic palmoplantar keratoses
Incidental finding
Perinuclear vacuoles and binucleated keratinocytes
With parakeratosis:
Congenital reticular
Ichthyosiform erythroderma
With orthokeratosis:
Ichthyosis hystrix Curth-Macklin
Epidermolytic ichthyoses (Keratin clumps !)
Follicular hyperkeratosis
Keratosis pilaris, lichen spinulosus, phrynoderma
Keratosis pilaris atrophicans
Ichthyosis vulgaris with follicular keratosis
Lamellar ichthyosis
Sjögren-Larsson syndrome
Ichthyosis follicularis with alopecia and photophobia
Congenital atrichia
HID-, KID syndrome
Hereditary mucoepithelial dysplasia
Pachyonychia congenita
Ectodermal dysplasias
Darier's disease
Pityriasis rubra pilaris
Psoriasis-like features
Psoriasis vulgaris
Dermatophytosis
Comèl-Netherton's syndrome
CHILD syndrome
Papillon-Lefèvre syndrome
 Ichthyosis 49

X-linked recessive ichthyosis

Clinical features
Also known as steroid sulfatase deficiency and ichthyosis nigricans, this
X-linked, recessively inherited disorder has an incidence of 1:6000 male
births.1–3 The disease is exceedingly rarely expressed in females.4 Cutaneous
lesions tend to be more conspicuous and severe than in the autosomal dom-
inant variant.2 The scales are large and dark and are seen particularly on
the trunk, the extensor surface of the extremities, the scalp, the preauricular
region, and the neck (Figs 3.4–3.7).2 Mild Involvement of the flexures is also
present (Fig. 3.8).1 However, differentiation from ichthyosis vulgaris can be
difficult as some patients present with fine, light scales and the flexures may
be spared. The palms and soles are usually unaffected and keratosis pilaris is
not a feature. Involvement of the trunk and neck often gives the skin a dirty
appearance. Lesions may improve or disappear in warm weather.2 The hair,
nails, and teeth are not affected.
Corneal opacities due to comma-shaped deposits in the posterior capsule
of Descemet's membrane or corneal stroma, visible with slit-lamp exami-
nation (Fig 3.9), are characteristic and may be detected in female carriers.5 Fig. 3.5
Inadequate cervical dilatation may lead to prolonged delivery of affected Sex-linked ichthyosis: the scale is coarser than that seen in ichthyosis vulgaris.
male newborns. Undescended testes and hypogonadism can be a feature in By courtesy of the Institute of Dermatology, London, UK.
as many as 25% of affected patients.6–8 Rarely, testicular cancer has been
documented.6

Pathogenesis and histological features

The disease is associated with a deficiency of the microsomal enzyme, ste-
roid sulfatase/STS (sterol sulfate sulfohydrolase/arylsulphatase C).9 This is a
membrane-bound enzyme, which hydrolyses the 3-β-sulfate esters of choles-
terol and the sulfated steroid hormones.10 Absence of this enzyme is associ-
ated with persistence of the sulfate moiety on a number of sulfated steroid
hormones and cholesterol sulfate.3
X-linked recessive ichthyosis is characterized by a raised serum choles-
terol sulfate.10 The corneocytes contain excess cholesterol 3-sulfate and
diminished free sterol.11 Steroid sulfatase deficiency possibly results there-
fore in persistence of the lipid contents of the membrane-coating granules
and hence increased or persistent adhesion between adjacent keratin plates
in the stratum corneum. Beyond that, increased amounts of cholesterol sul-
fate may inhibit the epidermal serine protease activity, which results in reten-
tion of corneodesmosomes leading to less shedding of scales and retention
hyperkeratosis. Steroid sulfatase deficiency can be detected using the patient's

Fig. 3.6
Sex-linked ichthyosis: the scales are large and disfiguring. By courtesy of
R.A. Marsden, MD, St George's Hospital, London, UK.

­ eripheral leukocytes and cultured skin fibroblasts. Diagnosis may also be

p
affected by lipoprotein electrophoresis, which shows increased mobility of
low density and very low density beta-lipoproteins in addition to the steroid
sulfatase deficiency.12,13
The gene locus for recessive X-linked ichthyosis is within the Xp22.3
region of the X chromosome.14–16 Recently, indirect genotypic analysis using
polymorphic DNA markers closely linked to the STS gene has been shown
to be a reliable method of detection of the carrier status.14,17 Complete dele-
tions of structural STS gene have been reported in 90% of patients with
X-linked ichthyosis;14,16–19 the other 10% show partial deletions or point
mutations.1 Carrier status can also be confirmed by fluorescent in situ
hybridization (FISH) analysis.19 Recently, rapid diagnosis and differentia-
tion from ichthyosis vulgaris using polymerase chain reaction (PCR) has
been documented.20 Other important genes are located close to the steroid
sulfatase gene.
Fig. 3.4 Lesions show non-specific features of compact hyperkeratosis and slight
Sex-linked ichthyosis: there is severe involvement. Note the large, dark confluent acanthosis associated with a granular cell layer, which may be normal
scales. or increased in thickness (Fig. 3.10).21,22 Keratohyalin granules show no
50 Disorders of keratinization

Fig. 3.7
Sex-linked ichthyosis:
in this example the
scales appear dirty. This
can be an extremely
embarrassing condition.
By courtesy of the
Institute of Dermatology,
London, UK.

Fig. 3.9
(A) Sex-linked ichthyosis: characteristic linear opacities at the level of Descemet's
membrane. Slit-lamp photograph. (B) Same lesion viewed by specular microscopy.
By courtesy of R.J. Buckley, MD, Moorfield's Eye Hospital, London, UK.

Syndromes with steroid sulfatase

deficiency
A number of other important genes are located close to the steroid sulfatase gene.
If a deletion is larger, it may include some of these genes, producing a contigu-
ous gene syndrome.1 Two closely linked genes are those for Kallmann syndrome
(hypogonadotropic hypogonadism and anosmia) and X-linked recessive chon-
drodysplasia punctata.2 Possible linkage to a gene for hypertrophic pyloric steno-
sis has also been described.2 Thus patients may present with the skin changes of
X-linked recessive ichthyosis but with a whole spectrum of other problems.2
Fig. 3.8
Sex-linked ichthyosis: Multiple sulfatase deficiency
involvement of the
flexures is sometimes a
Multiple sulfatase deficiency is a severe neuropediatric disorder inherited as an
feature of this variant. By autosomal recessive. Patients develop normally for the first several years and
courtesy of the Institute then begin to show striking loss of mental capacity and motor ­abilities. They
of Dermatology, London, usually die before puberty. The ichthyosis is typically mild and the least of
UK. their problems. In multiple sulfatase deficiency patients the ­ichthyosis is simi-
lar to but usually less severe than in X-linked recessive ­ichthyosis. Therefore,
ichthyosis in a child with unexplained neurological symptoms should always
prompt measurement of steroid sulfatase levels.1
abnormality. Follicular plugging is not a feature. Paradoxically, biopsies of
thicker scales can show massive orthohyperkeratosis with reduction of the
granular layer and a thin epidermis, causing confusion with ichthyosis vul-
Refsum syndrome
garis. A discrete lymphocytic perivascular inflammatory cell infiltrate may
be evident. Clinical features
Ultrastructural features include a high number of transitional cells and an Refsum syndrome (hereditary motor and sensory neuropathy type 4, here-
abnormal persistence of desmosomal disks in the horny layer while keratohy- dopathica atactica polyneuritiformis, phytanic acid deficiency) is a rare type
alin granules are normal. An increased melanosome transfer accounts for the of an autosomal recessive syndromic ichthyosis.1 The skin changes appear
dark appareance of the scales.23 in childhood and are similar to those seen in ichthyosis vulgaris including
 Ichthyosis 51

The more severe noneyrthrodermic phenotype of lamellar ichthyosis has an

estimated prevalence of 1:200 000–300 000. The infant is often born encased
in a thick ‘collodion’ plate-like shell of keratin (Figs 3.11, 3.12), and while
the term ‘collodion baby’ is most often applied to cases of lamellar ichthyosis,
similar appearances are sometimes found in a number of other disorders such
as autosomal dominant lamellar ichthyosis, Netherton's syndrome, Sjögren-
Larsson syndrome, trichothiodystrophy, and infantile cerebral Gaucher
syndrome.3,4 Hence, colloidon baby is a clinical description but not a dis-
ease. Within a few days the shell is shed to reveal a mild ­erythroderma with

Fig. 3.11
Autosomal recessive
lamellar ichthyosis: the
collodion membrane
is best seen on the
forehead. There is scaling
and erythema on the
trunk. By courtesy of
B
R.A. Marsden, MD,
St George's Hospital,
Fig. 3.10 London, UK.
(A, B) Sex-linked ichthyosis: there is hyperkeratosis and mild acanthosis. The
granular cell layer is normal.

hyperlinear palms. Due to lipid storage, melanocytic nevi may show a yellow
hue. Associated symptoms include loss of vision from retinitis pigmentosa,
in which night blindness is often the first problem, anosmia, cardiac arrhyth-
mias, and a whole spectrum of neurological problems including bilateral
sensorineural deafness, cerebellar ataxia, and peripheral polyneuropathies.2

Pathogenesis and histological features

Refsum syndrome is generally caused by a mutation in a gene encoding
perioxisomal phytanol-CoA hydroxylase, although it can also be caused by
­specific ­mutations in the peroxisomal receptor gene PEX7.3,4 Peroxisomes are
involved in the metabolism of bile acid and cholesterol biosynthesis. Elevated
levels of ­phytanic acid in plasma and tissue are diagnostic. Low-phytol diet
is mandatory.5
Routine histology of a skin biopsy does not differ from ichthyosis vulgaris.
When a biopsy is fixed in alcohol and a Sudan stain performed, lipid drop-
lets are found in the keratinocytes, in particular in biopsies from melanocytic
nevi. The same inclusions can be shown by ultrastructural examination.6 Fig. 3.12
Autosomal recessive
lamellar ichthyosis: note
Autosomal recessive lamellar ichthyoses the erythema. The skin
is shiny, taut, and shows
Clinical features fissuring around the
anterior aspect of the
Autosomal recessive lamellar ichthyoses include a group of mostly mono- ankle. By courtesy of D.
genetic disorders presenting at birth with generalized hyperkeratosis and Atherton, MD, Children's
­scaling (ichthyosis congenita). The clinical presentation varies considerably Hospital at Great Ormond
in ­severity and clinical course.1–5 Street, London, UK.
52 Disorders of keratinization
g­ eneralized scaling (Fig. 3.13). In nonerythrodermic phenotype of lamellar
ichthyosis the scales are large, dark and platelike and cover the entire body
including the palms, soles, scalp, and flexures.5–8 Fissuring of the hands and
feet occurs and the skin around the joints may become verrucous. There is
often associated difficulty with sweating, and hyperpyrexia may be a feature.7
There is nail dystrophy, hair involvement (scarring alopecia), severe ectro-
pion (up to 80% of patients) and eclabium are characteristic (Fig. 3.14). The
ectropion is of the cicatricial type and develops as a consequence of exces-
sive dryness and associated contracture of the anterior lamella of the eye-
lid. Complications include corneal ulceration, vascularization, and corneal
­scarring with eventual ­blindness.9 Primary conjunctival lesions have also been
Fig. 3.13
Autosomal recessive
lamellar ichthyosis:
note the widespread
and prominent large
dark brown scales. By
courtesy of D. Atherton,
MD, Children's Hospital
at Great Ormond Street,
London, UK.
Fig. 3.14
Autosomal recessive
lamellar ichthyosis: in
this infant, there is gross
ectropion and eclabion.
By courtesy of D. Atherton,
MD, Children's Hospital
at Great Ormond Street,
London, UK.
described including ichthyosis, keratinization, hyper- and parakeratosis, and
papilla development. The teeth are not affected.3
In contrast, other individuals show a more pronounced erythroderma
with fine, white scaling (non-bullous congenital ichthyosiform erythroderma,
NCIE). A collodion membrane is often present at birth.1 After shedding, the
infant typically presents with an intense generalized erythroderma.2 While
platelike scales may be seen on the extensor surfaces of the legs, the scalp,
face, upper extremities and trunk are covered with fine white scaling (Figs
3.15–3.20).8 Mild ectropion and eclabium may be complications and palmo-
plantar keratoderma is often more severe than in noneyrthrodermic forms of
AR-lamellar ichthyosis.3 Exceptionally, congenital ichthyosiform erythroderma
has been associated with retinitis pigmentosa.10 There is an increased risk of
developing skin cancer including basal and squamous cell carcinoma.11
Fig. 3.15
Nonbullous congenital
ichthyosiform
erythroderma: there is
intense erythema and fine
scaling is also present.
The scalp hair is sparse
and the eyebrows are
absent. By courtesy of
D. Atherton, MD, Children's
Hospital at Great Ormond
Street, London, UK.
Fig. 3.16
Nonbullous congenital ichthyosiform erythroderma: there is marked erythema with
severe scaling. Blistering is not seen in this variant of ichthyosis. By courtesy of
D. Atherton, MD, Children's Hospital at Great Ormond Street, London, UK.

Fig. 3.17
Nonbullous congenital ichthyosiform erythroderma: there is intensive erythema and
fine scaling. By courtesy of the Institute of Dermatology, London, UK.
Fig. 3.18
Nonbullous congenital ichthyosiform erythroderma: there is generalized platelike
scaling. By courtesy of the Institute of Dermatology, London, UK.
Pathogenesis and histological features
The most common cause of lamellar ichthyosis is transglutaminase-1 deficiency
which accounts for 30–40% of cases. Mutations in the ­transglutaminase-1gene
result in markedly diminished or lost enzyme activity and/or protein. In some
cases, this enzyme is present but there is little detectable activity, and in other
clinically similar cases, transglutaminase-1 levels appear to be normal.12–17
Since conventional enzyme assays and mutational analyses are tedious, an
assay for the rapid screening of transglutaminase-1 activity using covalent
incorporation of biotinylated substrate peptides into skin cryostat sections
has been developed.18 Coupled with immunohistochemical assays using
transglutaminase-1 antibodies, this allows rapid identification of those cases
caused by alterations in this enzyme.18
Ichthyosis 53
Fig. 3.19
Nonbullous congenital ichthyosiform erythroderma: the scales are large, thick and
white. By courtesy of the Institute of Dermatology, London, UK.
Fig. 3.20
Nonbullous congenital ichthyosiform erythroderma: there is severe palmar
involvement and constriction bands are evident. By courtesy of the Institute of
Dermatology, London, UK.
Other variants of transglutaminase mutations are characterized by dis-
tinct clinical features. In self-healing collodion baby the ­transglutaminase-1
mutation is pressure-sensitive so that while in utero the enzyme cannot
function properly, it resumes normal function after birth. About 10% of
collodion babies fall into this group.19 In bathing suit ichthyosis (BSI) the
mutation in transglutaminase-1 appears to be temperature sensitive so that
the face and extremities are almost completely spared apart from skin areas
overlaying blood vesssls. Digital thermography has validated a striking cor-
relation between warmer body areas and the presence of ­scaling, suggesting
a decisive influence of the skin temperature. In situ TGase testing in skin
of BSI patients has also demonstrated a marked decrease of enzyme activity
when the temperature is increased from 25 to 37 degrees Celsius.20
The second most common mutation in lamellar ichthyosis can be found
in the binding cassette protein.21,22 Missense mutations cause lamellar ich-
thyosis while deletions are responsible for the far more dramatic harlequin
fetus.23 Mutations in either transglutaminase-1 or the lipoxygenases are most
often responsible for the nonbullous congenital ichthyosiform erythroderma
phenotype. The ichthyin mutation also usually produces nonbullous con-
genital ichthyosiform erythroderma (Table 3.4).24–28 Attempts to refine the
classification of non erythrodermic and erythrodermic phenotypes by the use
54 Disorders of keratinization

Table 3.4
Types of autosomal recessive lamellar ichthyosis (LI)

Type Locus Gene Protein Defect

LI 1 14q11 TGM1 Transglutaminase-1 Impaired cross-linking of proteins and
lipids to the cornified cell envelope
LI 2 2q34 ABCA12 ATP binding cassette Abnormal lamellar body function and
lipid trafficking
LI 3 / LI 4 19p12-q12 FLJ39501 Cytochrome P450 family protein Epidermal lipid metabolism
LI 5 17p13 ALOX12B 12R-lipoxygenase Epidermal lipid metabolism
ALOXE3 Lipoxygenase-3
LI 6 5q33 ICHYN Ichthyin Transmembrane protein

of clinical, biochemical, and ultrastructural observations have so far failed to
yield a consistent scheme.29–31 This difficulty is illustrated by the fact that the
same transglutaminase-1 mutation can give rise to different phenotypes.31
Histologically, the epidermis in autosomal recessive lamellar ichthyosis
shows marked hyperkeratosis (which may be extreme in the collodion baby)
and mild acanthosis with a normal or thickened granular cell layer (Fig. 3.21).
The hyperkeratosis is much less marked in erythrodermic than in noneryth-
rodermic forms. Epidermal papillomatosis associated with a psoriasiform
appearance has also been documented. A perivascular lymphocytic infiltrate
is occasionally a feature.4 Dilatation and tortuosity of the dermal capillaries is
sometimes evident. Follicular hyperkeratosis may occasionally be seen.
Ultrastructural studies show a variety of features including defective devel-
opment of the cornified cell envelopes and electron-dense debris adjacent to
the plasma membranes, cholesterol clefts, lipid vacuoles, increased numbers
of small and dysmorphic lamellar bodies, elongated membrane structures,
or membrane packages.32–34 Prenatal diagnosis of lamellar ichthyosis can be
achieved by fetoscopy and biopsy.35
Harlequin ichthyosis
Clinical features
Harlequin ichthyosis (harlequin fetus, ichthyosis fetalis, ichthyosis congenita
gravis) is an extreme and rapidly fatal subtype, where babies are born with
a fissured ‘armor-plated’ skin (Fig. 3.22).1–4 Ectropion and eclabium are fre-
quent complications, and the ears and nose are often malformed.2 Harlequin
fetus has a very high mortality due to respiratory and feeding difficulties
accompanied by excessive fluid loss.3 Sometimes, treatment by retinoids and
intensive care is successful. Long-term survivors, following shedding of the
scales, develop a severe erythroderma reminiscent of nonbullous ichthyosi-
form erythroderma.5 Fortunately, antenatal diagnosis is possible.6,7

Pathogenesis and histological features

This very rare form of ichthyosis is due to an apparently dramatic loss of
function of the lamellar bodies, which results from nonsense mutations in
the ABCA12 gene. Less severe missense mutations cause a variant of lamellar
ichthyosis. This indicates that a severely truncated protein is the molecular
cause of Harlequin ichthyosis.8 The ATP-binding cassette (ABC) transporter
A
family encompasses a variety of membrane proteins involved in the energy-
dependent transport across membranes. In the epidermis, ABCA12 may have
an important function for the lamellar bodies, through exocytosis traffic of
lipids or proteases across the apical keratinocyte membrane.
The lesions are characterized by massive hyperkeratosis (sometimes
with lipid deposits) associated with a normal or absent granular cell layer
(Fig. 3.23). The hair follicles are usually affected first, during the second tri-
mester.2,7 Parakeratosis may also sometimes be evident.9 Acanthosis is often
marked and papillomatosis is sometimes a feature. A sparse mixed inflamma-
tory cell infiltrate can be present in the superficial dermis.7
Ultrastructurally, the harlequin fetus has recently been shown to be associated
with deficient or morphologically abnormal lamellar bodies ­(including concen­
trically lamellated forms) and deficient intercellular lipid lamellae within the
stratum corneum.1,2,9 Small vesicles, devoid of internal lamellation, may be pres-
ent in the granular cell layer (and retained in the stratum corneum), but show no
association with the keratinocyte cell membranes as is typical of normal lamel-
lar bodies.1,9 Recent immunohistochemical evidence suggests that these vesicles
­represent abnormal lamellar bodies characterized by an inability to discharge
B their lipid contents into the intercellular space. Keratin and filaggrin expression
have also been shown to be defective.2 In the harlequin fetus, the keratinocytes
Fig. 3.21 may display the hyperproliferative keratins K6 and K16 and show an inability to
Autosomal recessive lamellar ichthyosis: (A) there is very marked hyperkeratosis convert profilaggrin to filaggrin.2 The results of ultrastructural and ­biochemical
and the epidermis shows papillomatosis; (B) high-power view. analyses suggest that the harlequin fetus is a heterogeneous condition.

A B
Fig. 3.23
Harlequin ichthyosis: there is massive hyperkeratosis associated with a
conspicuous granular cell layer and a papillomatous epithelium. The dilated spaces
in the stratum corneum represent dilated ostial of eccrine ducts. By courtesy of
M.M. Black, MD, Institute of Dermatology, London, UK.
Autosomal dominant lamellar ichthyosis
Clinical features
Autosomal dominant lamellar ichthyosis is characterized by generalized scal-
ing with palmoplantar keratoderma.1 Patients may present as a collodion
baby. They are later covered by diffuse dark-gray scales that involve all areas
of the body but are most prominent on the extensor surfaces. Backs of the
hands and feet are characterized by lichenification. There may be massive
plantar hyperkeratosis with thick, yellow scales. The palms are usually only
minimally involved and show accentuated markings.1
Pathogenesis and histological features
This disorder appears to be genetically and clinically heterogeneous and of
variable penetrance. Its genetic defect has not been identified. Biochemically,
an abnormal lipid profile has been detected in the scales.2
Ichthyosis 55
Fig. 3.22
(A, B) Harlequin ichthyosis: the most extreme form
of congenital ichthyosis. There is an exceedingly high
mortality. The scales are very thick and are often referred to
as armor-plating.
Histologically, there is an acanthosis, papillomatosis, and compact ortho-
hyperkeratosis with focal parakeratosis that, paradoxically, is associated with
a thickened stratum granulosum (Fig. 3.24).2
Electron microscopy shows a high number of transitional cells and a
spongy appearance of the keratohyaline granules.2
Differential diagnosis
The differential diagnosis includes lichen simplex chronicus which, however,
differs by the presence of inflammatory changes and fibrosis of the papillary
dermis (see Table 3.3).
Congenital bullous ichthyosiform
erythroderma
Clinical features
Congenital bullous ichthyosiform erythroderma (also known as epidermo-
lytic hyperkeratosis, bullous ichthyosis, bullous ichthyosiform erythroderma of
Brocq) is a very rare disease (incidence of 1:300 000 births) and, although some-
times inherited by an autosomal dominant mode, it more often appears to arise
by spontaneous mutation. At birth the infant may show marked hyperkerato-
sis, erythroderma, or even present as a collodion baby. Although the scales are
soon lost, leaving a generalized moist, tender erythroderma, re-epithelialization
leads to further scale production followed by the development of widespread
blistering (Fig. 3.25) which heals without scarring. As the patient becomes
older, the erythema and blistering become less apparent and, later, the disease is
complicated by the development of verrucous hyperkeratosis, especially in the
flexures (Figs 3.26–3.31). In some cases, the scales have been said to assume
a porcupine quill-like appearance (ichthyosis hystrix) and scalp involvement
may simulate tinea capitis.1 The nape, axilla, groin, and flexural folds are sites
of predilection. Occasional blisters still arise, often in summertime and at sites
of pressure. In patients with keratin 1 but not with keratin 10 mutations, pal-
moplantar keratoderma is often present. Nail dystrophy may sometimes be a
feature. The patients suffer from an offensive body odor. Congenital bullous
ichthyosiform erythroderma is associated with considerable morbidity and sig-
nificant mortality due to sepsis, fluid loss, and electrolyte imbalance.1
A nevoid variant in which the lesions follow Blaschko's lines is also rec-
ognized.2 In the past, such lesions may have been mistaken for epidermal
nevi showing epidermolytic hyperkeratosis. Due to the possibility of gonadal
mutations, children of affected patients with the nevoid variant may develop
generalized congenital bullous ichthyosiform erythroderma
56 Disorders of keratinization

Fig. 3.26
Congenital bullous
ichthyosiform
erythroderma:
Hyperkeratosis and scales
follow re-epithelialization
of widespread blistering.

Fig 3.24
(A, B) Autosomal dominant lamellar ichthyosis: in this example there is marked
compact hyperkeratosis. The granular cell layer is prominent and there is focal
parakeratosis.

Fig. 3.27
Congenital bullous
ichthyosiform
erythroderma: adult
showing very generalized
scaling, particularly
severe on the legs. By
courtesy of the Institute
of Dermatology, London,
UK.

Pathogenesis and histological features

Fig. 3.25
Congenital bullous ichthyosiform erythroderma: close-up view of an infant showing
intense erythema and blistering. By courtesy of M. Liang, MD, The Children's
Hospital, Boston, USA.
An annular variant has also been described. Patients may have mild eryth-
roderma and blisters at birth, but the characteristic feature is the presence of
many annular gray hyperkeratotic plaques with a peripheral erythematous
border. 3,4
There is considerable evidence in the recent literature confirming that con-
genital bullous ichthyosiform erythroderma represents a genetic disorder of
keratin expression associated with hyperproliferation of the epidermis.5,6 In
the skin, basal keratinocytes predominantly express keratin 5 and 14, while
suprabasal cells switch to the expression of keratin 1 and 10. Keratin mono-
mers form obligate heterodimers in pairs of acidic (type I) and basic (type
II) keratins, which assemble into keratin intermediate filaments building a
cytoskeleton for the structural stability and flexibility of epidermal cells.
Transgenic mouse studies using a truncated human keratin 10 gene have
been shown to result in the pathobiological and biochemical phenotype of
epidermolytic hyperkeratosis.7 Epidermolytic hyperkeratosis shows linkage
 Ichthyosis 57

Fig. 3.28
Congenital bullous Fig. 3.30
ichthyosiform Congenital bullous
erythroderma: same ichthyosiform
patient as Figure erythroderma: blistering
3.27, showing elbow may sometimes be seen
involvement. By courtesy in adulthood. By courtesy
of the Institute of of the Institute of
Dermatology, London, UK. Dermatology, London, UK.

Fig. 3.29
Congenital bullous ichthyosiform erythroderma: the hands are particularly affected.
By courtesy of the Institute of Dermatology, London, UK.
to the keratin gene cluster either on chromosome 12q11–13 (type II keratin)
or chromosome 17q21-q22 (type I keratin).8–10 Direct sequencing of keratin
1 and 10 genes has identified point mutations in a number of affected fami-
lies.11–17 Most mutations are missense and clustered at the ends of the central
helical rod domains. Keratin 1 mutations are associated with severe pal-
moplantar hyperkeratosis while keratin 10 mutations are not because kera-
tin 10 is physiologically substituted by keratin 9 on palmoplantar skin.15
Mutations in the keratin 1 or 10 gene exhibiting mosaicism explain the
nevoid variant of congenital bullous ichthyosiform erythroderma.18,19 The
annular variant shows minor mutations in keratin 1 or 10 genes on distinct
keratin domains.4
The histological features are known as epidermolytic hyperkeratosis or
granular degeneration and are very striking.20,21 Suprabasal keratinocytes
appear vacuolated and typically contain distinct eosinophilic intracytoplas-
mic inclusions. The cell borders are ill defined and intraepidermal blister
Fig. 3.31
Congenital bullous
ichthyosiform
erythroderma: adult
showing very severe
verrucous flexural scaling.
By courtesy of R.A.J.
Eady, MD, Institute of
Dermatology, London, UK.
formation may be present. There is massive orthohyperkeratosis, papillo-
matosis, and acanthosis. The granular cell layer is prominent and contains
coarse and irregular keratoyhaline granules (Fig. 3.32).
By immunohistochemistry, epidermolytic hyperkeratosis shows a normal
distribution pattern of keratins 5/14 and 1/10, but in addition there is over-
expression of keratin 14 in the suprabasal epithelium accompanied by quite
marked labeling of the upper epithelial layers by keratin 16, as would be
expected in a hyperproliferative state.5,22
Ultrastructural studies have shown that the intracytoplasmic inclusions
seen on light microscopy are composed of abnormally aggregated keratin
58 Disorders of keratinization

Fig. 3.33
Congenital bullous
ichthyosiform
erythroderma: striking
perinuclear keratin
clumping is evident.
By courtesy of R.A.J.
Eady, MD, Institute of
Dermatology, London,
A UK.

Ichthyosis bullosa of Siemens

Clinical features
Ichthyosis bullosa of Siemens is inherited as an autosomal dominant. The
condition, which is milder than congenital bullous ichthyosiform eryth-
roderma, presents at birth with blistering subsequently replaced by dark
­lichenified hyperkeratosis of the limbs, predominantly affecting the ­flexures
and shins (Fig. 3.34).1,2 The skin remains fragile and blisters on mild trauma,
­giving rise to characteristic superficial peeling with a molting-like ­appearance
(Mauserung phenomenon) (Fig. 3.35).2,3 Symptoms usually improve with
age. Erythroderma is typically absent. Rarely, pustulation and ­hypertrichosis
may be additional features.3,4 There is considerable clinical overlap between
­ichthyosis bullosa of Siemens and congenital bullous ichthyosiform
­erythroderma, and their distinction can best be achieved by molecular genetic
B analysis.

Fig. 3.32
Congenital bullous ichthyosiform erythroderma: (A) there is massive hyperkeratosis
and acanthosis. The epidermis shows conspicuous superficial vacuolation which has
resulted in vesiculation, (B) there is intracellular edema, and irregular eosinophilic
granules (representing dense abnormal aggregates of keratin filaments) are present
in the superficial layers of the epidermis.

filaments. Since large areas of the cytoplasm lack a regular keratin skeleton,
the suprabasal keratinocytes appear vacuolated and contain irregular kera-
toyhaline granules. Impairment of desmosome-keratin complexes accounts
for the fragility of the epidermis (Fig. 3.33).18 These ultrastructural changes
may form the basis of prenatal diagnosis including amniotic fluid squame
analysis.20,21
Immunoelectron microscopy has identified that the keratin clumps are
composed of keratins 1 and 10.22

Differential diagnosis
Epidermolytic hyperkeratosis is a histopathologic pattern that is seen in
many conditions including ichthyosis bullosa of Siemens, epidermal nevus,
epidermolytic keratoderma, epidermolytic acanthoma, and epidermolytic
leukoplakia (see Table 3.3). It may also represent an incidental finding in
seborrheic keratosis, actinic keratosis, in situ squamous cell carcinoma, inva-
sive squamous cell carcinoma, melanocytic nevi, and epidermal and pilar Fig. 3.34
Bullous ichthyosis
cysts.23 Epidermolytic hyperkeratosis may also be seen in normal and par-
Siemens: flexural
ticularly actinically damaged skin. In such incidental lesions, the changes are hyperkeratosis with early
limited to the epidermis overlying just one or two dermal papillae in contrast blister formation.
to the much more extensive involvement of the other conditions mentioned By courtesy of W.A.D.
above. Therefore, accurate clinical information is necessary to avoid diagnos- Griffiths, MD, Institute of
tic confusion. Dermatology, London, UK.
 Ichthyosis 59

Fig. 3.35
Bullous ichthyosis Siemens: marked hyperkeratosis is present over the knees.
By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK.

Pathogenesis and histological features

Bullous ichthyosis is associated with a point mutation in the keratin 2e gene
on chromosome 12q11-q13.4–9 Since this keratin is not expressed on volar
skin, palmoplantar keratoderma does not develop.
Histologically and by electron microscopy, the features are indistinguish-
able from congenital bullous ichthyosiform erythroderma except that they
are milder and the vacuolation of the keratinocytes and cytoplasmic inclu-
sions are restricted to the more superficial prickle and granular cell layers
as opposed to involving almost the entire epidermis as is typical of the latter
condition. Subcorneal separation may be evident.10
B

Linear epidermolytic epidermal nevus Fig. 3.36

Linear verrucous epidermal nevi occasionally show the features of epi- Linear epidermolytic epidermal nevus: (A) low-power view showing massive
dermolytic hyperkeratosis (Fig 3.36). Some patients with such a lesion, hyperkeratosis and papillomatosis (B) high-power view showing epidermolytic
hyperkeratosis.
although by no means all, in reality suffer from the nevoid variant of con-
genital bullous ichthyosiform erythroderma.1–4 It is therefore important that
patients with apparent epidermolytic epidermal nevi are offered genetic
counseling.

Epidermolytic acanthoma
Clinical features
Isolated epidermolytic acanthoma (also termed disseminated epidermolytic
acanthoma) is an acquired lesion that presents as a verrucous papule or
plaque approximately 1.0 cm in diameter and sometimes resembles a viral
wart, nevus or seborrheic keratosis.1–3 Lesions may present at any site, but
the scrotum, head, neck, and leg are particularly affected.2,3 Although usually
solitary, occasional patients may present with multiple localized or dissemi-
nated lesions.4–8 Variants affecting the mucosae of the oral cavity and female
genital tract have also been documented.9,10 Caucasians and the Japanese are
predominantly affected.3

Pathogenesis and histological features Fig. 3.37

Although not proven, it has been suggested that epidermolytic acanthoma
develops as a consequence of keratin 1 and 10 gene mutation.3
The lesion is characterized by hyperkeratosis, parakeratosis, acanthosis,
and papillomatosis (Fig. 3.37).1,2 The upper prickle cell and granular cell lay-
ers show features of epidermolytic hyperkeratosis (i.e., marked vacuolation
of the keratinocytes with eosinophilic keratin inclusions) (Fig. 3.38).
Epidermolytic acanthoma: the lesion is papillomatous with massive hyperkeratosis.
There is a superficial perivascular chronic inflammatory cell infiltrate.
Epidermolytic acanthoma displays diminished expression of keratins
1 and 10 and increased expression of the hyperproliferative keratins 6
and 16.3
60 Disorders of keratinization

Fig. 3.38 Fig. 3.39

Epidermolytic acanthoma: there is superficial cytoplasmic vacuolation and Peeling skin syndrome: Erythematous lesions show peeling of the skin leaving
eosinophilic inclusions are conspicuous. superficially denuded red patches. By courtesy of H.Traupe MD and V.Oji MD,
Department of Dermatology, Munster, Germany.
Differential diagnosis
Identical histological changes are seen in congenital bullous ichthyosiform
erythroderma, linear epidermolytic epidermal nevus, epidermolytic palmo-
plantar keratoderma, and in focal epidermolytic hyperkeratosis (see Table
3.3). Clinical information is usually necessary to avoid diagnostic confusion.

Focal epidermolytic hyperkeratosis

Focal epidermolytic hyperkeratosis (incidental epidermolytic hyperkeratosis)
represents a non-specific finding of epidermolytic hyperkeratosis in the epi-
dermis overlying or adjacent to an unrelated lesion. It is very common and
has been described, for example, in seborrheic keratoses, overlying scars and
fibrous histiocytoma, in banal and dysplastic nevi, actinic keratosis, squamous
cell carcinoma in situ, and melanoma. It may also be seen in normal skin. 1–5

Peeling skin syndrome

Clinical features
Peeling skin syndrome (familial continual skin peeling, keratolysis exfoliativa Fig. 3.40
congenitale) is characterized by a spontaneous, lifelong peeling of the stratum Peeling skin syndrome:
corneum without bleeding or pain.1–6 The mode of inheritance is autosomal The skin of the backs
of hand and feet shows
recessive.1 Three types can be distinguished:
reddish scaly patches. By
• In type A a generalized continued shedding or peeling of the entire skin courtesy of H.Traupe MD
without signs of inflammation or other symptoms is present from birth and V Oji MD, Department
or develops during childhood (Fig. 3.39).2 of Dermatology, Munster,
• Type B appears, resembles and is characterized by isolated erythematous Germany
lesions which then peel, leaving burning superficially denuded red
patches with a peripheral collarette.3 Only recently a mutation of
corneodesmosin has been identified.3a
• In type C (acral peeling skin syndrome), involvement is confined to the backs Ichthyosis hystrix Curth-Macklin
of the hand and feet (Fig. 3.40).4,5 A homozygous missense mutation in the
gene of transglutaminase-5 has been identified in two unrelated families.6 Clinical features
‘Ichthyosis hystrix’ is a descriptive name for cornification disorders with spiny
Histological features and dark hyperkeratosis. Ichthyosis hystrix Curth-Macklin is characterised
• In type A, histology shows a plane of separation either within the lower by generalized verrucous plaques, involving the entire trunk, the flexural sur-
part of an otherwise normal horny layer or above the granular cell faces of the extremities and the palms and soles. The autosomal dominant
layer. Ultrastructural analysis reveals an intracellular splitting within the disorder sometimes resembles bullous ichthyosiform erythroderma, but there
corneocytes.2 is no clinical or histological evidence for blistering. 1–3
• In type B, the epidermis is psoriasiform with an absent or reduced
granular cell layer and marked parakeratosis. The split occurs at the level Pathogenesis and histological features
of the granular cell layer.3 Recent evidence suggests that in ichthyosis hystrix Curth-Macklin a mutation
• In type C peeling skin syndrome, the horny layer is detached from the in a keratin gene affecting the variable tail domain (V2) of keratin 1 results
stratum granulosum (Fig. 3.41).4,5 in a failure in keratin intermediate filament bundling and retraction of the
 Ichthyosis 61

Fig. 3.41
Peeling skin syndrome: the biopsy is taken from the edge of the lesion. Note that
the stratum corneum is clearly separated from the underlying epidermis.

cytoskeleton from the nucleus.2 This is the first in vivo evidence for the crucial
role of a keratin tail domain in supramolecular keratin intermediate filament
organization and barrier formation.2
Histologically, the epidermis is acanthotic and orthohyperkeratotic. The
suprabasal keratinocytes are vacuolated and a few of them appear ­binucleated.
In contrast to epidermolytic hyperkeratosis, eosinophilic intracytoplasmic
inclusions are not present.4
The significant ultrastructural observation in ichthyosis hystrix Curth-
Macklin is the presence of perinuclear concentric shells of tonofilaments. In
contrast to keratin mutations of the rod domain in epidermolytic hyperkera-
tosis, aggregations and clumping of keratin filaments are absent.4

Congenital reticular ichthyosiform B

erythroderma
Clinical features
Congenital reticular ichthyosiform erythroderma is a rare inherited disorder
of keratinization.1 Since only sporadic cases have been recognized, the mode of
inheritance is unknown. Most of the patients have been female. The patients
are born with congenital ichthyosiform erythroderma. During ­childhood the
integument clears gradually so that enlarging patches of normal skin appear
to be enclosed by erythrokeratotic and hyperpigmented areas in a reticular
arrangement. Because of this clinical appearance the genodermatosis has also
been termed ichthyosis ‘en confettis’ or, more precisely, ichthyosis variegata.2–8
Associated features are hypertrichosis, and palmoplantar hyperkerato-
sis, and, in single cases, hypogonadism, growth retardation, hepatomegaly,
­keratoacanthoma or squamous cell carcinoma.1,5,7
Pathogenesis and histological features
Histologically, the epidermis is pale staining and there is psoriasiform hyper-
plasia. The horny layer is thickened and parakeratotic. The parakeratotic
corneocytes have enlarged nuclei. The keratinocytes of the upper layers show
prominent perinuclear vacuolation and contain few keratohyalin granules.
Their cell borders are well defined and intracytoplasmic eosinophilic granules
are absent. Some of the vacuolated keratinocytes are binucleate (Fig. 3.42).
The dermal vessels are dilated, and there is a sparse perivascular inflamma-
tory cell infiltrate with scattered melanophages.
While keratin 2e is missing, the other epidermal keratins are regularly
expressed. At the ultrastructural level the arrangement of the keratin skeleton
is highly disturbed. Immuno-electron microscopy reveals complete absence
of keratin filaments in the perinuclear cytoplasm.1–3 The number of transi-
tional cells is increased and nick end labeling (TUNEL) for DNA fragmenta-
tion shows strong labeling of the parakeratotic corneocytes consistent with
Fig. 3.42
Ichthyosis variegata: (A) there is hyperkeratosis and well-developed psoriasiform
hyperplasia; (B) there is parakeratosis with prominent nuclei. Note the cytoplasmic
vacuolation. Eosinophilic intracytoplasmic inclusions are absent.
an apoptotic mode of cell death.9 Uptake and processing of melanosomes is
irregular. The basic genetic defect in congenital reticular ichthyosiform eryth-
roderma is due to dominant mutations is keratin 10 that causes mislocalisa-
tion to the nucleolus and disruption of the keratin filament network.9,10
Differential diagnosis
The absence of keratin clumping clearly distinguishes congenital reticular
ichthyosiform erythroderma from keratinization disorders characterized by
epidermolytic hyperkeratosis. Ichthyosis hystrix Curth-Macklin shares the
intraepidermal formation of binucleate, vacuolated keratinocytes but lacks
parakeratosis and shows formation of perinuclear shells of tonofibrils (see
Table 3.3).
Comèl-Netherton's syndrome
Clinical features
Comèl-Netherton's syndrome (Netherton's syndrome, ichthyosis linearis cir-
cumflexa) is a rare genodermatosis inherited as an autosomal recessive. It
is characterized by the triad of congenital ichthyosiform erythroderma, hair
shaft anomalies, and a severe atopic diathesis with high IgE blood levels and
eosinophilia.1 It is believed to affect approximately 1:200 000 of the pop-
ulation.2 Generally, the congenital ichthyosiform erythroderma gradually
evolves into a milder ichthyosis linearis circumflexa which is characterized
by an erythematous, scaly rash predominantly affecting the trunk and limbs.3
62 Disorders of keratinization
It is composed of polycyclic, migratory, annular and serpiginous lesions
with characteristic two parallel lines of scale at the periphery, the so-called
­double-edged scale (Figs 3.43–3.45). In infancy, erythema and scaling may
be widespread, but later the face is often predominantly affected (particularly
marked around the mouth and eyes), along with the perineum,4 and as such
the eruption can be mistaken for acrodermatitis enteropathica (Fig. 3.46).1
Later the scalp, face, and eyebrows may show a yellowish scaling.5 Ichthyosis
linearis circumflexa is typically nonpruritic,5 and the nails and teeth are not
involved.3 Rarely, infants may also show palmoplantar hyperkeratosis.6
Comèl-Netherton's syndrome is often misdiagnosed as seborrheic dermatitis,
atopic dermatitis, and psoriasis vulgaris.
Trichorrhexis invaginata (due to a transient and repeated defect of ker-
atinization, with resultant hair shaft intussusception)7 presents clinically as
coarse and lusterless hair, which is short, brittle, and fragile (Fig. 3.46). Pili
torti and trichorrhexis may also be evident (Fig. 3.47).5
Fig. 3.43
Comèl-Netherton's syndrome: ichthyosis linearis circumflexa. Note the serpiginous
lesions with characteristic double border. By courtesy of M. Judge, MD, Institute
of Dermatology, London, UK.
Fig. 3.44
Comèl-Netherton's syndrome: (A) hyperkeratotic lesions
may sometimes be prominent; (B) note the focal loss of the A B
polycyclic pattern.
Patients with Netherton's syndrome may in addition suffer from life
threatening neonatal dehydration with hypernatremia, failure to thrive, and
recurrent skin infections often caused by Staphylococcus aureus,4,8,9 amino-
aciduria,5 mental retardation,5,7 and immune defects.1,5 An impaired epider-
mal barrier is a potential risk for increased and even toxic absorption of
topical medications.
Pathogenesis and histological features
Netherton's syndrome results from mutations in the SPINK5 gene which
has been localized to 5q32.10,11 Nonsense, frameshift deletions and inser-
tions and splice site defects resulting in premature termination codons and
Fig. 3.45
Comèl-Netherton's
syndrome: there is
prominent involvement of
the trunk and limbs.

A B
Fig. 3.47
Comèl-Netherton's
syndrome: bamboo hair
(trichorrhexis invaginata).
By courtesy of M.
Judge, MD, Institute of
Dermatology, London,
UK.
a defective serine protease inhibitor, i.e., Lympho-Epithelial Kazal Type
Inhibitor (LEKTI), have been identified.11–13 The lack of LEKTI consequently
leads to a hyperactivity of the proteases involved in the desquamation pro-
cess or inflammatory response (kallikreins) and accounts for the ichthyotic
and inflammatory skin phenotype, which is associated with an extremely
impaired epidermal barrier.
For diagnostic features, the biopsy must be taken from skin just preced-
ing the lesion's scaly margin (Fig. 3.48).14,15 In this region the epidermis may
show psoriasiform hyperplasia with associated spongiosis. There is a thick
adherent parakeratotic scale. Small, dark, round or oval granules can be iden-
tified within the stratum granulosum. These are diastase-resistant, PAS and
Ichthyosis 63
Fig. 3.46
Comèl-Netherton's syndrome: (A) there is profound
erythema with scaling; (B) the hair is dull and appears short
and thin. The eyebrows are deficient. (A) By courtesy of M.
Judge, MD, Institute of Dermatology, London, UK,
(B) By courtesy of A. Griffiths, MD, Institute of
Dermatology, London, UK.
Sudan black positive and are thought to represent an influx of serum exu-
dates resulting from the accompanying dermal inflammation.4 Similar ‘inclu-
sions’ have been described in psoriasis and atopic eczema16 and as such they
are not specific. Rarely, the parakeratotic scale may be associated with the
presence of Munro microabscesses.6 Biopsies from the center of the lesion
shows the features of atopic dermatitis.
Electron microscopy reveals reduced numbers of lamellar bodies in kera-
tinocytes and the presence of lysosomal inclusion bodies with intercellular
amorphous deposits in the horny layer.14,16
Immunohistochemistry can demonstrate the absence of LEKTI antigen
and is highly specific.17
Differential diagnosis
The histologic distinction from psoriasis vulgaris may be histologically
extremely difficult (if not impossible) in the absence of clinical information.
Other genodermatoses, dermatophytosis, and inflammatory skin diseases
with a psoriasiform-like pattern must be differentiated (see Table 3.3). Atopic
dermatitis is another important differential diagnosis.
Sjögren-Larsson syndrome
Clinical features
This autosomal recessive inherited disorder combines the features of ichthyo-
sis, spastic bi- or quadriplegia and mental retardation.1–5 It is rare, with an
incidence of 0.4 per 100 000 of the population.4 Although the disease may
be encountered worldwide, the prevalence is particularly high in Northern
Sweden.2
The ichthyosis, which develops in the first year of life with a diffuse scal-
ing, affects the entire body with the exception of the central face and is typi-
cally intensely pruritic (Fig. 3.49).3,5 Later, the skin has a brownish-yellow
color and shows a cobblestone-like lichenification.4 Hyperkeratosis around
the umbilicus is said to be characteristic.5 Erythroderma is not a feature and
the hair, nails, and sweat glands are unaffected.3,4 The diagnosis should be
especially considered in preterm babies with congenital ichthyosis.5
The spasticity, which presents in early childhood, predominantly affects
the legs and is often associated with contractures. The majority of patients are
wheelchair bound.4 Kyphoscoliosis may also be present.3 Mental retardation
is typically present but is not invariable.1 Epilepsy is sometimes a feature.3
64 Disorders of keratinization

Visual acuity is often impaired and photophobia is a frequent complaint.

Macular degeneration associated with crystal deposition is characteristic
(Fig. 3.50).6

Pathogenesis and histological features

Sjögren-Larsson syndrome results from deficiency of microsomal fatty alde-
hyde dehydrogenase (FALDH).7 The gene has been mapped to 17p11.2 and
multiple mutations including missense mutations, deletions, and insertions
have been identified.8–10 The abnormal level of free fatty alcohols in cultured
fibroblasts, direct testing of FALDH activity, or the presence of LTB4 metabo-
lites in urine can provide biochemical screening and/or confirmation of the
clinical diagnosis, prior to molecular mutation analysis of the FALDH gene.5
Epidermal hyperproliferation has been demonstrated in Sjögren-Larsson
syndrome.11
Histologically, there is papillomatosis, acanthosis, and basket-weave hyperk-
eratosis with scattered mild parakeratosis and occasional follicular hyperkeratosis
(Fig. 3.51).12 The granular cell layer may be slightly thickened. A light lymphohis-
tiocytic infiltrate is sometimes present around the superficial dermal vasculature.
Ultrastructurally, there are lamellar inclusions in the prickle and granular
cell layers.12 Lipid inclusions are not a feature.
A

Fig. 3.48
Comèl-Netherton's syndrome: (A) scanning view showing a detached Fig. 3.50
thickened stratum corneum and psoriasiform hyperplasia; (B) note the marked Sjögren-Larsson syndrome: characteristic macular crystals. By courtesy of
parakeratosis. M. Willemsen, MD, University Medical Center, Nijmegen, Belgium.

Fig. 3.49 Fig. 3.51

Sjögren-Larsson syndrome: there is severe scaling and the skin has a yellowish- Sjögren-Larsson syndrome: there is hyperkeratosis, hypergranulosis and mild
brown color. By courtesy of M. Willemsen, MD, University Medical Center, papillomatosis. A light superficial perivascular lymphocytic infiltrate is present. By
Nijmegen, Belgium. courtesy of M. Willemsen, MD, University Medical Center, Nijmegen, Belgium.
 Other congenital ichthyotic syndromes 65

Conradi-Hünermann-Happle syndrome
Clinical features
Conradi-Hünermann-Happle syndrome is an X-linked dominant congeni-
tal ichthyosis with associated chondrodysplasia punctata. It is lethal in the
majority of male embryos. Chondrodysplasia punctata is defined as a ­stippled
calcification of the epiphyses. There are several forms but only the type
2 variant presents with severe ichthyosiform erythroderma. Later the
­erythema clears and a whorled scaling following the lines of Blaschko ­persists
(Fig. 3.52).1,2
Associated symptoms are scarring alopecia, follicular atrophoderma,
localized hypo-and/or hyperpigmentation, sectorial cataracts, and skeletal
­dysplasia, which leads to asymmetric shortening of the long bones or severe
kyphoscoliosis. Due to the individual differences in X-inactivation, ­expression
of the disease is rather variable even within families.1,2

Pathogenesis and histological features Fig. 3.53

Biochemical analyses using gas chromatography-mass spectrometry show Conradi-Hönermann-Happle syndrome: there is hyperkeratosis and acanthosis.
elevated plasma levels of 8-dehydrocholesterol and 8(9)-cholesterol, result-
ing from a block of a key enzyme in sterol metabolism, namely the 8–7 ste-
rol isomerase. This enzyme is encoded by the emopamil-binding protein
gene, which shows heterozygous mutations in Conradi-Hünermann-Happle
syndrome.3
The histologic features resemble those of ichthyosis vulgaris (Fig. 3.53).
There is hyperplasia of the epidermis, orthohyperkeratosis, a reduced stra-
tum granulosum, and dilated hair infundibula with follicular plugs. As a
pathognomonic finding in newborns, von-Kossa staining demonstrates cal-
cium deposits in the corneocytes which allows for discrimination of other
ichthyoses that share the feature of a reduced stratum granulosum (Fig. 3.54)
(see Table 3.3). At a later age the calcification is difficult to detect histologi-
cally but electron microscopy may reveal cytoplasmic vacuoles and electron-
dense calcium crystals in the granular cell layer.4

Other congenital ichthyotic syndromes

A
Many syndromes can be associated with congenital ichthyosis. In ichthyosis
prematurity syndrome there is associated polyhydramnios and the premature
neonates may suffer from transient asphyxia. The infants have a thick cheesy

Fig. 3.52
Conradi-Hünermann-
Happle syndrome:
Scaly erythema follow
the whorled lines of
Blaschko. By coutesy of
H Traupe MD, Dept of
Dermatology, Munster,
Germany.
Fig. 3.54
Conradi-Hönermann-Happle syndrome: (A) the granular cell layer is absent. Note
the basophilic deposits within the thickened stratum corneum, (B) the basophilic
deposits represent calcium as seen in this von Kossa preparation.
membrane which desquamates and then the skin improves within some weeks.
The skin shows compact orthohyperkeratosis and acanthosis. At ultrastruc-
tural level, characteristic masses of lipid membranes in lentiform paranuclear
swellings of granular and horn cells can be demonstrated which has lead to
the designation ichthyosis congenita type 4.1 A novel locus for the ichthyosis
prematurity syndrome has been assigned to chromosome 9q33–34.2
66 Disorders of keratinization

Type II or infantile cerebral Gaucher syndrome presents as a collodion

baby. The diagnosis of this fetal metabolic disease can be made by measure-
ment of glucocerebrosidase activity in peripheral blood leukocytes or in
extracts of cultured skin fibroblasts.3
Dorfman-Chanarin syndrome is a triglyceride storage disease with
impaired long-chain fatty acid oxidation resulting in cataract, hepatospleno-
megaly, neurosensorial deafness, myopathy or developmental delay. At birth,
generalized white scaling and a variable degree of erythema are present. The
skin findings resemble congenital ichthyosiform erythroderma although the
stratum granulosum may be thinned. Intracellular lipid vacuoles can be pres-
ent in circulating neutrophils, as well as in a variety of other cells including
keratinocytes. Thus a skin biopsy fixed in alcohol may be useful. Lipid vac-
uoles may also be found in the obligate carrier parents. Refsum syndrome
patients also have epidermal lipid vacuoles, but in Dorfman-Chanarin syn-
drome patients, the phytanic acid levels are normal.4
Trichothiodystrophy represents a heterogeneous group of autosomal
recessive disorders that share brittle hair and an abnormally low hair shaft
sulfur content (decrease of cysteine). Trichoschisis and alternating light and A
dark banding by polarizing microscopy are typical findings.5 At least two
subtypes of trichothiodystrophy are associated with congenital ichthyo-
sis: the acronym IBIDS (‘Tay syndrome’) refers to the clinical findings of
­ichthyosis (e.g., collodion membrane), brittle hair, intellectual impairment,
decreased fertility, and short stature. Other features are microcephaly, dys-
plasia of nails, failure to thrive, ‘progeria’-like symptoms, cataracts, and
photosensitivity (» PIBIDS).6 Half of all trichothiodystrophy patients show
an abnormal nucleotide excision repair of UV-damaged DNA.7 Histology of
the ichthyotic skin shows acanthosis with orthohyperkeratosis and a reduced
stratum granulosum.

Follicular ichthyosis
Clinical features
Follicular ichthyosis (ichthyosis follicularis) is a poorly documented ­condition
in which patients present with horny, follicular lesions which, although
­usually generalized, show a predilection for the head and neck (Fig. 3.55).1,2 B
In the report by Hazell and Marks, associated clinical findings included
pseudoacanthosis nigricans affecting the axillae, comedones on the cheeks Fig. 3.55
and ­fingers, and dental malocclusion.2 Literature subsequent to these two Follicular ichthyosis: (A) there are bilateral follicular lesions; (B) the follicles are plugged
papers has focused on the association of ichthyosis follicularis with alopecia with thornlike scale. By courtesy of the Institute of Dermatology, London, UK.
and photophobia (see below).3

Pathogenesis and histological features Pathogenesis and histological features

Follicular ichthyosis (ichthyosis follicularis) is an umbrella term or histologic
pattern that is present in many conditions and is defined by follicular ortho-
hyperkeratosis with or without hypergranulosis in the infundibulum.
For differential diagnosis see Table 3.3.
Ichthyosis follicularis with alopecia and
photophobia
Clinical features
Ichthyosis follicularis with alopecia (atrichia) and photophobia (IFAP syn-
drome) is an exceedingly rare disorder characterized by the presence of
non-inflammatory thorn-like (filiform) follicular hyperkeratosis that often
improves during the first year of life (Fig. 3.56). Other features are ichthyosi-
form dry skin, generalized complete nonscarring alopecia (with absence of
eyelashes and eyebrows), and severe photophobia.1–6 Ocular findings may
include corneal deformity and opacity with surface vascularization.6 Angular
cheilitis, keratotic psoriasiform plaques on the extensor surfaces of the
extremities, and nail dystrophy with chronic infection may also be present.2,6
Additional findings including hypohidrosis, recurrent respiratory infections,
skeletal abnormalities, cryptorchidism or progressive deteriorating neuro-
logic symptoms such as generalized seizures and cerebellar symptoms have
been reported.5
The mode of inheritance and pathogenesis of this disorder is unknown
although autosomal dominant and X-linked recessive forms have been
described. The complete IFAP phenotype seems to be only observed in male
patients. It is therefore thought to be of X-linked recessive inheritance. Female
carriers may present with linear ‘lesions of Blaschko’ showing circumscribed
hairless, anhidrotic or ichthyotic areas of skin 2,5,6
The follicular lesions are characterized by projecting hyperkeratotic plugs
showing focal parakeratosis and associated hypergranulosis.7 Hair follicles
are atrophic and lack hair shafts and sebaceous glands (Figs 3.57, 3.58).1
Sweat glands are normal but hyperkeratosis of the acrosyringia may occlude
the openings of sweat ducts.5
The psoriasiform plaques show hyperkeratosis with parakeratosis, acan-
thosis, spongiosis, and a bandlike upper dermal lymphohistiocytic infiltrate.7
Differential diagnosis
Other forms of atrichia and follicular keratosis should be considered (see
Table 3.3).
Lichen spinulosus
Clinical features
Lichen spinulosus is a rare dermatosis of unknown etiology which par-
ticularly affects the extensor surfaces of the arms and legs, back, chest,

B infundibula and a perivascular and perifollicular lymphohistiocytic infiltrate.1
Fig. 3.56
Ichthyosis follicularis with alopecia and photophobia: (A) the skin is dry and
ichthyosiform, (B) on the scalp a non-scarring alopecia with follicular hyperkeratosis
is characteristic. By courtesy of H Traupe MD, Dept of Dermatology, Munster,
Germany.
Fig. 3.57
Ichthyosis follicularis with alopecia and photophobia: there is marked follicular
atrophy. Note the small arrector pili muscles.
Other congenital ichthyotic syndromes 67
Fig. 3.58
Ichthyosis follicularis with alopecia and photophobia: there is hyperkeratosis
centered on an acrosyringium.
buttocks, face, and neck.1 Occasionally, lesions are generalized. Lesions pres-
ent in the second and third decades as round to oval, 2–6-cm flesh-colored
and sometimes pruritic, symmetric plaques composed of multiple 1–3-mm
thorny, grouped follicular papules which protrude above the surface of the
skin.1–3 The texture has been likened to a nutmeg grater. Males are affected
more often than females. There is no racial predilection.2 Other than a cos-
metic nuisance, the condition is of no clinical significance. Lichen spinulosus
has been described in association with Crohn's disease, human immunodefi-
ciency virus (HIV) infection, and as an adverse drug reaction.4–7
Histological features
Lichen spinulosus is characterized by keratotic plugging of dilated follicular
Sebaceous glands may be atrophic or absent. Perforating folliculitis-like fea-
tures can be superimposed.
Differential diagnosis
There is considerable histological overlap with keratosis pilaris and the follic-
ular lesions of pityriasis rubra pilaris. The distinction is best made clinically.
Phrynoderma
Clinical features
Phrynoderma (toad skin) most often develops as a consequence of vitamin A
deficiency.1–4 Other proposed etiological factors include deficiencies of the vita-
min B complex, riboflavin, vitamin C, vitamin E, and essential fatty acids.4 In
Western countries most cases develop as a result of malabsorption.4,5 Patients
present with xerosis, hyperpigmentation and multiple 2–6-mm, red-brown,
dome-shaped papules with a central folliculocentric crater filled with lami-
nated keratinous debris.1,4 The elbows and knees are predominantly affected
but lesions may extend to involve the thighs, upper arms and buttocks.1
Histological features
The papules consist of a cystically dilated follicular infundibulum filled with
keratinous debris.4
Keratosis pilaris
Clinical features
This fairly common condition, which has an autosomal dominant mode of
inheritance, is probably a follicular variant of ichthyosis and, indeed, fre-
quently accompanies ichthyosis vulgaris.1–3 The age at presentation is most
68 Disorders of keratinization

A
A

Fig. 3.59
Keratosis pilaris:
(A) typical follicular
papules and pustules on
the thigh; (B) note the
conspicuous plugged
follicles. (A) By courtesy
Fig. 3.60
of R.A. Marsden, MD,
Keratosis pilaris: (A) there
St George's Hospital,
is follicular dilatation and
London, UK, (B) By
plugging; (B) note the
B courtesy of the Institute of
B atrophy of the infundibular
Dermatology, London, UK.
epithelium.

often in the first two decades with a peak during adolescence.2 Up to 40%
of adults may be affected.2 There is no racial predilection. There is an appar-
ent increased incidence in females and lesions present as pruritic small fol-
licular keratoses, sometimes containing small distorted hairs. They are most
often found on the lateral aspects of the arms and thighs, although the face,
trunk, and buttocks may also be affected (Fig. 3.59).2 Seasonal variation,
with lesions being much more severe in winter, is often documented.2 There is
an increased incidence of atopy.2
Although keratosis pilaris most often presents as an isolated phenom-
enon, occasionally it may develop in association with systemic disease
including Hodgkin's lymphoma, vitamins B12 and C deficiency, hypo-
thyroidism, Cushing's disease, and treatment with adrenocorticotropic
hormone.3,4,5
Histological features
Keratosis pilaris is characterized by follicular dilatation and keratin plugs,
which may contain a single or several distorted hair shafts (Fig. 3.60).4 A
mild, non-specific chronic inflammatory cell infiltrate surrounds the dermal
blood vessels and sometimes involves the hair follicles themselves.
Keratosis pilaris atrophicans
Clinical features
Keratosis pilaris atrophicans combines the features of follicular hyper-
keratosis and scarring.1 Although some authors believe this to represent a
­single ­disease entity, others prefer to subdivideit into a number of categories
­including ulerythema ophryogenes, atrophoderma vermiculata, and keratosis
­follicularis spinulosa decalvans.2 Evidence of different modes of inheritance,
clinical differences, and variable associations supports the latter.2
Ulerythema ophryogenes (keratosis pilaris atrophicans facei, KPAF) pres-
ents at birth or in early infancy with follicular papules and surrounding ery-
thema followed by atrophic scarring affecting the lateral aspect of the eyebrows
(Fig. 3.61).3–5 The cheeks, forehead, temples, and neck may also be involved
(Fig. 3.62). Later on, the entire eyebrow may be lost. Keratosis pilaris affect-
ing the extensor aspects of the arms and thighs is also sometimes present.3 The
condition is believed to be inherited as an autosomal dominant.
It may be associated with a number of other inherited disorders including
Noonan's syndrome, woolly hair, cardiofaciocutaneous syndrome, Cornelia de
Lange syndrome, Rubinstein-Taybi syndrome, and partial monosomy 18.3,6–12

Fig. 3.61
Ulerythema ophryogenes: there is intense erythema with loss of follicles. The
eyebrow is a commonly affected site. By courtesy of the Institute of Dermatology,
London, UK.
Fig. 3.62
Ulerythema ophryogenes:
the cheek is also
frequently involved. By
courtesy of the Institute
of Dermatology, London,
UK.
The association with Noonan's syndrome is of particular importance since
such patients suffer from potentially life-threatening congenital pulmonary
stenosis. Ulerythema ophryogenes is also associated with atopy.13
Atrophoderma vermiculata (ulerythema acneiforme, atrophoderma ver-
miculatum, atrophoderma reticulata, acne vermoulante, folliculitis ulery-
thema reticulata, folliculitis ulerythematosa, honeycomb atrophy) is an
exceedingly rare form of atrophic keratosis pilaris thought to be inherited as
an autosomal dominant. Patients present with follicular keratoses and pit-
ted depressions separated by normal skin (worm-eaten appearance) affect-
ing the cheeks, ears, and forehead (honeycomb atrophy).2,14–17 The disorder
presents in patients after 5 years of age.2 Unilateral nevoid variants following
Blaschko's lines have been documented.15–17
Keratosis follicularis spinulosa decalvans is characterized by diffuse
atrophic keratosis pilaris associated with scarring alopecia affecting the
scalp.18–20 Other conditions sometimes present include atopy, palmoplantar
Acquired ichthyosis-like conditions 69
Fig. 3.63
Keratosis pilaris atrophicans: (A) low-power view showing gross follicular
hyperkeratosis and dilatation of the ostium; (B) high-power view. Note the
perifollicular fibrosis.
hyperkeratosis, photophobia, and punctate keratitis.18 In some patients it
is inherited as an X-linked recessive disorder which has been mapped to
Xp21.13-p22.2.21,22 X-linked dominant and autosomal dominant variants
have also been proposed.19
Pathogenesis and histological features
The pathogenesis of keratosis pilaris atrophicans is unknown although it
involves blockage of the follicular ostium by a keratinous plug.
All variants of keratosis pilaris atrophicans are characterized by follicular
hyperkeratosis with ostial dilatation, atrophy of the sebaceous gland, and a
scanty perifollicular or perivascular lymphohistiocytic infiltrate. Comedones
and milia may be found. There is a variable perifollicular fibrosis that extends
into the reticular dermis (Fig. 3.63).3,11,12,16
Acquired ichthyosis-like conditions
Acquired ichthyosis-like or ichthyosiform conditions refer to patients who
develop diffuse ichthyosis-like scaling during their life (Table 3.5). The adult
onset renders the term acquired ichthyosis inappropriate. It is an important
paraneoplastic manifestation of a number of malignancies: Hodgkin's lym-
phoma is most often encountered, but non-Hodgkin's lymphoma including
mycosis fungoides and a range of carcinomas have all been associated.1–8
Ichthyosiform skin changes may also accompany malnutrition, HIV and
other infectious diseases, sarcoidosis, collagenoses, celiac disease and other
70 Disorders of keratinization

Table 3.5
Acquired ichthyosis-like conditions

Etiology Diseases
Dry skin None
Paraneoplastic Hodgkin and non-Hodgkin lymphoma
Kaposi sarcoma
Various carcinomas
Infections Leprosy
Tuberculosis
HIV/AIDS
Malnutrition Pellagra
Vitamin A deficiency
Drugs Lipid-lowering agents (statins)
Nicotinic acid
Allopurinol
Cimetidine
Lithium A
Retinoids
Gastrointestinal diseases Crohn's disease
Celiac disease
Gastrectomy
Endocrinopathies Hyperparathyroidism
Hypothyroidism
Miscellaneous Renal insufficiency
Sarcoidosis
Graft-versus-host disease
Dermatomyositis and systemic lupus
erythematosus
Down's syndrome

gastrointestinal diseases, renal insufficiency, hypothyroidism, and graft-

­versus-host disease.4,9–15 Ichthyosiform skin changes following administra-
tion of lipid-lowering agents and other various drugs or kava consumption
has been documented.13,14 Dry skin, especially in blacks, leads to the develop- B
ment of lamellar scales on the legs and trunk. The features of acquired ich-
thyosis-like skin conditions most often resemble those of ichthyosis vulgaris Fig. 3.64
both clinically and histologically (Figs 3.64–3.67). Acquired ichthyosis: (A) cutaneous manifestations most often resemble ichthyosis
Clinical differential diagnosis includes xerosis cutis which lacks thick vulgaris; (B) close-up view of the scale. By courtesy of the Institute of Dermatology,
scales, develops at later age, and can be easily treated by fatty emolients. London, UK.

Pityriasis rotunda
Clinical features
Also known as pityriasis circinata, this acquired disorder of keratinization
was originally described in the Japanese.1 It is also not uncommon in South
Africans (Bantu) and West Indian blacks,2,3 but has only rarely been reported in
Caucasians with the exception of a subpopulation of Italians in Sardinia.4–7 Fig. 3.65
Patients present with persistent, very sharply defined, circular or oval areas Acquired ichthyosis:
of hyper- or hypopigmentation associated with a fine scale (Fig. 3.68). Lesions, there is intense erythema
which are usually multiple and frequently numerous, are characteristically non- and scaling. This patient
inflammatory and asymptomatic. Often, they are confluent. They measure 0.5– also suffered from graft-
28 cm in diameter and are particularly located on the trunk and limbs. The sex versus-host disease.
incidence is equal. Lesions are sometimes associated with gradual remission By courtesy of B. Solky,
during the summer months and relapse in winter.6 The maximum incidence is MD, Department of
Dermatology, Brigham
in the third to fifth decades. There is often a family history of ichthyosis vul-
and Women's Hospital
garis.8 It may occasionally be associated with a familial incidence.8,9 and Harvard Medical
Pityriasis rotunda sometimes appears to be a cutaneous marker of severe inter- School, Boston, USA.
nal disease including tuberculosis,1 cancer (particularly hepatoma),10,11 leukemia,12 cir-
rhosis,6 ovarian and uterine disease,13 undernutrition, and favism.8 Pityriasis rotunda
might best be regarded as an acquired circumscribed variant of ichthyosis.12 Increased pigmentation of the basal keratinocytes may be evident. A mild
perivascular chronic inflammatory cell infiltrate is sometimes present in the
Histological features superficial dermis. A superficial fungal infection, for example tinea (pityr-
The histological features are subtle and comprise hyperkeratosis with a dimin- iasis) versicolor, should always be excluded by a PAS reaction or silver
ished or absent granular cell layer and loss of the epidermal ridge pattern. stain.14
 Erythrokeratodermas 71

Fig 3.66
Acquired ichthyosis: this patient developed ichthyosis in a background of mycosis Fig. 3.68
fungoides. Low-power view showing marked focally compact hyperkeratosis and Pityriasis rotunda: characteristic lesion showing circumscription, scaling, and
acanthosis. hyperpigmentation. By courtesy of R.A. Marsden, MD, St George's Hospital,
London, UK.

transmembrane proteins that form gap junctions and are involved in epider-
mal differentiation.The KID/HID syndrome and Vohwinkel's syndrome are
associated with sensorineural hearing loss. In others, the genetic defect has
yet to be identified.2

Fig 3.67
Acquired ichthyosis: high-power view to emphasize the atypical lymphocyte population
and atypia. Note the well-developed retraction artifact so typical of this condition.
Erythrokeratodermas
‘Erythrokeratoderma’ or ‘erythrokeratodermia’ refers to a group of geno-
dermatoses characterized by localized erythematous lesions, hyperkeratotic
plaques, and, infrequently, a mild palmoplantar keratosis.1 Many of these
diseases represent connexin mutations (Table 3.6). Connexin genes code for
Table 3.6
Diseases with connexin mutations
Erythrokeratoderma variabilis
Clinical features
This rare ichthyosiform dermatosis generally has an autosomal dominant
mode of inheritance although an autosomal recessive variant has recently
been described.1–5 Lesions usually present soon after birth or during the first
year of life and are of two types, typically present simultaneously:
• Type 1 lesions are symmetrically distributed, discrete figurate, and
often bizarre patches of erythema, which vary in size, shape, number,
and location over periods of hours and days (Fig. 3.69).3 These are
sometimes temperature or stress related.1,6
• Type 2 lesions are well-defined, fixed geographical, reddish-yellow-
brown greasy, hyperkeratotic plaques arising either within the
erythematous lesions or, more often, independently (Fig. 3.70). Lesions
are usually asymptomatic although occasionally mild pruritus or burning
sensations are a feature.4
The condition particularly affects the face, buttocks, and extensor surfaces
of the extremities.7 While cold weather in winter and emotional ­problems
may sometimes exacerbate the condition, the symptoms often improve in the
summer months.4 Erythrokeratoderma variabilis is occasionally ­associated
with high estrogen levels and symptoms may worsen with estrogen-contain-
ing oral contraceptive therapy.1,2,4 Hypertrichosis (of vellus hairs) and mild

Disease Inheritance Locus Gene Protein

Erythrokeratoderma variabilis AD or AR 1q35.1 GJB3 Connexin 31
AD 1q35.1 GJB4 Connexin 30.3
Erythrokeratoderma variabilis with AD 1q35.1 GJB4 Connexin 30.3
erythema gyratum repens-like lesions
Keratitis-ichthyosis-deafness syndrome/Hystrix-like- AD 13q11-12 GJB2 Connexin 26
ichthyosis deafness syndrome (KID/HID Syndrome)
Oculodentodigital dysplasia AD 6q22-24 GJA1 Connexin 43
Vohwinkel keratoderma AD 13q11-12 GJB2 Connexin 26
Hidrotic ectodermal dysplasia of Clouston AD 13q11-12 GJB6 Connexin 30
72 Disorders of keratinization
Fig. 3.69
Erythrokeratoderma variabilis: annular and serpiginous erythematous lesions
showing scaling and the characteristic trailing edge. By courtesy of R.A. Marsden,
MD, St George's Hospital, London, UK.
Fig. 3.70
Erythrokeratoderma
variabilis: in these lesions
there is more pronounced
scaling.
­ eratoderma of the palms and soles may additionally be evident.3,6 The
k with pyknotic nuclei reminiscent of the grains of Darier have been described
mucous membranes, hair, teeth, and nails are unaffected and there are no
associated systemic manifestations.4
Pathogenesis and histological features
Connexin genes code for proteins that form intercellular channels called gap
junctions that allow for transport and signaling between neighboring cells
in the epidermis. In the skin, Cx31 and Cx30.3 are expressed in the stra-
tum granulosum of the epidermis with a suggested role in late keratinocyte
differentiation.8
Initially linked to the RH1 locus on 1p, erythrokeratoderma variabilis
has been mapped to 1p34-p35, which includes the connexion genes GJB3
and GJB4.7,8 However, erythrokeratoderma variabilis appears to be hetero-
geneous since not all individuals that have been clinically diagnosed with
Fig. 3.71
Erythrokeratoderma variabilis: (A) low-power view showing hyperkeratosis,
acanthosis with an undulating skin surface and a very light superficial perivascular
chronic inflammatory cell infiltrate; (B) high-power view showing marked
parakeratosis overlying a thickened orthokeratotic stratum corneum. Note the
presence of a granular cell layer.
erythrokeratoderma variabilis harbor Cx31 or Cx30.3 mutations.8–11 A subset
of patients with connexin 30.3 mutations manifest with a unique clinical
feature, namely transient erythematous patches with a peculiar, circinate or
gyrate border reminiscent of erythema gyratum repens, i.e., erythrokerato-
derma with erythema gyratum repens-like lesions.12
The histopathological features of this disease are not specific, consisting of
orthohyperkeratosis, variable parakeratosis, irregular acanthosis, and papil-
lomatosis with an undulating skin surface (Fig. 3.71).3,13 Dyskeratotic cells
in one case.6 The granular cell layer appears normal. A perivascular lympho-
histiocytic inflammatory cell infiltrate may be present in the superficial der-
mis. Pilosebaceous follicles and sweat glands are normal.13
Connexin immunohistochemistry discloses an irregular distribution of the
epidermal gap junction proteins.14
Ultrastructural observation have shown an increased number of gap junc-
tions, some of which display four layers, suggesting a loosened connection of
the keratinocyte plasma membrane through the gap junctions.15 Other studies
have revealed markedly diminished numbers of Odland bodies in the granu-
lar cell layer.6,14 Conspicuous nonmyelinated nerve fibers and Schwann cells
have been described in the papillary dermis.6,14 These, however, are not con-
sistent findings.16 Nuclear encirclement by condensed keratin filaments and
keratohyalin has also been recorded.16

Differential diagnosis
Progressive symmetrical erythrokeratoderma is characterized by symmetrical
distribution and a more fixed or very slow progression of erythema and scaly
plaques. Since mutations in the the loricrin gene have been identified (loricrin ker-
atoderma), this condition should no longer be grouped as a connexin disorder.
Progressive symmetric erythrokeratodermia
Clinical features
Also known as erythrokeratodermia progressiva symmetrica or Gottron's
syndrome, this condition is inherited as an autosomal dominant with incom-
plete penetrance, although sporadic cases may also be encountered.1,2 It usu-
ally presents in the first year of life with fixed, symmetrical, and sometimes
pruritic, erythematous scaly plaques on the extensor surfaces including
the elbows, knees, buttocks, dorsal surfaces of the feet and hands, and head
(Fig. 3.72).1–5 The face, chest, and abdomen are typically unaffected.2 The
plaques gradually extend during the first few years and then become static.3
Additional features include palmoplantar keratoderma and pseudoainhum
(constriction bands on the fingers and toes). The sex incidence is equal.2 There
is clinical overlap with erythrokeratoderma variabilis and indeed patients
may present with features of both diseases. However, progressive symmetric
erythrokeratoderma lacks transient migratory erythema.1
Pathogenesis and histological features
A mutation in the loricrin gene on chromosome 1q21 has been identified in
one family with progressive symmetric erythrokeratoderma.6 Similar muta-
tions have been reported in the ichthyotic variant of Vohwinkels's syndrome.
As a result, more definitive genotype-phenotype correlation within the con-
nexin gene disorders or other causative genes will have to be established to
define symmetrical progressive erythrokeratoderma as a separate entity.
Histologically, there is marked basket-weave hyperkeratosis with focal
parakeratosis, hypergranulosis, and psoriasiform hyperplasia.2,3 Paranuclear
vacuolation may be evident in the granular cell layer.3,7 A perivascular lym-
phocytic infiltrate is present in the superficial dermis.5
Ultrastructurally, characteristic loricrin-rich intranuclear granules are seen
in the granular cell layer.6 Lamellar granules are increased in number and lipid
droplets may be evident in the cornified cells.3 Immunohistochemically, the
cornified cell envelopes show greatly reduced staining for loricrin.6 Swollen
Fig. 3.72
Progressive symmetric
erythrokeratodermia:
Erythematous scaly
plaques gradually appear
on the extensor surfaces
on the extremities and
then persist.
Erythrokeratodermas 73
mitochondria in the granular cell layer are said to be a helpful ultrastructural
diagnostic pointer.3–5,7
Differential diagnosis
Progressive symmetric erythrokeratodermia can be distinguished from pso-
riasis by the absence of suprapapillary plate thinning, neutrophil infiltration,
and Munro microabscesses.2 In addition, the parakeratosis tends to be very
focal and hypergranulosis is usually present.
Keratitis-ichthyosis-deafness syndrome
Clinical features
Keratitis-ichthyosis-deafness syndrome (KID syndrome, palmoplantar ectoder-
mal dysplasia type XVI) is a very rare genodermatosis. Spontaneous mutations,
autosomal dominant, and autosomal recessive modes of inheritance have all
been documented.1–4 There is an equal sex incidence.5 It may present at birth
as a ‘vernix-like’ covering, which soon progresses to a dry, scaling erythema,
particularly affecting the face (especially the cheeks) and extremities, including
the palms and soles.1,3,4,6,7 The skin may be thickened and leathery.7,8 Later the
lesions become verrucous and hyperkeratotic, brownish-yellow, sharply circum-
scribed plaques (Fig. 3.73).1 Circumoral furrows may lead to a progeria-like
appearance.9 Follicular keratoses sometimes develop on the head and extremi-
ties and a ‘prickly’ spiculated appearance on the backs of the hands is occasion-
ally evident.3,4,8 Palmar and plantar involvement with accentuation of the skin
markings has been likened to heavily grained leather.10 There does, however,
appear to be some variation in presentation.1 Some patients have therefore been
described as being normal at birth, developing dry, scaly skin in later childhood,
while others have been reported as ‘red and wizened at birth’.11,12
Inflammation of the cornea with photophobia is usual and a vascularizing
keratitis leads to severe visual impairment.8 The end result is destruction of
the cornea by a pannus of vascular or fibrous tissue (keratoconus).1
Deafness is of the congenital neurosensory type, but is occasionally due to
recurrent otitis media; conduction defects may also be present.1,7,8 It is often
total and frequently present at birth although not usually recognized until
sometime later in early childhood.8
Ectodermal dysplasia is variably present and features include alope-
cia (either partial or complete, including eyebrows and eyelashes), small
Fig. 3.73
KID syndrome: there is
marked scaling of the
scalp with alopecia. Note
the facial erythema and
dark plaques on the
cheeks. By courtesy
of R.J.G. Rycroft, MD,
St John's Dermatology
Centre, London, UK.
74 Disorders of keratinization

malformed teeth with increased caries, scrotal tongue, leukokeratosis, and a

variety of dystrophic nail changes including fragility, hyperkeratosis, dyspla-
sia, leukonychia, and aplasia.1,4,8
Additional features that may be detected include increased susceptibility to
superficial and systemic chronic infections (bacterial and fungal), neuromus-
cular disease, retraction of the Achilles tendon, hypohidrosis, heat intolerance,
and growth deficiency.1,3,8,13–15 The reason for the increased risk of cutaneous
infection is unknown. While an abnormality of immunity has been proposed,
it is felt more likely that colonization of greatly increased and degenerate
keratin is the more important etiological factor.16 No consistent abnormal-
ity of immune function has so far been reported.3,11,14 Mental retardation is a
rare feature, which may be seen in patients with the autosomal recessive vari-
ant.1 Liver disease including cirrhosis has been present in autosomal recessive
patients.1,2 Squamous carcinoma of the tongue and skin (sometimes multiple)
are important complications (Fig. 3.74).3,13,17–19

Pathogenesis and histological features

KID syndrome, at least in some families, has been shown to be associated Fig. 3.75
with mutations in the connexin 26 gene.20,21 KID syndrome: scanning
The histological appearances of the skin lesions are non-specific and view showing basket-
include basket-weave hyperkeratosis with occasional foci of parakerato- weave hyperkeratosis. In
sis, acanthosis, and papillomatosis (Figs 3.75, 3.76).8 Some authors have this example the eccrine
observed prominence and vacuolization of the stratum granulosum.22,23 sweat glands are normal.
Follicular plugging is commonly present and occasionally the orifices of the
eccrine ducts are similarly affected.5,11 A superficial perivascular lymphohistiocytic
infiltrate is sometimes evident.8 Eccrine sweat glands may be diminished in num-
ber and atrophic, with thickened, hyalinized basement membranes and absent or
atrophic hair follicles are seen in the areas of alopecia.3,8,22 Electron microscopic
studies of the epidermis have revealed no significant abnormalities.7,15
A recently reported autopsied case has described both ocular and aural
changes:16
• Ocular changes were limited to the cornea and conjunctiva. Dyskeratosis
and atrophy of the corneal surface epithelium accompanied by
neovascularization and mild chronic inflammation of the substantia
propria were evident. The bulbar conjunctiva showed epithelial
atrophy, dyskeratosis, and mild chronic inflammation. Late changes are
characterized by the development of an inflammatory and vascular pannus.8
• Aural changes related not only to epithelial maturation abnormalities
of the external auditory meatus and tympanic membrane, but also to
cochleal maldevelopment.16 The essential features of the former included

Fig. 3.76
KID syndrome: high-power view emphasizing the basket-weave keratin overlying a
zone of compact keratin. There is focal parakeratosis. There is vacuolization of the
granular cell layer.

parakeratosis of the squamous epithelium overlying the tympanic

membrane. Immaturity and parakeratosis of the ridge pattern of the
epithelium covering the bony aspect of the external auditory meatus may
also be present. Changes of the internal ear included maldevelopment of
the cochlea and absence of the tectorial membrane and organ of Corti,
accompanied by reduction in the number of nerve fibers and spiral
ganglion nerve cells.16 These features are very much in keeping with
sensorineural deafness of cochleal origin.
The liver changes include micronodular cirrhosis, cholestasis, Kupffer cell
hyperplasia, abundant Mallory's hyaline and marked copper storage.1

Hystrix-like ichthyosis with deafness

Fig. 3.74
KID syndrome: squamous
carcinoma on the knee.
Tumors may be multiple.
By courtesy of M. Judge,
MD, Institute of
Dermatology, London,
UK.
Clinical features
Hystrix-like ichthyosis-deafnesss (HID) syndrome (ichthyosis hystrix type
Rheydt) presents with spiky and cobblestone-like hyperkeratosis.1,2 There
are many similarities with keratitis-ichthyosis-deafness syndrome. However,
HID patients show multiple red patches shortly after birth, which develop
into ichthyotic erythroderma. In contrast to the KID syndrome, patients with
 Palmoplantar keratoderma 75

HID show a more widespread involvement of the trunk but less palmoplan-
tar hyperkeratosis. Keratitis of the eyes is less prominent in HID patients, but
they also suffer from neurosensorial deafness, proneness to mycotic/bacterial
skin infections, and skin cancer.2
Pathogenesis and histological features
Both HID and KID syndromes are associated with an identical connexin
26 missense mutation.3 Therefore they may represent a spectrum of pheno-
typic variability instead of separate entities.3
Histologically, there is orthohyperkeratosis with foci of parakeratosis,
acanthosis, and the nuclei are surrounded by empty spaces reminiscent of
a bird's eye. At the ultrastructural level, keratinocytes show reduction of
tonofibrils and abnormal membrane-bound granules containing mucous sub-
stances that are discharged into the intercellular spaces.4 The absence of these
features in KID syndrome may result from sampling errors, with some skin
areas being more severely affected than others.3
Palmoplantar keratoderma
The palmoplantar keratodermas (PPKs) consist of a large heterogeneous
group of localized cornification disorders characterized by hyperkeratosis
of the palms and soles. Ichthyotic skin disorders and erythrokeratoderma
may also show palmoplantar hyperkeratosis but mainly affect other body
areas. PKKs are classified on the basis of mode of inheritance, distribution of
lesions, additional clinical features, and associated abnormalities.1–5 Many of
these genodermatoses have a late onset. At least 30 subtypes are recognized
and subdivided into two broad subtypes, one in which lesions are restricted
to the skin (Table 3.7) and the other in which there is a much broader spec-
trum of ectodermal defects affecting skin, mucosae, nails, hair, teeth and neu-
rological abnormalities (Table 3.8).4,5 Where more than a single ectodermal
structure is involved Stevens et al. coined the term ‘palmoplantar ectodermal
dysplasia’ to emphasize the generalized nature of the disorder and identified
a total of 19 subtypes.6

Table 3.7
Isolated palmoplantar keratodermas (PPK)
Palmoplantar keratoderma Inh. Locus Protein Disease
Diffuse AD 17q12-q21 Keratin 9 Epidermolytic palmoplantar keratoderma (Vörner-Unna-Thost)
12q11-13 Keratin 1 Epidermolytic PPK Vörner-Unna-Thost, Epidermolytic hyperkeratosis
with polycyclic psoriasiform plaques
12q11-13 Keratin1 Progressive palmoplantar keratoderma (Greither) and other
nonepidermolytic palmoplantar keratoderma
8p22-23 unknown Keratolytic winter erythema
AR 8qter SLURP1 Mal de Meleda
12q11-13 unknown Gamborg-Nielson palmoplantar keratoderma
Circumscribed AD 18q12.1-12.2 Desmoglein1 Keratosis palmoplantaris areata et striata (type 1–3)
6q24 Desmoplakin
12q Keratin1
unknown unknown Keratosis palmoplantaris nummularis (hereditary painful callosities)
Punctate AD 8q24 unknown Punctate palmoplantar keratoderma (Buschke-Fischer-Brauer)
unknown unknown Marginal papular acrokeratoderma

Table 3.8
Palmoplantar keratodermas (PPK) with associated symptoms

Palmoplantar
keratoderma Disease Inh Locus Protein Symptoms
Diffuse Huriez syndrome AD 4q23 ? Sclerodactyly, nail dystrophy, squamous cell
carcinomas in atrophic areas
Vohwinkel syndrome 13q11-12 Connexin 26 Mutilating keratoderma, sensorineural deafness
Loricrin keratoderma 1q21 Loricrin Associated ichthyosis
Clouston syndrome 13q12 Connexin 30 Diffuse palmoplantar keratoderma, alopecia, nail
dystrophies
Olmsted [1927] syndrome ? ? ? Diffuse mutilating palmoplantar, periorificial
keratoses, ectodermal dysplasia
Papillon-Lefèvre AR 11q14 Cathepsin C Diffuse palmoplantar keratosis with severe
syndrome periodontitis
Naxos syndrome 17q21 Plakoglobin Wooly hair, cardiomegaly, tachycardia
McGrath syndrome 1q32 Plakophilin 1 Painful diffuse palmoplantar keratosis, Skin
fragility, dystrophic nails, sparse hairs
Circumscribed Pachyonychia congenita 1 AD 12q13 Keratin 6A Thickened nails, focal palmoplantar keratoderma,
Jadassohn-Lewandowsky 17q12-q21 Keratin 16 folliculare hyperkeratosis, leukokeratosis
Pachyonychia congenita 2 12q13 Keratin 6B Thickened nails, focal palmoplantar keratoderma,
  Jackson-Lawler 17q12-q21 Keratin 17 cysts, natal teeth
Howel-Evans syndrome 17q24 ? Association with carcinoma of esophagus
Tyrosinemia II AR 16q22.1-q22.3 Tyrosine ­ Focal, often painful palmoplantar keratoderma
(Richner-Hanart amino-transferase
syndrome)
Carvajal-Huerta syndrome 6p24 Desmoplakin Epidermolytic PPK, wooly hair, arrhythmogenic
left cardiomyopathy
Punctate Schöpf-Schulz-Passarge ? ? ? PPK with lid cysts, hypodontia and hypotrichosis
syndrome
76 Disorders of keratinization

Table 3.9
Histologic patterns of PPK

Epidermolytic hyperkeratosis Epidermolytic palmoplantar

keratoderma (Vörner-Unna-Thost)
Keratosis palmoplantaris
nummularis
PKK with polycyclic psoriasiform
plaques
Carvajal-Huerta syndrome
Hyperkeratosis overlying depressed Keratosis palmoplantaris punctata
area of the epidermis
Paranuclear eosinophilic globular Pachyonychia congenital
inclusions Tyrosinemia type II
(Richner-Hanhart)
Orthohyperkeratosis and, Other forms of PKK
inconsistently,
focal parakeratosis, epidermal
hyperplasia, discrete perivascular
inflammation Fig. 3.77
Diffuse palmoplantar
keratoderma Vörner-
Unna-Thost: there is
There are three major clinical categories: diffuse, circumscribed, and punctu- hyperkeratosis affecting
ate (Tables 3.7 and 3.8).4,5 Histologically, there are four main histologic patterns the entire sole of the foot.
that are characterized by epidermolytic hyperkeratosis, orthohyperkeratosis By courtesy of W.A.D.
with hypergranulosis and acanthosis, hyperkeratosis ­overlaying depressed areas Griffiths, MD, Institute of
Dermatology, London, UK.
of the epidermis, and paranuclear eosinophilic inclusions (Table 3.9). In many
subtypes, the underlying molecular defect has been ­identified and can be related
to structural proteins (keratins), cornified envelope (loricrin, transglutaminase),
cohesion (plakophilin, desmoplakin, desmoglein1), cell-to-cell communication
(connexins), and transmembrane signal transduction (cathepsin C).7

Keratosis palmoplantaris diffusa

Vörner-Unna-Thost
Clinical features
Keratosis palmoplantaris diffusa Vörner-Unna-Thost is an epidermolytic pal-
moplantar keratoderma (PPK) and represents the most common form of pal-
moplantar keratoderma with an incidence of 1:100 000. Reinvestigation of
the original family with Unna-Thost PPK showed that epidermolytic forms
existed within the family as has been described by Vörner. Therfore, it is not
justified to separate Vörner disease from Unna-Thost disease.1
The condition is inherited as an autosomal dominant and usually presents
in the first months or else when the patients start running.1–6 Patients pres-
ent with symmetrical, well-demarcated yellowish, smooth and waxy plaques
covering the palms and soles, and, to some extend, the ventral surface of
fingers and toes (Figs 3.77, 3.78). The lesions reach the lateral aspects of
hands and feet but not beyond. The periphery is bordered by an erythematous
margin (Fig. 3.79).2 Painful blisters are not uncommon. Hyperhidrosis and
maceration may be present and facilitate dermatophytosis.3,6 Rarely, associ-
ated knuckle pads or clubbed digits have been documented.7 Identification
of the epidermolytic form of PPK has therapeutic consequences since lesions
become inflammatory and erosive with systemic retinoid therapy.
Pathogenesis and histological features
Epidermolytic palmoplantar keratoderma was initially mapped to17q12-q21, the
locus of the type I acidic keratin cluster where different point mutations of keratin
9 were identified.8 Epidermolytic palmoplantar keratoderma, however, has also
been reported to be associated with keratin 1 mutations that map to 12q11–13,
the site of the keratin II genes.9,10 Keratin 1 and 9 are the major structural keratins
in the suprabasal keratinocytes of palmoplantar epidermis. Mutations in keratin
9 are associated with more severe manifestations than mutations in keratin 1.
Most of the keratin mutations affect the central regions of the protein,
which are important for filament assembly and stability of the keratin skel-
eton. As a consequence, tonofilament clumping causes cellular degeneration
and disruption, e.g., epidermolytic palmoplantar keratoderma. Mutations in
Fig. 3.78
Diffuse palmoplantar keratoderma Vörner-Unna-Thost: in this patient the palms
of the hands were also affected. By courtesy of W.A.D. Griffiths, MD, Institute of
Dermatology, London, UK.
the rod domain are associated with only mild focal signs of epidermolytic
hyperkeratosis in the spinous layer of palmoplantar epidermis.11
Epidermolytic palmoplantar keratoderma is not associated with malig-
nancy. Patients in one large kindred showed a high incidence of breast and
ovarian cancer.10 It is now believed that this represented a coincidental co-
segregation of a keratin 9 mutation with a BRCA1 mutation on 17q21.2
Histologically, there is a massive orthohyperkeratosis, hypergranulosis,
papillomatosis, and acanthosis accompanied by features of epidermolytic
hyperkeratosis in the prickle and the granular cell layers with unstained,
vacuolated cytoplasm, intracytoplasmic eosinophilic granules, and coarse
keratohyalin granules (Figs 3.80, 3.81). A superficial dermal perivascular
lymphohistiocytic infiltrate may sometimes be present. Epidermal spongiosis
and vesiculation may indicate mycotic superinfection.
Electron microscopy shows aggregations of keratin filaments and keratin
clumps that accounts for the intracytoplasmic eosinophilic granules seen by
light microscopy. Large areas of the cytoplasm that are devoid of a keratin
 Palmoplantar keratoderma 77

Fig. 3.79 Fig. 3.81

Diffuse palmoplantar keratoderma Vörner-Unna-Thost: the border of the lesion is Diffuse palmoplantar keratoderma Vörner-Unna-Thost: high-power view
marked by a linear zone of erythema. By courtesy of W.A.D. Griffiths, MD, Institute demonstrating the features of epidermolytic hyperkeratosis.
of Dermatology, London.

Histological features
Histopathologic examination of the psoriasiform plaques demonstrates the
characteristic features of epidermolytic hyperkeratosis. Sequencing of the ker-
atin 1 gene in affected family members reveals a mutation within the highly
conserved helix termination motif of the helix 2B segment.1

Diffuse nonepidermolytic palmoplantar

keratoderma
Clinical features
Diffuse nonepidermolytic palmoplantar keratoderma is a heterogenous, ill-
defined group of conditions. It includes an autosomal recessive disorder with
a high incidence in Sweden and characterized by a thick, horny layer sharply
demarcated from the normal skin and knuckle pads on the dorsal aspect of
the finger joints.1 Symptoms usually present in the first 3 years of life.1 Many
patients suffer from increased sweating and, therefore, maceration is com-
Fig. 3.80 mon. There is a greatly increased risk of dermatophyte infections.1 Patients
Diffuse palmoplantar with this variant may also show axillary and groin involvement, subungual
keratoderma Vörner- hyperkeratosis, onychodystrophy, and central facial lesions.2 Another non-
Unna-Thost: scanning epidermolytic variant of diffuse PPK is Mal de Meleda (see below).
view showing massive Although diffuse palmoplantar keratoderma was originally believed
hyperkeratosis, to be associated with esophageal carcinoma (Howell-Evans syndrome),
papillomatosis, and
­re-examination of the affected kindreds disclosed that the keratoderma would
acanthosis.
better be classified as focal (see focal nonepidermolytic palmoplantar kera-
toderma with esophageal squamous carcinoma).3 There are, however, rare
instances of diffuse palmoplantar keratoderma associated with cutaneous
skeleton explain the vacuolar change. Keratohyalin granules cluster in a ran- squamous cell carcinoma, for example Huriez syndrome (palmoplantar kera-
dom fashion around the keratin aggragates. toderma with sclerodactyly) and Schöpf-Schulz-Passarge syndrome (palmo-
plantar keratoderma with squamous carcinoma arising in the areas affected
Epidermolytic hyperkeratosis with polycyclic by keratoderma).4,5
Acquired diffuse palmoplantar keratoderma may also be associated with
psoriasiform plaques malignancy.6

Clinical features Pathogenesis and histological features

Epidermolytic hyperkeratosis with polycyclic psoriasiform plaques is a
unique palmoplantar keratoderma with an autosomal dominant inheri-
tance.1 Clinically, affected individuals manifest transient blistering at birth
followed by chronic diffuse palmoplantar keratoderma. Intermittent flares
of fixed polycylic erythematous psoriasiform plaques which characteristi-
cally deteriorate and then improve are seen although there is marked indi-
vidual variation in both the severity and duration of lesions, ranging from
weeks to months.1
Diffuse nonepidermolytic palmoplantar keratoderma has been mapped to 12q11–
13, the site of the keratin II genes.7,8 The disease mutation described by Kimonis
and coworkers was the first to be identified in a keratin chain variable end region.9
The fact that epidermolysis was not present suggests that the amino-terminal
domain of keratins may be involved in supramolecular interactions of keratin fila-
ments rather than stability.9 There is, however, genetic heterogeneity.10
This disorder is characterized by marked hyperkeratosis, hypergranulosis,
acanthosis, and an exaggerated epidermal ridge pattern (Fig. 3.82). A chronic
78 Disorders of keratinization

Fig. 3.82
Diffuse nonepidermolytic
palmoplantar
keratoderma: there is
massive hyperkeratosis,
hypergranulosis, and
acanthosis.

inflammatory cell infiltrate is sometimes evident in the superficial dermis. The

presence of spongiosis and vesiculation should suggest a concomitant der-
matophyte infection and prompt evaluation of a PAS or silver stained section
(Figs 3.83, 3.84).11 In the diffuse recessive variant, the hyperkeratosis is even
more marked than in the dominant form and the epidermis shows prominent
psoriasiform hyperplasia.1

Progressive palmoplantar keratoderma B

Clinical features Fig. 3.83

Progressive palamoplantar keratoderma, (syn: Greither syndrome, keratosis Diffuse nonepidermolytic palmoplantar keratoderma: (A) in this example, there
palmoplantaris diffusa transgrediens et progrediens) is an autosomal dom- is massive hyperkeratosis with an undulating growth pattern. Intra-epidermal
inantly inherited disease. In childhood, a diffuse symmetric palmoplantar vesiculation is apparent, (B) high-power view.
keratoderma with small pits or fissures and hyperhidrosis develops that pro-
gressively extends to the back of the hands and feet, the region of the Achilles
tendon, ankles, knees or elbows where patchy hyperkeratosis develops. In the
middle of life amelioration occurs (Figs 3.85, 3.86).1

Pathogenesis and histological features

The previously reported cases of Greither's syndrome showed phenotypic
variability suggestive of different underlying gene defects. At least some cases
of Greither's syndrome are caused by keratin mutations.2
Histopathology shows acanthosis with focal orthohyperkeratosis located
on delled areas of the epidermis (Fig. 3.87). There are generally no features
of epidermolytic hyperkeratosis with the exception of a case where a keratin
mutation was detected.3

Keratolytic winter erythema

Clinical features
Keratolytic winter erythema (synonyms: erythrokeratolysis hiemalis,
Oudtshoorn disease) is an autosomal dominant disorder first described in
South Africa.1 Sporadic cases have been reported from other countries.2,3 The
disorder manifests at an early age and is characterized by recurring cycles of
erythema involving the palms and soles, followed by mild hyperkeratosis and
nonpruritic and nonpainful peeling. In severe cases the limbs and trunk are Fig. 3.84
affected with gyrate scaling erythemas. Most remarkably, the onset of symp- Diffuse nonepidermolytic palmoplantar keratoderma: fungal hyphae are apparent in
toms occurs during cold weather.2 the thickened stratum corneum (PAS stain).
 Palmoplantar keratoderma 79

Fig. 3.85
Progressive palmoplantar
keratoderma: (A) diffuse
hyperkeratosis with fissures
progressively extends to the
back of the hands and feet
A B and (B) affects the region of
the Achilles tendon.

Fig. 3.86 Fig. 3.87

Progressive palmoplantar Progressive palmoplantar keratoderma: massive hyperkeratosis with a central small
keratoderma: Patchy dell (arrowed).
hyperkeratosis develops
on the knees.

Pathogenesis and histological features
The disorder has been mapped to chromosome 8p22–23 with some genetic
heterogeneity, but a causative gene has not yet been identified.4,5
The epidermis is acanthotic with a thickened stratum granulosum.
At the advancing edge spongiosis and vesicle formation can be observed.
More centrally, the stratum granulosum becomes pale staining and
pyknotic. Concommitantly, parakeratotic layers form on top. In the
horny layer a cleft appears that contains remnants of parakeratotic cells.1
A superficial perivascular lymphocytic infiltrate has been reported by
some authors.3
Mal de Meleda
Clinical features
Mal de Meleda is inherited as an autosomal recessive with a high prevalence
in Meleda in the Adriatic Sea. The diffuse keratoderma progresses onto the
dorsal aspects of the fingers and toes (keratosis palmoplantaris transgre-
diens et progrediens Meleda). Further features are inflammatory borders,
severe hyperhidrosis, maceration, and unpleasant smell. In addition, con-
stricting bands (pseudoainhum), brachydactyly, nail dystrophy, lesions on
knees and elbows, the perioral region and even oral leukokeratosis can be
observed.1,2
80 Disorders of keratinization

Pathogenesis and histological features

Mutations have been identified in the ARS component B gene on chromo-
some 8, encoding a protein named SLURP1.3–6 It is postulated that SLURP1
interacts with neuronal acetylcholine receptors present in keratinocytes and
sweat glands. Since SLURP1 may act as a secreted epidermal neuromodula-
tor essential for both epidermal homeostasis and inhibition of TNF-alpha
release by macrophages during wound healing, this may explain both the
hyperproliferative as well as the inflammatory clinical phenotype of Mal de
Meleda.3–6
Histology shows orthohyperkeratosis with focal parakeratosis, acanthosis
without epidermolytic changes, and a superficial perivascular lymphocytic
infiltrate

Keratosis palmoplantaris areata et striata

Clinical features
Keratosis palmoplantaris areata et striata (striate palmoplantar keratoderma,
Brünauer-Fuchs-Siemens syndrome, acral keratoderma) is an autosomal dom-
Fig. 3.88
inant disorder characterized by linear bands of keratoderma affecting the pal-
Keratosis palmoplantaris areata et striata: linear hyperkeratotic bands are present
mar aspects of the palms and fingers (Fig. 3.88) accompanied by island-like best seen along the ulnar border of the palm. By courtesy of the Institute of
areas of hyperkeratosis on the soles of the feet.1,2 Lesions typically present Dermatology, London, UK.
in adolescence or early adulthood and are exacerbated by manual labor. A
background palmar hyperkeratosis may be present and fissuring can also be
seen.3 Abnormalities of the nails (ridging and cuticle hyperkeratosis), teeth,
described.6 The granular/filamentous material represents condensed kera-
and hair (wooly hair) may also sometimes be encountered.3,4 There are no
tin filaments. Premature expression of involucrin and filaggrin has been
systemic associations.
found.9 In one family, immunohistochemistry demonstrated diminished
lesional desmoplakin staining.6 Electron microscopy displays diminished
Pathogenesis and histological features
numbers of small and/or rudimentary desmosomes accompanied by keratin
Striate palmoplantar keratoderma is a heterogeneous condition. A transi- filament aggregates and enlarged malformed keratohyalin granules.6,8,9
tion mutation in desmoglein 1, mapped to chromosome 18q12.1, has been
identified in one family.5–7 In another, a transition mutation in desmoplakin,
mapped to chromosome 6p21, was identified, and in a third type, mutation
Keratosis palmoplantaris nummularis
of keratin 1 with partial loss of the glycine loops in the V3 domain has been
reported.3,8 Clinical features
Histologically, striate palmoplantar keratoderma is characterized by In keratosis palmoplantaris nummularis (hereditary painful callosities)
massive hyperkeratosis, hypergranulosis, and acanthosis (Fig. 3.89). patients present with nummular keratotic lesions overlaying plantar pres-
Dark-staining granular and filamentous material within the prickle cell sure points. Keratoses develop when children start to walk. Pain is the major
layer accompanied by slight separation of the keratinocytes has also been complaint.1

Fig. 3.89
Keratosis palmoplantaris areata et striata: (A) there
A B is massive hyperkeratosis with hypergranulosis and
acanthosis; (B) high-power view.
 Palmoplantar keratoderma 81

Pathogenesis and histological features

The gene defect has not been identified as yet.
Histology shows epidermolytic hyperkeratosis similar to epidermolytic
palmoplantar keratoderma of Vörner-Unna-Thost.1

Punctate palmoplantar keratoderma

Clinical features
Punctate palmoplantar keratoderma (keratosis punctata palmaris et plan-
taris, keratoderma hereditarium dissipatum palmare et plantare, Buschke-
Fischer-Brauer disease, Davis-Colley disease) is characterized by an autosomal
dominant mode of inheritance.1–4 There is an increased incidence in blacks.2
Sometimes, lesions are associated with excessive manual labor.2 In an estab-
lished case, the patient has numerous discrete yellow-brown, small (1–3 mm),
depressed keratotic lesions on the palms and soles and also on the ventral
aspects of the fingers and toes (Figs 3.90, 3.91).5 If the keratin plug is dis-
lodged, a deeply depressed pit remains. Lesions are usually asymptomatic,
but occasionally pain, tenderness or burning are features.2,5
Fig. 3.91
There are occasional reports of punctate palmoplantar keratoderma asso-
Punctate palmoplantar keratoderma: close-up of lesions shown in Figure 3.90.
ciated with internal malignancies including carcinomas of the colon, kidney,
By courtesy of the Institute of Dermatology, London, UK.
breast, and pancreas and Hodgkin's lymphoma.6,7
Punctate keratoderma-like lesions affecting the palms and the soles have
been described as a complication of dioxin exposure.8

Pathogenesis and histological features

The pathogenesis is unknown. A locus has been genetically mapped on chro-
mosome 15q22-q24. The keratin gene clusters have been excluded by linkage
analysis.9
Histologically marked hyperkeratosis is seen overlying areas of epithelial
depression (Fig. 3.92).

Keratosis punctata of the palmar creases

Clinical features
Keratosis punctata of the palmar creases (keratotic pits of the palmar creases)
is a variant of punctate keratoderma in which the lesions are confined to
the palmar and digital creases.1–5 The soles of the feet and heels may also be

Fig. 3.92
Punctate palmoplantar keratoderma: there is massive hyperkeratosis overlying a
dell to the right of center.

involved.3,6 The sexes are equally affected and the disease is predominantly
seen in young to middle-aged adults.7 Although very rare in white patients,
it is common in black adults.3,5,8,9 The development of lesions appears to be
trauma related in many patients since outdoor workers are particularly affected
and the condition improves during a vacation. Although in the majority of
patients the condition appears to be a sporadic occurrence, in some reports an
autosomal dominant mode of inheritance has been documented.2,4
Lesions are small (1–3 mm) depressed yellowish keratotic plugs which are
usually asymptomatic but sometimes may be painful. They are localized to the
flexor creases and when removed leave a cone-shaped depression (Fig. 3.93).
Although usually seen as an incidental finding, on occasions they have been asso-
ciated with ichthyosis vulgaris.4,7 There are also reports of keratosis punctata of
Fig. 3.90 the palmar creases developing in patients with Dupuytren's contracture, derma-
Punctate palmoplantar titis herpetiformis with psoriasis, striate keratoderma, and knuckle pads.7,10
keratoderma:
discrete yellow foci Histological features
of hyperkeratosis are
present over the weight- The lesions are characterized by a hyperkeratotic plug, sometimes with foci of
bearing surfaces. By parakeratosis below which are deep cone-shaped depressions sometimes cen-
courtesy of the Institute tered on the acrosyringium.4 The adjacent epidermis shows acanthosis with
of Dermatology, London, hypergranulosis and in some cases a perivascular lymphohistiocytic infiltrate
UK. is present in the superficial dermis.
82 Disorders of keratinization
Fig. 3.93
Keratosis punctata of the palmar creases: minute punctate lesions are localized
solely to the palmar creases. There is often a history of manual labor.
By courtesy of the Institute of Dermatology, London, UK.
Marginal papular acrokeratoderma
Clinical features
Marginal papular acrokeratoderma refers to a complex, confusing, and
overlapping group of disorders which includes acrokeratoelastoidosis
of Costa, focal acral hyperkeratosis, mosaic acral keratosis, degenerate
collagenous plaques of the hands, digital papular calcific elastosis, and
keratoelastoidosis marginalis of the hands.1 All present with frequently
crateriform, keratotic papules along the borders of the hands and feet
(Fig. 3.94).1 Although usually discrete, in some patients the papules may
coalesce into plaques.
Acrokeratoelastoidosis presents in childhood and adolescence with yel-
lowish, warty, and crateriform keratotic or pearly papules predominantly
affecting the sides of the hands, wrists, fingers, and feet.2–5 There is no racial
predilection and the sexes are affected equally. Patients may also develop cir-
cumscribed keratodermatous knuckle padlike lesions, palmoplantar hyperk-
eratosis, and hyperhidrosis (Fig. 3.95).1,3 Sporadic and autosomal dominant
variants have been described. The disorder may be linked to chromosome 2.6
Repeated trauma is believed to be of etiological importance.
Fig. 3.94
Marginal papular acrokeratoderma: there is a linear band of scaling along the border
of the foot. By courtesy of the Institute of Dermatology, London, UK.
Fig. 3.95
Acrokeratoelastoidosis: knuckle pads are conspicuous in this patient. By courtesy of
the Institute of Dermatology, London, UK.
Focal acral hyperkeratosis is clinically identical to acrokeratoelastoidosis,
patients presenting with keratotic papules along the sides of the hands, fingers, and
feet.7,8 It has also been designated acrokeratoelastoidosis without elastorrhexis.9
Other reported cases have been mistakenly documented as acrokeratoel­astoidosis.10
Females are affected more often than males. Although originally thought to be a
­disorder of black children, more recently it has been described in whites.11
Mosaic acral keratosis is similar if not identical to focal acral hyper­
keratosis, being characterized by keratotic papules distributed in a mosaic
or ­jigsaw-puzzle pattern along dorsal aspects of the feet and adjacent lower
legs.12 Hyperkeratosis may be seen on the palms and soles.1 Only females,
predominantly black, are affected.1
Degenerative collagenous plaques of the hands affect the sun-damaged
skin of the elderly and present as symmetrical yellowish, keratotic or smooth
papules and plaques affecting the thumb, first web, and side of the index
­finger.4,13–18 The ulnar border of the hand and volar aspect of the wrist may
also be involved. Keratoelastoidosis marginalis of the hands is a similar
­condition described in Australians in which keratotic papules develop at sites
of trauma along the index finger and thumb.19 The skin is typically grossly
sun damaged. Calcified variants of degenerative collagenous plaques are
known as digital papular calcific elastosis.20,21
Histological features
Acrokeratoelastoidosis is characterized by massive orthohyperkeratosis over-
lying a crateriform dell lined by acanthotic epidermis. Hypergranulosis may
be present. The dermis shows fragmentation and loss of the elastic tissue
(elastorrhexis) (Fig. 3.96). Collagen may be disorganized or appear homog-
enized and pale staining.2,3
Focal acral hyperkeratosis and mosaic acral keratosis are histologically
identical with the exception that the elastic tissue appears normal.7–12
Degenerative collagenous plaques of the hands are characterized by a
dense zone of thickened and distorted collagen with fragmentation of elastic
fibers and overlying hyperkeratosis and acanthosis.4,13–18 The papillary dermis
is spared. Calcification is sometimes a feature (digital papular calcific elasto-
sis).19–21 Telangiectatic vessels may also be seen and increased dermal mucin
has been described.19
Huriez syndrome
Clinical features
In Huriez syndrome (keratosis palmoplantaris diffuse with sclerodactyly, scle-
rothylosis) patients present with a diffuse mild palmoplantar keratoderma,
scleroatrophic skin of the limbs, hypohidrosis, hypoplasia, and dystrophy of
the nails (Fig. 3.97).1 Aggressive squamous cell carcinoma may develop in the

A B
A B
Fig. 3.97
Huriez syndrome: (A) the leading features are sklerodactyly, hypotrophic and dystrophic nails, (B) there is mid palmar keratosis.
affected skin in approximately 15% of the cases. It has an early onset with a
high risk of metastasis in the third to fourth decades.1
Pathogenesis and histologic features
The genetic cause of this autosomal dominant condition is still unknown.
Histology shows a mild acanthosis, orthohyperkeratosis and well developed
granular layer (Fig. 3.98). Most interestingly, immunohistochemical and ultra-
structural studies revealed an absence of Langerhans cells in involved skin.2
Vohwinkel's syndrome
Clinical features
Vohwinkel's syndrome (keratoderma hereditarium mutilans, keratosis pal-
moplantaris mutilans, mutilating palmoplantar keratoderma, palmoplantar
Palmoplantar keratoderma 83
Fig 3.96
Acrokeratoelastoidosis:
(A) there is marked
hyperkeratosis; (B) there is
diminution of the dermal
elastic tissue.
ectodermal dysplasia type VII) is a rare keratoderma which is usually inher-
ited as an autosomal dominant although a recessive variant has also been
described.1–3 Onset is in infancy or early childhood.2 Caucasians are pre-
dominantly affected and there is a predilection for females.3 The clini-
cal features include palmoplantar keratoderma with a yellowish papular
and honeycomb-like appearance and hyperhidrosis. Other characteristics
are starfish-like keratoses affecting the dorsal surfaces of the hands, feet,
wrists, forearms, elbows. and knees (Figs 3.99 and 3.100).3 Flexion con-
tractures and circumferential hyperkeratotic constriction bands (pseudoain-
hum) affecting the interphalangeal joints associated with autoamputation
are also present.2,3 Additional features include alopecia, nail dystrophy, and
onychogryphosis.2 In the classical variant, sensorineural deafness is an inte-
gral feature.1,4,5 The ichthyosis-associated variant of Vohwinkel is a com-
pletely different entity (see Loricrin keratoderma or Camisa variant form of
Vohwinkel's syndrome).6–9
84 Disorders of keratinization
Fig. 3.98
Huriez syndrome. There are mild acanthosis, orthohyperkeratosis and well
developed granular layer.
Fig. 3.99
Vohwinkel's syndrome: there is marked palmoplantar keratoderma. By courtesy of
W.A.D. Griffiths, MD, Institute of Dermatology, London, UK.
Pathogenesis and histological features
Classical, deafness-associated Vohwinkel's syndrome is due to mutations in
the connexin 26 gene.8
Histologically, the keratoderma is characterized by hyperkeratosis, hyper-
granulosis, and acanthosis.3
Loricrin keratoderma
Clinical features
Loricrin keratoderma (Camisa variant form of Vohwinkel's syndrome,
Vohwinkel keratoderma with ichthyosis) is inherited in an autosomal dom-
inant fashion and characterized by a diffuse palmoplantar keratoderma
that is very similar to that of Vohwinkels' syndrome including the honey-
comb-like appearance (Fig. 3.101).1 In contrast, however, the palmoplantar
­keratoderma is less mutilating, and warty papules and starfish-like keratosis
are absent. A concomitant ichthyosis with generalized fine scaling is a con-
stant feature and often presents congenitally prior to the development of the
palmoplantar keratoderma.2 The patients also do not suffer from the deafness
seen in Vohwinkel's keratoderma.
Fig. 3.100
Vohwinkel’s syndrome: in
this example there is very
disfiguring keratoderma,
hence the alternative title,
keratoderma hereditarium
mutilans. By courtesy
of W.A.D. Griffiths, MD,
Institute of Dermatology,
London, UK.
Pathogenesis and histologic features
Mutations on chromosome 1q21 that result in aberrant, elongated C-terminal
domains of one loricrin allele may lead to an abnormal loricrin expression, and
impairment of cross-linking to itself and other cornified envelope ­proteins.3–5
Loricrin keratoderma and some cases of progressive symmetrical erythro-
keratoderma may share the mutation and light and ultrastructural ­features.6
Therefore some authors have proposed that the loricrin keratoderma should
include cases of what has been termed either (Vohwinkel's) keratoderma with
ichthyosis and progressive symmetrical erythrokeratoderma.7
As with progressive symmetrical erythrokeratoderma acanthosis, a promi-
nent stratum granulosum and parakeratosis is present in loricrin keratoderma
(Figs 3.102, 3.103).
Electron microscopy characteristically reveals formation of a well-formed
transitional layer, intranuclear granules in the upper stratum granulosum, and
a thin cornified envelope.4 Immunoreactivity for loricrin can be detected in
the nuclei of the stratum granulosum and of the parakeratotic cells.4 Mutant
loricrin in the nucleus is thought to impair the function of profilaggrin to
mediate nuclear dissolution in the course of apoptosis which represents an
integral part of keratinocyte terminal differentiation.6
Clouston's syndrome
Clinical features
Clouston's syndrome (hidrotic ectodermal dysplasia, palmoplantar ectoder-
mal dysplasia type X) is an uncommon disorder with an autosomal dominant
mode of inheritance. Nail dystrophy is often predominant, but hair defects
and palmoplantar keratoderma are also found (Fig. 3.104).1–7 Rare manifesta-
tions include sensorineural deafness, ocular abnormalities, skin hyperpigmen-
tation, polydactyly, syndactyly, mental retardation, epilepsy, and dwarfism.5,6
Changes in the nails are variable, but usually they are short and thickened
with longitudinal striations, often with discoloration, and may have grooves,
pits and ridges.5,6 Development of paronychia is a frequent complication.
Scalp alopecia (from hair thinning to complete baldness) is the rule, and facial,
axillary, and pubic hair is usually sparse or totally absent.6 The patients have a
normal facies and no involvement of the dentition or abnormal sweating.
Although hidrotic ectodermal dysplasia has been documented predomi-
nantly in French Canadian families, kindreds have been described in French,
Scottish-Irish, and Indians.4,7–10

A B
Fig. 3.102
Loricrin keratoderma: there is hyperkeratosis and mild acanthosis.
Pathogenesis and histological features
The gene responsible for this condition has been mapped to 13q11–
12.1.11–14 Hidrotic ectodermal dysplasia results from a connexin 30
mutation.15–18
The palmoplantar keratoderma is typified by hyperkeratosis, thickening
of the granular cell layer, and acanthosis.5,7 Elsewhere, eccrine sweat glands
are normal, but hair and sebaceous glands are greatly reduced in number and
apocrine glands completely absent.8
Olmsted syndrome
Clinical features
Olmsted syndrome is exceedingly rare and combines the features of mutilat-
ing palmoplantar keratoderma with periorificial plaques. Approximately 20
cases have been documented.1–5 It is usually associated with sporadic occur-
rence although X-linked dominant transmission has been suggested at least in
Palmoplantar keratoderma 85
Fig. 3.101
Loricrin keratoderma:
(A) there is a generalized fine
scaling and (B) palmoplantar
keratoderma with a yellowish
popular and honeycomb-like
appearance less mutilating
than in classical Vohwinkel's
syndrome.
Fig. 3.103
Loricrin keratoderma: the stratum granulosum is prominent. Scattered cells (on
the right side of the field) show perinuclear vacuolization and the parakeratotic
keratinocytes in the lower horny layer represent transitional cells.
one family.6 There is no racial predilection. There is a striking predominance
in males (5:1).
The keratoderma is present at birth or begins in early infancy and when
fully developed presents as bilateral and symmetrical massively thickened,
yellow, macerated, keratotic plaques covering the whole of the sole and palm
and often extending to the lateral and even the dorsal surface of the hands
and feet (Fig. 3.105).3,4 The heels and forearms may also be affected. The
border of the plaque is sharply defined and surrounded by a pruritic ery-
thematous border. Lesions are often fissured and extremely painful, mak-
ing walking exceedingly difficult or impossible.3,4 Blistering has occasionally
been described.5 Flexion contractures, ainhum-like constriction bands, and
autoamputation are common complications. Superinfection with bacteria
and fungi, particularly Candida albicans, contributes to the problems and as
a result lesions are frequently very malodorous. Squamous carcinoma is an
occasional complication.7,8
86 Disorders of keratinization
Fig. 3.104
Clouston's syndrome: there is nail dystrophy accompanied by hyperkeratosis of the
fingertips, thereby accentuating the epidermal surface ridges.
By courtesy of D. Atherton, MD, the Children's Hospital at Great Ormond Street,
London, UK.
Fig. 3.105
Olmsted syndrome: in this variant, the lesions are very disfiguring. Constriction
bands and autoamputation are important complications. By courtesy of W.A.D.
Griffiths, MD, Institute of Dermatology, London, UK.
Affected children also develop erythematous keratotic papules and plaques
around the body orifices including the mouth, nares, ears, and anus.3,4 The eye-
lids, umbilical region, inguinal region, and gluteal cleft can also be involved.
Additional features include scarring alopecia, keratosis pilaris, and nail
dystrophy including ridging, transverse striae, thickening, curvature, subun-
gual keratosis, and infection.3,4 Hyperkeratotic linear streaks may develop in
the axillae and cubital fossae. Growth retardation, laxity of the large joints,
and corneal involvement are occasional manifestations.3,4
Histological features
The plaques are characterized by massive hyperkeratosis, often with foci of
vertically orientated parakeratosis.2–5 There is hypergranulosis with large
coarse granules under the former whereas the granular cell layer is absent
beneath the areas of parakeratosis. The epidermis is acanthotic and shows
psoriasiform hyperplasia or papillomatosis and there is edema and increased
vascularity of the superficial dermis where a lymphohistiocytic infiltrate is
also seen.
The plaques show increased mitotic activity, increased Ki-67 expres-
sion and increased argyrophilic nucleolar organizer regions (AgNORS).4,9
Keratinization is abnormal with aberrant expression of keratins 5, 10 and
14, filaggrin, and involucrin.4,5 It has, however, been proposed that the kera-
tin abnormalities might be a result of isotretinoin and etretinate therapy.10
Papillon-Lefèvre syndrome
Clinical features
Palmoplantar keratoderma with periodontopathia (palmoplantar kerato-
derma with periodontopathia, palmoplantar ectodermal dysplasia type IV)
is rare and has an autosomal recessive mode of inheritance.1 The incidence
is 1–4 per million of the population.2 There is an equal sex incidence and
onset is usually in the first decade. It is characterized by symmetrical and
marked palmoplantar keratoderma sometimes affecting the dorsal aspects of
the hands and feet (Fig. 3.106).3 Hyperhidrosis may also be present, associ-
ated with gingivitis and marked periodontosis involving both deciduous and
permanent teeth.4,5 Periodontosis is unrelated to oral hygiene and results in
loss of attachment of teeth to the periodontal ligament (Fig. 3.107) and atro-
phy of the alveolar processes (maxillar and mandibular) with eventual loss
of teeth. The periodontal ligament, which is a dense fibrous band, attaches
the tooth to the alveolar bone and carries the blood vessels, lymphatics, and
nerves.6 Psoriasiform lesions may be evident on the knees and elbows and
Fig. 3.106
Papillon-Lefèvre
syndrome: (A) there is
marked hyperkeratosis
affecting the soles of the
feet; (B) in this patient,
the dorsal aspects of
the hands, particularly
the knuckles are also
affected. By courtesy
of W.A.D. Griffiths, MD,
B Institute of Dermatology,
London, UK.

Fig. 3.107
Papillon-Lefèvre syndrome: gingival inflammation and swelling with the particularly
characteristic irregular positioning of the teeth which, as a result of destruction of
supporting tissues, have shifted under the forces of mastication. This patient is
a 12-year-old child, but the severity of the periodontal destruction is what might
be expected in a person aged 60 years. By courtesy of R.A. Cawson, MD, Guy's
Hospital, London, UK.
onychogryphosis has been documented (Fig. 3.108).3 The adnexae are not
usually affected. Presentation is usually in the early years of life (2–4 years
of age).
There is sometimes associated calcification of the falx cerebri and chor-
oid plexus.6 Other features, which may sometimes be present, include deaf-
ness, deformity of the terminal phalanx, follicular hyperkeratosis, and mental
retardation. Patients show an increased risk of infection, particularly furun-
culosis; this has been associated with defective neutrophil chemotaxis and
phagocytosis and impaired B- and T-cell mitogenic responses.7
Pathogenesis and histological features
Papillon-Lefèvre syndrome has been mapped to 11q14–21.8 The disease
is associated with missense and nonsense mutations, deletions, and inser-
tions in the gene for the lysosomal cysteine protease cathepsin C (dipeptidyl
aminopeptidase I).9–12 In homozygous patients, loss of cathepsin C activ-
ity results in impaired activation of bone marrow myeloid and macrophage
Fig. 3.108
Papillon-Lefèvre syndrome: a scaly psoriasiform plaque is present over the elbow.
By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK.
Palmoplantar keratoderma 87
Fig. 3.109
Papillon-Lefèvre
syndrome: there
is hyperkeratosis,
hypergranulosis and
acanthosis.
granule serine proteases with resultant defective bacterial phagocytosis.11,12
The cathepsin C gene is also expressed in squamous epithelium of the palms,
soles, knees, and the oral keratinized gingiva.9 At this site, its function is
unknown.
The histopathological features of the palmoplantar lesions show marked
hyperkeratosis with acanthosis and a thickened granular cell layer (Fig.
3.109).3 Parakeratosis and epidermal psoriasiform hyperplasia have also
been described.7 The elbow and knee lesions show epidermal psoriasiform
hyperplasia with parakeratosis, elongation of the dermal papillae, and dilata-
tion of the superficial dermal vasculature.3
Naxos syndrome
Clinical features
Naxos syndrome (keratosis palmoplantaris with arrhythmogenic cardiomy-
opathy) is an autosomal recessive inherited disease defined by palmoplan-
tar keratoderma, curly hair, and other ectodermal features associated with
dilatative cardiomyopathy leading to arrhythmogenic episodes.1,2 It was first
reported in families on the Greek island of Naxos.1
Pathogenesis and histological features
A deletion in the plakoglobin gene which results in a frameshift mutation in
plakoglobin, an important component of desmosomes, has been identified in
Naxos syndrome.3 Histology shows compact hyperkeratosis, hypergranulo-
sis, and acanthosis.2
McGrath syndrome
Clinical features
McGrath syndrome (skin fragility and hypohidrotic ectodermal dysplasia) is
inherited in an autosomal recessive mode and is characterized by a diffuse,
sometimes verruciform palmoplantar keratoderma, trauma-induced skin
­fragility, and congenital ectodermal dysplasia affecting nails, hair, and sweat
glands.1 In some cases plantar hyperkeratosis is painful and there is disabling
cracking. The nails are thickened and markedly dystrophic. The integument
shows fragility, with trauma-induced blisters and crusting on pressure points.
Hairs are noted to be short and sparse. Sweating may be reduced.
88 Disorders of keratinization

Pathogenesis and histologic features described.11 The follicular lesions show plugging of the ostia with surround-
ing hyperkeratosis, parakeratosis, and acanthosis (Fig. 3.114).6 A mononu-
The disease has been shown to be associated with mutations in the
clear perivascular chronic inflammatory cell infiltrate may be present in the
­ lakophilin-1 gene (PKP1) leading to complete ablation of plakophilin 1
p
superficial dermis. The oral lesions are indistinguishable from those of the
which is responsible for recruitment of desmosomal proteins to the plasma
white sponge nevus, consisting of parakeratosis, acanthosis, and epithelial
membrane and keratin interaction.1,2
vacuolation (Fig. 3.115). No evidence of dysplasia is seen.
Light microscopy of the skin shows thickening of the epidermis and exten-
sive widening of keratinocyte intercellular spaces, extending from the first
suprabasal layer upward. There is complete absence of cutaneous immunos- Pachyonychia congenita type II
taining for plakophilin-1. Electron microscopy reveals loss of keratinocyte–
keratinocyte adhesion. Desmosomes, particularly in the lower suprabasal
layers, are small and reduced in number. The inner and outer desmosomal
Clinical features
plaques are poorly developed.3 Pachyonychia congenita type II (palmoplantar ectodermal dysplasia type
II, Jackson-Lawler syndrome, Jackson-Sertoli syndrome) is inherited as an
autosomal dominant. It is characterized by limited and usually mild focal
Pachyonychia congenita type I
Clinical features
Focal (nonepidermolytic) palmoplantar keratoderma with oral hyperkera-
tosis (Jadassohn-Lewandowsky syndrome, focal palmoplantar keratoderma
with oral hyperkeratosis, palmoplantar ectodermal dysplasia type I) is usu-
ally associated with an autosomal dominant mode of inheritance although an
autosomal recessive variant has been described.1,2 It has a high incidence in
Croatia and Slovenia and also appears to be more commonly seen in Jews.3,4
Clinical features may be present at birth or appear within the first 6 months
of life.1,5 The sex incidence is equal.
The features include massive hyperkeratosis of the distal nail beds of the
fingers and toes, resulting in elevation and apparent thickening of the nail
plate (Fig. 3.110). Also present are palmoplantar keratoderma, hyperhidro-
sis and follicular keratosis, xerosis, and verrucous lesions, which most often
arise on the elbows, knees, and lower legs (Fig. 3.111). Patients also develop
alopecia and nail bed infections.1,5,6 Erythema and blistering of the soles of the
feet, and to a lesser extent on the palms of the hands, are sometimes present;
leukokeratosis oris is almost invariably evident (Fig. 3.112).1,6,7 Laryngeal
involvement has also been documented.8 Fig. 3.111
Pachyonychia congenita
Pathogenesis and histological features type 1: discrete, yellow,
hyperkeratotic plaques on
This variant of focal palmoplantar keratoderma is heterogeneous. Mutations
the soles of the feet are
have been described in keratin K16 and K6a genes.9–14 a common manifestation.
The nail beds show massive hyperkeratosis.1 The palmoplantar lesions By courtesy of R.A.
are characterized by hyperkeratosis, hypergranulosis, and acanthosis (Fig. Marsden, MD, St
3.113).1 Round to oval darkly staining perinuclear inclusions represent- George's Hospital,
ing densely aggregated keratin filaments in the prickle cell layer have been London, UK.

A B

Fig. 3.110
Pachyonychia congenita type 1: (A) there is gross nail deformity with transverse arching of the distal portion. Although the nail plate appears to be thickened, most of the
changes are, in fact, due to massive hyperkeratosis of the nail bed, resulting in elevation and bending of the nail plate; (B) in this view, the subungual hyperkeratosis is more
obvious. (A) By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK, (B) By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK.

Fig. 3.112
Pachyonychia congenita type 1: leukoplakia of the buccal mucosa is a frequent
accompanying feature. By courtesy of R.A. Marsden, MD, St George's Hospital,
London, UK.
Fig. 3.113
Pachyonychia congenita
type 1: volar skin showing
massive hyperkeratosis,
hypergranulosis, and
acanthosis.
palmoplantar keratoderma over pressure areas, subungual hyperkeratosis,
epidermal cysts, steatocystoma multiplex, abnormal eyebrows and body
hair (pili torti), natal teeth, angular cheilosis, and hoarseness.1,2 Plantar
lesions may be delayed until late childhood. In contrast to pachyonychia
congenita type I, patients do not develop leukokeratosis oris. This palmo-
plantar ectodermal dysplasia has no known association with malignancy.
Pathogenesis and histological features
Pachyonychia congenita type II results from mutations in keratin 17 and ker-
atin 6b genes.3–7 Interestingly, mutations in keratin 17 may also result in ste-
atocystoma multiplex in isolation.3
Histologically, the subungual changes and keratoderma are similar to
those described in the type I variant, although milder. The epidermoid cysts
and steatocystomata show typical features.
Palmoplantar keratoderma 89
Fig. 3.114
Pachyonychia congenita
type 1: follicular lesion
showing keratin plugging
of the ostium with
adjacent hyperkeratosis
and associated
acanthosis.
Tyrosinemia type II
Clinical features
Tyrosinemia type II (Richner-Hanhart syndrome, tyrosine aminotransferase
deficiency, keratosis palmoplantaris with corneal dystrophy) is an oculocu-
taneous syndrome characterized by herpetiform corneal ulcers that develop
during the first months of life. Later painful punctuate, sometimes striated
and circumscribed hyperkeratoses of digits, palms, and soles evolve, often
accompanied by hyperhidrosis. Aberrant keratotic plaques have been sporad-
ically observed on the elbows, knees, and even the tongue. Other symptoms
include severe mental and somatic retardation.1
Pathogenesis and histological features
Tyrosinemia type II is caused by autosomal recessively inherited deficiency
of hepatic tyrosine aminotransferase. Point mutations in the tyrosine amin-
otransferase gene have been identified which map to the long arm of chro-
mosome 16. 2,3 Diagnosis can be confirmed by identifying tyrosinemia and
phenylacetic acidemia with excessive levels of P-hydroxyphenylactic acid in
the urine. Clinical and biochemical improvement may be achieved by a low
phenylalanine-low tyrosine diet.1
Histologically the epidermis is acanthotic, the granular layer is thickened,
and the keratinocytes contain eosinophilic globular inclusions. 4
Electron microscopy demonstrates an increased synthesis of tonofibrils
and keratohyalin, large numbers of microtubules, and unusually tight pack-
ing of tonofibrillar masses, which contain tubular channels or inclusions
of microtubules.4 Presumably, excessive amounts of intracellular tyrosine
enhance cross-links between aggregated tonofilaments leading to a globular
appearance.4
Carvajal-Huerta syndrome
Clinical features
The Carvajal-Huerta syndrome is an autosomal recessively inherited dis-
ease with palmoplantar keratoderma, woolly hair, and dilated cardiomy-
opathy.1,2 The patients are born with woolly hair. Around the first year,
palmoplantar keratoderma and other keratotic signs appear. The clinical
symptoms of Carvajal-Huerta syndrome resemble those of Naxos disease
90 Disorders of keratinization

At the ultrastructural level, loosening of intercellular connections, disrup-

tion of desmosome–keratin intermediate filament interactions, and rudimen-
tary desmosomal structures can be demonstrated.2

Howell-Evans syndrome
Clinical features
The combination of autosomal dominant focal nonepidermolytic palmoplan-
tar keratoderma with esophageal squamous carcinoma was first recognized
in 1958 and subsequently termed the Howell-Evans syndrome.1–5 Although
initially regarded as a diffuse keratoderma, a subsequent clinical re-evalu-
ation determined that the lesions were focal, sparing nontraumatized areas
(Fig. 3.116).4 The condition typically presents between 6 and 15 years of
age. The patients develop painful hyperkeratoses on the pressure areas,
which ­disappear with prolonged bed rest.5 Palmar involvement may be seen

A
B

Fig. 3.115
Pachyonychia congenita type 1: (A) scanning view of oral mucosa showing
massive acanthosis with large blunt rete ridges; (B) high-power view showing focal
parakeratosis and vacuolization of superficial keratinocytes. A single dyskeratotic
cell is evident (arrowed).

but the PPK in the former is of a striated and not diffuse type. The first car-
diac abnormalities are exclusively electrocardiographic and occur in asymp-
tomatic patients. In these patients, dilatation of the left ventricle, together
with alterations in muscle contractility, may lead to congestive heart failure
and death.

Pathogenesis and histological features

Mutations in the gene on chromosome 6p24 encoding desmoplakin have
been found.3 Desmoplakin is a major constituent of desmosomes and as such
is crucial for the rigidity and strength of the epidermis and cardiac tissue.
Biopsies of skin lesions show features of epidermolytic hyperkeratosis.1
Immunohistochemistry confirms perinuclear localization of keratin in the
suprabasal keratinocytes. This suggests collapse of the intermediate filament
network as a response to the failure of desmoplakin to attach the intermediate
filaments to the desmosomes.
B
Fig. 3.116
Howell-Evans syndrome: (A) focal autosomal dominant palmoplantar keratoderma
is associated with an increased risk of esophageal squamous carcinoma; (B) in
this patient, the palms were also severely affected. By courtesy of the Institute of
Dermatology, London, UK.

in ­manual workers. This syndrome, also termed palmoplantar ectodermal
dysplasia type III, includes keratosis pilaris particularly affecting the upper
arms and thighs, multiple epithelial cysts, and gray-white buccal mucosal
hyperkeratosis (This last feature typically predates the onset of keratoderma
and may therefore represent a clinical diagnostic clue of early involvement in
family members of a pedigree.).5–9 Nails are unaffected.6 In the largest kin-
dred reported to date, 28% developed esophageal squamous carcinoma (89
affected members) of whom 84% died of their tumor.4
Pathogenesis and histological features
The condition has been mapped to 17q23-qter region (TEC locus) distal to
the keratin gene cluster, thereby excluding a keratin gene mutation.10–12
The cutaneous lesions are characterized by hyperkeratosis, hypergranulo-
sis, and acanthosis. Features of epidermolytic hyperkeratosis are absent.
The buccal mucosal lesions are characterized by parakeratosis, acantho-
sis, and spongiosis accompanied by cytoplasmic vacuolation of the prickle
cell layer.4
Schöpf-Schulz-Passarge syndrome
Clinical features
The Schöpf-Schulz-Passarge syndrome (palmoplantar keratoderma with eye-
lid cysts, hypodontia, and hypotrichosis) is probably inherited in an auto-
somal recessive pattern.1 Patients have a relatively mild, diffuse erythematous
keratoderma association with hypodontia, hypotrichosis, nail dystrophies,
and late-onset eyelid cysts.
Histological features
The eyelid lesions represent apocrine hidrocystomas. Multiple eccrine syrin-
gofibroadenomas and squamous cell carcinomas may arise on the acral sur-
faces in older patients.1,2 The underlying defect remains unknown.3
Acquired palmoplantar keratoderma and
internal malignancy
Acquired diffuse palmoplantar keratoderma may represent a paraneoplas-
tic phenomenon associated with a number of internal malignancies includ-
ing carcinoma of the bronchus, esophagus, stomach, urinary bladder, and
myeloma (Fig. 3.117).1–6 There are also reports of acquired filiform (filiform
palmoplantar keratoderma) and punctate (punctate porokeratotic kerato-
derma) variants associated with a range of visceral cancers including breast,
kidney, colon, and lung.7,8
Fig. 3.117
Acquired palmoplantar
keratoderma: acquired
disease may be a
manifestation of
underlying malignancy. By
courtesy of the Institute
of Dermatology, London,
UK.
Acquired palmoplantar keratoderma and internal malignancy 91
Keratoderma climactericum
Clinical features
Keratoderma climactericum (Haxthausen's disease, climacteric kerato-
derma) is an acquired disorder which is restricted to menopausal women.1,2
Lesions present on the weight-bearing surfaces of the sole of the foot as ery-
thematous hyperkeratotic and fissured plaques and then spread to involve
the rest of the plantar skin (Fig. 3.118). Patients are often overweight.
Palmar involvement is sometimes seen with lesions affecting the area
between the thenar and hypothenar eminences.2 Similar lesions have been
documented in younger women who have undergone bilateral oophorec-
tomy.3 The condition is distinguished from congenital palmoplantar kerato-
derma by its late onset.
Histological features
The plantar skin shows massive hyperkeratosis, hypergranulosis, acanthosis,
and spongiosis with lymphocytic exocytosis.2 A superficial perivascular der-
mal lymphohistiocytic infiltrate is present and vertically orientated dermal
collagen associated with atypical myofibroblasts is often seen.2
Clavus
Clavi (corns) are extremely common painful keratotic lesions that develop
on the dorsal or lateral aspect of the toes, often as a consequence of ill-fitting
shoes. Histologically, they are characterized by a deep keratin-filled depres-
sion often associated with atrophy of the underlying epidermis (Fig. 3.119).
They are distinguished from plantar warts by the absence of koilocytes and
irregular keratohyalin granules.
Callus
In contrast to a clavus, a callus is a nonpainful localized focus of hyperkerato-
sis usually arising on the ball of the foot or heel from pressure or foot defor-
mity. Palmar lesions arise as a consequence of chronic rubbing. Histologically,
they are similar to a clavus, consisting of a keratin-filled epidermal dell with
hypergranulosis. Parakeratosis is often present.
Acrokeratosis verruciformis of Hopf
Clinical features
This is an exceedingly rare dermatosis with an autosomal dominant mode of
inheritance.1–3 The disease presents in infancy or early childhood as dry, rough,
brownish or skin-colored verrucoid, keratotic papules, located particularly on
Fig. 3.118
Keratoderma climactericum: there is massive hyperkeratosis with fissuring over the
heels. By courtesy of the Institute of Dermatology, London, UK.
92 Disorders of keratinization
Fig. 3.119
Clavus: massive
hyperkeratosis overlies an
epidermal depression.
the backs of the hands (Fig. 3.120) and feet, and on the knees and elbows.4
Keratotic punctate pits are found on the palms and soles. Lesions, which are
clinically and histologically indistinguishable, may occasionally be seen in
Darier's disease.5–7 Exceptionally, a similar association with Hailey-Hailey dis-
ease has been documented and there is a report of acrokeratosis verruciformis
presenting in a patient with nevoid basal cell carcinoma syndrome.8,9 Nail
involvement, including longitudinal splitting, striations and subungual hyper-
keratosis may also be seen.10
Pathogenesis and histological features
Loss of function of the sarco- (endo-) plasmic reticulum Ca2+ ATPase2
mutant in acrokeratosis verruciformis provides evidence that acrokeratosis
verruciformis and Darier's disease are allelic disorders.11 However, identifica-
tion of mutations in genes other than ATP2A2 suggests genetic heterogeneity
of acrokeratosis verruciformis.12
The lesions are acanthotic with a prominent granular cell layer, typically
showing a ‘church spire’ appearance (Fig. 3.121). There is usually moderate
to marked hyperkeratosis. Parakeratosis is not a feature. Step sections some-
times reveal acantholytic dyskeratosis in those cases associated with Darier's
disease.
Differential diagnosis
Acrokeratosis verruciformis-like features may occasionally be seen in lin-
ear epidermal nevi.13 There is also considerable histological overlap with
stuccokeratosis.
Porokeratosis
Clinical features
Porokeratosis is a not uncommon pathological process. It consists of a pig-
mented or reddish atrophic center bordered by a peripheral grooved keratotic
ridge, from the center of which a keratotic core (cornoid lamella) projects
at an obtuse angle.1 There are six major categories: classical, localized, lin-
ear, punctate, disseminated superficial porokeratosis (DSP), and disseminated
superficial actinic porokeratosis (DSAP), all of which may be inherited as an
autosomal dominant, but sporadic cases also occur.
• In the classical variant described by Mibelli, patients develop one or
several plaquelike lesions on the extremities (Fig. 3.122). It usually
Fig. 3.120
Acrokeratosis
verruciformis: numerous
brown flat-topped
papules are symmetrically
distributed over the dorsal
aspects of the hands.
By courtesy of
R.A. Marsden, MD,
St George's Hospital,
London, UK.
Fig. 3.121
Acrokeratosis verruciformis: there is hyperkeratosis and church-spire papillomatosis.
presents in adulthood as persistent lesions that are highly resistant to
therapy.
• Localized porokeratosis usually consists of a single large lesion.
• Disseminated superficial actinic porokeratosis, the most common variant,
is characterized by numerous small, dry, shallow lesions arising on
the sun-damaged skin of adults (Figs 3.123 and 3.124).2 It may also
complicate PUVA therapy and develop in the immunosuppressed.3–5 It
presents in the third and fourth decades and, despite its relationship
to sunlight, rarely affects the face. The legs, forearms, back, upper
arms, and thighs are most commonly affected, in decreasing order of
frequency.6
• Disseminated superficial (nonactinic) porokeratosis (porokeratosis
palmoplantaris et disseminata) is characterized by asymptomatic lesions
with a tendency to involve the trunk, genitalia, palms, and soles. An
intensely itchy eruptive variant of this has recently been described.7
• In linear porokeratosis, the lesion is clinically reminiscent of an epidermal
nevus affecting the extremities and usually presents in infancy or early

A B
Fig. 3.123
Disseminated superficial
actinic porokeratosis:
there are numerous small,
reddish or brownish
keratotic macules on sun
damaged skin.
childhood (Fig. 3.125).8 A zosteriform variant has also been described
which generally affects children and shows a predilection for the lower
limbs, upper limbs, and trunk.9
• In punctate porokeratosis (porokeratosis palmoplantaris punctata, spiny
keratoderma) tiny spines develop on palms and soles in the second or
third decade. Some argue that the typical ultrastructural changes of
porokeratosis of Mibelli are not present. It must be distinguished from
other forms of punctate keratoderma.6
Porokeratosis may involve the mucous membranes, cause nail dystrophy,
and result in patchy alopecia. It is associated with a slightly increased risk of
cutaneous neoplasia. Lesions of porokeratosis may therefore be complicated
by the development of Bowen's disease, and basal cell and squamous cell
Acquired palmoplantar keratoderma and internal malignancy 93
Fig. 3.122
Porokeratosis of Mibelli: (A) these lesions have an
extensive and linear distribution; (B) the lesions are
erythematous, atrophic and scaly, with sharply defined and
slightly raised margins By courtesy of M.M. Black, MD,
Institute of Dermatology, London, UK.
Fig. 3.124
Disseminated superficial actinic porokeratosis: in this variant, the lesions are small
and discrete. Note the characteristic raised edge. By courtesy of the Institute of
Dermatology, London, UK.
carcinoma.1,8,10–15 The reported incidence has varied from 6.8% to 11.6%.10,13,14
In some instances there is a probable causal relationship with previous treat-
ment with radiotherapy.10 Tumors usually develop many years after the onset
of the disease, are frequently multiple, and arise most often on large or coalesc-
ing lesions.8,10,16 They are most often found on the trunk and extremities.8
Pathogenesis and histological features
The pathogenesis of porokeratosis is unknown. The presence of localized
dysplastic features was suggested by Reed and Leone to indicate that the
disease represented a focal, expanding clone of abnormal keratinocytes asso-
ciated with the development of a cornoid lamella.17 The more recent literature
appears to support this claim.
Porokeratotic lesions have been shown to be associated with abnormal
epidermal DNA ploides in association with increased DNA indices, midway
between normal skin and Bowen's disease.18,19 Uninvolved skin, however, is
usually diploid.8 Chromosomal abnormalities have been identified within
94 Disorders of keratinization
cultured keratinocytes and fibroblasts derived from patients suffering from
both the localized and Mibelli variants.8,10,20,21 These findings have since been
confirmed in both cultured fibroblasts from normal untreated skin and lym-
phocytes, and it has been shown that chromosome 3 is preferentially affected.22
Mutations in the proximal segment of the short arm of chromosome 3 have
been associated with a wide variety of malignancies.22 Ionizing radiation, ultra-
violet light including sun tanning beds, and PUVA may be associated with the
development of new skin lesions in porokeratosis.23 The first may be of par-
ticular relevance to the development of malignancy in these lesions.14,24
Cultured fibroblasts from porokeratosis patients have been shown to be
hypersensitive to the lethal effects of X-radiation, but not ultraviolet radia-
tion.21,22 This has been shown to be associated with chromosomal instability
in approximately 50% of patients.20 While it has been proposed that this may
result from abnormal DNA repair mechanisms (see xeroderma pigmentosa)
the evidence necessary to support such a hypothesis is not yet available.21
Porokeratosis of Mibelli, disseminated superficial porokeratosis, and
disseminated superficial actinic porokeratosis may also develop against a
background of solid organ transplantation or blood transfusion, possibly
Fig. 3.125
Linear porokeratosis: in
this variant, the lesion
has a linear, nevoid
distribution.
A B
Fig. 3.126
Porokeratosis of Mibelli: (A) there is hyperkeratosis with two well-developed cornoid lamellae. Note the epidermal depression at their bases. (B) The cornoid lamella can be
seen to be composed of an angulated tier of parakeratosis.
causally related to hepatitis C infection, Crohn's disease, renal failure, and
hemodialysis.25–29
p53 and pRb proteins are overexpressed within keratinocytes immedi-
ately beneath and adjacent to the cornoid lamellae; mdm-2 and p21waf-1 are
reduced.30–33 This imbalance in cell cycle control mechanisms offers a poten-
tial explanation for the development of malignancy in porokeratosis although
to date p53 mutation has not been identified.32,34
Recently, a gene for disseminated superficial actinic porokeratosis has been
mapped to chromosome 12q23.2–24.1 in a large Chinese family.35
The biopsy must be taken through the peripheral grooved ridge. If the long
axis of the specimen does not transact the border, the diagnostic features will be
missed. These consist of a keratin-filled epidermal invagination with an angu-
lated parakeratotic tier, the cornoid lamella (Fig. 3.126). Despite its name,
the lesions of porokeratosis are rarely related to the ‘pore’ of the eccrine duct.
While they may involve the follicle, their most common origin is from nonad-
nexal epithelium. The corneocytes of the cornoid lamella contain characteristic
PAS-positive granules. The epithelium deep to the tier is vacuolated and devoid
of a granular cell layer (Fig. 3.127). Dyskeratotic cells may be present and
Fig. 3.127
Porokeratosis of Mibelli:
the epidermis at the base
of the cornoid lamella
is vacuolated and the
granular cell layer absent.
 Acquired palmoplantar keratoderma and internal malignancy 95

Fig. 3.128
Disseminated superficial actinic porokeratosis: in this example, the cornoid lamella
has arisen overlying an acrosyringium. The epidermis towards the center on the
lesion appears atrophic and the papillary dermis contains ectatic blood vessels.

epithelial dysplasia, ranging from mild changes through to carcinoma in situ, A

is occasionally a feature. Liquefactive degeneration of the basal cell layer of the
epithelium is sometimes present and occasionally there are conspicuous cytoid
bodies. The adjacent epithelium towards the center is often atrophic, but may
be of normal thickness or even acanthotic. In the dermis, a non-specific chronic
inflammatory cell infiltrate and telangiectatic vessels are sometimes seen. The
typical features are best seen in the Mibelli variant. The changes tend to be less
pronounced in the other subtypes (Fig. 3.128). In the actinic variant there is
often solar elastosis and atrophy of the adjacent epidermis.6

Differential diagnosis
With the appropriate clinical information, the histopathological changes
of porokeratosis are diagnostic. Cornoid lamella formation, however, does
occur as a non-specific finding in a variety of conditions including psoriasis
vulgaris, seborrheic, solar keratosis, verruca vulgaris, and squamous cell and
basal cell carcinomas.36 Cornoid lamellae are also features of verrucous epi-
dermal nevus and porokeratotic eccrine nevus.37,38 They are also not uncom-
mon in normal, and particularly actinically damaged, skin. PAS-positive
B
structures in the cornoid lamella may be a useful marker for porokeratosis
although this has not been authors experience.39 Fig. 3.129
Flegel's disease: (A) there are characteristic disseminated erythematous scaly
lesions; (B) the lower legs are commonly affected. Lesions are small, multiple
Hyperkeratosis lenticularis perstans and covered by a well-developed scale. By courtesy of M. Price, MD, Institute of
Dermatology, London, UK.

Clinical features
Hyperkeratosis lenticularis perstans (Flegel's disease) is a not uncommon der-
matosis that is sometimes mistaken for Kyrle's disease.1–5 It has an equal sex
incidence and patients present most often in their fourth or fifth decade. It is
characterized by a very protracted course, many patients having lesions for
decades. Patients present with large numbers of 1–5-mm discrete, gray, gray-
brown or red-brown, circular scaly papules (Fig. 3.129). Initial lesions often
arise on the dorsum of the foot. Other sites of predilection include the lower
legs, upper arms, and pinnae. The buttocks, trunk, and dorsal aspects of the
hands may also be affected, and punctate keratoses have been described on
the palms and soles. The lesions are either asymptomatic or mildly pruritic.
Characteristically, removal of the scale is associated with pinpoint bleeding,
a feature that distinguishes this disorder from stucco keratoses. Other than
an isolated report of an increased incidence of both basal cell and squamous
carcinomas, there is no particular associated disease process (compare
with Kyrle's disease).6 Although most cases appear to be sporadic, there is
some ­evidence to support an autosomal dominant mode of inheritance in a
­proportion of cases.
Pathogenesis and histological features
Flegel's disease is of unknown etiology and pathogenesis and is characterized
by focal areas of abnormal hyperkeratinization.7–10 Early lesions are not diag-
nostic, showing merely lamellar hyperkeratosis, focal parakeratosis, and an
essentially normal epidermis. In an established lesion, in addition to hyper-
keratosis and occasional parakeratosis, there is epidermal atrophy with an
inconspicuous or absent granular cell layer (Figs 3.130, 3.131). The lower
layers of the epithelium may show intercellular edema and occasional foci of
basal cell degeneration. Cytoid bodies are sometimes evident. Typically, the
papillary dermis is edematous and a chronic inflammatory cell infiltrate is
often present, adopting a perivascular or lichenoid distribution. Pigmentary
incontinence is not usually a feature.
The lymphocytes are an admixture of CD4+ T-helper cells and, less fre-
quently CD8+ T-suppressor cells.8,9 Sézary-like forms have been described.
Langerhans cells are highly reduced.9 In the atrophic areas, differentiation
96 Disorders of keratinization
B The etiology is unknown. It has been suggested that the condition develops
Fig. 3.130
Flegel's disease: (A) scanning view of an established lesion showing focal
hyperkeratosis, parakeratosis, and a superficial bandlike chronic inflammatory
cell infiltrate; (B) there is hyperkeratosis, focal epidermal atrophy and basal cell
liquefactive degeneration. Note the cytoid bodies
markers such as cytokeratin 1 and 10, filaggrin, and loricrin are absent.
Ultrastructurally, the most commonly documented changes have been
­rudimentary keratohyalin granules, absence, vacuolation or abnormally
lamellated membrane coating (Odland) bodies, failure to form a compact
keratin, and cornified envelope in the corneocytes.8,9
Differential diagnosis
Clinically, Flegel's disease differs from Kyrle's disease by the absence of
­keratin-filled penetrating plugs and the frequent presence of palmar and plan-
tar lesions, which are not seen in Kyrle's disease. Flegel's disease is sometimes
confused with stuccokeratoses, but these do not affect the trunk, palms, and
soles and the lesions may be readily removed without bleeding. Histologically,
stucco keratoses are characterized by orthohyperkeratosis and ‘church spire’
papillomatosis. Although there may be histological overlap with other condi-
tions showing lichenoid features, the striking keratotic tier with parakeratosis
and absent granular cell layer are useful diagnostic pointers.
Granular parakeratosis
Clinical features
Granular parakeratosis is a distinctive acquired disorder of keratinization
originally reported in 1991.1–4 The condition most often affects the axillae
but it has also been described involving other intertriginous areas including
submammary and intermammary skin, groins, vulva, perianal region and,
Fig. 3.131
Flegel's disease: high-power view showing spongiosis with microvesiculation,
cytoid bodies, and a predominantly lymphocytic infiltrate.
less commonly, in nonintertriginous skin including the lower back, buttocks,
and flanks.5–8 Women are affected more commonly than males. The disease
mainly affects the middle aged to elderly; children are rarely involved.8–10
It presents as pruritic or burning erythematous, hyperpigmented, and
hyperkeratotic patches, papules, or plaques (Fig. 3.132). Fissures and a
­‘cobblestone’ appearance may be seen. The condition has been documented
to respond to retinoids and to calcipotriene and ammonium lactate.11,12
Pathogenesis and histological features
as a result of a contact reaction to an antiperspirant or as a result of exces-
sive use of other topical products including creams, shampoos, and soaps.1–6,8
However, this does not explain the involvement of areas distant from the
axilla. The molecular mechanism proposed to explain the disease consists of
a failure to transform profilaggrin to filaggrin with the resultant failure in
degradation of keratohyalin granules.1,7
The histological appearances typically consist of a massive hyperkerato-
sis with parakeratosis and retention of keratohyalin granules in the stratum
corneum (Fig. 3.133). The underlying epidermis may show mild acanthosis
or even some degree of thinning. Hair infundibula are occasionally affected.
Necrotic areas with invasion of neutrophils or perforation of the epidermis
are rarely found. The superficial dermis contains a sparse perivascular lym-
phocytic infiltrate.1–7
Differential diagnosis
Apart from representing a dermatosis, granular parakeratosis is a diagnos-
tic feature in solitary keratosis, i.e., granular parakeratotic acanthoma.13
Granular parakeratosis can be also found as an incidental finding in many
diseases, e.g., dermatophytosis, molluscum contagiosum, dermatomyositis,
solar keratosis, squamous cell carcinoma, keratoacanthoma, lymphomatoid
papulosis, and basal cell carcinoma (Fig. 3.134).14 As such, granular parak-
eratosis can best be considered as a histologic pattern similar to focal acan-
tholytic dyskeratosis or epidermolytic hyperkeratosis.14
Circumscribed palmar or plantar
hypokeratosis
Clinical features
Circumscribed palmar or plantar hypokeratosis is a recently described
entity that is characterized by the development of well-circumscribed,
 Acquired palmoplantar keratoderma and internal malignancy 97

Fig. 3.132
Granular parakeratosis: (A)
in the axilla of a middle-
aged woman erythematous,
hyperpigmented and
hyperkeratotic papules
develop in a reticulated
A B fashion, (B) a few of them
are erosive.

A B

Fig. 3.133
Granular parakeratosis: (A) there is marked thickening of the horny layer with parakeratosis, (B) high-power view showing retention of the keratohyalin granules.

depressed, ­erythematous lesions on the thenar and hypothenar regions of
the palms or the medial side of the soles (Fig. 3.135).1 The lesions some-
times have an arcuate or polycyclic outline, a slightly scaling border, range
in diameter from a few millimeters up to 3 centimeters, and are symp-
tomless. All patients were middle aged or elderly with a predominance of
women.2
Pathogenesis and histological features
The pathogenesis of circumscribed palmar or plantar hypokeratosis is a mat-
ter of debate. While some authors favor the interpretation of an epidermal
malformation in view of persistence over years, others dispute this because
of the continuous growth of some lesions, and suggest a trauma or a human
papillomavirus type 4 as a causative.1–5
Histologically, the lesional depression relates to a sharply circumscribed
loss of the cornified layer above an otherwise normal epidermis (Fig. 3.136).1–7
Other authors observed a thin layer of parakeratosis in the hypokeratotic
zone and some psoriasiform hyperplasia of the epidermis with expression of
the hyperprolifertaive keratin 16.6,7
Additional features are hyperplasia of sweat ducts, and tortuous and elongated
capillaries in the papillary dermis; still, an inflammatory cell infiltrate is lacking.5
Ultrastructurally, breakage of the corneocytes within their cytoplasm
­suggests enhanced corneocyte fragility.7
98 Disorders of keratinization

Fig. 3.134
Granular parakeratosis:
(A) this example arose
against a background of
A B lymphomatoid papulosis;
(B) high-power view.

Fig. 3.136
Circumscribed palmar or plantar hypokeratosis: (A) scanning view from the edge of
a lesion, (B) note the focal thinning of the stratum corneum.

Fig. 3.135
Circumscribed palmar or plantar hypokeratosis: (A) on the thenar a well-
circumscribed, depressed, erythematous lesion is present, (B) a closer view reveals
a scaly border.
 Inherited and autoimmune Chapter

See
www.expertconsult.com
for references and
additional material
subepidermal blistering diseases
4
Split skin immunofluorescence 100 Lichen planus pemphigoides  131 Dermatitis herpetiformis  144
Immunoperoxidase antigen mapping  101 Mucous membrane pemphigoid (cicatricial Linear IgA disease  147
pemphigoid)  133
Epidermolysis bullosa  101
Epidermolysis bullosa acquisita (dermolytic
Bullous pemphigoid  117
pemphigoid)  137
Pemphigoid gestationis  127
Bullous systemic lupus erythematosus  142

Blisters, which are clinically subdivided into vesicles (L. vesicula, dim. of
­vesica, bladder) and bullae (L. bubble), are defined as accumulations of fluid
either within or below the epidermis and mucous membranes. Although
somewhat arbitrary, the term ‘vesicle’ is applied to lesions less than 0.5 cm in
diameter and ‘bulla’ to those greater than 0.5 cm. Subepidermal blisters, i.e.,
those that develop at the epidermal or mucosal basement membrane region,
include inherited variants and acquired (often autoimmune mediated)
­conditions. The former are usually classified as noninflammatory (cell-poor)
­blisters whereas the latter are commonly inflammatory (cell-rich) in nature
(Fig. 4.1).
Subepidermal blisters may develop within the lower epidermis, the lamina
lucida (e.g., bullous pemphigoid) or deep to the lamina densa (e.g.,
­epidermolysis bullosa acquisita) (Fig. 4.2). In addition to clinical observa-
tions, the precise diagnosis of a blistering disorder requires careful histologi-
cal and immunofluorescence correlation. When possible, the last should
include indirect studies and, in particular, NaCl-split skin should be used as
substrate as a mechanism of localizing the site of epidermodermal ­separation.1
If a sample has not been taken for indirect immunofluorescence, immunoper-
oxidase antigen mapping on paraffin-embedded material may on occasions
be of value at least as a screening procedure. Although the results of electron
microscopic investigations and, in particular, molecular studies have formed
the basis of the current classification of subepidermal bullous dermatoses,
such techniques are usually not essential to the everyday investigation of a
patient with an acquired blistering disorder.
The mechanisms involved in the development of a subepidermal blister are
variable. They include inherited mutational defects of basement membrane
proteins, i.e., epidermolysis bullosa, acquired autoimmune bullous diseases
such as bullous pemphigoid, cellular immunity-mediated disorders (e.g.,
­erythema multiforme and toxic epidermal necrolysis), metabolic ­diseases
including porphyria cutanea tarda, and profound subepidermal edema such
as may be seen in bullous arthropod bite reactions and dermal acute
­inflammatory processes (e.g., Sweet's disease).

Fig. 4.1
Classification of subepidermal
blisters: lesions may be
A B subdivided into (A) cell-poor
and (B) cell-rich variants.
100 Inherited and autoimmune subepidermal blistering diseases

Intact skin
K5, K14 (IF)
Epidermis

300K>IFAR LL
LD
Plectin BP230

a6
HD
CM Dermis
BP180 b4

LL
NaCL split skin
Laminin-5
LD Epidermis

AF

AP Artificial
blister cavity

Fig. 4.2
Basement membrane constituents: blisters can be classified into those that develop LD
within the lamina lucida (LL) and those that arise below the lamina densa (LD). (AF,
anchoring fibrils; AP, anchoring plaque; CM, cell membrane.) Dermis Fig. 4.3
Split skin immunofluorescence.

In this chapter, only those conditions in which subepidermal blister forma-

tion represents an inherited or autoimmune primary event are considered.
Other conditions, which may be associated with subepidermal blistering, are
dealt with in more appropriate chapters.
Split skin immunofluorescence
This technique represents a modification of indirect immunofluorescence
(IMF) where normal skin is split through the lamina lucida of the basement
membrane region to produce an artificial blister cavity (with the lamina densa
lining the floor) for use as substrate. Artificial separation can be achieved by
the suction technique (in vivo) or by immersion of normal skin in 1 M NaCl
for 48 hours at 4°C (Fig. 4.3). In general, the latter technique is preferred.2 As
such a split is invariably through the lamina lucida region ­(confirmed by
­electron microscopy or immunofluorescence) (Figs 4.4, 4.5), the technique
enables precise localization of a circulating basement membrane zone anti-
body to either the floor or the roof of the artificial blister cavity. In bullous
pemphigoid, pemphigoid gestationis, and the majority of cases of mucous
membrane pemphigoid, linear immunofluorescence is found along the roof of
the artificial blister whereas in diseases characterized by a sublamina densa
split (e.g., epidermolysis bullosa acquisita, antilaminin mucous membrane
­pemphigoid, anti-p105 pemphigoid, anti-p200 pemphigoid, and bullous der-
matosis of bullous lupus erythematosus), the immunofluorescent signal is
found along the floor of the blister (see references 3 and 4 for a review)
(Fig. 4.6). In some diseases, positive immunofluorescence may be found on
either the roof or the floor or even at both sites simultaneously (e.g., ­linear IgA
disease and some variants of mucous membrane pemphigoid). Such variable
labeling reflects the antigen heterogeneity in a number of bullous dermatoses.

A B

Fig. 4.4
(A, B) Split skin immunofluorescence: the split is through the lamina lucida, the lamina densa lining the floor of the artificial blister cavity.

Fig. 4.5
Split skin immunofluorescence: type IV collagen lines the floor of the split skin
artificial blister which therefore forms within the lamina lucida. By courtesy of B.
Bhogal, FIMLS, Institute of Dermatology, London, UK.
Fig. 4.6
Split skin immunofluorescence: (left) linear IgG at the basement membrane;
(middle) in epidermolysis bullosa acquisita (EBA), the antibody binds to the floor of
the blister cavity; (right) in bullous pemphigoid (BP), the antibody binds to the roof
of the blister. By courtesy of B. Bhogal, FIMLS, Institute of Dermatology, London,
UK.
Immunoperoxidase antigen mapping
As an alternative to split skin immunofluorescence, paraffin-embedded
sections of lesional skin have been proposed in a direct immunoperoxidase
antigen mapping technique to identify the level of the epidermodermal
separation.5–8This procedure localizes known basement membrane region
constituents such as keratins 5/14, laminin, and type IV collagen to the roof
or floor of the blister cavity. The site of blister formation can therefore be
characterized as intrabasal, within the lamina lucida or deep to the lamina
densa. For example, in epidermolysis bullosa simplex variants, all of these
immunoreactants are present along the floor of the blister cavity. In bullous
pemphigoid, keratin is present along the roof of the blister while laminin and
type IV collagen are found along the floor (Fig. 4.7). In dystrophic epidermolysis
bullosa, epidermolysis bullosa acquisita, and bullous systemic lupus
erythematosus, all three immunoreactants are present in the roof of the blister
(Fig. 4.8). However, in many hereditary and acquired blistering diseases
the relevant antibodies against the target antigens do not work well in
paraffin-embedded material and false-positive and false-negative results are
common, making this method unreliable for use in routine diagnosis. For
example, antigen mapping of the group of hereditary subepidermal blistering
diseases is done exclusively on frozen sections with excellent results.
Epidermolysis bullosa 101
Fig. 4.7
Paraffin-embedded immunoperoxidase antigen mapping: in bullous pemphigoid,
type IV collagen is present along the floor of the blister.
Fig. 4.8
Paraffin-embedded immunoperoxidase antigen mapping: in epidermolysis bullosa
acquisita, type IV collagen is present along the roof of the blister cavity.
Epidermolysis bullosa
Epidermolysis bullosa (EB) refers to a heterogeneous group of diseases in
which the skin and sometimes the mucous membranes blister easily in
response to mild trauma, hence the alternative title ‘mechanobullous derma-
tosis’, which has sometimes been applied.1 All are rare conditions; the estimated
incidence for the group as a whole is in the order of 1:20 000. Apart from the
acquired autoimmune variant (epidermolysis bullosa acquisita), they are all
autosomal inherited disorders.
EB was initially described as a defined entity in 1886.2 This group of con-
ditions has been classified in several ways over the years. The three major
types were defined in a groundbreaking electron microscopy study in 1962.3
In 1988, the contemporary classification and subtyping of the major variants
commenced with the first consensus meeting of the Steering Committee of
the National EB Registry (established in 1986) held in conjunction with the
American Academy of Dermatology.4,5 At that time, 23 seemingly clinically
distinct variants were recognized (Table 4.1).5 In the following decade, a
second consensus conference was held.6 As a result of the considerably
increased number of cases available for study, a much greater degree of clinical
overlap between the various subtypes was recognized. For this reason and
because of a much better understanding of the molecular basis for many of
102 Inherited and autoimmune subepidermal blistering diseases

Table 4.1 Table 4.2

First consensus conference (1988): classification of subepidermal blisters Second consensus conference (1999): classification of epidermolysis bullosa
EB simplex
Major EB Protein/gene
Localized Major EB type subtype systems involved
EB simplex of hands and feet (Weber-Cockayne variant)
EBS (‘epidermolytic EBS-WC K5, K14
EB simplex with anodontia/hypodontia (Kallin syndrome)
EB’) EBS-K K5, K14
Generalized EBS-DM K5, K14
EB simplex, Koebner variant EBS-MD Plectin
EB simplex herpetiformis (Dowling-Meara variant)
Junctional EB JEB-H Laminin-5*
EB simplex with mottled or reticulate hyperpigmentation with or without
HEB-nH Laminin-5; type XVII collagen
punctate keratoderma
EB simplex superficialis JEB-PA† α6β4 integrin‡
EB simplex, Ogna variant DEB (‘dermolytic EB’) DDEB Type VII collagen
Autosomal recessive EB simplex (letalis) with or without neuromuscular RDEB-HS Type VII collagen
disease RDEB-nHS Type VII collagen
EB simplex, Mendes da Costa variant
Reproduced with permission from Fine, J.D. et al (1991) Pediatrician, 18, Reproduced from Fine et al (2000) J Am Acad Dermatol, 42, 1051–1066 from American
175–187. Academy of Dermatology.
DDEB, dominant dystrophic EB; DEB, dystrophic EB; RDEB, recessive DDEB, dominant dystrophic EB; EBS-DM, EBS Dowling-Meara; EBS-K, EBS, Koebner;
EBS-MD, EBS with muscular dystrophy; EBS-WC, EBS, Weber-Cockayne; JEB-H,
dystrophic EB.
junctional EB, Herlitz; JEB-nH, junctional EB, non-Herlitz; JEB-PA, junctional EB with
Junctional EB pyloric atresia; RDEB-HS, recessive dystrophic EB, Hallopeau-Siemens; RDEB-nHS,
Localized recessive dystrophic EB, non-Hallopeau-Siemens.
*Laminim-5 is a macromolecule composed of three distinct (α3, β3, γ2) laminin chains;
Junctional EB, inversa
mutations in any of the encoding genes result in a junctional EB phenotype.
Junctional EB, acral/minimus †Some cases of EB associated with pyloric atresia may have intraepidermal cleavage
Junctional EB, progressiva variant or both intralamina lucida and intraepidermal clefts.
Generalized ‡α β integrin is a heterodimeric protein; mutations in either gene have been
6 4

Junctional EB, gravis variant (Herlitz variant)
Junctional EB, mitis variant (non-Herlitz variant; EB atrophicans
generalisata mitis; generalized atrophic benign EB)
Cicatricial junctional EB
Dystrophic EB
Localized
RDEB, inversa
DDEB, minimus
DDEB, pretibial
RDEB, centripetalis
Generalized
Autosomal dominant forms of DEB
DDEB, Pasini variant
DDEB, Cockayne-Touraine variant transient bullous dermolysis
of the newborn
Autosomal recessive forms of DEB
RDEB, gravis (Hallopeau-Siemens variant)
RDEB, mitis
the variants of EB, a considerably simplified classification system was rec-
ommended at that time (Table 4.2).7,8 Most recently, at the Third International
Consensus Meeting on Diagnosis and Classification of EB, the classification
scheme was further revised and this current proposed scheme forms the
framework for the discussion in this chapter (Tables 4.3, 4.4).9 Research
over the past two decades has generated a wealth of literature ­specifically
addressing the molecular basis of the various subtypes of EB. As a result, it
is now possible to subgroup EB on the basis of the level of ­separation within
the ­basement membrane region as well as on specific molecular findings.
Though molecular classification now drives our understanding of this dis-
ease group, knowledge of the traditional clinical subtypes can be helpful in
explaining the disease course to patients, despite the often overlapping
­spectrum of manifestations.
Traditionally, EB has been classified into three major groups based on
­clinical differences, antigen mapping, and electron microscopic observations:
• simplex (epidermolytic; in which the level of split is within the basal
keratinocyte),
• junctional (lucidolytic; where the level of split is within the lamina
lucida),
• dystrophic (dermolytic; where the level of split is deep to the lamina
densa).
associated with the JEB-PA syndrome.
In 1999, a fourth category – hemidesmosomal EB (where the level of split
is within the hemidesmosome) – was added.10 This provisional category has
now been removed and Kindler syndrome now constitutes a fourth major cat-
egory. The most recent classification, which takes into account the current
precise molecular data which is now known for virtually all of the subtypes
of this disease, is particularly valuable when considering the pathological
basis of EB and forms the basis for this account. There have been some
changes in nomenclature based on an attempt to produce names that are
more accurately descriptive of the diseases and concordant with current
molecular classification of this disease.
Mutations of sundry types in a variety of genes encoding plakophilin-1
(PKP1), desmoplakin (DSP), keratins 5 and 14 (KRT5, KRT14), plectin
(PLEC1), BP180, α6 and β4 integrin subunits (ITGA6, ITGB4), laminin-5
(now termed laminin-332 and encoded by LAMA3, LAMB3, LAMC2), types
XVII and VII collagen (COL17A1, COL7A1) and kindling-1 (KIND1) cur-
rently account for the different subtypes of EB (a more detailed account of
these basement membrane proteins is given in Chapter 1).10–12
Molecular studies including Western blot and ­immunoprecipitation,
­however, are not always available for every case of EB, particularly at
­presentation, and therefore initially at least the patient may well be
­provisionally subclassified on the basis of:
• clinical variation,
• presence or absence of extracutaneous manifestations,
• mode of inheritance,
• immunoepitope mapping and/or electron microscopy.
Clinical evaluation of a patient with suspected EB should include the age
of onset and nature and distribution of the cutaneous lesions and whether or
not scarring and contractures are present. In addition, the family pedigree
should be studied and the patient investigated for the presence or absence of
extracutaneous involvement (eyes, oropharynx, larynx, gastrointestinal and
genitourinary tracts, and musculoskeletal system) and other specific lesions
(including enamel hypoplasia, anodontia or hypodontia, pyloric atresia, and
muscular dystrophy) that might point towards a particular variant.4,5
Four major subtypes of EB are now recognized: simplex, junctional,
­dystrophic and Kindler Syndrome: 4–7,9
• EB simplex (historically also known as the epidermolytic variant) is
characterized by the level of separation within the epidermis, usually as a
 Epidermolysis bullosa 103

Table 4.3
Third consensus conference (2007): classification of epidermolysis bullosa

Major EB type Major EB subtype Protein involved

EBS Suprabasal
Lethal acantholytic EB Desmoplakin
Plakophilin deficiency Plakophilin-1
EBS superficialis (EBSS) ?
Basal
EBS, localized (EBS-loc)+ K5, K14
EBS, Dowling-Meara (EBS-DM) K5, K14
EBS, other generalized (EBS, gen-nonDM; EBS, gen-nDM)^ K5, K14
EBS with mottled pigmentation (EBS-MP) K5
EBS with muscular dystrophy (EBS-MD) Plectin
EBS with pyloric atresia (EBS-PA) Plectin, α6β4 integrin‡
EBS, autosomal recessive (EBS-AR) K14
EBS, Ogna (EBS-Og) Plectin
EBS, migratory circinate (EBS-migr) K5
Junctional EB JEB, Herlitz (JEB-H) Laminin-332 (laminin-5)*
JEB, other (JEB-O)
JEB, non-Herlitz, generalized (JEB-nH gen)$ Laminin-332; type XVII collagen (BP180)
JEB, non-Herlitz, localized (JEB-nH loc) Type XVII collagen
JEB with pyloric atresia (JEB-PA)† α6β4 integrin‡
JEB, inversa (JEB-I) Laminin-332
JEB, late onset (JEB-lo)# ?
LOC syndrome (laryngo-onycho-cutaneous syndrome) Laminin-332 α3 chain
DEB (‘dermolytic EB’) Dominant dystrophic EB (DDEB)
DDEB, generalized (DDEB-gen) Type VII collagen
DDEB, acral (DDEB-ac) Type VII collagen
DDEB, pretibial (DDEB-Pt) Type VII collagen
DDEB, pruriginosa (DDEB-Pr) Type VII collagen
DDEB, bullous dermolysis of the newborn (DDEB-BDN) Type VII collagen
Recessive dystrophic EB (RDEB)
RDEB, severe generalized (RDEB-sev gen)@ Type VII collagen
RDEB, generalized other (RDEB-O) Type VII collagen
RDEB, inversa (RDEB-I) Type VII collagen
RDEB, pretibial (RDEB-Pt) Type VII collagen
RDEB, pruriginosa (RDEB-Pr) Type VII collagen
RDEB, centripetalis (RDEB-Ce) Type VII collagen
RDEB, bullous dermolysis of the newborn (RDEB-BDN) Type VII collagen
Kindler syndrome Kindlin-1

Adapted from Fine et al (2008) J Am Acad Dermatol, 58, 931–50 from American Academy of Dermatology.
Rare variants are italicized.
+Previously termed EBS, Weber-Cockayne
^Includes cases previously termed EBS-Koebner
‡α β integrin is a heterodimeric protein; mutations in either gene have been associated with both EBS-PA and JEBS-PA. Some cases of EB associated with pyloric atresia may have
6 4
intraepidermal cleavage or both intralamina lucida and intraepidermal clefts.
*Laminin-332 (laminin-5 is a macromolecule composed of three distinct (α3, β3, γ2) laminin chains; mutations in any of the encoding genes result in a junctional EB phenotype.
$Previously termed generalized atrophic benign EB (GABEB).

#Previously termed EB progressiva.

@Previously termed RDEB, Hallopeau-Siemens.

Dominant dystrophic EB; EBS-DM, EBS Dowling-Meara; EBS-K, EBS, Koebner; EBS-MD, EBS with muscular dystrophy; EBS-WC, EBS, Weber–Cockayne; JEB-H, junctional EB, Herlitz;
JEB-nH, junctional EB, non-Herlitz; JEB-PA, junctional EB with pyloric atresia; RDEB-HS, recessive dystrophic EB, Hallopeau-Siemens; RDEB-nHS, recessive dystrophic EB, ­
non-Hallopeau-Siemens.
†Some cases of EB associated with pyloric atresia may have intraepidermal cleavage or both intralamina lucida and intraepidermal clefts.

‡α β integrin is a heterodimeric protein; mutations in either gene have been associated with the JEB-PA syndrome.
6 4

consequence of cytolysis. Traditionally, all variants have been associated
with mutations in the genes encoding keratin 5 or 14.8,9 However, the
most current classification scheme divides this group into suprabasal and
basal forms, and now certain rare variants are known to be associated
with mutations in the genes encoding desmoplakin, plakophilin-1,
plectin, and α6 and β4 integrin subunits.9
• Epidermolysis bullosa with late-onset muscular dystrophy, which had
traditionally been included in the simplex category, is now known to
result from a mutation in the plectin gene and was included in the
provisional hemidesmosomal group of EB as delineated by Pulkkinen and
Uitto in the 1999 classification scheme.10,13 Hemidesmosomal EB was
distinguished by the split through the hemidesmosome. The group
included EB with late-onset muscular dystrophy (previously included in
the simplex group), some examples of generalized atrophic benign EB
(others associated with laminin-332 mutations are included within the
junctional group) and EB with pyloric atresia (previously included in the
junctional group).10,14–16 These three variants of EB develop as a
consequence of mutations of genes encoding the hemidesmosomal
proteins plectin, BP180, and the α6 and β4 integrin subunits
respectively.10 In the newest classification scheme, these are now
included in the suprabasal and basal types of EB simplex (Table 4.4).
The hemidesmosomal group designation is no longer used as the
104 Inherited and autoimmune subepidermal blistering diseases
Table 4.4 a recently described inherited disease known as ectodermal dysplasia-skin
Simplified classification of epidermolysis bullosa
Subtype Mutation
Simplex Suprabasal Plakophilin-1; desmoplakin
Basal Keratin 5 or 14; plectin; α6β4 integrin
Junctional Herlitz Laminin-332 (laminin-5)
Non-Herlitz Laminin-332; type XVII collagen;
α6β4 integrin
Dystrophic Dominant Type VII collagen
Recessive Type VII collagen
Kindler syndrome Kindlin-1
consensus conference considered its application to be less useful than the
current scheme. The main reason for this decision is that it is a somewhat
artificial category. It separated non-Herlitz junctional EB into two
categories namely, junctional EB and hemidesmosomal EB, based only on
the presence of mutations in the genes encoding either laminin-332 or
type XVII collagen, respectively. Both conditions have very similar
clinical features and cannot be separated on clinical grounds, making this
distinction confusing for clinicians, patients, and their parents. Thus all
the diseases in the hemidesmosomal category are now reclassified into
either the junctional or simplex types of EB.
• Junctional EB is characterized by the development of cleavage within the
lamina lucida. It results from mutations in one of the three genes
encoding the hetrotrimeric subunits of laminin-332 (laminin-5), α6 and β4
integrin subunits, and type XVII collagen.17 As mentioned above, some of
these cases were deamed in the provisional hemidesmosomal category in
the previous classification scheme (e.g., α6 or β4 integrin subunits with EB
with pyloric atresia).
• Dystrophic EB (also known as the dermolytic variant) is defined by a
split developing immediately below the lamina densa in the region of the
anchoring fibrils. This type is composed of genetically dominant and
recessive subtypes invariably due to type VII collagen gene mutations.18,19
Clinical features
EB simplex (EBS)
Two major types of EB simplex (with 12 subtypes) are now recognized:
• suprabasal,
• basal.
Suprabasal EBS
Three suprabasal subtypes are recognized; all of them are rare variants.
Lethal acantholytic EB
Lethal acantholytic EB has been described in two cases with severely defective
skin and mucosal epithelia.19 The disease was lethal in the neonatal period
due to epidermolysis that was first noted during parturition leading to uncon-
trollable loss of fluid from the skin. Additional defects included universal
alopecia and complete shedding of nails and the presence of neonatal teeth.
Histology revealed clefting of the suprabasal layer producing a tombstone-type
appearance reminiscent of pemphigus vulgaris. Molecular investigation
revealed that the patient had inherited two different nonfunctional copies of
the gene encoding desmoplakin (DSP, a desmosomal protein that links the
transmembrane cadherins to the various proteins of the cytoplasmic interme-
diate filaments), one from each parent, indicating that the disease is autosomal
recessive. The mutations both lead to truncation of the desmoplakin protein
and an inability to act as a linker. Additional cases will be necessary to further
define this syndrome.
Plakophilin deficiency (ectodermal dysplasia-skin fragility syndrome,
McGrath syndrome)
Plakophilin is a required component of desmosomes and an important pro-
tein in ectodermal development. The rare deficiencies in this protein result in
fragility syndrome. Plakophilin-1 (PKP1) deficiency is an autosomal recessive
disease that is associated with skin fragility and an inflammatory response
resulting in erosions, scale-crust, and progressive palmoplantar keratoderma.
Ectodermal effects such as sparse hair and anhidrosis and astigmatism are
also noted.20 While initially described in a single child, approximately ten
cases with mutations in this gene have now been described.20,21
Epidermolysis bullosa simplex superficialis
This rare form of EB transmitted in an autosomal dominant fashion was first
described in 1989. It specifically differs from the other simplex variants by
the site of epidermal cleavage: variable subcorneal split between the stratum
corneum and granular cell layer or sometimes within the stratum spinosum
rather than intrabasal.22 Patients present at birth or within the first 2 years of
life with erosions and crusts sparing the palms and soles. Atrophic scarring,
nail dystrophy, and milia are additional common features; oral and ocular
epithelia can be affected.23 As well as the cutaneous manifestations, anemia
and gastrointestinal lesions affect a minority of patients. Some cases are asso-
ciated with mutations causing structural dysfunction of type VII collagen.23
The condition may be clinically confused with peeling skin syndrome but in
the latter there are no blisters and peeling is continous and spontaneous.
Basal EBS
Nine subtypes of basal EBS are currently recognized, five of which are very
rare.
EB simplex, localized (Weber-Cockayne; EB simplex of the
hands and feet)
This is the most common form of epidermolysis bullosa and has an ­autosomal
dominant mode of inheritance.4 5 Lesions are limited to the palms and soles
and are usually detected in infancy or the first few years of life (Fig. 4.9).
Occasionally, in patients with mild involvement, blisters and erosions may
not develop until childhood or even early adulthood in association with
strenuous activity. The lesions, which sometimes heal with atrophic scarring,
show seasonal variation, often occurring only in the summer months.
Hyperhidrosis may sometimes be present. Milia, atrophic scarring, and nail
dystrophy are uncommon features.5,7 The teeth are uninvolved and there is no
evidence of any systemic involvement, except perhaps for oral erosions, which
may affect an appreciable number of patients in infancy.7 Ocular lesions are
not a feature. Repeated episodes of secondary infection may occur in some
patients. Postinflammatory hyper- and hypopigmentation may sometimes
be a cosmetic problem.8
EBS, Dowling-Meara (EBS herpetiformis)
This variant, which is the second commonest form of EB simplex, shows clin-
ical features resembling dermatitis herpetiformis and has an autosomal domi-
nant mode of inheritance (Fig. 4.10).7,24–27 Herpetiform grouping of blisters is
characteristic. Lesions are usually present at birth and have a distribution
sometimes mimicking severe dystrophic or junctional disease.7 Some patients
die in early infancy due to infection, fluid loss or electrolyte imbalance.1 Milia
formation is common, but atrophy and scarring are rare.7 Distal flexural
contractures are occasionally present.25 Nail dystrophy is often found and
palmoplantar keratoderma is characteristic. Anodontia and hypodontia have
also been described. Normalization during episodes of high fever is a typical
finding but seasonal variation is not a feature.26 Blistering significantly
improves with advancing years.27 Mutations in keratins 5 and 14 underlie this
disease.28–31 Death as a result of complications of the disease is rare and gener-
ally occurs by age 1 as a result of sepsis or respiratory failure.32
EBS, other generalized (includes Koebner variant)
This group has an autosomal dominant mode of inheritance and includes pri-
marily those cases previously termed Koebner-type and all other generalized
subtypes of EBS.5 In the Koebner variant, blisters are present at birth or
shortly thereafter and, although the entire body may be affected, lesions are
particularly severe on the extremities, where the dorsal surfaces tend to be
involved (Fig. 4.11).5 The blisters usually heal without scarring or atrophy
and milia are very uncommon.5 The eruption often worsens in the summer
months. The nails are rarely dystrophic and teeth abnormalities are typically
 Epidermolysis bullosa 105

A B

Fig. 4.9
EB simplex (Weber-Cockayne): typical lesions affecting (A) the fingers and (B) the toes. The pale color of the latter is due to the marked thickness of the roof of the blister.
By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.11
EB simplex (Koebner):
intact blisters are present
in the axilla and on the
chest. By courtesy of
M.J. Tidman, MD, Guy's
Hospital, London, UK.
Fig. 4.10
EB bullosa simplex:
Dowling-Meara variant involvement.36–38 Blisters and erosions present at birth or soon ­thereafter and
showing characteristic are usually generalized. Patients may also suffer from atrophic ­scarring, milia,
grouping of blisters and
nail dystrophy or anonychia, alopecia, and oral lesions36,37 Severe mucose
erosions. By courtesy
of R.A.J. Eady, MD,
membrane involvement is rare.39 The mortality of this variant is high.6
Institute of Dermatology, Mutations in plectin are associated with these forms of the disease.40–42 Plectin
London, UK. is a large (greater than 500 kD) intermediate filament binding protein that pro-
vides mechanical rigidity to cells by acting as crosslinking adaptor to the
cytoskeleton.43 The PLEC1 gene bears a domain structure similar to BPAG1,
indicating they belong to a common family and may have similar functions.
absent. Although oral lesions may be present in infancy, systemic involvement
A lethal variant of EBS with mutations in plectin at the level of the plakin
is not a feature of this variant.
domain may occur exceptionally and it is associated with aplasia cutis of the
EBS with mottled pigmentation limbs and developmental impairment.42
This autosomal dominant variant was originally described in six members of
EBS with pyloric atresia
a single kindred.33 The cutaneous lesions are similar to the Dowling-Meara
This category was placed in the provisional hemidesmosomal category in the
variant with the addition of mottled or reticulate pigmentation, particularly
prior edition of this book. Cases with pyloric atresia are currently considered
affecting the neck and trunk. Atrophic scarring, milia, and nail dystrophy are
in two groups: EBS discussed here, and another category in junctional EB dis-
uncommon. Punctate keratoderma affecting the palms and warty hyperkera-
cussed below. This is a rare variant of epidermolysis bullosa in which affected
totic lesions involving the hands, elbows, and knees may be additional fea-
infants are at risk of ureterovesical junction obstruction with fibrosis involv-
tures.33–35 Dental caries is also sometimes present and intraoral lesions are
ing the entire urinary tract and aplasia cutis congenita in addition to pyloric
occasionally seen.
atresia (Figs 4.12, 4.13).44–47 Polyhydramnios is also seen. The pyloric atresia
EBS with muscular dystrophy (pseudojunctional EB) may be due to a diaphragm or stenosis (Fig. 4.14). The mortality rate of this
This is an autosomal recessive variant in which patients concomitantly develop variant is very high, up to 78% of affected infants succumbing.46 It appears to
muscular dystrophy or exceptionally myasthenia gravis and even cardiac be the most lethal form in the EBS category. Mutations in both plectin and
106 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.12
EB with pyloric atresia:
stillborn infant with
widespread blistering.
By courtesy of M.J.
Tidman, MD, Institute of
Dermatology, London, UK.

Fig. 4.14
(A, B) EB with pyloric atresia: pyloric canal is obliterated by fibrous connective tissue.

Fig. 4.13
EB with pyloric atresia: in addition to blistering there is also deep ulceration.
By courtesy of M.J. Tidman, MD, Institute of Dermatology, London, UK.
α6β4 integrin subunits (junctional EB) have been described.48 Since both α6β4
integrin and plectin are expressed in villous trophoblast from the first trimes-
ter of pregnancy this feature has been used successfully for the prenatal diag-
nosis of this group of conditions.49
EBS, autosomal recessive
Autosomal recessive EBS is generalized with onset at birth. Blistering is prom-
inent with mild atrophic scarring. Ichthyotic plaques and focal palmoplantar
keratoderma are sometimes encountered. Nails may be dystrophic or absent.
Anemia, growth retardation, dental caries, and constipation can be complica-
tions.9 Mutations in keratin 14 underlie this disease; keratin 5 mutations have
not been described.50,51
EBS, Ogna
This form is autosomal dominant and presents at birth. It primarily involves
acral sites, but can become widespread. Blistering is prominent and ony-
chogryphosis is common. A tendency to bruise has been described.9,52 Lack of
muscular involvement distinguishes this form of disease from EBS with mus-
cular dystrophy described above; the mutation genotype may be predictive of
disease expression.42,53
Mutations in plectin underlie this syndrome.39,52
EBS, migratory circinate
This generalized form of EBS presents at birth with an autosomal dominant
inheritance pattern. Blistering is very prominent and associated with a migra-
tory circinate erythema and postinflammatory hyperpigmentation.9 Mutations
in keratin 5 have been described, but none is currently reported in keratin
14.39,54,55
Hemidesmosomal EB
This group previously included three variants:
• patients with generalized atrophic benign EB (GABEB) (others were
included in the junctional group; see below),
• EB with late-onset muscular dystrophy (formerly included in the simplex
group),
• EB with pyloric atresia (formerly included in the junctional category).
This subtype is of historical interest only as it no longer exists in the most
current classification scheme.

Junctional epidermolysis bullosa
Two major subtypes of this variant are recognized: junctional EB-Herlitz and
junctional EB-non-Herlitz (Other). This later group encompasses both local-
ized and generalized forms, cases with pyloric atresia, and three additional very
rare variants under the newly revised classification scheme.9 Junctional EB with
pyloric atresia was classified in the hemidesmosomal group in the prior classi-
fication scheme. All have an autosomal recessive mode of inheritance.
Junctional EB, Herlitz (Herlitz, gravis variant of junctional
EB, EB hereditaria letalis, EB atrophicans generalisata
gravis)
Within this generalized variant, no additional subtypes are recognized. Blisters
and erosions are present at birth accompanied by scarring and atrophy
(Fig. 4.15).56–58 Milia may be a feature.7 Healing with the formation of
­exuberant, vegetative or tumorous granulation tissue is a pathognomonic
­feature (Fig. 4.16).5 This is found particularly around the mouth, sides of the
neck, trunk, and about the nails.4 The nails may be dystrophic or absent and
scarring alopecia is sometimes evident.5 Severe oral involvement (including
­scarring and microstomia) is usually present and pitted dystrophic enamel is
characteristic (Fig. 4.17). Dental caries are frequently severe. Other ­features
may include musculoskeletal deformities, gastrointestinal lesions, laryngotra-
cheal stenosis, and genitourinary and ocular involvement. Esophageal involve-
ment may result in stenosis. Perforation with resultant infection is an
important cause of death. Severe growth retardation and anemia are usually
evident. Infantile mortality is high (42.2%).7 Mutations in one of the three
subunits of ­laminin-332 underlie this syndrome.59–61
Junctional EB, Other
The category contains six subtypes, two common and four rare.
JEB, non-Herlitz, generalized (generalized non-Herlitz junctional EB,
EB atrophicans generalisata mitis, generalized atrophic benign EB
(GABEB), hemidesmosomal EB, junctional EB mitis)
This somewhat milder form, in which the cutaneous features are similar to
the gravis form, includes some patients with laminin-332 gene mutations and
others with mutations in type XVII collagen previously classified in the hemi-
desmosomal group.9,62 Systemic involvement is typically mild or absent.63–66
Patients present at birth with extensive blistering and erosions accompanied
by mild scarring and widespread cigarette paper-like atrophy. Variable
Fig. 4.15
Junctional EB (Herlitz):
newly born infant with
blistering and nail
involvement. By courtesy
of J. McGrath, MD,
Institute of Dermatology,
London, UK.
Epidermolysis bullosa 107
Fig. 4.16
Junctional EB (Herlitz): infant showing granulation tissue at the edge of a healing
blister. By courtesy of the Institute of Dermatology, London, UK.
­ yperpigmentation and hypopigmentation are characteristic.63 Skin lesions
h
may be exacerbated during summer. Milia are variably present. Exuberant
­granulation tissue is less common than in the Herlitz variant. Other features
include dystrophic or absent nails (Fig. 4.18), oral erosions with mild scar-
ring, pitted dystrophic enamel, and severe dental caries. Ocular lesions include
recurrent corneal erosion, blistering, and corneal scarring.64 Follicular atro-
phy with resultant alopecia involving the scalp, axillary, and pubic hair in
addition to sparse eyelashes and eyebrows is common (Fig. 4.19).63 Large or
multiple melanocytic nevi have also been described as part of the phenotype58
but this is not currently believed to be a specific feature.5 Contractures do not
develop. Systemic involvement is usually limited to mild laryngeal and/or
esophageal lesions.4 Growth may be retarded and anemia is present in some
patients. Infantile mortality is high (up to 44.7%).7,32
JEB, non-Herlitz, localized
This milder and localized form of JEB is associated with mutations in type
XVII collagen rather than laminin-332.67,68 Genotypic correlations and immu-
nofluorescence antigen mapping may allow distinction of this form from the
more several generalized form.68
JEB with pyloric atresia
All EB with pyloric atresia was previously placed in the now defunct hemides-
mosomal category. These cases are now divided into two categories within
EBS and JEB. While both plectin and α6β4 integrin subunit mutations have
been noted in EBS with pyloric atresia, only the latter is believed associated
with JEB with pyloric stenosis.69–71 The clinical features are similar, with gen-
eralized blisters present from birth associated with atrophic scarring, dystro-
phic or absent nails, and milia on occasion. Large areas of aplasia cutis have
been described.67 This disease is usually fatal at an early age.
JEB inversa
Lesions, which are present at birth or develop in early infancy, are initially gen-
eralized, but later are predominantly localized to inverse (flexural) sites includ-
ing the axillae and groin.5 Blisters and erosions are accompanied by atrophic
scarring and nails may be dystrophic or absent. Other features that are some-
times evident include mouth erosions, maldeveloped teeth with enamel hyp-
oplasia, and occasional gastrointestinal lesions, particularly affecting the
esophagus and anus. Mutations in the subunits of laminin-332 are noted.9,58
JEB-late onset (progressiva)
In this variant, lesions do not present until late childhood, and consist of
blisters and erosions affecting the hands, elbows, knees, and feet.5 Nails
may be dystrophic or absent and enamel hypoplasia is characteristic. Mouth
erosions may be evident. Mild finger contractures are sometimes a compli-
cation.3,5 The mutation underlying this form of the disease is unclear.9
108 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.17 Fig. 4.19

Junctional EB (Herlitz): note the scarring with microstomia and severe dental involvement. Generalized atrophic benign EB: note the sparsely distributed eyebrows and eye
By courtesy of J. McGrath, MD, St John's Dermatology Centre, London, UK. lashes. By courtesy of the Institute of Dermatology, London, UK.

Dominant dystrophic EB
Five subtypes are recognized; four of these are rare.
Dominant dystrophic EB, generalized
Autosomal dominant EB, generalized includes both the Cockayne-Touraine
and Pasini variants. This is because the two conditions are characterized by
identical type VII gene mutations and the albopapuloid lesions (white perifol-
licular papules and plaques) have been found to be an inconsistent finding
(Fig. 4.20).6,7 Generalized blisters are seen at birth (Fig. 4.21a).4,8 Alopecia
may be present and milia, atrophic scarring, and dystrophic or absent nails
are typical features (Fig. 4.21b). Oral involvement may be mild or absent.
Enamel hypoplasia is sometimes evident. Gastrointestinal and genitourinary
tract involvement is seen in a minority of patients. There is a slightly increased
risk of basal cell carcinoma and melanoma.75

Dominant dystrophic EB, acral

In this mild autosomal dominant localized variant, lesions present at birth or
in early childhood, particularly in an acral distribution. Blisters and erosions
in the absence of other significant lesions except for atrophic scarring, milia,
Fig. 4.18
Generalized atrophic benign EB: there is scarring and complete absence of nails.
By courtesy of the Institute of Dermatology, London, UK.

Laryngo-onycho-cutaneous (LOC) syndrome

A mutation in the gene encoding the laminin-332 α3 chain resulting in an
unusual N-terminal deletion underlies this syndrome.72 It was first described
by Shabbir and colleagues in 22 patients of Punjabi extraction and about 10
additional cases have been described.73,74 So far, this autosomal recessive con-
dition has not been described outside of this population. It can occur in a
nonconsanguineous context. It consists of epithelial defects resulting in cuta-
neous erosions, nail dystrophy, and chronic conjunctival and laryngeal granu-
lation tissue. Symblepharon and blindness are serious complications. Airway
obstruction and infection can also be problematic. The degree of skin fragility
is less than that seen in other variants of JEB. Under the new classification
system, based on molecular and clinical similarities to JEB, this syndrome has
been added as a rare variant.9,59

Dystrophic EB
Two major subtypes – dominant dystrophic EB and recessive dystrophic EB
(Hallopeau-Siemens) – are recognized and these are categorized into three
major subtypes (one dominant and two recessive) and nine rare dominant or
recessive groups. All subtypes are associated with mutations in the gene
encoding type VII collagen. 9
Fig. 4.20
Dystrophic EB: albopapuloid lesions on the lumbosacral area. These are an
inconstant finding in dystrophic EB. The lesions are not preceded by blistering and
probably represent connective tissue nevi. By courtesy of M.J. Tidman, MD, Guy's
Hospital, London, UK.

A B
and nail dystrophy may cease altogether after childhood.1 Extracutaneous
manifestations have not been recorded.
Dominant dystrophic EB, pretibial
This is a mild, localized, and typically symmetrical autosomal dominant form.
An autosomal recessive variant has recently been described (see below).76 The
onset is often delayed, patients usually presenting in early ­childhood.77 Blisters
and erosions accompanied by atrophic scarring and milia are ­particularly
seen on the pretibial region and dorsal aspects of the feet (Figs 4.22, 4.23).
The scarring may have a violaceous appearance reminiscent of hypertrophic
lichen planus.76 Lesions are also sometimes seen on the forearms and trunk.76
Pruritus and nail dystrophy are common. There are no teeth or hair
changes.77
Dominant dystrophic EB, pruriginosa
This variant, which presents in childhood, includes dominant and ­recessive
variants (see below).78 Patients present with highly pruritic, violaceous
Fig. 4.22
Dystrophic EB–pretibial: extensive erosions with scarring are localized to the front
of both shins. By courtesy of the Institute of Dermatology, London, UK.
Epidermolysis bullosa 109
Fig. 4.21
Dominant dystrophic EB
(Cockayne-Touraine): (A)
truncal involvement is present
in addition to the more typical
limb lesions; (B) hemorrhagic
blisters, scarring, milia and
nail dystrophy. By courtesy of
the Institute of Dermatology,
London, UK.
Fig. 4.23
Dystrophic EB–pretibial: close-up view. By courtesy of the Institute of Dermatology,
London, UK.
­ odular prurigo-like nodules developing against a background of blisters,
n
milia, nail dystrophy, and albopapuloid lesions.
Dominant dystrophic EB, bullous epidermolysis of the newborn
This exceptionally rare, self-limiting condition presents in the newborn with
blisters that usually resolve within the first 2 years and heal with mild atro-
phy, milia, and scarring.79,80 Most cases have been inherited as an autosomal
dominant, although recessive variants have also been documented.6
Recessive Dystrophic EB
This category is composed of seven subtypes, of which five are rare.
Recessive dystrophic EB, severe generalized (Hallopeau-Siemens;
polydysplastic EB; EB gravis)
This autosomal recessive variant is a much more serious form than its auto-
somal dominant counterpart.4,8 Blisters and erosions are present at birth and,
atrophy, scarring, anemia, and growth retardation are consistently present
(Figs 4.24, 4.25). Nikolsky's sign is positive. Destructive involvement of the
distal peripheries results in contractures and severe deformities including the
characteristic ‘mitten lesions’ (pseudosyndactyly) of the hands and feet (Figs
4.26–4.28).81 If the latter is left untreated, there may eventually be resorption
of the underlying bones (autoamputation). Nail dystrophy and milia are
marked, and scarring alopecia is common (Fig 4.29). Oral involvement is
severe, with blisters, erosions, and scarring. Excessive caries are usual.
110 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.24
Recessive dystrophic EB (Hallopeau-Siemens): extensive blistering present at birth.
The disease process has involved the nails and those of the first two toes are
absent. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 4.27
(A, B) Recessive dystrophic EB (Hallopeau-Siemens): in addition to the gross mitten
deformity, there is very severe scarring and scaling. (A) By courtesy of R.A.J.
Eady, MD, and B. Mayou, MD, St Thomas' Hospital, London; (B) by courtesy of the
Institute of Dermatology, London, UK.
Fig. 4.25
Recessive dystrophic EB (Hallopeau-Siemens): note the scarring and extensive
erosions. By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.26
Recessive dystrophic EB (Hallopeau-Siemens): weblike folds enveloping the toes Fig. 4.28
have resulted in a clublike appearance. By courtesy of R.A. Marsden, MD, St George's Recessive dystrophic EB (Hallopeau-Siemens): there is gross deformity of the knees.
Hospital, London, UK. By courtesy of J. McGrath, MD, Institute of Dermatology, London, UK.
 Epidermolysis bullosa 111

Fig. 4.30
Recessive dystrophic EB:
extensive esophageal
involvement with
complete separation of
Fig. 4.29 the mucosa has resulted
Recessive dystrophic EB in this dramatic, but
(Hallopeau-Siemens): note fortunately very rare,
the conspicuous milia. manifestation. By courtesy
By courtesy of the of R.A. Marsden, MD,
Institute of Dermatology, St George's Hospital,
London, UK. London, UK.

Gastrointestinal and renal complications are common.82,83 There is often con-

junctival involvement with keratitis and scarring, and lesions of the mucous
membranes result in difficulty in opening the mouth, dysphagia, and esopha-
geal stricture formation, with some infants eventually succumbing to terminal
respiratory infections (Fig. 4.30).84 Anal and genitourinary involvement may
also be present. Squamous cell carcinoma is a common complication of the
cutaneous scarring (occurring in 39.6% of cases) and is a significant cause of
mortality (Figs 4.31–4.33).85,86 Tumors are frequently multiple, have an aggres-
sive behavior, and may be associated with extensive metastatic spread.
Melanoma much less commonly develops. This variant of EB has a high mor-
tality: 38.7%.7

Recessive dystrophic EB, generalized other

This type is often referred to as non-Hallopeau-Siemens type. In contrast to
the severe generalized form, anemia and mental retardation are less common
and dental caries are not increased. In this variant the features are similar to
the Hallopeau-Siemens variant except that the extracutaneous lesions and
complications (e.g., anemia, mental retardation, and dental caries) are less
severe and the risk of developing cutaneous squamous cell carcinoma is
diminished (14.3%).4,8 The mortality for this variant of EB is 10.0%.87
Genotypic differences in mutational types and sites in the gene encoding type Fig. 4.31
VII collagen likely underlie differences in the phenotypic expression of this Recessive dystrophic EB (Hallopeau-Siemens): in this patient numerous large
disease.88 keratoses are evident. Many of these progress to squamous cell carcinoma. Courtesy
of R.A.J. Eady, MD, and B. Mayou, MD, St Thomas' Hospital, London, UK.
Recessive dystrophic EB, inversa
In this autosomal recessive form, lesions are present at birth and consist of
blisters, erosions, milia, and atrophic scarring, found particularly about the
flexural sites, including the inguinal regions, axillae, neck, and the lower Recessive dystrophic EB, centripetalis
back.89,90 Nail dystrophy is usually evident and sometimes scarring alopecia is This autosomal recessive localized form has been described in a single
seen. Severe oral and esophageal involvement (erosions and scarring) is patient. Presentation was at birth with widespread blisters. In adulthood,
characteristic.91 however, the distribution became acral. The blisters, milia, and severe scar-
ring with atrophy then showed a characteristic centripetal spread. Nail dys-
Recessive dystrophic EB, pretibial trophy and/or absence were also present. Despite the severe scarring,
The pattern of involvement is similar to the dominant form (see above), but contractures and deformities were not features.92 There were no extracuta-
can be more severe. neous manifestations.

Recessive dystrophic EB, pruriginosa Recessive dystrophic EB, bullous dermolysis of the newborn
The pattern of involvement is similar to the dominant form (see above), but The pattern of involvement is similar to the dominant form (see above), but
can be more severe. can be more severe.
112 Inherited and autoimmune subepidermal blistering diseases
Fig. 4.32
Recessive dystrophic EB (Hallopeau-Siemens): in addition to severe scarring
accompanied by autoamputation of the fingertips, there is a large ulcerated squamous
cell carcinoma. Courtesy of R.A.J. Eady, MD, and B. Mayou, MD, St Thomas' Hospital,
London, UK.
Fig. 4.33
Recessive dystrophic EB (Hallopeau-Siemens): in this patient there is a massive
squamous carcinoma, which has destroyed much of the knee. Courtesy of R.A.J.
Eady, MD, and B. Mayou, MD, St Thomas' Hospital, London, UK.
Kindler syndrome
Kindler syndrome has been added to the EB classification scheme due to simi-
larities to EB, and the hope that patients with this disease may benefit from the
greater molecular and pathogenetic understanding of EB as a whole. It does
not readily fit into any of the EB types as the level of blistering separation can
be intraepidermal, junctional or below the lamina densa. This disease is caused
by a mutation in the KIND1 gene that encodes the protein kindlin-1, a component
of contact foci in basal keratinocytes.93,94 First described in 1954, more than
50 cases are now published in the literature.95,96 Significant heterogeneity is
noted, but this rare autosomal recessive disease is associated with skin fragility
similar to other forms of EB associated with the symptoms of poikiloderma
and photosensitivity not seen in other forms of EB. Trauma-induced blistering
and photosensitivity often improve with age. Squamous cell carcinoma and
transitional cell carcinoma of the bladder have been described.97
All types of hereditary epidermolysis bullosa (simplex, junctional, and
­dystrophic) may rarely present with large nevi that often simulate melanoma on
clinical grounds. Histology, however, shows no evidence of mali­gnancy.98,99
Pathogenesis and histological features
The investigation of a patient with suspected EB should ideally include immu-
nofluorescence antigen mapping, ultrastructural, and molecular genetic
­studies. In general, routine histopathology often contributes little, other than
to confirm the presence of a subepidermal blister.
Immunofluorescent antigen mapping of basement membrane determinants
is a method of identification of the plane of cleavage in the various types of
EB that can sometimes avoid the need for ultrastructural studies.100,101
Essentially, the location of three antigens – type IV collagen, laminin-332,
and bullous pemphigoid antigen-1 – is determined by standard indirect immu-
nofluorescence of lesional (either naturally occurring or mechanically induced)
skin:7
• In simplex variants, all three antigens are found along the floor of the blister.
• In junctional lesions, bullous pemphigoid antigen-1 is identified mainly in
the roof of the blister, whereas laminin-332 and type IV collagen are
present along the floor.
• In dystrophic EB, the plane of cleavage is below the lamina densa and
therefore all three basement membrane antigens are present in the roof of
the blister.
The immunofluorescent investigation of skin samples for a wide range of
recognized basement membrane constituents known to be absent or
­diminished in the various subtypes of epidermolysis bullosa has proved to be
particularly valuable, and has also been shown to be of use in antenatal
(16–18 weeks' gestation) diagnosis.102–104
The monoclonal antibody KF-1, which localizes to the lamina densa, shows
an absence of labeling in nonlesional skin from patients with the severe
recessive dystrophic form of EB, whereas in the dominant variant it is
reduced.105,106
The monoclonal antibodies AF1 and AF2, which recognize antigens in and
immediately below the lamina densa (probably constituents of anchoring fibrils),
show an absence of immunolabeling in both normal and lesional skin from the
recessive dystrophic form, but appear normal in dominant dystrophic EB.107
LH7:2 is a monoclonal antibody directed against the NC-1 globular
domain of type VII collagen, which binds to the lamina densa and attached
anchoring fibrils.108,109 Labeling is absent or markedly reduced in the severe
recessive dystrophic form, patchily reduced in mild or localized recessive dys-
trophic variants, and normal in the dominant dystrophic variant.110,111
Immunolabeling with the monoclonal antibody GB3, which recognizes
laminin-332 (nicein/kalinin/epligrin), is reduced or absent in the junctional
(Herlitz) form of EB. It may be normal, reduced or absent in the non-Herlitz
junctional variants.112,113 Laminin-332 is a major constituent of the anchoring
filaments, which stretch from the hemidesmosomes to the lamina densa.
Two further antibodies, 19-DEJ-1 and AA3, characteristically fail to label
the basement membrane zone in all patients with junctional epidermolysis
bullosa and are therefore of additional diagnostic value.114 19-DEJ-1, which
recognizes uncein, has been recommended as the most reliable antibody for
evaluation and diagnosis of the major junctional variants.115,116
Bullous pemphigoid 180-kD antigen is demonstrably diminished or absent
as determined by immunofluorescence in many patients with generalized
atrophic benign EB.117
EB simplex
In EB simplex variants, blisters develop as a consequence of basal cell ­cytolysis
(Fig. 4.34). The plane of cleavage lies deep to the nuclei of the keratinocytes
such that wispy remnants of basal cell cytoplasm may be identified along the
floor of the blister cavity, which is therefore intraepidermal in location
(Figs 4.35, 4.36).118 In older lesions the blister often appears to be subepidermal
due to continued lytic changes of the residual keratinocyte cytoplasm
(Fig. 4.37). By direct immunoperoxidase antigen mapping on paraffin-embedded
sections, keratin, laminin, and type IV collagen staining may be identified along
the floor of the blister, confirming its intraepidermal location (Fig. 4.38).
Ultrastructural studies have shown that the earliest change is loss of keratin
filaments (tonofilaments).118,119 As a consequence, there is structural instabil-
ity and fragility of the keratinocytes. Keratin clumps similar to those described
in the Dowling-Meara variant (see below) have been a rare finding in EB simplex
Koebner.120 Loss of keratin filaments is subsequently followed by dissolution
 Epidermolysis bullosa 113

Fig. 4.34
EB simplex: the earliest histological feature in the development of a blister is Fig. 4.37
marked vacuolation of the basal keratinocytes, so-called cytolysis. EB simplex: old lesion; the features are those of a cell-free subepidermal blister and
are not specific.

Fig. 4.35
EB simplex: established lesion showing ‘subepidermal’ vesiculation.
Fig. 4.38
EB simplex: paraffin
immunoperoxidase
displays type IV collagen
along the floor of the
blister cavity (same case
as Fig. 4.37).

of the other keratinocyte cytoplasmic constituents. Suprabasal desmosomes

appear unaffected. The lamina densa and anchoring fibrils are normal. While
the hemidesmosomes generally appear normal, reduplication and increased
electron density have been described in a recent case report.121
The Dowling-Meara variant (including the subset with mottled pigmenta-
tion) is characterized by 1–5-μm homogenous intracytoplasmic clumps of
keratin filaments in addition to cytolysis (Fig. 4.39).122 These are present in
the basal keratinocytes and extend into the overlying prickle cell layer. They
may also be identified in the follicular outer root sheaths, dermal eccrine
sweat ducts, and sebaceous glands. The clumps are composed of keratins
5 (type II) and 14 (type I).122 In addition to intraepidermal vesiculation,
Fig. 4.36 ­intrakeratinocyte cleavage may also be found in the follicular infundibula.
EB simplex: basal keratinocyte cytoplasmic remnants are visible along the floor of The other skin appendage structures are not affected. The dermis may contain
the blister cavity. an infiltrate of lymphocytes and eosinophils.
114 Inherited and autoimmune subepidermal blistering diseases
A B
The keratoderma shows hyperkeratosis and acanthosis. Clumps of keratin
may also be evident.
Ultrastructurally, the level of cleavage is low within the basal keratinocytes, just
above the level of the hemidesmosomes (Figs 4.40, 4.41). In ­addition to cytolysis,
however, acantholysis may also sometimes be evident. The keratin filament
abnormalities include irregular whorled bundles in addition to homogeneous
clumps. They are present in normal skin in addition to lesional material
(Fig. 4.42).122,123 Desmosomes may appear diminished in number in the keratinocytes
showing tonofilament clumps. Basement membrane zone constituents are normal.
In EB simplex superficialis the plane of cleavage is in the upper epidermis
just beneath the stratum corneum.22 Additional clefts may also be evident in
the lower third of the epidermis.
It is now apparent that the majority of EB simplex develop as a direct
­consequence of keratin gene mutation, but mutations in desmoplakin,
­plakophilin, plectin, and α6β4 integrin subunits are seen in some of the rare
subtypes (see Table 4.2).124,125 Following the initial discovery of keratin
­filament clumps in Dowling-Meara EB and their subsequent identification as
keratins 5 and 14, it was shown that keratinocyte cultures from patients with
this disease exhibited an identical morphological abnormality.120 Genetic
linkage studies showed that EB simplex was associated with keratin gene
Fig. 4.40
EB simplex (Koebner): the
M blister cavity forms within
the basal keratinocyte.
Note the cytoplasmic
remnants along the
floor of the blister.
(M, melanosome.)
Fig. 4.39
EB simplex (Dowling-Meara): (A) electron micrograph
showing intrakeratinocyte splitting; (B) close-up view of
tonofilament clumps. By courtesy of J.A. McGrath, MD, and
R.A.J. Eady, MD, Institute of Dermatology, London, UK.
clusters on chromosomes 12 and 17.126–130 The gene for keratin 5 is carried on
chromosome 12q and that for keratin 14 is located on 17q. Truncated mutant
human keratin 14 gene induces the EB phenotype when introduced into trans-
genic mice and similarly causes an identical keratin abnormality when
expressed in ­transfected human keratinocytes.131,132 Specific missense muta-
tions or ­deletions have now been identified in patients with Dowling-Meara
(K5 and K14), localized (K5 and14), other generalized (K5 and14) subtypes,
and the the rare EB simplex subtypes with mottled pigmentation (K5), autosomal
recessive (K14), and migratory circinate (K5).133–138 The highly conserved end
domains of the keratin rod are particularly susceptible to significant mutation
with resultant instability of the filament assembly and consequent fragility of
basal keratinocytes following mild trauma.124
Plectin, which localizes to the inner plaque of the hemidesmosome, is a
member of the plakin family and in concert with BP230 is believed to be of
importance in keratin filament anchorage.10,14 Recently, mutation of the gene
PLEC1 encoding this protein has been described in patients with the muscular
dystrophy-associated, pyloric atresia, and Ogna subtypes.39 Plectin is associ-
ated with the Z-lines in the desmin cytoskeleton and this explains its
importance in myocyte adhesion and their role in the pathogenesis of EBS
with muscular dystrophy.139 Mutations in the genes encoding desmoplakin
and plakophilin-1, respectively, are associated with lethal acantholyic EB and
­plakophilin deficiency.19,20
EB (both the simplex and junctional forms) associated with pyloric atresia
results from α6β4 integrin missense mutations resulting in premature termina-
tion codons with synthesis of defective or nonfunctional α6 or β4 subunits.140–142
As a result, hemidesmosomes are hypoplastic or reduced in number.10 Mutations
in the gene encoding plectin are also noted in the simplex form.48,143
Exceptionally, amlyoid has been described in the Weber-Cockayne type of
EB.144 Dyskeratosis has been reported as a histologic feature in Dowling-Meara
EB but not in other variants, including Koebner EB or Weber Cockayne EB.145
The sample in this study, however, was small and further investigation is
required to confirm the specificity of this finding.
Junctional EB
Junctional EB variants are also characterized by subepidermal ­blistering, usually
unaccompanied by any substantial inflammatory cell infiltrate (Fig. 4.43).146
Ultrastructurally, the site of cleavage is through the lamina lucida (Fig. 4.44). The
hemidesmosomes may appear malformed, be ­diminished in number or

Fig. 4.41
EB simplex (Koebner): this high-power view shows the floor of the blister cavity.
Note the lamina densa (arrowed), hemidesmosomes (arrowheads) and basal
keratinocyte cytoplasm. (A, blister; B, cytoplasm; C, dermis.)
Fig. 4.42
Epidermolysis bullosa simplex (Dowling-Meara): numerous tonofilament clumps are
present in the adjacent clinically normal skin (arrowed). By courtesy of J.A. McGrath,
MD, Institute of Dermatology, London, UK.
absent.147–150 Hemidesmosome alterations as detected by electron microscopy,
however, are heterogeneous. In a morphometric study of numbers of hemidesmo-
somes per unit length of basement membrane, one of five patients with the Herlitz
variant and two of three patients with non-Herlitz variants had normal results.151
The same authors recorded an association between junctional EB and a reduction
in the numbers of hemidesmosomes with associated sub-basal plates.
Junctional EB is characterized by mutations in the genes that encode the
α3, β3 or γ2 chains of laminin-332 (laminin-5).152–158 Mutations resulting in
premature termination codons in the laminin-332 genes are present, for
example, in all cases of the Herlitz lethal variant.7,10 Nonsense mutations,
out-of-frame deletions or insertions and splicing errors affect both alleles,
resulting in reduced synthesis and defective assembly of trimeric laminin-5
molecules.10 The majority of mutations have affected the LAMB3 gene
although LAMA3 and LAMC2 gene abnormalities have also been docu-
mented. Non-Herlitz junctional EB variants, including some cases of general-
ized atrophic benign EB, are associated with milder missense mutations or
deletions in the laminin-332 genes.152,159,160 Laminin-332 is located within
anchoring filaments and in the lamina densa. The abnormal laminin-332
results in defective anchoring filaments with resultant instability at the base-
ment membrane region.
Epidermolysis bullosa 115
Fig. 4.43
Junctional EB: subepidermal cell-free blister.
Fig. 4.44
Junctional EB: lesional skin showing separation within the lamina lucida of the
dermoepidermal junction. By courtesy of R.A.J. Eady, MD, Institute of Dermatology,
and M.J. Tidman, MD, Guy's Hospital, London, UK.
Junctional EB, non-Herlitz (generalized and localized) is most commonly
a result of BP180 mutations (BPAG2/type XVII collagen).161–163 Nonsense
mutations or insertions/deletions with resultant premature termination
codons result in absence of type XVII collagen. This is a transmembrane col-
lagen that is thought to contribute to the anchoring filaments via its carboxy-terminal
segment.10 The amino-terminal globular domain resides within the cytoplasm
of the basal keratinocyte localizing to the outer plaque of the hemidesmo-
some. Less often, laminin-332 mutations are responsible for this clinical
phenotype.
Dystrophic EB
In the dystrophic variants the histological features are those of subepidermal
vesiculation or blister formation in the absence of any significant inflamma-
tory content (Fig. 4.45). The clinical subtypes show no particular distinguishing
features. The adjacent dermis is often markedly scarred due to previous epi-
sodes of blistering.
The squamous carcinoma that develops in association with recessive dys-
trophic EB is very often well differentiated (Fig. 4.46) and occasionally its
appearance suggests a verrucous variant. Whether this latter form has the
good prognosis usually evident with verrucous carcinoma is uncertain.
116 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.45 Fig. 4.47

Dystrophic EB (Hallopeau-Siemens): in addition to obvious subepidermal blistering Dystrophic EB (Hallopeau-Siemens): lesional skin demonstrates cleavage
there is dermal scarring and chronic inflammation. immediately beneath the lamina densa of the dermoepidermal junction (arrowed).
By courtesy of R.A.J. Eady, MD, Institute of Dermatology, and M.J. Tidman, MD,
Guy's Hospital, London, UK.

Ultrastructurally, the site of cleavage is immediately below the lamina

densa (Fig. 4.47).164,165 In the autosomal dominant and some localized
recessive groups, anchoring fibrils are decreased in number, but may
appear ­morphologically normal, whereas in the generalized recessive
­variants (and occasionally in severe dominant cases), the fibrils are very
sparse or more often absent.166–168 Frequently, thin wispy filaments imme-
diately adjacent to the lamina densa are all that are visible. In a recent
morphometric study of basement membrane in various dystrophic forms,
using nonblistered skin, anchoring fibrils were completely absent in gen-
eralized recessive dystrophic EB. Reduced numbers of morphologically
normal anchoring fibrils were found in localized recessive and dominant
dystrophic variants.169 Type VII collagen expression in dystrophic EB,
however, as determined by LH7:2 immunolabeling, is not an all-or-none
phenomenon. Even in the recessive variant, some positive staining of thin,
­ill-formed filamentous structures may be seen immediately below the lam-
ina densa. Collagenolysis in the superficial dermis may also be seen in the
A more severe variants.
In transient bullous dermolysis of the newborn, in addition to reduced
numbers of anchoring fibrils, intracytoplasmic inclusions are seen in the basal
keratinocytes. These have a stellate appearance and represent retained type
VII and type IV collagen.170–172
Dystrophic EB variants are all caused by mutations in the type VII collagen
gene COL7A1.173–175 Over 100 distinct mutations have been identified.10 The
Hallopeau-Siemens severe recessive variant is characterized by nonsense
mutations, insertions, deletions or splicing errors, which cause premature ter-
mination codons affecting both alleles, resulting in very low levels of mRNA
and virtual absence of type VII collagen synthesis.10,172,173 Premature termina-
tion codon, missense, deletion, and substitution mutations have been identi-
fied in a number of the less severe dystrophic variants.7 Dominant dystrophic
EB is caused by a glycine substitution mutation resulting in a less severe vari-
ant in which type VII collagen, although defective, is still produced and
anchoring filaments are present albeit in reduced numbers.176,177 Transient
bullous dermolysis of the newborn also results from a mutation in
COL7A1.79,80
B Milia, which are most commonly seen in dystrophic EB, are small cysts within
the upper dermis, consisting of a mass of keratinized squames surrounded by a
Fig. 4.46 wall of squamous epithelium, thereby representing miniepidermoid cysts. They
(A, B) Dystrophic EB (Hallopeau-Siemens): biopsy from the forearm of a 30-year-old are not specific to epidermolysis bullosa, being found in a variety of conditions
patient showing a cell-free subepidermal blister. In addition, a well-differentiated associated with damage to the cutaneous adnexal structures (e.g., severe burns
squamous cell carcinoma extends into the subcutaneous fat. and porphyria cutanea tarda) and other blistering disorders.
 Bullous pemphigoid 117

Differential diagnosis (Fig. 4.51). Often they contain clear or bloodstained fluid. Any area of the
body may be affected, but the blisters are most commonly located about the
With the appropriate clinical information the histological diagnosis of EB
lower abdomen, the inner aspect of the thighs and on the flexural surfaces of
should not pose any problems. With the exception, however, of the
the forearms, the axillae, and groin (Fig. 4.52).14 Grouping of lesions as seen
Dowling-Meara variant, it is not usually possible to predict which subtype
the patient suffers from although, in specimens from early lesions, it is in dermatitis herpetiformis is not usually a feature and symmetry is character-
sometimes possible to identify the simplex variants of the basis of cytolysis. istically absent. A ‘cluster of jewels’ appearance of new blisters arising at the
Cell-free subepidermal blisters, however, may be seen in a variety of conditions edge of resolving lesions as seen in linear IgA disease may, however, ­occasionally
be a feature of bullous pemphigoid (Fig. 4.53).15 The lesions are often pruritic
including autolysis, EB acquisita, cell-free pemphigoid, suction blisters,
and a burning sensation is sometimes a feature. Nikolsky's sign is usually
bullous cutaneous amyloidosis, bullous lichen sclerosus, porphyria cutanea
negative. In contrast to mucous membrane pemphigoid, generalized bullous
tarda, and pseudoporphyria.
pemphigoid is not associated with scarring.
Because the genetic defects for so many of the EB subtypes are now known,
Reported mucosal involvement (frequently as ulcers) is highly variable,
prenanatal testing is possible.178 It is hoped that understanding of the molecu-
lar pathobiology of this disease may eventually lead to successful gene ther- ranging from 8% to 58%.16–18 In a series of 115 patients, 24% had oral
involvement and 7% had genital lesions.18 Lesions are found most often on
apy as was recently described for a patient with junctional EB using
the palate, the cheeks, lips, and tongue (Fig. 4.54). Other sites less commonly
transplanted epidermal stem cells genetically modified to express wildtype
involved include mucosae of the nose, pharynx, conjunctiva and, rarely, the
LAMB3.179,180
urethra and vulva (see below) (Fig. 4.55).17 In contrast to mucous membrane
pemphigoid, mucosal involvement in generalized bullous pemphigoid is not
associated with scarring.
Bullous pemphigoid
Clinical features
Bullous pemphigoid is not a single disease entity. Rather, there are many sub-
types, which have been classified into primary cutaneous and mucosal vari-
ants and into generalized and localized forms (Fig. 4.48).1–4 Bullous
pemphigoid (BP) is the most frequently encountered autoimmune bullous
dermatosis with an annual incidence of 6.6 new cases per one million of the
population.5,6

Generalized cutaneous pemphigoid

Any age group may be affected, but the generalized variant demonstrates
a predilection for the later years of life, showing a maximum incidence in
the seventh decade and over. Rarely, however, children and even infants
may be affected.7,8 The disease is associated with a worldwide distribu-
tion and shows no racial propensity. There are no significant human leu-
kocyte antigen (HLA) associations and the sex incidence is approximately
equal.
Prodromal events are numerous and include erythematous, urticarial and,
rarely, eczematous phases.9,10 Erythroderma, either preceding the bullous Fig. 4.49
phase or occurring simultaneously, is a very rare manifestation (erythroder- Erythrodermic BP: blistering has developed against a background of generalized
mic pemphigoid).11,12 Similarly, patients may present with a history of gener- erythroderma. By courtesy of the Institute of Dermatology, London, UK.
alized pruritus in the absence of visible skin lesions (pruritic pemphigoid). In
such circumstances, immunofluorescence investigations are essential to estab-
lish the correct diagnosis.13
The characteristic lesions of established disease are tense and often intact
blisters arising on normal or erythematous skin (Figs 4.49, 4.50). They may
measure up to several centimeters in diameter and are typically dome-shaped

Generalized
Vesicular
Polymorphic
Widespread Vegetans
Nodularis
Erythrodermic
Cutaneous
Seborrheic

Pretibial
Localized
Brunsting-Perry

Widespread Mucous Membrane

Mucosal
Desquamative Gingivitis
Localized
Oral
Fig. 4.50
Fig. 4.48 BP: early tense blister arising on an erythematous base. By courtesy of the Institute
Bullous pemphigoid: classification. of Dermatology, London, UK.
118 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.51 Fig. 4.53

BP: tense, dome-shaped blisters. The flexures are typically affected. By courtesy of BP: new blisters arising at the edge of a healing lesion (‘cluster of jewels’ sign). Although
the Institute of Dermatology, London, UK. typically seen in childhood linear IgA disease, this is sometimes a feature of bullous
pemphigoid. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 4.54
Fig. 4.52 BP: oral erosions are an occasional finding. Intact blisters are rare. By courtesy of
BP: widespread, fluid- R.A. Marsden, MD, St George's Hospital, London, UK.
filled, hemorrhagic blisters
on the arms and legs
of an elderly female. By
courtesy of the late M.
Beare, MD, Royal Victoria
Hospital, Belfast, N.
Ireland.

Although bullous pemphigoid has been reported in association with a

variety of internal malignancies, this may just be coincidental, merely reflect-
ing the age incidence of these two diseases.19 In a series of almost 500 patients
from Sweden, no increased incidence of cancer was observed.20 Other stud-
ies, however, have shown that there may be a positive correlation between
internal malignancy and seronegative bullous pemphigoid patients.21
Generalized bullous pemphigoid is a serious condition with a significant
mortality ranging from 10% to 20%.1 Since the advent of steroid therapy and
immunosuppressive agents, patients are more at risk of developing severe iat-
rogenic disorders than of dying from their disease.22 Morbidity from this dis-
ease may be related more to the age and general state of health of the patient
than to the severity of blistering.23 Although mortality from the disease is low, Fig. 4.55
there has been a reported increase in mortality in the last 20 years of the BP: conjunctival injection is present. By courtesy of R.A. Marsden, MD, St George's
twentieth century.24 Hospital, London, UK.

Fig. 4.56
Bullous pemphigoid: occasionally erythematous urticarial lesions may be the
presenting feature. Blisters may not evolve until several weeks later. By courtesy of
R.A. Marsden, MD, St George's Hospital, London, UK.
Clinical variants of generalized pemphigoid
Urticarial bullous pemphigoid presents with large persistent erythematous
plaques, which sometimes display an annular or gyrate peripheral component
(Fig. 4 56, 4.57).1 Rarely, small vesicles are also to be found.
Vesicular pemphigoid is a rare clinical variant in which the cutaneous
manifestations show a striking overlap with dermatitis herpetiformis.25–28
Patients present with numerous small tense vesicles that may be symmetrical,
intensely pruritic, and therefore associated with conspicuous excoriation.
Polymorphic pemphigoid is a somewhat confusing entity, which is similar
to vesicular pemphigoid, but probably shows overlap with linear IgA
disease.29–31
Patients present with burning and itching lesions predominantly affecting
the extensor aspects of the limbs, back, and buttocks. Symmetry, grouping,
and a polymorphic clinical appearance of papules, vesicles, and variably sized
bullae emphasize a similarity to dermatitis herpetiformis. It has been sug-
gested that polymorphic pemphigoid is not an entity sui generis, but repre-
sents a potpouri of conditions including vesicular pemphigoid, linear IgA
disease, and mixed subepidermal bullous disease in which patients show both
linear IgG and linear IgA or dermal papillary granular IgA on direct
immunofluorescence.30
Pemphigoid vegetans is an exceedingly rare vegetative intertriginous vari-
ant that may be associated with chronic inflammatory bowel disease.32–39
Fewer than 10 cases have been documented. Patients present with vegetative,
crusted, purulent, and sometimes eroded lesions in the groin, axillae, neck,
hands, eyelids, inframammary, and perioral regions (Fig. 4.58). Vesicles and
bullae may also be evident. Scarring has been described.39 The etiology of the
vegetative lesions is unknown.
Seborrheic pemphigoid is a variant in which the clinical features are sug-
gestive of pemphigus erythematosus.31
Pemphigoid nodularis represents the extremely rare association of lesions
of bullous pemphigoid with intensely pruritic papules and nodules of nodular
prurigo predominantly affecting the trunk and extremities (Fig. 4.59).40–42
The association of pemphigoid nodularis with immune dysregulation, poly-
endocrinopathy, enteropathy, and X-linked (IPEX) syndrome is the subject of
a single case report.43
Exceptionally, patients may show immunofluorescent evidence of bullous
pemphigoid in the absence of clinical blistering.42 The cause of this unusual
phenomenon is unknown although in some patients at least, chronic scratch-
ing probably damages the basement membrane region with exposure of
bullous pemphigoid antigens. There is a female predilection (2:1).42 The age
range of this variant extends from 24 to 80 years but, as with classical bullous
pemphigoid, the majority of patients are elderly.
Bullous pemphigoid 119
Fig. 4.57
Bullous pemphigoid: close up view. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
Dyshidrosiform pemphigoid is a rare variant of pemphigoid in which
patients develop 1–2-mm, tense ‘sago-grain-like’ vesicles on the palms and
soles resembling dyshidrosiform dermatitis (pompholyx).44–50 Lesions may be
localized, or precede or occur simultaneously with generalized disease.
Overlap with pemphigoid nodularis has been described.51
Childhood pemphigoid exhibits lesions that are similar to their adult coun-
terparts, but there is some tendency for lesions to be localized around the
face, lower trunk, thighs, and genitalia, reminiscent of linear IgA disease in
childhood (Fig. 4.60).7,8,52–61 Similarly, a ‘cluster of jewels’ ­appearance is
sometimes evident.7 Palmar, plantar, and oral lesions are often present and
may be the sole site of involvement in infants (Fig. 4.61). The mucous mem-
branes may be affected but scarring is absent. A number of children with pri-
mary localized penile and vulval lesions have also been described (Fig.
4.62).47,48,59,62,63 This is of particular clinical importance since it may be mis-
taken for evidence of sexual abuse. Childhood pemphigoid has a good prog-
nosis and, as in adults, is usually self-limiting. Although the etiology is
generally unknown, in some infant cases there appears to be a relationship to
prior vaccination or immunization.59,64 Differences between childhood and
infant cases have been described, but the importance of further subdividing
this group is unclear.64
Localized cutaneous pemphigoid
Although classical bullous pemphigoid not uncommonly presents initially as
localized lesions that after a few months become generalized, occasional
patients present with localized blisters that do not subsequently disseminate
(localized bullous pemphigoid).65 Traditionally, this group has been ­subdivided
into two variants:
• Brunsting-Perry pemphigoid predominantly affects the head and neck
and is associated with scarring.66
• Localized cutaneous nonscarring bullous pemphigoid (Eberhartinger and
Niebauer variant)67 predominantly affects the lower legs (in particular the
pretibial region) of females.
The former variant is considered in the section on mucous membrane
pemphigoid. Although the latter nonscarring cutaneous form particularly
affects the lower legs (Fig. 4.63), it may also present at a variety of other sites
including forearms and hands, breasts, chest, buttocks, and umbilicus. Lesions
in localized bullous pemphigoid may be related to trauma.67 This variant
shows a peak incidence in the sixth decade. As with generalized bullous pem-
phigoid, patients present with tense, sometimes hemorrhagic, bullae that arise
on normal or erythematous-appearing skin. Localized cutaneous nonscarring
bullous pemphigoid is generally associated with a good prognosis.67
120 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.58
(A, B) Pemphigoid vegetans:
presentation as verrucous
lesions in the flexures
may result in considerable
diagnostic difficulties. By
courtesy of R.K. Winkelmann,
A B MD, The Mayo Clinic,
Scottsdale, Arizona, USA.

Fig. 4.60
Childhood BP: very rarely
this disease affects young
Fig. 4.59 children and infants.
Pemphigoid nodularis: in There is a widespread
addition to bullous lesions, distribution of bullae,
this patient also developed which characteristically
these pruritic nodules. arise on an erythematous
By courtesy of H. Shimizu, base. By courtesy of
MD, Keio University R.A. Marsden, MD,
School of Medicine, Tokyo, St George's Hospital,
Japan. London, UK.

Rare patients present with localized bullous pemphigoid at the site of
trauma without much evidence of disease elsewhere.68
Mucosal pemphigoid/desquamative gingivitis
Localized oral pemphigoid is a recently described variant of desquamative gin-
givitis.69–71 The latter, of multifactorial etiology by definition, affects the mar-
ginal and attached gingivae. It shows a female predominance (9:1) and presents
most frequently in the middle aged. Desquamative gingivitis may also be a
manifestation of lichen planus, mucosal pemphigoid, and pemphigus.41 The
diagnosis of localized oral pemphigoid depends upon the presence of a linear
band of immunoreactants at the epithelial basement membrane region on
direct immunofluorescence.69 Clinical features include erythema, edema, erosions,
and ulcers.72 The oral lesions are nonscarring. Bullous pemphigoid-associated
desquamative gingivitis may remain confined to the gingiva (the localized oral
pemphigoid type), but approximately an equal proportion of patients goes on
to develop full-blown cutaneous pemphigoid (Fig. 4.64).69
 Bullous pemphigoid 121

Fig. 4.63
Localized pemphigoid,
nonscarring variant:
lesions are found
particularly on the lower
Fig. 4.61 legs of females. The
Childhood BP: plantar involvement is sometimes the only site of disease. By courtesy prognosis is usually good,
of M. Liang, MD, The Children's Hospital, Boston, USA. but occasionally the
condition can become
generalized. By courtesy
of R.A. Marsden, MD,
St George's Hospital,
London, UK.

Fig. 4.62
Childhood BP: note the perineal scarring and isolated blister. By courtesy of M. Liang,
MD, The Children's Hospital, Boston, USA.

Pathogenesis and histological features Fig. 4.64

The histological features of bullous pemphigoid depend to some extent upon
the age of the lesion biopsied. Early erythematous and urticarial lesions most
often show upper dermal edema associated with a perivascular lymphohistio-
cytic infiltrate accompanied by usually conspicuous eosinophils (Figs 4.65
and 4.66). Eosinophilic spongiosis is sometimes evident and occasionally, if
eosinophils are present in sufficient numbers, flame figures may be a feature.
Mild interface changes characterized by basal cell hydropic degeneration can
be seen in early or prodromal lesions.
If the biopsy is taken from an established blister, the changes are most
often those of an inflammatory (cell-rich) variant.73 The blister, which is sub-
epidermal, is typically unilocular and covered by attenuated epithelium (Fig.
4.67). In early lesions the roof epidermis may appear unaffected or show
occasional to even confluent necrotic basal keratinocytes. The blister contents
include coagulated serum, fibrin strands, and large numbers of inflammatory
cells including conspicuous eosinophils (Fig. 4.68). Variable numbers of neu-
trophils may be present.
A typical finding in bullous pemphigoid is retention of the dermal papil-
lary outline (festooning) which project like sentries into the vesicle cavity
(Fig. 4.69). The underlying dermis is inflamed and usually shows widespread
Desquamative gingivitis: note the intense gingival erythema and retraction. Such
features may also be seen in mucous membrane pemphigoid and pemphigus. By
courtesy of P. Morgan, FRCPath, London, UK.
severe edema. An infiltrate of eosinophils and mononuclears surrounds the
blood vessels and extends between the adjacent collagen bundles.
Leukocytoclasis is not seen and features of vasculitis are absent. The adjacent
papillary dermis is often edematous and, very occasionally, eosinophil
microabscesses are a feature (Fig. 4.70). Exceptionally rarely, neutrophil
microabscesses may be seen (see vesicular pemphigoid), raising diagnostic
confusion with dermatitis herpetiformis. Eosinophilic spongiosis is also some-
times evident in the adjacent epidermis (Fig. 4.71).74
Cell-poor (noninflammatory) features are occasionally seen if biopsies are
taken from lesions arising on noninflamed skin (Fig. 4.72). Because inflam-
matory cells are sparse or, exceptionally, even absent in such cases, there may
be considerable problems with the differential diagnosis, particularly if ade-
quate clinical information and immunofluorescence findings are not
available.
122 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.65 Fig. 4.68

Prebullous pemphigoid: there is upper dermal edema and a perivascular lymphohis­ BP: the blister cavity contains large numbers of eosinophils.
tiocytic infiltrate with conspicuous eosinophils.

Fig. 4.69
BP: preservation of the dermal papillary outline (festooning) is a characteristic
Fig. 4.66 feature.
Prebullous pemphigoid: there are numerous eosinophils.

Fig. 4.67 Fig. 4.70

BP: an established lesion showing a subepidermal tense, dome-shaped blister BP: the presence of eosinophil microabscesses in the dermal papillae is a useful
containing edema fluid, fibrin, and inflammatory cells. although rare diagnostic marker.

Fig. 4.71
BP: eosinophilic
spongiosis is sometimes
seen in the epidermis
adjacent to the blister.
Fig. 4.72
Cell-poor pemphigoid: this is a very uncommon variant and is most often seen if a
very early lesion is sampled. The blister contains only a little edema fluid and there
is a light chronic inflammatory cell infiltrate in the superficial dermis.
Vesicular/polymorphic pemphigoid is characterized by subepidermal vesi-
cles with features suggesting either bullous pemphigoid or dermatitis herpeti-
formis or both (Fig. 4.73). Neutrophil dermal papillary microabscesses,
which are often regarded as pathognomonic of dermatitis herpetiformis, may
be seen in this variant (Fig. 4.74).
Pemphigoid vegetans is characterized by acanthosis, often with pseudoepi-
theliomatous hyperplasia, papillary dermal edema with subepidermal clefting
or frank vesicle formation and an inflammatory cell infiltrate of eosinophils,
mononuclears, and occasional neutrophils.
Pemphigoid nodularis exhibits pruriginous lesions which are characterized
by hyperkeratosis and acanthosis, and which may amount to pseudoepithe-
liomatous hyperplasia and dermal fibrosis (Fig. 4.75). In the dermis, a
perivascular infiltrate of lymphocytes and eosinophils is present. The blisters
show typical features of bullous pemphigoid (Fig. 4.76).
Bullous pemphigoid 123
Fig. 4.73
Vesicular pemphigoid: (A) low-power view showing a multilocular blister; (B) the
blister contains a neutrophil-rich infiltrate.
Localized nonscarring (pretibial) bullous pemphigoid usually shows the his-
tology of cell-rich bullous pemphigoid. Localized oral pemphigoid is typified by
a subepithelial vesicle (when present) and cannot be distinguished histologically
from oral involvement in mucous membrane pemphigoid (see below).
Ultrastructurally, in early lesions of bullous pemphigoid, the dermoepider-
mal cleavage is seen to have developed between the plasma membrane of the
basal keratinocyte and the lamina densa, through the lamina lucida.75 The
lamina densa is therefore located along the floor of the blister
(Figs 4.77, 4.78). Degenerative changes in the basal cells, including villous
­process formation, mitochondrial swelling, and cytoplasmic vacuolization,
are frequently found. Hemidesmosomes may appear reduced in number or
may even be absent.76 Intercellular edema between adjacent basal cells is a
common finding.77 If specimens from established inflammatory lesions are
examined, the lamina densa is sometimes fragmented or entirely absent.48
Bullous pemphigoid is characterized by a linear antibasement membrane
zone antibody using the indirect immunofluorescent technique.78 Although
IgG is invariably present (and most commonly of the IgG4 subclass), other
immunoglobulins, including IgE, may be represented.79 Such antibodies are
present in around 75–80% of patients.80–83 Sensitivity can, however, be
increased to 90% if split skin is used as substrate.18 Although the antibody
titer does not correlate with disease activity or severity, more recently it has
been shown that serum antibodies to the NC16A domain of BP180 (a subunit
of the bullous pemphigoid antigen) do correlate with disease activity (see
below).84,85
Split skin indirect studies are essential in the investigation of a patient in
whom a linear IgG antibasement membrane antibody has been detected.86–88
124 Inherited and autoimmune subepidermal blistering diseases

A B

Fig. 4.74
Vesicular pemphigoid: (A) neutrophil microabscesses in the adjacent dermal papillae heighten the resemblance to dermatitis herpetiformis. It would be impossible to establish
the diagnosis of bullous pemphigoid without appropriate immuno-fluorescent findings; (B) preservation of the dermal papillae may be a clue to the correct diagnosis of
pemphigoid.

Fig. 4.75
Pemphigoid nodularis: this is a biopsy of a pruritic nodule showing hyperkeratosis,
irregular acanthosis, dermal chronic inflammation, and scarring.
Fig. 4.77
BP: electron micrograph showing the lamina densa lying along the floor of the
blister cavity.

Fig. 4.76
Pemphigoid nodularis: this subepidermal blister comes from the same patient as
shown in Figure 4.75. Pemphigoid nodularis is of particular importance because Fig. 4.78
the nodular lesions may precede clinical evidence of blistering. BP: high-power view of the lamina densa.

Such antibodies are also characteristic of mucous membrane pemphigoid, her-
pes (pemphigoid) gestationis, inflammatory epidermolysis bullosa, and bullous
systemic lupus erythematosus. The antibodies in pemphigoid variants (with the
exception of the anti-p105 and anti-p200 variants discussed below) bind to the
epidermal side of 1 M NaCl-split skin whereas those of inflammatory epider-
molysis bullosa and bullous systemic lupus erythematosus bind to the floor.
In those patients in whom indirect fluorescent studies are not available,
similar information may sometimes be obtained through the localization of
lamina densa constituents such as type IV collagen or laminin-1 using
­paraffin-embedded direct immunoperoxidase techniques. In pemphigoid, the
staining is found along the floor of the blister, whereas in inflammatory
­epidermolysis bullosa and bullous systemic lupus erythematosus it is located
along the roof (see Figs 4.7 and 4.8).
Bullous pemphigoid antibodies are capable of complement fixation in as
many as 75% of patients.89,90 Most of complement fixation in bullous pem-
phigoid antibody resides in the IgG4 subclass.91
Linear in vivo-bound immunoglobulin at the epidermodermal interface on
direct immunofluorescence is present in 90% or more of patients (Fig.
4.79).18,92 Complement (C3) is also usually present and is sometimes the sole
immunoreactant (Fig. 4.80).93 Other immunoglobulin subclasses including
IgM, IgA, and IgE may be detected occasionally.83,89,94 In addition to C3, the
other components of the classical complement pathway, in particular C5b-9
(the membrane attack complex) and members of the alternative complement
pathway, including properdin, factor B and B-1H-globulin, may also be iden-
tified.83,95 There is therefore evidence that both the classical and alternate
complement pathways are involved in the pathogenesis of bullous pemphig-
oid.96 The classical complement pathway, however, predominates. A recent
mouse model underscores the necessity of an intact innate immune system, as
depletion of complement or neutrophils or blockage of mast cell activation
prevents blister formation.97
The immunofluorescence findings in erythematous, pruritic, urticarial,
and eczematous prodromal lesions and childhood, dyshidrosiform, vesicular,
nodular, and vegetans variants are similar to those seen in the conventional
generalized disease.25–28,32–49,98,99 In polymorphic pemphigoid either linear IgG
or IgA deposits may be identified along the basement membrane region.29–31
The serum may contain either IgG or IgA antibodies.30
Immunofluorescence findings in localized cutaneous disease are variable.
In some reports, patients show positive direct immunofluorescence for IgG
and C3 at the epidermodermal junction and a positive indirect immunofluo-
Fig. 4.79
BP: direct
immunofluorescence of
perilesional skin showing
intense linear basement
membrane zone staining
(IgG).
Bullous pemphigoid 125
Fig. 4.80
BP: direct immunofluorescence showing C3 deposition (left), no staining is
seen in the negative control (right). By courtesy of B. Boghal, FIMLS, Institute of
Dermatology, London, UK.
rescent test for bullous pemphigoid antibody, while others may be positive for
in vivo-bound complement, but negative on indirect examination.66,67,99 One
series has shown that almost 70% of patients with localized pemphigoid have
circulating IgG antibodies in their sera and the presence of these can be rele-
vant for serum-based testing, as discussed below.67,100 A caveat is that in one
study, antibodies were also detected in more than half of normal subjects who
did not subsequently develop the disease.101,102 This finding is further dis-
cussed below.
By direct immunoelectron microscopy, the immunoreactants (IgG and C3)
are seen to be located within the hemidesmosomal plaque and upper lamina
lucida (Fig. 4.81).103–107 Indirect immunoelectron microscopic ­studies show
that the bullous pemphigoid antigen is most often detected ­intracellularly in
the region of the cytoplasmic face of the hemidesmosome (Fig. 4.82).104,108–110
The immunoelectron microscopic observations in childhood bullous pem-
phigoid, vesicular pemphigoid, polymorphic pemphigoid, pemphigoid nodu-
laris, pemphigoid vegetans, and localized pemphigoid are identical to those of
classic bullous pemphigoid.111,112
Two principal bullous pemphigoid antigens are recognized by Western
blot and immunoprecipitation studies: one is 230 kD (BPAG1) and the other
is approximately 180 kD (BPAG2) (Fig. 4.83).113–119 These represent products
of distinct genes.120–123
BP230 maps to the short arm of chromosome 6, locus 6p11-12.121 It
belongs to the plakin family and shows homology with plectin and the
­desmogleins.122 It is wholly intracellular and localizes to the hemidesmosome.
BP230 is not involved in the early stages of the pathogenesis of blistering but
is of importance as a secondary event; antibodies against this antigen are not
required for blister formation in most cases.124–126
BP180 (collagen type XVII) is the major pathogenic antigen in bullous
pemphigoid. The BPAG2 (COLI7A1) maps to the long arm of chromosome
10, locus 10q24.3.121 It is a transmembrane adhesion molecule comprising an
­intracytoplasmic N-terminal fragment, a transmembrane region, and a col-
lagenous ­extracellular C-terminal ectodomain.127 The latter constitutes part
of the anchoring ­filament and distally merges with the lamina densa. The
antibodies directed against BP180 in bullous pemphigoid most commonly
react with a short extracellular noncollagenous locus – NC16A (regions
MCW0-MCW3) – located within the upper lamina lucida proximal to the
collagenous segment (Fig. 4.84).127–130 It now appears that antibodies specific
to this area are ­generally required for blister formation and, while antibodies
may also target BP180 non-NC16A domains, these latter antibodies do not
appear to be pathogenic in most cases.124–26 This finding reconciles the fact
that antibodies to both BP180 and BP230 can be seen in a significant portion
of the population without blister formation as these are not against the criti-
cal NC16A region of BP180.84
126 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.81 Fig. 4.83

BP: direct immunoperoxidase reaction using frozen tissue substrate showing BP: Western blot
electron-dense deposits in the lamina lucida. demonstrating the two
quite separate bullous
pemphigoid antigens.
By courtesy of M.M.
Black, MD, Institute of
Dermatology, London, UK.

More recently, two patients with a nonscarring, bullous pemphigoid-like

illness characterized by neutrophil-rich subepidermal blisters resembling
­dermatitis herpetiformis and antibodies to a unique 105-kD protein – ­so-called
anti-p105 pemphigoid – have been documented.141–143 This antigen localizes
to the dermal side of split skin on indirect immunofluorescence. Its precise
nature has not yet been determined.
Anti-p200 pemphigoid is characterized by antibodies to a lower lamina
lucida basement membrane antigen.144–146 Patients generally present with a

Basal keratinocyte

HD plaque

NH2 Globular cytoplasmic domain

Fig. 4.82
BP: immunogold electron microscopic preparation. Note that the immunoreactant
NC16a
to BP180 and BP230 is particularly located on the hemidesmosomes (open arrows). Transmembranous domain Cell membrane
However, deposits are also present within the lamina lucida, black arrows. (BC,
basal cell; DER, dermis.) By courtesy of H. Shimizu, MD, Keio University School of
Medicine, Tokyo, Japan.

Lamina lucida Rod-like interrupted

Between 50% and 90% of patients with generalized bullous pemphigoid collagenous domain
have antibodies that react with BP230 and 35–50% have antibodies that
react with BP180 that are readily detected by immunoblotting.131 However,
the sera in 100% of patients react with BP180 NC16A domain recombinant
protein.131 This latter finding underscores the usefulness of recent testing for
anti-NC16A domain antibodies from peripheral blood to distinguish bullous
pemphigoid from other disorders.100,132–134 COL1
Flexible ‘tail’
Circulating antibodies against BP180 or BP230 have also been defined in
Lamina densa COOH
many of the other less common variants of bullous pemphigoid, including
localized and vesicular forms, pemphigoid vegetans, erythrodermic pemphig-
oid, and pemphigoid nodularis.131,135–139
In childhood pemphigoid, the antibodies also react against the same anti- Fig. 4.84
A schematic representation of the BP180 molecule showing the globular
gens.140 In addition, rarely there may also be antibodies that react with the
intracellular NH2 domain, the membrane proximal NC16A domain and the flexible
linear IgA 120-kD antigen.140 The BP180 antigen is most often ­targeted, and rod-like interrupted collagenous structure of the extracellular domain. (HD,
immunoblot analyses have shown that the antibodies react ­specifically with hemidesmosome). Collagen XVII/BP180: a collagenous transmembrane protein
the NC16A domain as in adult patients. In some children at least, the IgG and component of the dermoepidermal anchoring complex. (Powell AM, ­
subclasses differ from adult disease, consisting of all IgG subclasses or IgG2 Sakuma-Oyama Y, Oyama N, Black MM. Department of Immunodermatology,
in isolation.18 IgE antibodies are not a feature of c­ hildhood disease. St John's Institute of Dermatology, St Thomas' Hospital, London, UK.)

nonscarring bullous pemphigoid-like illness although linear IgA disease-like
and dermatitis herpetiformis-like variants have also been reported.144 The dis-
ease has also been described in association with psoriasis.145 With split skin
indirect IMF, the antibodies bind to the floor of the blister cavity.144 With
indirect immunoelectron microscopy, the antibodies bind to the lower lamina
lucida.147,148 The identity of the 200-kD antigen has yet to be determined but
it is neither laminin nor type VII collagen.148
Anti-p450 pemphigoid has been documented in a single patient. The anti-
gen, which has been localized to the basal keratinocyte, belongs to the plectin
family.149 Its precise nature has yet to be determined.
Exceptionally, bullous pemphigoid may be associated with antiplectin
antibody.150
Bullous pemphigoid has been described following PUVA therapy for myco-
sis fungoides. More recently, a case arising in the setting of radiation therapy
has also been noted, perhaps suggesting a role for tissue damage in the patho-
genesis of this disease.151
A mechanism for blister development in bullous pemphigoid has been pro-
posed by Jordon et al.80,152 and is outlined as follows. Following antibody–
antigen interaction and complement fixation, various chemotactic agents
including C3a and C4a are produced.153 Mast cells degranulate under the
influence of the latter or IgE, and release ECF-A, NMW-NCF, ESM, hista-
mine, and enzymes.154 Eosinophils and neutrophils, so recruited, bind (possi-
bly via C3b receptors) to the basement membrane region. By direct cytotoxic
action (eosinophils are capable of antibody-dependent cellular cytotoxicity)
or via released proteases, particularly elastase, damage at the basement mem-
brane region results in the development of a vesicle. Lymphocytes elaborate
histamine-releasing factor (HRF), which increases mast cell degranulation
and perpetuates the process. A broad range of cytokines are involved in this
inflammatory reaction including interleukin (IL)-1, IL-4-IL-8, IL-10-IL-13,
IL-15 and interferon gamma (IFN-γ).155 As yet, their relative importance and
time sequences are unknown.
Bullous pemphigoid is therefore a true autoimmune disease in which
­antigen–antibody reaction and complement fixation results in a character-
istic and reproducible train of events, which is inevitably accompanied by
the development of subepidermal blister formation. The etiology or
­initiator (other than those associated with drugs or PUVA therapy, which
are the ­minority) is unknown. The question as to why self-tolerance breaks
down with the ­formation of symptomatic autoantibodies in patients with
this d
­ isease is an important question for further investigation.
Differential diagnosis
The inflammatory cell-rich variant of bullous pemphigoid must be distin-
guished from other subepidermal blistering dermatoses in which a heavy
inflammatory cell component is a typical finding. These include dermatitis
herpetiformis, linear IgA disease, inflammatory epidermolysis bullosa
acquisita, and bullous systemic lupus erythematosus (see Table 4.5).
Table 4.5
Differential diagnosis of cell-rich pemphigoid
Parameter BP EBA
DIMF Linear IgG, C3 Linear IgG, C3
IIMF IgG antibodies 75–80% IgG antibodies 25–50%
Split skin IMF Roof Floor
Type IV collagen Floor Roof
EM: site of split LL Sub-LD
Western blot BP180 kD 290 kD
BP230 kD (type VII collagen)
BP, bullous pemphigoid; BSLE, bullous systemic lupus erythematosus; DH, dermatitis herpetiformis; DIMF, direct immunofluorescence; EBA, epidermolysis bullosa acquisita; EM,
electron microscopy; IIMF, indirect immunofluorescence; IMF, immunofluorescence; LAD, linear IgA disease; LL, lamina lucida; sub-LD, sub-lamina densa.
Pemphigoid gestationis 127
Successful differentiation depends upon careful clinicopathologic correlation
and immunofluorescent studies or, more recently, serum-based immunologic
(ELISA) testing. Split skin indirect immunofluorescence or lamina densa anti-
gen mapping by type IV collagen or laminin-1 direct immunoperoxidase is
essential to determine the level of the split. Although electron microscopy,
immunoelectron microscopy, and immunoprecipitation or Western blotting
provide definitive information, such techniques are not necessary in the
majority of cases.
The cell-poor variant of bullous pemphigoid has a very wide range of ­differential
diagnoses including epidermolysis bullosa (congenital and acquired), porphyria
cutanea tarda, bullous amyloidosis, bullosa diabeticorum, and autolysis.
Pemphigoid gestationis
Pruritus is a very common symptom in pregnancy, occurring in up to 18% of
gravid females.1–4 When it occurs in the absence of significant cutaneous stig-
mata it is known as pruritus gravidarum. This may occasionally be associated
with a cholestatic pathogenesis. The specific pregnancy eruptions have long
been a source of considerable confusion and controversy in the literature,
largely due to a diverse range of terminologies and classifications. Recently,
Holmes has attempted to clarify the situation with the introduction of a new
and much simplified classification and others have proposed similar schemes.2,5
Therefore the specific dermatoses of pregnancy may be divided into:
• polymorphic eruption of pregnancy, where the predominant lesions are
urticarial; in the United States, the term pruritic urticarial papules and
plaques of pregnancy (PUPPP) has achieved greater popularity;
• pregnancy prurigo in which the lesions consist of itchy papules;
• pemphigoid (herpes) gestationis, an autoimmune dermatosis belonging to
the bullous pemphigoid group of diseases.
Pemphigoid gestationis is a bullous dermatosis of pregnancy and the puer-
perium. It may be exacerbated by the use of oral contraceptives and rarely
complicates hydatidiform mole and gestational (but not nongestational) cho-
riocarcinoma. The current evidence implicates an autoimmune-mediated
pathogenesis in which hormonal influences play a significant role.6,7
Clinical features
The term herpes (gestationis) is neither appropriate nor satisfactory. It is not
of viral etiology, nor has it anything to do with creeping (Gr. herpes, to creep).
It was originally so named because of the tendency of the disease to show
‘progressive involvement by peripheral extension’.3 Because of its intimate
relationship to bullous pemphigoid, the designation pemphigoid gestationis is
preferred. As the major larger series have consisted of patients derived from a
variety of sources, estimates of incidence have been very variable, ­ranging
from 1:3000 to 1:50 000 pregnancies.4,8–10 The more recent figures where
cases have had immunofluorescent confirmation would suggest that the latter
figure is the most accurate.3
BSLE LAD DH
Linear IgG, C3 Linear IgA Granular IgA
IgG antibodies 60% IgA antibodies 30% Antitransglutaminase antibodies
Floor Roof or floor or both N/A
Roof Roof or floor N/A
Sub-LD LL, sub-LD or both Papillary dermis
290 kD BP180 kD Antigen uncertain
(type VII collagen) BP230 kD
200/280 kD
285 kD
250 kD
290 kD
128 Inherited and autoimmune subepidermal blistering diseases

Pemphigoid gestationis may present in the first or any subsequent preg-

nancy.3 It may first also rarely present in the postpartum period. In one series,
30% of patients were primigravidae.9 In addition to developing in pregnant
or postpartum patients, pemphigoid gestationis has rarely been described fol-
lowing a hydatidiform mole and gestational choriocarcinoma.11,12 It has not,
however, been reported in nongestational variants such as those occurring in
Fig. 4.86
the ovary, mediastinum, and testis, or complicating malignant teratoma. Pemphigoid gestationis:
Pemphigoid gestationis is predominantly a disease of white females, being the blisters are tense and
exceedingly rare in blacks.13,14 Presentation is usually in the second or third dome-shaped.
trimester, most often developing in the sixth or seventh month, but the range By courtesy of R.C.
is variable from 2 months to 4 days postpartum.10,15 Although the disease Holmes, MD, Warneford
may rarely completely remit before delivery, most patients (up to 75%) Hospital, Oxford, UK.
develop an exacerbation, which is frequently severe, in the immediate puerpe-
rium when progesterone levels have fallen.15,16 Exceptionally, the infant may
contain clear fluid, but at times the fluid may become hemorrhagic (Fig.
show transient urticated erythema and blistering.4
4.86). They typically heal without scarring.
Pemphigoid gestationis usually complicates subsequent pregnancies, fre-
The umbilicus is frequently the site of initial involvement; spread to the
quently presenting earlier on and with more severe symptomatology.10
trunk and extremities then follows (Figs 4.87, 4.88).3 Surprisingly, lesions on
Sometimes, however, it may skip intervening pregnancies.3 This may be
the face and mucous membranes are distinctly uncommon. Eventually palmar
related to a change in paternity, or else due to compatibility at the HLA-D
and plantar manifestations may appear. Other than pruritus, symptoms are
locus.
usually mild, with stinging, burning, and pain being relatively infrequent.10
Pemphigoid gestationis may develop into a very protracted ‘postpartum’
illness associated with considerable morbidity and lasting up to 12 years.17,18
In the majority of patients, however, the disease resolves by about 6 months
postpartum.4 The disease may first present following a change in sexual part-
ner.3,19 Alternatively, recurrent disease may persist even when there has been
a change of sexual partner.7 This obviously calls into question the role of spe-
cific paternal antigens.
Exacerbation following the use of the oral contraceptive is a common
complication,10,20–23 affecting 20–50% of patients.3 Estrogens in particular
have been implicated.22 The condition may also relapse during menstruation
for some weeks or months postpartum and the return of symptoms (pruritus)
has also been noted to coincide with ovulation (again suggesting an estrogen
influence), although this is rare.3,10,22
Evidence has been published relating the duration of symptoms postpar-
tum to the practice of breast-feeding. Bullous lesions lasted only 5 weeks in
those who breast-fed compared to 24 weeks in those who bottle-fed. Although
hormonal factors must be implicated, the precise pathogenetic implications
underlying this observation are not fully understood.22
Pemphigoid gestationis is associated with intense pruritus, which may be
present for days or weeks before the onset of typical cutaneous manifesta-
tions.1 The dermatosis is characteristically polymorphous, consisting of ery-
thematous or urticarial papules and plaques, some with a polycyclic ­pattern,
and later vesicles and bullae develop at the periphery of spreading erythema-
tous plaques (Fig. 4.85).3,10,24 When fully evolved, the blisters are tense and

Fig. 4.87
Fig. 4.85 Pemphigoid gestationis: slightly raised erythematous lesions with a propensity to
Pemphigoid gestationis: prebullous phase showing erythema and small papules. cluster on the abdomen. By courtesy of R.C. Holmes, MD, Warneford Hospital,
By courtesy of the Institute of Dermatology, London, UK. Oxford, UK.
 Pemphigoid gestationis 129

Fig. 4.88
Pemphigoid gestationis: umbilical involvement is a common mode of presentation.
By courtesy of the Institute of Dermatology, London, UK.
Fig. 4.89
Pemphigoid gestationis: early erythematous lesion showing marked edema of the
papillary dermis and conspicuous eosinophils.

Occasionally, the presence of target or iris lesions may mimic erythema mul-
tiforme.25 Less commonly, features may initially suggest classical bullous
pemphigoid.25 Very occasionally, there is clinical overlap with dermatitis
herpetiformis.
Pemphigoid gestationis is not associated with pre-eclamptic toxemia and
there is no related maternal mortality.
Pemphigoid gestationis is accompanied by a significant increased risk of
developing Graves' disease and an increased risk of autoantibodies.26
The literature concerning the incidence and nature of fetal morbidity and
mortality is a source of some confusion. Kolodney therefore considered that
there was no evidence of an increased incidence of stillbirths or abortions;
however, his report predates the immunofluorescence era.5 An investigation
by Lawley et al.20 of a large series of cases where immunofluorescent confir-
mation was available, suggested that there was an increased risk of fetal mor-
bidity and mortality. More recently, evidence has been presented that patients
with pemphigoid gestationis are liable to deliver low weight and small-for-
dates infants, prematurely.27 In contrast, however, Shornick et al. failed to
show any evidence of significant fetal complications.7 It has been shown that Fig. 4.90
the onset of the disease in the first and second trimester and the presence of Pemphigoid gestationis: early erythematous lesion showing eosinophilic
blisters is associated with higher morbidity including premature birth and spongiosis.
low birth weight children.28 Morbidity, however, still remains low. The anti-
body can cross the placenta and, in approximately 5% of cases, this may be
associated with a mild and transient vesiculobullous eruption.29–32

Pathogenesis and histological features

The histopathologic features seen in biopsies from patients with pemphigoid
gestationis are variable, depending upon whether early erythematous lesions,
urticarial papular lesions, or fully established vesicles and bullae are
studied.33
In early lesions, the major pathological features are seen in the superficial
dermis where there is a perivascular inflammatory cell infiltrate consisting of
lymphocytes, histiocytes, and typically very large numbers of eosinophils.
This is associated with edema of the papillary dermis, which when marked
may result in a ‘teardrop’ appearance (Fig. 4.89).33 Sometimes there is accom-
panying spongiosis and this may be associated with large numbers of eosino-
phils (eosinophilic spongiosis, Fig. 4.90). Occasionally the infiltrate of
lymphocytes, histiocytes, and eosinophils is present in a linear distribution
along the dermoepidermal junction.3
Vacuolar degeneration of the basal keratinocytes, sometimes accompa-
nied by individual cell necrosis, may be a feature of the early lesions, but is
often more evident in the fully established vesicular or bullous stage.33 In the
latter, the blister is subepidermal in location and frequently contains large Fig. 4.91
numbers of eosinophils (Figs 4.91, 4.92).33 The underlying and adjacent Pemphigoid gestationis: established subepidermal blister.
130 Inherited and autoimmune subepidermal blistering diseases
Fig. 4.92
Pemphigoid gestationis: the blister cavity contains a heavy eosinophil infiltrate.
dermis is edematous and contains a predominantly perivascular lympho/his-
tiocytic infiltrate with large numbers of eosinophils. Leukocytoclasis and
eosinophil dermal papillary microabscesses are only rarely identified.33,34
Ultrastructural studies show that the cleavage plane lies within the lamina
lucida.33,35
Direct immunofluorescence of perilesional skin in pemphigoid gestationis
shows a linear basement membrane zone deposition of C3 in all patients.3,36–41
About 30–50% of cases also have an IgG band (less frequently IgM or IgA).36
They are present in nonlesional (perilesional) as well as in lesional skin.36
Recently, it has been suggested that demonstration of linear C3d deposition
at the dermoepidermal junction may be a useful tool in the diagnosis of the
disease.42 The authors of this study used immunohistochemistry in paraffin-
embedded, formalin-fixed material with good results. Complement pathway
components including properdin and properdin factor-B may also be identi-
fied.1 IgG and complement can often be detected along the amniotic basement
membrane region using direct immunofluorescence.38,43,44 Pemphigoid gesta-
tionis antigen has been detected in the placenta from early in the second
­trimester onwards.45 The antibody may also be found in the skin of infants of
affected mothers.29 Interestingly, serologic evidence of pemphigoid gestationis
without manifestation of the disease may be seen, An exceptional case of neo-
natal pemphigus in a child whose mother had clinical and serologic evidence
of pemphigus vulgaris but only serologic evidence of pemphigoid gestationis
has been described.46
Circulating complement-fixing (via the classical pathway) IgG antibodies
(pemphigoid (herpes) gestationis (HG) factor) can be detected in 50–75% of
cases by indirect complement immunofluorescence (Fig. 4.93).20,36,47–51 The so-
called HG factor is nothing more than a low titer IgG complement-fixing
antibasement membrane antibody.36 The antibody can be of any IgG subclass;
IgG1 and IgG4 have been reported as predominent.38,51 If monoclonal antibod-
ies directed against IgG are used, 100% of patients can be shown to possess
circulating HG factor.38 Approximately 25% of patients have ­antibasement
membrane zone antibodies detectable by conventional ­techniques.51 These bind
to the roof of 1 M NaCl-split skin.36 The antibody also reacts with amnion and
chorion basement membrane.42,44 The autoantibodies in the disease are directed
against collagen XVII which is the BP ­180-kD protein (BPAG2). The latter
plays a major role in cell adhesion and signaling. It has been demonstrated that
collagen XVII is present in the epithelial cells of the amniotic membrane and in
syncitial and cytotrophoblastic cells.52 Although the exact pathogenetic mecha-
nism of the disease is still unknown (see below), the presence of collagen XVII
in these tissues seems to play a major role in the mechanism of the disease.
With immunoelectron microscopy the immunoreactants are deposited
within the upper lamina lucida where they are most probably associated with
the sub-basal dense plate.53,54 In pemphigoid gestationis the antibody recog-
nizes BPAG2 (collagen type XVII) on Western ­immunoblot and localizes to the
Fig. 4.93
Pemphigoid gestationis: indirect complement immunofluorescence showing linear
deposition of IgG.
same NC16A domain as described in bullous pemphigoid.55–62
This can be detected in serum using the same test employed for bullous
­pemphigoid.60–62 Antibodies that recognize the 230-kD bullous ­pemphigoid
antigen are present in 10–26% of cases.56,57 Experimental models indicate that
antibodies against the NC16A domain of BP180 are the ­pathogenic antibodies
in pemphigus gestationis just as they are for bullous pemphigoid 7,62
Patients with pemphigoid gestationis have an increased incidence of HLA-
B8 (43–79%), HLA-DR3 (61–80%) and HLA-DR4 (52–53%). The paired
haplotypes HLA-DR3 and -DR4 are present in 54% of patients compared
with 3% in the general population.1,3,22,63,64 The phenotype, however, does not
appear to correlate with the clinical features of pemphigoid gestationis.3,65
Patients with pemphigoid gestationis also have a high incidence (100%) of
anti-HLA cytotoxic antibodies, particularly directed against the paternal
­antigens.36,63–66 These are, however, found in 25% of normal multiparous
women and therefore their possible role in the pathogenesis of pemphigoid
gestationis is uncertain.26
The pathogenesis of pemphigoid gestationis relates to antibody-associated
complement fixation with the production of leukocyte chemotactic factors,
mast cell degranulation, and associated dermoepidermal separation.36
The presence of pemphigoid gestationis antigen in both skin and amnion
raises the possibility that an initial antiplacental antibody cross-reacts with
skin, giving rise to the clinical features of pemphigoid gestationis.29 Support
for this theory has been the discovery that the HLA antigens -DP and -DR are
consistently expressed in the placentas of patients with this condition.64,67 The
main antigen present in both the skin and placenta seems to be collagen type
XVII and this, associated with genetic predisposition and specific HLA
­genotype, appears to trigger the disease.68
Differential diagnosis
The differential diagnosis includes epidermolysis bullosa acquisita, dermatitis
herpetiformis, linear IgA disease, and bullous systemic lupus erythematosus (see
Table 4.4). Pemphigoid gestationis must also be distinguished from pruritic urti-
carial papules and plaques of pregnancy (PUPPP) and pregnancy prurigo.
PUPPP is predominantly a disorder of first pregnancies. Lesions particu-
larly develop around abdominal striae, and periumbilical sparing is a charac-
teristic feature (Fig. 4.94). Eosinophilic spongiosis and subepidermal
blistering may be seen in established lesions and therefore, in the absence of
clinical details and immunofluorescence findings, distinction from pemphig-
oid gestationis may be impossible.
Pregnancy prurigo, which typically develops in the third trimester, ­presents
with pruritic papules and nodules (Fig. 4.95). Blisters are not a feature.
Histologically, the changes are those of a low-grade, non-specific spongiotic
dermatitis.

Fig. 4.94
Pruritic papules and plaques of pregnancy: note the erythematous papules
particularly related to the abdominal striae, and characteristic umbilical sparing.
By courtesy of R.C. Holmes, MD, Warneford Hospital, Oxford, UK.
Fig. 4.95
Pregnancy prurigo: there are erythematous papules and excoriations. Blisters are
not a feature of this condition. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
Lichen planus pemphigoides
Clinical features
Lichen planus (lichen ruber) pemphigoides (Kaposi) must be distinguished
from the vesicles occasionally seen in lichen planus as a consequence of severe
hydropic degeneration (lichen planus vesiculosis).1,2 Rarely, lichen planus is
associated with a generally benign, bullous pemphigoid-like disease: lichen
planus pemphigoides. This represents a heterogeneous condition characterized
by basement membrane antibodies directed towards a number of antigens.
Clinically, the pemphigoid-like lesions are usually preceded by typical
lichen planus although rarely the blisters may develop first (Fig. 4.96). The
bullae, which are most numerous on the extremities, may arise on normal
skin, in areas of erythema or on lichenoid papules (Figs 4.97 and 4.98).
In some patients the blisters are generalized. Exceptionally, the blisters are
localized with typical lichen planus-like lesions elsewhere. A case with single
blisters on the soles has been described.3 They are tense, dome-shaped and
hemorrhagic or contain clear fluid. Evolution to pemphigoid nodularis-like
lesions has been described.4 Lichen planus pemphigoides more commonly
affects males and presents most often in the fourth and fifth decades.5,6
Exceptionally, however, cases have been documented in childhood.7–9 All
races may be affected.
Lichen planus pemphigoides 131
Fig. 4.96
Lichen planus pemphigoides: typical lichenoid papules are present on the anterior
aspect of the wrist. By courtesy of M.M. Black, MD, Institute of Dermatology,
London, UK.
Fig. 4.97
Lichen planus pemphigoides: note the blisters and erosions arising on an erythematous
base. Atypical target lesions are present. By courtesy of M.M. Black, MD, Institute of
Dermatology, London, UK.
Pathogenesis and histological features
The lichenoid lesions show the typical histopathological and immunofluores-
cent changes of lichen planus, but the bullae have features more suggestive of
bullous pemphigoid (Fig. 4.99). A variety of findings have been described.
Early erythematous lesions show intense dermal edema with a dense
­perivascular and interstitial eosinophil infiltrate; eosinophilic spongiosis may
also sometimes be evident. Established blisters are subepidermal and both
inflammatory (cell-rich) and cell-poor variants have been documented (Figs
4.100, 4.101).5 Eosinophils are variably present but often may be numerous.
Immunofluorescent examination of biopsies from peribullous skin reveals
linear deposition of IgG and complement.10–13 The serum contains an IgG
antibasement membrane antibody in up to 50–60% of patients. With NaCl-split
skin, the antibody generally labels the roof of the blister cavity. Ultrastructural
investigations have shown that the level of separation is ­usually through the
lamina lucida. By immunoelectron microscopy, the immunoreactants ­typically
localize to the hemidesmosome and lamina lucida.5,13,14 Mucous membrane
pemphigoid and epidermolysis bullosa acquisita ­(EBA)-like variants have,
however, also been documented.15
132 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.98
Lichen planus pemphigoides: note the intact dome-shaped tense blister. By courtesy
of M.M. Black, MD, Institute of Dermatology, London, UK.

Fig. 4.100
Lichen planus
pemphigoides: there is a
subepidermal blister.

Fig. 4.99
Lichen planus
pemphigoides: the
lichenoid papules show
typical features of lichen
planus.

A number of antigens have been recognized in lichen planus pemphigoides
including BP180, BP230, and an as yet uncharacterized 200-kD protein of
keratinocyte derivation.1,15–23 The segment of the NC16A domain recognized
in lichen planus pemphigoides differs from BP, localizing to MCW-4 (the
more C-terminal end of the domain) as opposed to MCW-0 to MCW-3.24,25
Type VII collagen has also been implicated in the EBA-like variant although
the immunoblot was negative.15
Although the pathogenesis of lichen planus pemphigoides has not been
fully unraveled, it is likely that the basement membrane zone damage associ-
ated with lichen planus results in antigen exposure with subsequent autoanti-
body production and resultant bullous disease. So far, it is uncertain why only
a small percentage of patients with lichen planus are affected. The pathogen-
esis in those patients in whom the blisters develop first is unknown although a
different antigen may be involved. Exceptionally, cases have been documented
as an adverse drug reaction (e.g., to angiotensin-converting enzyme inhibitors,
complicating PUVA therapy, or in a patient taking paracetamol, ibuprofen,
and having narrowband UVB).26–35 There has been a suggestion that lichen
Fig. 4.101
Lichen planus
pemphigoides: the blister
contains eosinophils.
planus pemphigoides might be associated with internal malignancy but the
diagnosis lacked substantiation by immunofluorescence studies.36 Two addi-
tional cases involving a patient with multiple keratoacanthomas and colonic
adenocarcinoma indicating a Torre-Muir-like syndrome and association with
retroperitoneal Castleman disease have been noted more recently.37,38
Differential diagnosis
Lichen planus pemphigoides differs from typical bullous pemphigoid clini-
cally by its earlier age of presentation and predilection for the lower limbs. In
those cases associated with antibodies to BP180, epitope mapping may make
the distinction.
 Mucous membrane pemphigoid (cicatricial pemphigoid) 133

Mucous membrane pemphigoid (cicatricial

pemphigoid)
Mucous membrane pemphigoid represents a spectrum of diseases (e.g., ocular
pemphigoid, oral pemphigoid, benign mucous membrane pemphigoid) which
affect the mucosa and skin.1–4 With the advent of molecular studies identifying
the antigens involved, it is becoming clear that there are a number of ­relatively
well-defined clinicopathological variants that arise as a consequence of auto-
immune diseases directed against a number of different basement ­membrane
antigens. Although multiple systems are often affected, there is increasing
­evidence that pure ocular and oral variants may also be encountered.1,2

Clinical features
Mucous membrane pemphigoid is a rare blistering disorder in which mucosal
lesions predominate and in which scarring is a characteristic feature (although
not generally in the oral lesions).1,2,5 It is often associated with severe morbid-
ity, largely due to the effects of the scarring. As ocular and oral lesions pre-
dominate, many patients come to the attention primarily of the dental and
oral surgeons or ophthalmologists rather than dermatologists.
The incidence is estimated as being between 1:12 000 and 1:20 000 of the
population per year.2 It is associated with a female preponderance (2:1) and it
not uncommonly presents in the seventh decade. Very rare instances of child-
hood involvement have been reported.3,6–10 Mucous membrane pemphigoid is
a chronic disease and is rarely self-limiting. It shows no racial or geographic
predilection.
Oral lesions occur in 85–95% of patients and commonly follow mild
trauma.11 Bullae, erosions, and erythema most commonly affect the gingival
or buccal mucosa, but the hard and soft palate, tongue, and lips are also fre-
quently involved (Figs 4.102, 4.103). Desquamative gingivitis is the most
common manifestation.12,13 Patients with this condition present with painful,
swollen, erythematous lesions of the gums, which may be associated with
bleeding, blistering, erosions, and ulceration.14 Most cases of desquamative
gingivitis have lichen planus and only in a low percentage, around 9%, is the
process a manifestation of mucous membrane pemphigoid.15 Lesions limited
to the oral cavity is a distinctive subset, usually associated with a good
­prognosis although characterized by chronicity.1 Pharyngeal (19% of patients)
and esophageal (4% of patients) lesions may be complicated by scarring,
resulting in stenoses. Aspiration pneumonia is sometimes a fatal complica-
tion. Nasal lesions, which may occur in up to 15% of patients, lead to obstruc-
tion and occasionally cicatricial stenoses and septal ­perforation.16 Laryngeal
involvement, which occurs in 8% of patients, is sometimes ­complicated by
such severe stricture formation and edema that tracheotomy may be a life-
saving necessity.14
Fig. 4.103
Mucous membrane pemphigoid: in addition to erosions, intact blisters are evident.
By courtesy of P. Morgan, FRCPath, London, UK.
Ocular lesions, which occur in approximately 64% of patients, are a
source of considerable morbidity.17–19 The eye (in particular the conjunctiva)
may be a sole site of involvement.14 Early symptoms are those of a non-spe-
cific ­conjunctivitis. In more advanced lesions, subconjunctival fibrosis
­develops.20,21 Patients may therefore present with fibrous bands (sym-
blephara) stretching between the fornices and the globe (Fig. 4.104).
Eventually, ­contractures may obliterate the conjunctival sac. An essential
feature of ocular cicatricial ­pemphigoid is the production of an abnormal
tear film. This develops because of diminished lacrimal gland secretion (due
to ductal stenosis), impaired ­goblet cell mucus secretion and ocular exposure
due to impaired eye ­closure.20 The end result is ocular drying and eventual
keratinization of the ocular surface epithelium. Other important sequelae
include entropion, trichiasis (maldirected eyelashes, which can result in cor-
neal abrasion), ­erosions and perforation, corneal neovascularization and
scarring with opacification (Figs 4.105, 4.106). Primary corneal bullae have
been described but are very rare, and erosions are more typical.11 Corneal
lesions manifest as ­foreign body ­sensation, photophobia, and eventual
­blindness, which may be bilateral, occurring in up to 16% of patients.9
Ocular involvement may be classified into a number of stages of ­progression
(modified Foster staging system).22

Fig. 4.104
Fig. 4.102 Mucous membrane pemphigoid: there is a dense fibrous adhesion (symblepharon)
Mucous membrane pemphigoid: there is erosion of the buccal mucosa. By courtesy between the conjunctiva lining the eyelid and that covering the globe. By courtesy
of P. Morgan, FRCPath, London, UK. of the Institute of Dermatology, St Thomas' Hospital, London, UK.
134 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.105 Fig. 4.107

Mucous membrane pemphigoid: in this advanced case there is entropion and Mucous membrane
trichiasis (inwardly directed eyelashes). By courtesy of D. Kerr-Muir, MD, pemphigoid: in addition to
St Thomas' Hospital, London, UK. erosions, marked scarring
of the vulva is present. By
courtesy of R.A. Marsden,
MD, St George's Hospital,
London, UK.

Fig. 4.106
Mucous membrane pemphigoid: here there is dense corneal scarring with complete
opacification. By courtesy of D. Kerr-Muir, MD, St Thomas' Hospital, London, UK.
Ocular involvement should not be confused with drug-induced pemphig-
oid (pseudo-ocular mucous membrane pemphigoid).2 This is a self-limiting
unilateral scarring disease of the eye, which most commonly develops as a
consequence of long-term use of eyedrops containing pilocarpine, echothio-
phate iodide, idoxuridine, timolol, and adrenaline (epinephrine) in the treat-
ment of glaucoma.23,24
Lesions of the female genitalia, which occur in 20% of patients, predomi-
nantly affect the labia majora and minora.14 Scarring is common and may
occasionally be associated with labial fusion (Fig. 4.107). In males, genital
lesions most often affect the prepuce and the glans penis and are occasionally
complicated by urethral stricture formation. Anal lesions affect up to 4% of
patients and sometimes cause stenosis.14
Cutaneous lesions are found in approximately 25–33% of patients with
mucous membrane pemphigoid and most often affect the scalp, face, and
neck.2,14,15 In some patients, presentation is similar to that of bullous pemphi-
goid, and fibrosis is not a feature.2 Lesions are generally few in number and
present as itchy, sometimes burning, tense bullae situated on an erythematous
or urticated base (Fig. 4.108). They tend to recur on previously affected sites.
Rarely, patients may suffer from a transient generalized bullous eruption.14
Nikolsky's sign is negative.21
Fig. 4.108
Mucous membrane
pemphigoid: note the
localized blistering and
erosion with scarring on
the lower leg of an elderly
female. By courtesy
of R.A. Marsden, MD,
St George's Hospital,
London, UK.
In the Brunsting-Perry variant of localized mucous membrane pemphig-
oid, scarring lesions are found predominantly on the head and neck
(Fig. 4.109).25,26 This condition shows a male predominance (2:1) and pres-
ents most often in the sixth decade. The lesions are slowly enlarging, ­atrophic
or scarred plaques measuring several centimeters or more in diameter and
­showing vesiculation and/or bullae formation, both centrally and at the
enlarging margin.27 The anterior portion of the scalp, the face ­(forehead,
­temporal regions, and cheeks), and the anterolateral aspects of the neck are
most often affected.27 In some patients, lesions are few in ­number and,
because of crusting, they may be clinically treated as actinic keratosis,
thereby ­delaying the diagnosis. Transient mucous membrane lesions may be
a feature, but ­scarring is not seen.25
 Mucous membrane pemphigoid (cicatricial pemphigoid) 135

Fig. 4.109
Brunsting–Perry localized pemphigoid: there is extensive alopecia in addition to
multiple erosions with scarring. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
Fig. 4.110
Mucous membrane pemphigoid: in this example of a recurrent lesion, the
subepidermal blister is cell free and there is dermal scarring.

An exceptional case of anti-BP180 mucous membrane pemphigoid

­ resenting with concomitant pemphigus vulgaris limited to mucosal surfaces
p
has been described.28
Autoimmune blistering diseases are very rarely associated with HIV infec-
tion and only a single exceptional case of mucous membrane pemphigoid has
been reported in association with HIV.29

Pathogenesis and histological features

Mucous membrane pemphigoid has been described as a complication of
D-penicillamine therapy for rheumatoid arthritis, practolol and clonidine.14,30
Immunologically, characteristic cicatricial pemphigoid has also been described
following acute, severe, ocular inflammation in patients with Stevens-Johnson
syndrome.31 Although the results of HLA associations have been variable, an
increased frequency of HLA-DR4 and -DQw3 (DQB1*0301) correlates with
a heightened risk of developing ocular disease.32
The cutaneous lesions of mucous membrane pemphigoid are often indis-
tinguishable from those of cell-rich (inflammatory) bullous pemphigoid, com-
prising a subepidermal vesicle containing fibrin, edema fluid, and variable
numbers of inflammatory cells. Although eosinophils are usually evident, Fig. 4.111
they tend to be much less numerous than in generalized bullous pemphigoid. Mucous membrane
The dermis contains a perivascular lymphohistiocytic infiltrate, sometimes pemphigoid: high-power
with conspicuous plasma cells and accompanied by neutrophils and eosino- view of a similar lesion
phils. In older or recurrent lesions, scarring may be a feature (Fig. 4.110).
Less commonly, a cell-poor subepidermal blister is seen (Fig. 4.111). In late
lesions all that may be observed is a band of scarring in the superficial dermis
with or without a subepidermal split. If the latter is present, this is a good clue
to the diagnosis, especially in localized variants where the diagnosis is not
suspected on clinical grounds.
The histopathology of lesions in antilaminin 332 mucous membrane pemphi-
goid has been studied in a small number of cases.33 The features are nondiagnos-
tic and do not allow distinction from other autoimmune blistering diseases. There
is subepidermal blistering and a mild to moderate, superficial mixed inflamma-
tory cell infiltrate composed of lymphocytes, histiocytes, and neutrophils and/or
eosinophils. Scarring is not often seen as biopsies are taken from early lesions.
Oral lesions may rarely be characterized by vesiculation developing
between the stratified squamous epithelium (mucosa) and lamina propria
(Figs 4.112, 4.113). The latter is usually edematous and contains a mixed
inflammatory cell infiltrate consisting of lymphocytes, histiocytes, plasma
cells, and varying numbers of eosinophils and neutrophils (Fig. 4.114). More
commonly, however, the features seen are those of erosions or ulcers lined by
granulation tissue or fibrous tissue and showing non-specific acute or chronic
inflammation. The histology is frequently modified by intense acute inflam- Fig. 4.112
matory changes due to secondary infection. Mucous membrane pemphigoid: oral lesion showing an intact subepithelial blister.
136 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.113 Fig. 4.115

Mucous membrane pemphigoid: note the preservation of the papillae. Mucous membrane pemphigoid: this specimen of conjunctiva shows complete
squamous metaplasia. Neovascularization of the lamina propria is evident. By
courtesy of A. Garner, MD, Institute of Ophthalmology, London, UK.

Fig. 4.114
Mucous membrane pemphigoid: in this example the infiltrate consists of Fig. 4.116
lymphocytes and histiocytes. Eosinophils are not a feature. Mucous membrane pemphigoid: section of cornea. The overlying pannus shows squamous
metaplasia, chronic inflammation, and neovascularization. Blood vessels are also present in
the cornea. By courtesy of A. Garner, MD, Institute of Ophthalmology, London, UK.
Conjunctival vesicles or bullae are very rarely seen in ocular cicatricial
pemphigoid. Although erosions may be a feature, more commonly one may
anticipate conjunctival squamous metaplasia with foci of hyperkeratosis and
parakeratosis accompanied by goblet cell depletion (Fig. 4.115).14 The lam-
ina propria is infiltrated by a mixed inflammatory cell population consisting
of lymphocytes, plasma cells, mast cells, and occasional eosinophils and neu-
trophils.21 Granulation tissue may be seen in early lesions, but dense scarring
is a feature of the later stage. In more severely affected patients, a variety of
intraocular manifestations, including iridocyclitis, rubiosis iridis, and the
development of synechiae, may be seen (Figs 4.116–4.118).
Laryngeal, pharyngeal and esophageal lesions occasionally show subepithe-
lial bullae, erosions, ulcers, inflammatory changes, and fibrosis are more likely
to be seen (Fig. 4.119). Chronic involvement may result in serious stenosis.
The histological features of the localized cutaneous scarring (Brunsting-
Perry) variant are indistinguishable from those of mucous membrane
pemphigoid.27
Electron microscopic observations are variable. In some patients, the split is in
the lamina lucida with the lamina densa lining the floor of the blister cavity
whereas in others, lamina densa is found along the roof of the blister, and occa-
sionally the lamina densa may be split, lining the roof and the floor.2,34 Fig. 4.117
Direct immunofluorescent findings in cicatricial pemphigoid are similar to Mucous membrane pemphigoid: this section shows iris impaction with anterior
those found in generalized bullous pemphigoid. Therefore a linear deposit of synechiae. Iritis and posterior synechiae are also present. By courtesy of A. Garner,
IgG (and sometimes IgA) and C3 is found at the basement membrane region MD, Institute of Ophthalmology, London, UK.

Fig. 4.118
Mucous membrane pemphigoid: this field shows anterior uveitis. There is
inflammation of the iris and ciliary body. By courtesy of A. Garner, MD, Institute of
Ophthalmology, London, UK.
Fig. 4.119
Mucous membrane
pemphigoid: postmortem
specimen showing
laryngeal erosion,
ulceration, and scarring.
of perilesional mucosa (the site of choice) or perilesional skin in approxi-
mately 80–97% of patients.35–39 The presence of IgA at the basement mem-
brane region accompanied by IgG and C3 is a diagnostic pointer towards
cicatricial pemphigoid.2 Examination of the oral mucosa is also of value in
the diagnosis of ocular disease.2 Direct immunoperoxidase of paraffin-embed-
ded tissue can be a satisfactory alternative if a specimen has not been taken
for direct immunofluorescence studies.40
Circulating antibasement membrane zone autoantibodies (IgG and/or IgA)
are sometimes present (26–36%) and are usually of low titer.36,41,42 Substitution
of normal buccal mucosa as substrate does not increase the yield of circulat-
ing antibodies.41 The antibody consists predominantly of IgG4 and IgG1
­subclasses, the presence of the latter conferring complement-­fixing ­ability.43
The presence of IgA may be linked to the mucosal membrane ­distribution of
this disease.44
Investigations of cicatricial pemphigoid antibodies using 1 M NaCl-split
skin have yielded variable results.45–47 Circulating antibodies may be detected
Epidermolysis bullosa acquisita (dermolytic pemphigoid) 137
in from 50% to 100% of cases with active disease.48,49 Although the majority
of sera have reacted with the epidermal side of the split, some have labeled the
floor (dermal side, subsequently shown to be due to antilaminin 332 antibod-
ies: see below), and exceptionally both the roof and the floor have been
labeled.45–49 There is also variation in indirect immunofluorescence findings
depending upon the predominant site of involvement. Thus, for example,
split skin indirect immunofluorescence may be positive in up to 81% of
patients with combined skin and mucosal disease whereas much lower figures
have been found in patients with mucosal disease only (18%) or isolated ocu-
lar disease (7%).2,50
The immunofluorescent findings in the Brunsting-Perry variant are the
same as those described for mucous membrane pemphigoid.51–54
Immunoelectron microscopic observations in mucous membrane pemphi-
goid have revealed two patterns of immune reactant deposition. IgG and C3
may be localized to the lower lamina lucida and lamina densa or else ­identified
overlying the hemidesmosome.55–61 There is no involvement of the sublamina
densa region. The variation can be explained by the different ­target antigens
involved, i.e., BP180, laminin 332 or β4 integrin.
In the Brunsting-Perry variant of localized chronic pemphigoid the immu-
noreactants are localized within the lamina lucida and on the undersurface of
basal keratinocytes.62 In a single case it was demonstrated that the ­antibodies
in the serum reacted with the C-terminal domain of the BP180 (BPAG2) pro-
tein.63 Additionally, however, the complement components C3 and C4 may
also be detected within the lamina densa and the upper papillary dermis. It is
­suggested that this latter finding might account for the scarring characteristic
of this disease process.62
A number of subsets of cicatricial pemphigoid have been delineated by
antigen analysis including variants characterized by antibodies to BP180,
laminin-332, and β4 integrin.43,47,57,64–74 Traditionally, this group of diseases
has been classified together, but the increasing demonstration of autoimmune
reactions to different cell adhesion molecules will likely ultimately lead to
subtyping of this disease similar to the cutaneous forms. For now, since the
clinical features are more uniform than those seen in the skin, these mucosal
cases are considered together. BP180 (collagen XVII) antibodies react with at
least two different sites on the extracellular domain of BP180. One is located
on the noncollagenous domain NC16A; the other is located within the
carboxy-terminal region.68,75–78 Antilaminin-332 (also called epiligrin) antibodies
to the γ3 subunit (sometimes accompanied by antilaminin type-6 antibodies)
are present in a minority of cases and, although the antibodies are usually
IgG, IgA, and IgE, antibodies against laminin-332 may also be found in a sub-
set of patients.79 Patients with antilaminin-332 antibodies have been classified
as having antiepiligrin mucous membrane pemphigoid (AEMMP). Some of
such cases are associated with internal malignancies (including lung, colon,
endometrium, stomach, ovary, pancreas, prostate, non-Hodgkin's lymphoma,
cutaneous T-cell lymphoma, and acute myeloblastic leukemia).80–84 Integrin
has been implicated in patients with ocular disease and an as yet unidentified
45-kD antigen, which binds to the epidermal side on split skin immunofluo-
rescence, has been identified in some patients with IgA antibodies.70,72,73
Autoantibodies to type VII collagen is of importance in some cases of
Brunsting-Perry cicatricial pemphigoid (these patients might be better classi-
fied within the epidermolysis bullosa acquisita spectrum, see below).85
Differential diagnosis
Apart from the presence of scarring in older lesions, mucous membrane pem-
phigoid is indistinguishable from bullous pemphigoid.
Epidermolysis bullosa acquisita (dermolytic
pemphigoid)
Epidermolysis bullosa acquisita (dermolytic pemphigoid) is a rare, chronic
blistering disease, which is characterized by variable clinical presentations
and which may therefore be mistaken for a number of other blistering disor-
ders including congenital epidermolysis bullosa and the other acquired auto-
immune bullous dermatoses.1,2 Annual incidence figures from France and
Central Germany are 0.17–0.26 per million of the population.3,4 In contrast
to its congenital counterpart, epidermolysis bullosa acquisita (EBA) usually
138 Inherited and autoimmune subepidermal blistering diseases

develops in adult life although cases in childhood have been documented.5,6 e­ pidermolysis bullosa. Scarring may then be extreme with resultant contrac-
Initially it was characterized as a porphyria cutanea tarda-like mecha- tures and syndactilism. Rarely, esophageal involvement has been documented
nobullous dermatosis. More recently, however, patients have been described with resultant stricture formation.10,13,14
in whom the disease has presented as a generalized inflammatory bullous der-
matosis.1 For many decades the diagnosis of EBA was one of exclusion. As a Bullous pemphigoid-like EBA
result of immunofluorescence and immunoultrastructural techniques This is the most commonly encountered inflammatory variant.15 On the basis
­combined with immunoblotting and immunoprecipitation, EBA is now of split skin indirect immunofluorescence (see below) it has been suggested
­recognized as an autoimmune dermatosis, type VII collagen (290 kD) repre- that a BP presentation may account for up to 50% of cases of EBA and that
senting the target antigen.1,8 A 145-kD antigen is also sometimes identified. 10–15% of patients diagnosed as BP, in fact, have EBA.15 Other authors,
This represents a cleavage product of the 290-kD antigen. however, have found that EBA is very rare compared to BP, the relative inci-
dence being approximately 25–50 cases of BP for every one case of EBA
Clinical features diagnosed.16,17
EBA was defined in 1971 by Roenigk and colleagues5 as follows: Patients present with a generalized eruption of large tense blisters, which
are often associated with erythema and show a predilection for the flexural
• clinical lesions resembling dystrophic epidermolysis bullosa (blisters
developing on the hands, feet, elbows, and knees following mild trauma and intertrigenous areas.18,19 Pruritus is common.15 Skin fragility is typically
and complicated by atrophic scarring, milia formation and nail dystrophy), absent and scarring and/or milia are not usually features unless the patient
concomitantly shows or evolves towards a mechanobullous phase.1,15
• an adult onset,
Infrequently, the clinical manifestations may resemble dermatitis herpetiformis
• a negative family history of epidermolysis bullosa,
(Fig. 4.122). Exceptionally, prurigo nodularis-like lesions may be seen.20
• exclusion of all other recognized bullous dermatoses including porphyria
cutanea tarda, bullous pemphigoid, dermatitis herpetiformis, pemphigus,
erythema multiforme, and bullous drug reactions.9
It has a wide age incidence ranging from 11 to 77 years, with a mean age
of 47 years. It is associated with a slight female predominance.
In addition to the mechanobullous classical form of EBA, inflammatory
variants, including bullous pemphigoid-like, mucous membrane pemphigoid-
like, and linear IgA disease-like variants, may also be encountered.1,10,11
A case of familial EBA has been described.12

Classical variant
The classical variant is the most commonly encountered variant of EBA.
Patients present with a porphyria cutanea tarda-like illness showing extreme
skin fragility, developing erosions, blistering and crusting in response to mild
trauma including shearing forces.5 Lesions are located on the backs of the fin-
gers and hands in particular and at other sites that are susceptible to trauma,
including the knees, elbows, and buttocks, but virtually any site may be
affected (Fig. 4.120).1,5 The blisters are characteristically noninflammatory,
painless, and tense, and may contain clear or bloodstained fluid.
Healing is usually associated with postinflammatory hyperpigmentation,
considerable scarring, and atrophy. Milia are frequently conspicuous, and
nail changes, including distal onycholysis, dystrophy, and anonychia with Fig. 4.121
nail bed scarring, are common complications (Fig. 4.121). More widespread Epidermolysis bullosa acquisita: conspicuous milia are present on the back of the
involvement may resemble dominant or more often recessive dystrophic hand. By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.122
Fig. 4.120 Epidermolysis bullosa acquisita: in this patient with the dermatitis herpetiformis-like
Epidermolysis bullosa acquisita: there is a tense fluid-filled blister on the ankle. An inflammatory variant, blisters, erosions, and erythematous plaques are evident on
old lesion is also evident. By courtesy of the Institute of Dermatology, London, UK. the elbow. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
 Epidermolysis bullosa acquisita (dermolytic pemphigoid) 139

Mucous membrane pemphigoid-like variant

Some patients present with a mucous membrane pemphigoid-like variant,
characterized by mucous membrane involvement. The oral cavity is commonly
affected. Erosions, ulcers, and blisters may be seen on the tongue, gums, ­palate,
and buccal mucosa.11 Rarely, the larynx and esophagus are affected with
­resultant stricture formation.10 The anus, vulva, vagina, and bladder can very
occasionally be involved.21 Conjunctival lesions are an important, but infre-
quent, cause of morbidity.10,11,22 Symblepharon, epiphora, and even blindness
may occur. Alopecia is sometimes an additional feature.7,13

Brunsting-Perry variant
Some patients with the Brunsting-Perry variant of mucous membrane pem-
phigoid (characterized by blistering and scarring confined to the head and
neck) have antibodies against type VII collagen and therefore might better be
classified within the epidermolysis bullosa acquisita spectrum.7,23,24 Facial
involvement predominates.24,25 A very unusual localized case with periorbital Fig. 4.123
papulovesicular blisters has been reported.26 Epidermolysis bullosa acquisita (classical variant): there is a cell-free subepidermal
vesicle. Note the dermal scarring.
Linear IgA disease-like variant (IgA-EBA)
Epidermolysis bullosa acquisita may also present as a linear IgA disease-like
variant in which both adult and childhood patients have IgA autoantibodies
directed against type VII collagen (see below).27–29 In adults, ocular involve-
ment is often severe and blindness is not uncommon.28

Childhood EBA
Childhood EBA is extremely rare. Mucosal disease is often severe, and clini-
cal manifestations have included classical bullous pemphigoid and linear IgA-
like variants.6,8,30–33

Systemic disease
Epidermolysis bullosa acquisita has long been known to be associated with a
number of systemic illnesses, many with an immunologically mediated patho-
genesis. Most important are inflammatory bowel disease and diabetes melli-
tus.2,10,15,34–45 Approximately 30% of patients with EBA manifest inflammatory
bowel disease, predominantly Crohn's disease.42,46 Control of this improves
the skin condition in some patients. Interestingly, although up to 68% of
patients with inflammatory bowel disease have antibodies against collagen
type VII, only very few develop EBA.47 Presentation as a paraneoplastic phe-
Fig. 4.124
nomenon in association with internal malignancy has also on occasion been
Epidermolysis bullosa acquisita (classical variant): high-power view. There is fibrin
described.48,49 along the floor of the blister cavity. Note the absence of inflammatory cells.

Pathogenesis and histological features

The histological features are somewhat variable depending upon whether a
mechanobullous or an inflammatory lesion is biopsied.
The mechanobullous lesion is characterized by a bland, ‘cell-free’
­subepidermal vesicle containing only a few erythrocytes and a little fibrin
(Figs 4.123, 4.124). Usually, no significant inflammatory cell infiltrate is
present either within the blister cavity or in the adjacent or underlying dermis.
Sometimes, however, a small number of neutrophils, histiocytes, and eosino-
phils may be present. The basement membrane lines the roof of the blister.
Marked scarring of the adjacent dermis is often a feature and milia are
­frequently identified.
The inflammatory variant is characterized by a subepidermal vesicle
accompanied by a mixed inflammatory cell infiltrate comprising lympho-
cytes, histiocytes with prominent neutrophils, and eosinophils. Neutrophils
are usually the predominant cell type and in incipient lesions they may be
identified in a linear distribution adjacent to the epidermodermal junction.15
Occasionally, however, eosinophils predominate.24 Such inflammatory lesions
may resemble bullous pemphigoid or dermatitis herpetiformis (Figs 4.125,
4.126).2,50 Oral lesions show similar features of submucosal vesiculation with
an erythrocyte and inflammatory cell content.
By direct immunoperoxidase using paraffin-embedded material, type IV
collagen is found in the roof of the blister cavity (see Fig. 4.8).
Ultrastructurally, the level of the split in EBA is situated within the super-
ficial dermis immediately below the lamina densa (Fig. 4.127).51–53 The basal
keratinocytes appear normal. Anchoring fibrils have been variably reported
as reduced in number or absent.47–53
An occasional finding is the presence of electron-dense, amorphous granu-
lar material within the superficial papillary dermis close to, but separated
from, the lamina densa (Fig. 4.128).9,35 When present, the split is usually
below the electron-dense amorphous material, which is therefore located
within the roof of the blister.
By direct IMF, IgG and C3 are present in a linear distribution along the
basement membrane region (identical to BP) in a very high proportion of
cases of EBA (Fig. 4.129).9,10,36 Less commonly, IgM, IgA, properdin, and fac-
tor B may also be identified.1,52,53 In linear IgA disease-like patients, IgA may
be present in the absence of IgG.27–29 Positive direct immunofluorescence has
also been reported at a variety of other sites including the oral mucosa, con-
junctiva, cornea, esophagus, duodenum, and bladder.9,28,34
IgG antibasement membrane antibodies may be identified in 25–50% of
patients, thereby increasing the similarity to BP.2,47,51,54 In many patients the
antibasement membrane antibodies are associated with complement-fixing
properties.55 With split skin indirect IMF, which is more sensitive than con-
ventional indirect IMF, the immunoreactants line the floor of the induced
blister cavity.56–59
Direct and indirect immunoelectron microscopic studies have determined
that the immunoreactants lie on or below the lamina densa, corresponding to
the site of the electron-dense amorphous material mentioned above
140 Inherited and autoimmune subepidermal blistering diseases

A
A

B
B

Fig. 4.125
Fig. 4.127
(A, B) Inflammatory epidermolysis bullosa acquisita: in this bullous pemphigoid-like
(A, B) Epidermolysis bullosa acquisita: electron micrograph showing the lamina
variant, subepidermal blistering is associated with an eosinophil-rich infiltrate.
densa in the roof of the blister. (BC, blister cavity.)

Fig. 4.126
Inflammatory
epidermolysis bullosa
acquisita: dermatitis Fig. 4.128
herpetiformis-like variant, Epidermolysis bullosa acquisita: occasional deposits of finely granular electron-
with a neutrophil-rich dense material (immunoreactant) as seen in this field may be a useful diagnostic
infiltrate. pointer.

Fig. 4.129
Epidermolysis bullosa acquisita: (left) direct immunofluorescence shows linear
IgG deposition along the basement membrane region; (right) with split skin the
immunoreactant lines the floor of the induced lesion. By courtesy of Department of
Immunofluorescence, Institute of Dermatology, London, UK.
Fig. 4.130
Epidermolysis bullosa acquisita: direct immunoelectron microscopy showing
reactant deposition below the lamina densa.
(Fig. 4.130).1,51,52,60,61 Immunogold labeling confirms that the immunoglobu-
lin deposits are related to the anchoring fibrils (Fig. 4.131).62 As a conse-
quence of these additional observations, a modified set of criteria for the
diagnosis of EBA has been recommended:1,63
• clinical lesions of trauma-induced bullae occurring over the joints of the
hands, feet, elbows and knees, atrophic scars, milia and nail dystrophy,
or else presentation as a clinically inflammatory bullous or mucous
membrane pemphigoid-like process,
• postinfancy onset of the disease,
• no family history of EBA,
• exclusion of other bullous diseases,
• IgG at the basement membrane zone on direct immunofluorescence,
• demonstration of blister formation beneath the lamina densa,
• demonstration of IgG associated with anchoring fibrils beneath the basal
lamina by immunoelectron microscopy,
• localization of the immunoreactants to the floor of 1 M NaCl-split skin
by direct and or indirect immunofluorescence.
The EBA antigen (290 kD) is the globular (noncollagenous) carboxyl ter-
minus of type VII procollagen (Fig. 4.132).64–68 Type VII collagen is the major
constituent of anchoring fibrils which anchor the basement membrane
Epidermolysis bullosa acquisita (dermolytic pemphigoid) 141
Fig. 4.131
Epidermolysis bullosa acquisita: immunogold preparation showing localization of
the immunoglobulin to the anchoring fibrils. By courtesy of H. Shimizu, MD, Keio
University School of Medicine, Tokyo, Japan.
Fig. 4.132
Epidermolysis bullosa
acquisita: there are two
distinct antigens: one the
290-kD major antigen; the
other the 145-kD minor
antigen. By courtesy of I.
Leigh, MD, Royal London
Hospital Trust, London, UK.
through the lamina densa to the connective tissue constituents of the adjacent
dermis and is composed of three identical alpha-chains (each 290 kD). It is
synthesized by both human keratinocytes and fibroblasts in culture, and is
found in other mammalian skin including dog, cat, guinea pig, rat, mouse,
and hamster, but not in avian, reptilian, amphibian, or fish skin.69–72 Type VII
collagen has also been identified within the esophagus, mouth, anus, and
vagina. It has a high affinity for fibronectin, which is thought to be respon-
sible (at least in part) for adhesion between cells and matrix within the der-
mis.73 The interaction between the EBA antibody and type VII collagen is
thought to somehow upset this delicate relationship with consequent der-
moepidermal separation.74 Passive transfer of human EBA autoantibodies to
mice and immunization of mice with type VII collagen both lead to EBA dis-
ease models, confirming the importance of this autoantibody.75–78 An animal
model and human antibody characterization indicate that the pathogenic
antibodies of epidermolysis bullosa acquisita are often against the cartilage
142 Inherited and autoimmune subepidermal blistering diseases

matrix protein subdomain of the N-terminal noncollagenous domain of type

VII collagen.79 In some cases of inflammatory EBA the antibodies react against
epitopes in the triple-helical collagenous domain.80
The parallel between EBA and BP is obvious and it is tempting to extrapo-
late a similar downstream pathogenesis after autoantibody binds to its pro-
tein target.81 Although the current concept for EBA points to such a similarity,
additional confirmatory evidence is required. Recent studies have shown that
the pathogenesis is related, at least in part, to neutrophil recruitment medi-
ated by complement activation, and the generation of complement-derived
chemotactic activity (C5A) at the epidermal basement membrane region.74
Experimental models in which immune complexes are produced by treating
normal skin in organ culture with EBA complement-fixing antibodies has
been shown to result in complement-dependent neutrophil migration to the
basement membrane region and eventual dermoepidermal separation.55,82
Lack of complement-fixing function in the autoantibodies does not result in
tissue injury in one model.83 The precise mechanism whereby such blisters
evolve is unknown, but it has been suggested that leukocyte-derived proteases
and reactive oxygen intermediates may be important.54
The pathogenesis of the ‘cell-free’ mechanobullous variant is poorly under-
stood. It is also associated with antibasement membrane antibody, but there is Fig. 4.133
Bullous systemic lupus erythematosus: West Indian female with perioral blistering.
little if any evidence for neutrophil chemotactic activity. It has been proposed
By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
that separation at the dermoepidermal junction may result from an abrogation
of affinities between the type VII collagen and laminin-332 in addition to matrix
proteins such as fibronectin due to a direct effect of autoantibody deposition at
that site.1,84–86 An additional potential mechanism proposed is a direct effect of both sexes may develop the disease (Fig. 4.133).4,6–11 Presentation in children
the autoantibody on type collagen VII antiparallel dimer assembly leading to is exceptional.12,13
diminished anchoring fibril formation.1,87 The finding of domain specificity in Patients present with a widespread, sometimes pruritic, tense, vesicu-
EBA autoantibodies will direct focus toward the function of this cartilage matrix lobullous eruption that may affect both sun-exposed and nonsun-exposed
protein subdomain.81 It is intriguing that the pathogenetic autoantibodies in skin (Figs 4.134–4.136). The eruption can precede the onset of SLE or
EBA are against type VII collagen, the same protein genetically interrupted in develop subsequently.8,14 Lesions develop on flexural and extensor surfaces,
dystrophic epidermolysis bullosa, leading to nonfunctional anchoring fibrils. and mucosal (mouth and pharynx) lesions have been documented.4,8,15
Nonetheless, the clinical presentation of EBA is broad and includes features not A predilection for involvement of the upper trunk and supraclavicular
seen in dystrophic EB, such as bullous pemphigoid-like lesions. regions has been reported.4 Lesions may arise against a background of
­erythema or less commonly urticaria. Unlike EBA with which this disease
shares much in common, mechanobullous lesions are not seen, nor is there
Differential diagnosis ­evidence of scarring.4 Milia formation, although rare, has been recorded on
‘Cell-free’ EBA must be distinguished from congenital EB, porphyria cutanea two occasions and in both instances affected children.9,10 Postinflammatory
tarda, pseudoporphyria, and cutaneous bullous amyloidosis. Diagnosis can ­hyperpigmentation is a not uncommon complication. Surprisingly, patients
be achieved easily with the use of immunofluorescence. with bullous SLE do not usually develop other cutaneous manifestations of
Inflammatory EBA can be distinguished from bullous pemphigoid, mucous lupus. Bullous SLE has been recorded in a patient whose primary ­disease
membrane pemphigoid, and linear IgA disease by split skin IMF and, when developed as a consequence of hydralazine therapy and identical features
necessary, by Western blot (see Table 4.4). (including immunological) have been recorded in a patient with mixed
It is also important that dermoepidermal separation due to autolysis is not ­connective tissue disease.16
confused with in vivo blister formation. In autolysis the epithelium typically
shows marked eosinophilia and the nuclei are often lost.

Bullous systemic lupus erythematosus

Blisters may rarely develop as a manifestation of systemic lupus erythemato-
sus (SLE). They can therefore arise in a background of vasculitis or compli-
cate sunburn and photosensitivity.1,2 Occasionally vesicles form after extreme
basal cell hydropic change and consequent dermoepidermal separation.3
Patients with SLE manifest a wide range of antibodies resulting in numer-
ous complications, which include the development of autoimmune bullous
dermatoses such as bullous pemphigoid, dermatitis herpetiformis, pemphigus
vulgaris, pemphigus foliaceus, linear IgA disease, and ­epidermolysis bullosa
acquisita.4,5 More recently, an apparently unique dermatosis ­comprising a
widespread vesiculobullous eruption characterized by a ­dermatitis herpeti-
formis-like histology, linear basement ­membrane zone ­antibody deposition
(reacting with type VII collagen), and a striking response to dapsone has been
described in patients with SLE.6 This c­ onstitutes bullous SLE.

Clinical features Fig. 4.134

Bullous SLE – also termed bullous eruption of SLE, vesiculobullous SLE, SLE Bullous systemic lupus erythematosus: in this example there is a conspicuous
with herpetiform blisters – tends to present in the second and third decades inflammatory background. By courtesy of the Institute of Dermatology,
and although young black women are most often affected, all ages, races, and London, UK.

Fig. 4.135
Bullous systemic lupus erythematosus: numerous erosions are present over the
chest, shoulders, and upper arms. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
Fig. 4.136
Bullous systemic lupus
erythematosus: tense
bullous pemphigoid-like
lesions. By courtesy of the
Institute of Dermatology,
London, UK.
Pathogenesis and histological features
Patients with bullous SLE (and EBA) have a significantly higher incidence of
HLA-DR2 compared to the normal population.4 This is thought to be associ-
ated with an increased risk of developing autoimmune diseases.17
The histological features of bullous SLE (BSLE) are those of a subepidermal
vesicle, often indistinguishable from dermatitis herpetiformis. The roof is usu-
ally intact and the blister cavity contains fibrin with large numbers of neutro-
phils and karyorrhectic debris (Fig. 4.137). Occasionally ­lymphocytes,
histiocytes, and eosinophils are also evident.4 The adjacent, nonbullous skin
characteristically shows subepidermal neutrophil microabscesses (Fig. 4.138).
The upper dermis contains a perivascular mixed inflammatory cell infiltrate
consisting of neutrophils, occasional eosinophils, lymphocytes, and histio-
cytes. Sometimes the features of a leukocytoclastic vasculitis are also present
(Figs 4.139–4.141).
Electron microscopy shows that the site of the split is below the lamina densa.4
Bullous systemic lupus erythematosus 143
Fig. 4.137
Bullous systemic lupus erythematosus: this shows the typical features of a
subepidermal, neutrophil-rich vesicle.
Fig. 4.138
Bullous systemic lupus
erythematosus: the
presence of a neutrophil
abscess in the papillary
dermis increases the
histological similarity of
this condition to dermatitis
herpetiformis.
Using direct immunofluorescence, the disease is characterized by the pres-
ence of immunoglobulin and complement at the epidermal basement mem-
brane region of both lesional and perilesional skin. Immunoglobulins are
frequently multiple: IgG is present in 100% of patients, IgA in 67%, and IgM
in 50%.4,7,8,17,18 Two patterns are recognized: granular in 40% of cases and
linear in 60%.8 Sometimes immunoreactants are also present within the walls
of the upper dermal vasculature, particularly venules.4 Indirect immunofluo-
rescence using 1 M NaCl-split skin as substrate shows the presence of a low
titer antibasement membrane antibody in those patients who demonstrate
linear positive direct IMF (type 1 BSLE).1,4,8,15,16,19–22 The antibodies generally
label the floor of the blister cavity although a roof (epidermal) variant has
rarely been described.8 Those that are negative on indirect IMF have been
classified as type 2 BSLE.4 Type 3 BSLE refers to those cases in which the
­target antigen is an epidermal rather than dermal epitope.6
Direct immunoelectron microscopy shows that the immunoreactants are
present on and immediately below the lamina densa, obscuring the anchoring
144 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.139
Bullous systemic lupus erythematosus: this scanning view shows a central focus
of subepidermal vesiculation. Striking inflammatory changes outline the dermal
vasculature.
fibrils, and also occasionally somewhat deeper in the papillary dermis similar
to those seen in nonbullous SLE.4, 23–25 The antibody binds to the lamina
densa and sublamina densa in a manner identical to that seen in epidermoly-
sis bullosa acquisita.4,24
Western immunoblot has shown that these antibodies bind to antigens of
290 kD and 145 kD as described for EBA (i.e., type VII collagen).19 Recently,
rare patients with SLE have been shown to have circulating antibodies to type
VII collagen in the absence of blisters, and occasional patients with bullous
SLE have been shown to have antibodies which bind to both the roof and the
floor of NaCl-split skin, suggesting that a number of different basement mem-
brane antigens may be involved.1,4 The target antigen in the epidermal variant
of bullous SLE has not yet been identified although bullous pemphigoid anti-
gen 1 was identified in addition to type VII collagen and laminins-332 and -311
in one patient with combined epidermal and dermal staining on NaCl-split
skin indirect IMF, most likely representing a manifestation of postinflamma-
tory epitope spreading.25
The bullous SLE antibodies are associated with complement activation
activity, which results in neutrophil migration and adherence to the basement
membrane region.4 Neutrophil enzyme release is associated with basement
membrane damage and subsequent dermoepidermal separation.
Differential diagnosis
Bullous SLE shows obvious overlap with EBA. There are, however, a number
of discriminatory features. Bullous SLE is not associated with a mecha-
nobullous pathogenesis and scarring is not a feature. It develops most often
in a younger age group than EBA. The dermatitis herpetiformis-like histologi-
cal features are rarely seen in EBA and probably of greatest importance;
bullous SLE responds dramatically to dapsone therapy, but EBA does not.3

Dermatitis herpetiformis
Clinical features
Dermatitis herpetiformis and celiac disease are highly interrelated conditions
and best regarded as variable expressions of a common inherited tendency to
autoimmune disease.
Dermatitis herpetiformis (Duhring-Brocq disease) is a widespread, intensely
pruritic, papulovesicular eruption affecting all ages, but particularly people in
their second to fourth decades.1–4 The male to female ratio is 2:1.
The incidence of dermatitis herpetiformis is highest in Northern Europe,
Fig. 4.140 Scotland, and Ireland.2,5,6 It is less frequently seen in the United States.
Bullous systemic lupus erythematosus: this view shows florid leukocytoclastic Caucasians are mainly affected, the disease being rare in Asians and blacks.
vasculitis.
Case clustering is common and familial involvement (either dermatitis
­herpetiformis or celiac disease), possibly autosomal dominantly inherited, has
been documented in up to 10.5% of cases.2,7 Relatives of patients with
­dermatitis herpetiformis have an increased risk of developing celiac disease.2
The lesions, which may be symmetrical, are grouped mainly on the
­posterior scalp, shoulders, back, buttocks, and extensor aspects of the limbs
(Figs 4.142, 4.143). Scratching is often severe and therefore excoriation and/
or lichenification typically predominate with intact vesicles rarely being seen.
However, occasionally, larger blisters similar to those found in bullous
­pemphigoid may be evident. Patients sometimes present with urticarial
plaques and crusted erosions.2 Oral involvement is rare.3 Rarely, the initial
presentation may be with localized lesions in areas such as the scalp.8 The lat-
ter is not infrequently involved in more generalized disease. In one patient,
the presenting symptom was petechiae on the fingertips.9
The clinical response to dapsone (50–200 mg/day) is dramatic; therefore,
the drug is commonly administered for diagnostic as well as ­therapeutic
­purposes. Relief from pruritus occurs within a few hours of commencing
treatment and is soon followed by clearing of the rash. The eruption returns
2–3 days after dapsone is discontinued. The disease persists for many years
and is usually lifelong. A gluten-free diet may result in prolonged remission in
Fig. 4.141 some patients or lowering of the daily dapsone requirement in others.
Bullous systemic lupus erythematosus: this is a close-up view of the subepidermal At least 65–75% of patients with dermatitis herpetiformis show histological
vesicle shown in Figure 4.139. evidence of celiac disease (gluten-sensitive enteropathy, GSE). However, only
 Dermatitis herpetiformis 145

Pathogenesis and histological features

Fig. 4.142
Dermatitis herpetiformis:
excoriations are present
on the elbow and back of
the arm. Intact blisters are
uncommon in dermatitis
herpetiformis because of
the intense pruritus. By
courtesy of the Institute of
Dermatology, London, UK.
Patients with dermatitis herpetiformis (and celiac disease) have a high
incidence of HLA-B8 (80–90%), HLA-DR3 (90–95%) and HLA-DQ2
­(95–100%) compared to a normal control population (21%, 23%, and
40%, respectively).3,24–27 More recent studies, however, have demon-
strated that the increased incidence of HLA-B8 and -DR3 are due to
positive linkage disequilibrium. 28 The most current data suggest that the
significant positive HLA association in dermatitis herpetiformis lies with
the class II antigen DQ2.2,29 These HLA associations can be helpful
diagnostically.30
All patients with dermatitis herpetiformis have granular deposits of IgA
in the dermal papillae of perilesional skin, and many also show in vivo-
bound fibrin (Fig. 4.144).31,32 IgA has also been identified in the oral
mucosa.33 A  granular linear pattern may be seen and it seems to be more
common than previously reported.34 In patients with a linear pattern, careful
attention should be paid to the presence of granularity to avoid a misdiagno-
sis of ­linear IgA disease. Recently, a fibrillar pattern has also been docu-
mented.35 Two of the three patients reported with this pattern had clinical
features of dermatitis herpetiformis but lacked antitransglutaminase and
antiendomysial antibodies. Other immunoglobulins are not usually found,
but C3 is often present.36 This is associated with formation of the membrane
attack complex (C5–C9), which is thought to result in neutrophil chemo­
taxis and the evolution of subepidermal vesiculation.3,37 Cutaneous IgA

Fig. 4.143
Dermatitis herpetiformis: the buttocks are frequently affected. By courtesy of the
Institute of Dermatology, London, UK.

about 20% have clinical manifestations of malabsorption, these being usually

mild.10–15 The actual incidence of celiac disease is likely to be higher because the
mucosal abnormality in dermatitis herpetiformis is patchy and may be missed
unless multiple jejunal biopsies are taken.16–18 Interestingly, patients who appar-
ently do not have enteropathy may develop the ­condition when challenged with
large doses of gluten (latent GSE).13 It is therefore believed that all patients with
dermatitis herpetiformis have GSE to a greater or lesser extent.1–3 Relatives of
patients with dermatitis herpetiformis may show no evidence of the skin dis-
ease, but can have subclinical or overt s­ ymptoms of the enteropathy.
Patients with dermatitis herpetiformis may have antigastric parietal cell
antibody (10–25%), gastric hypochlorhydria (50–90%), and gastric ­atrophy
(50–70%).3 They may also have antithyroid antibodies and show an increased B
incidence of thyroid disease, insulin-dependent diabetes mellitus, and connec-
tive tissue diseases including systemic lupus erythematosus and Sjögren's syn- Fig. 4.144
drome.19,20 As with isolated celiac disease, there is an increased risk of Dermatitis herpetiformis: direct immunofluorescence showing (A) deposits of granular
intestinal lymphoma.21 IgA in the dermal papillae; (B) fibrin deposition in the dermal papillae. (A) By courtesy
Exposure to iodine may trigger or flare the disease.22,23 of the Department of Immunofluorescence, Institute of Dermatology, London, UK.
146 Inherited and autoimmune subepidermal blistering diseases

deposits may still be detected after dapsone therapy. They do, however, many levels of the biopsy will have to be examined before a microabscess is
sometimes disappear after a prolonged gluten-free diet.2 Cutaneous IgA found.
deposition is not seen in patients with celiac disease.2 Abscess evolution depends upon the initial presence of fibrin and
Electron microscopy reveals electron-dense, amorphous granular deposits ­polymorphs within the tips of the dermal papillae (Fig. 4.146), both of
in the superficial dermis showing no particular relationship with the base- which are associated with degenerative changes of the collagen and the
ment membrane region or any other specific structure.38,39 development of edema. Development of small subepidermal microvesicles
Immunoelectron microscopic observations initially suggested that the IgA follows, leading on to the formation of multilocular subepidermal
deposits were associated with elastic-containing microfibrillar bundles, but blisters.
more recently published work using antifibrillin antibodies has discounted Typically, the blister cavity contains edema fluid, a reticular network of
this theory.38,40 fibrin, and numerous polymorphs (Figs 4.147, 4.148). In contrast to bullous
Antigliadin antibodies, which are often used to assess celiac disease status, pemphigoid, the floor of the blister cavity usually shows effacement of the
are of limited value in the diagnosis of dermatitis herpetiformis.13 They have dermal papillary outline.
high specificity, but low sensitivity.13 Anti-smooth muscle endomysial anti- Within the dermis is a mixed inflammatory cell infiltrate consisting of lym-
body correlates with the gluten-sensitive state and appears before the devel- phocytes, histiocytes, and abundant neutrophils. Leukocytoclasis (nuclear
opment of any small intestinal histological abnormality in patients with dust, Fig. 4.149) is characteristic. Although blood vessels frequently show
dermatitis herpetiformis.13,41,42 Such endomysial antibodies are present in up endothelial swelling, there is no evidence of vasculitis. Occasionally, eosino-
to 70% of patients and are highly specific; they react with tissue transglu- phils are quite numerous in the infiltrate, but usually they are late arrivals,
taminase (tTG) (antitransglutaminase antibodies).43 Antibodies against epi- appearing 24–48 hours after the neutrophils. On occasions, biopsies from
dermal transglutaminase are found more frequently than the latter. typical dermatitis herpetiformis may show acantholysis, a cause of consider-
Antitransglutaminase antibodies, particularly those to epidermal tranglutam- able confusion (Fig. 4.150).
inase, seem to be the most sensitive serological marker of dermatitis herpeti-
formis.33,44 Patients with high levels of IgA and IgG transglutaminase
antibodies usually have more prominent mucosal villous atrophy and more
severe clinical disease.45 Gliadin is an important substrate for tissue transglu-
taminase forming gliadin–gliadin or gliadin–tTG complexes.46 Circulating
IgA antibodies to tTG are pathognomonic of dermatitis herpetiformis and
celiac disease.47 The gut subtype of transglutaminase is TG2 while that in the
skin is TG3. Cross-reactivity between these homologous proteins or antigenic
drift may underlie some of the mucosal and cutaneous features of this condi-
tion.48,49 Whatever the underlying mechanism, the IgA in some way ‘fixes’ in
the skin, resulting in complement activation via the alternative pathway.50–52
Neutrophil chemotaxins are then released and the ensuing inflammatory
reaction leads to dermal papillary edema, fibrin deposition, and eventual
vesiculation. There may be a role for cell-mediated ­immunity in this disease
as well, perhaps involving γ/δ T cells.53
The histological hallmark of dermatitis herpetiformis is the dermal papil-
lary neutrophilic microabscess, best seen in early erythematous lesions or well
away from the blister in an established eruption (Fig. 4.145).54–56 Occasionally,

Fig. 4.146
Dermatitis herpetiformis: in this early lesion, there are thin strands of fibrin visible
above the neutrophilic infiltrate.

Fig. 4.145
Dermatitis herpetiformis:
biopsy from an early
lesion showing Fig. 4.147
conspicuous neutrophil Dermatitis herpetiformis: an established subepidermal blister. Although early lesions
microabscesses. are usually multilocular, by 24–48 hours the lesion becomes unilocular.
 Linear IgA disease 147

Fig. 4.148
Dermatitis herpetiformis:
floor of the blister in
Figure 4.147 showing
an intense neutrophil
infiltrate.

Fig. 4.150
(A, B) Dermatitis herpetiformis: in this example acantholysis may result in
diagnostic confusion with pemphigus. Note that the blister is subepidermal.

Linear IgA disease

Fig. 4.149
Dermatitis herpetiformis: nuclear debris (karyorrhexis) within the dermis is a
characteristic feature.
Jejunal biopsy may reveal villous blunting, intestinal crypt elongation,
flattening of surface epithelial cells with loss of microvilli, and intraepithe-
lial γ/δ lymphocytic infiltration to a degree ranging from partial to subtotal
villous atrophy.57 If gluten is withheld from the diet, these changes revert to
normal.
Differential diagnosis
A neutrophil-predominant subepidermal vesicle accompanied by neutrophil
dermal papillary microabscesses in addition to dermatitis herpetiformis may
also be seen in the following conditions: vesicular pemphigoid, bullous sys-
temic lupus erythematosus, inflammatory epidermolysis bullosa, and linear
IgA disease. Distinction depends upon clinical information and the results of
immunofluorescent studies (see Table 4.4).
Linear IgA disease of adults by definition presents after puberty. It is
­characterized by the development of a sometimes self-remitting dapsone or
­sulfonamide-responsive dermatosis typified by subepidermal vesicles and
blisters in association with in vivo deposition of linear (homogeneous) IgA at
the basement membrane region on direct immunofluorescence of normal or
­perilesional skin.1–3 Childhood linear IgA disease (chronic bullous dermatosis
of childhood) is almost identical to the adult counterpart; however, there are
differences in clinical presentation and therefore these particular aspects are
described separately.
Linear IgA disease of adults is a rare disease, which was originally thought
to represent a variant of dermatitis herpetiformis4–6 or bullous pemphigoid.7,8
Some cases were reported under the rubric polymorphic pemphigoid (see
above) or intermediate (mixed) forms of bullous disease.9,10 More recently,
particularly following the application of immunoelectron microscopic and
immunoblotting techniques, it has been confirmed as a disease (or at least a
disease spectrum) sui generis.11–15
Its approximate incidence in the south of England is 1:250 000.16 In France
and central Germany, the incidence is 0.5 per million of the population.17,18 In
Singapore, the incidence has been estimated at 0.26 per million population.19
Although data for the United States are limited, the incidence in Utah has
been reported as 0.6 per 100 000.20 Some consider that this disease is
underdiagnosed.
148 Inherited and autoimmune subepidermal blistering diseases

Clinical features
Linear IgA disease of adults affects the sexes equally and, while the age distribu-
tion is wide, there are peaks in teenagers and young adults and in patients in
their sixties.1 It may present as a somewhat atypical bullous eruption showing
features suggestive of dermatitis herpetiformis or more commonly bullous pem-
phigoid (Fig. 4.151). Occasionally, it may initially resemble and be ­mistaken
clinically for erythema multiforme.21 Pruritus and/or a burning sensation are
common manifestations and early lesions may include urticarial, ­annular,
­polycyclic, and targetoid eruptions.15,22 The established dermatosis may be
vesicular or more often frankly bullous; blisters arising at the edge of erythema-
tous annular lesions (‘string of beads’ sign) are said to be characteristic.15
Sites affected in decreasing order of frequency include the trunk, limbs,
hands, scalp, face, and perioral region. The perineum and vagina may also be
affected with erosions and blisters.1 Mucous membrane involvement, which
is common, is of particular importance because it can be associated with scar-
ring. Important sites that may be affected include the eyes (conjunctivitis,
symblepharon, trichiasis, corneal opacification, and rarely blindness; Fig.
4.152), the mouth (erosions, blisters, and chronic ulceration), nasal cavity
(crusting and bleeding) and the pharynx (hoarseness).1,23–25 When these Fig. 4.152
mucosal symptoms are severe there is clinical overlap and diagnostic confu- Adult linear IgA disease: there is marked conjunctival injection and blepharitis.
sion with mucous membrane pemphigoid. By courtesy of the Institute of Dermatology, London, UK.
Childhood linear IgA disease (chronic bullous disease of childhood) not
uncommonly develops after an upper respiratory tract illness, often following
treatment with penicillin.26–29 Females are affected more often than males
(1.6:1) (Fig. 4.153). The average age of onset is 6 years, but very rare cases
in neonates have been described.30
Lesions, which can be pruritic or burning in the early stages, may be
urticated, annular or polycyclic in appearance and usually arise on normal
skin. Vesicles and large bullae (sometimes hemorrhagic) then predominate,
and although the perioral regions and genitalia are particularly affected, the
face, ears, trunk, limbs, hands, and feet are also often involved (Fig. 4.154).
Usually, the new lesions appear around those that are resolving (the ‘cluster
of jewels’ sign, Fig. 4.155). In older and black African children the clinical
appearances can suggest bullous pemphigoid. Healing is sometimes associ-
ated with postinflammatory hyper- or hypopigmentation. Mucous membrane
lesions are common (64%). Ocular symptoms of pain, grittiness, discharge
and redness are found in 40% of children; conjunctival scarring is present in
approximately 21%; oral lesions are found in up to 57%.
Fig. 4.153
Childhood linear IgA
disease: in this case
widespread erosions
on an erythematous
background are present
on the buttocks and legs.
Occasional intact vesicles
are also evident. By
courtesy of R.A. Marsden,
MD, St George's Hospital,
London, UK.

Although linear IgA disease in children was originally thought to be self-

Fig. 4.151
Adult linear IgA disease:
in this example the clinical
appearances of excoriated
lesions are suggestive of
dermatitis herpetiformis.
By courtesy of the
Institute of Dermatology,
London, UK.
limiting, it is now appreciated that symptoms may last over 5 years (25%)
and occasionally extend beyond puberty into adult life. Exceptionally, an
association with IgA nephropathy may be seen.31
Linear IgA disease is associated with increased expression of HLA-Cw7,
-B8, -DR2, -DR3 and -DQ2.32 The incidence of HLA-B8 association is vari-
able, with reported figures varying from 28% to 56% (normal range
20–25%).15,22 There is no evidence of an increase in HLA-B12.15 Linear IgA
disease is also associated with HLA-Cw7 and -DR3.1
Although in the earlier literature as many as 24% of patients with linear
IgA disease were thought to have associated gluten-sensitive enteropathy, the
incidence is almost certainly considerably lower.1 There are, however,
­occasional recent references documenting occasional patients with linear IgA
disease with clinical and histological evidence of gluten-sensitive enteropathy
in the presence of antiendomysial and antitransglutaminase antibodies.33,34

Fig. 4.154
Childhood linear IgA disease: groups of blisters are present on the vulva and inner
thighs. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 4.155
Childhood linear IgA
disease: the arrangement
of blisters called the
‘cluster of jewels’. By
courtesy of R.A. Marsden,
MD, St George's Hospital,
London, UK.
It is possible that these cases represent dermatitis herpetiformis with linear
granular deposits of IgA in which the granularity has not been detected.
There are a number of reports documenting an association between linear
IgA disease and internal malignancy, including lymphoma and leukemia,
although whether this has significance is uncertain.35–38
Pathogenesis and histological features
Histologically, linear IgA disease is characterized most frequently by dermati-
tis herpetiformis-like features (Fig. 4.156).26,39,40 Occasionally, however, the
histological changes suggest bullous pemphigoid or sometimes a mixture of
both diseases (Fig. 4.157). Eosinophilic spongiosis may rarely be a feature.26
Ultrastructurally, the site of cleavage may be through the lamina lucida or
below the lamina densa.21
Linear IgA disease 149
Fig. 4.156
(A, B) Linear IgA disease: in this example the features are those of a neutrophil-rich
subepidermal vesicle reminiscent of dermatitis herpetiformis.
A homogeneous linear deposition of IgA along the basement membrane
region is found by direct immunofluorescence in 100% of patients (Fig.
4.158).26,41–43 Uninvolved skin (particularly of the back) is suitable.1 Oral
mucosa and conjunctiva may also show IgA deposition.1 The linear IgA anti-
gen is present in all stratified squamous epithelia and amnion but, in contrast
to the bullous pemphigoid antigen, is not found in bladder mucosa.42 IgG
may also be demonstrable in up to 25% of cases.12,15 IgM and C3 are occa-
sionally present.43
A low titer circulating IgA antibasement membrane zone antibody is pres-
ent in approximately 30% of patients.1 Use of conjunctiva as substrate may,
however, substantially increase this figure (up to 50%).23 Circulating IgG or
C3-binding antibasement membrane antibodies are seen only in those patients
with overlap syndrome.44 The IgA antibody is of pathogenetic significance
since it causes dermoepidermal separation after incubation with whole skin
cultures.45 Passive transfer of antibodies into a mouse model with human skin
graft also produces characteristic lesions.46 Blister fluid is also satisfactory for
indirect IMF.1
With split skin immunofluorescence, the titer may be higher and sensitiv-
ity is increased. The IgA antibasement membrane zone antibody variably
labels the epidermal side, the dermal side or both sides of the artificial ­blister
­cavity.47–49 Immunoelectron microscopy has shown similar results, with IgA
being present within the lamina lucida or below the lamina densa in associa-
tion with anchoring fibrils, and sometimes in both locations
(Fig. 4.159).50–55
Studies by Western immunoblotting indicate that linear IgA disease is a
heterogeneous condition. Thus, in those cases associated with dermal binding
on indirect NaCl-split skin IMF, the dermal antigens include 285-kD and
150 Inherited and autoimmune subepidermal blistering diseases

A B

Fig. 4.157
(A, B) Linear IgA disease: in this field the presence of eosinophils is more suggestive of bullous pemphigoid.

Fig. 4.158
Linear IgA disease: direct
immunofluorescence
showing linear IgA
deposition. By courtesy
of the Department of
Immunofluorescence,
Institute of Dermatology,
London, UK.
250-kD proteins and type VII collagen.14,49,56,57 Epidermal binding ­antibodies
react with BP230 (BPAG1), BP180 (BPAG2), and 200/280-kD antigens dis-
tinct from either of the BP antigens.58–60 The antigens 120 kD (LAD1) and
97 kD described in earlier reports represent proteolytic cleavage products of
BP180.61–64 Linear IgA disease 180-kD antibodies recognize the NC16A
domain of collagen XVII (BPAG2) also critical for bullous pemphigoid, pem-
phigoid gestationis, mucous membrane pemphigoid, and lichen planus pem-
phigoides described above.65–68 This fact is remarkable considering the variable
Fig. 4.159
Linear IgA disease: direct immunoperoxidase reaction using frozen tissue substrate.
There is an abundance of granular IgA beneath the basal lamina.
clinical features of these various ­autoimmune bullous disorders. LAD1 has
been identified as ladinin localizing to the extracellular domain of BP180 kD.69
Those patients with mixed IgA and IgG antibody-mediated disease also target
BP180.44 Recent reports suggest that antibodies against the NC16A domain
may be more important than those against the LAD1 cleavage product of
BP180, but not all cases contain the anti-NC16A antibodies.70–72
Drug-induced linear IgA disease is considered in chapter 14.
Differential diagnosis
The diseases from which linear IgA disease must be differentiated are derma-
titis herpetiformis, bullous pemphigoid, and inflammatory epidermolysis
bullosa. Points of distinction are considered in Table 4.4.
 Chapter

See
www.expertconsult.com
for references and
additional material
Acantholytic disorders
5
Introduction  151 Paraneoplastic pemphigus  163 Linear Darier's disease  173
IgA pemphigus  165 Transient acantholytic dermatosis  174
Pemphigus  151 Acantholytic dermatosis of the genitocrural area  176
Drug-induced pemphigus  167
Pemphigus vulgaris  152
Contact pemphigus  167 Warty dyskeratoma  176
Pemphigus vegetans  156
Familial dyskeratotic comedones  177
Pemphigus foliaceus  157 Acantholytic dermatoses with dyskeratosis  167 Acantholytic acanthoma  178
Endemic pemphigus foliaceus (fogo selvagem)  160 Hailey-Hailey disease  167
Acantholytic dyskeratotic acanthoma  179
Pemphigus herpetiformis  162 Relapsing linear acantholytic dermatosis  169
Focal acantholytic dyskeratosis  179
Pemphigus erythematosus  162 Darier's disease  169

Table 5.1
Introduction Antigens targeted in the pemphigus variants

The term acantholysis derives from the Greek akantha, a thorn or prickle, and Pemphigus variant Autoantigen
lysis, a loosening. In its simplest definition, the term is used to reflect a primary Pemphigus vulgaris Dsg3 (mucosal), Dsg1 (cutaneous),
disorder of the skin (and sometimes the mucous membranes) ­characterized desmocollins, pemphaxin, α9-acetylcholine
by separation of the keratinocytes at their desmosomal junctions (Fig. 5.1). receptor
A wide range of conditions are characterized by this feature, from inherited Pemphigus vegetans Dsg3, Dsc1, and Dsc2 in some patients
disorders such as Darier's disease and Hailey-Hailey disease in which a cal-
Pemphigus foliaceus Dsg1
cium pump gene mutation results in desmosomal instability through to the
autoimmune pemphigus group of diseases whereby autoantibodies directly Pemphigus erythematosus Dsg1
damage desmosomes with resultant keratinocyte separation and blister for- Fogo selvagem Dsg1, rarely also Dsg3
mation (Table 5.1). Desmosomes may also be damaged by secondary phe-
IgA pemphigus Dsc1, Dsg1 or Dsg3
nomena, for example following severe edema, either ­intercellular (spongiosis)
or intracellular (e.g., ballooning degeneration as is seen in ­various viral infec- Herpetiform pemphigus Dsg1, rarely also Dsg3
tions). Such processes, however, are not included in the acantholytic ­category Paraneoplastic pemphigus Desmoplakins I and II, envoplakin,
periplakin, BP230, plectin, Dsg1, and Dsg3
Drug-induced pemphigus Dsg1 or Dsg3
Dsc, desmocollin; Dsg, desmoglein. Modified from Martel, P., Joly, P. (2001)
Pemphigus: autoimmune diseases of keratinocyte's adhesion molecules. Clinical
Dermatology, 19, 667.

and are discussed elsewhere. The histological features of the conditions

described in this chapter show considerable overlap. The diagnosis is there-
fore dependent upon adequate clinical information and the results of immu-
nofluorescence investigations.

Fig. 5.1
Acantholysis: the keratinocytes are rounded and separated from each other to form
an intraepidermal blister. Villi formed from the underlying dermal papillae typically
project into suprabasal cavities.
Pemphigus
Pemphigus (Gr. pemphix, blister) refers to a group of chronic blistering dis-
eases which develop as a consequence of autoantibodies directed against a
variety of desmosomal proteins.1–5 The condition as a whole is rare, with an
annual incidence ranging from 0.1–0.7 per 100 000 of the general ­population.2
It is commoner in the Jewish population in which the annual incidence rises
to 1.6–3.2 per 100 000.6 Ashkenazi Jews are the most frequently affected.6
The incidence in India also appears to be higher than in other countries.7
There is no sex predilection.
152 Acantholytic disorders
The clinical features and, therefore, classification of these disorders
depends upon the level of separation within the epidermis:
• In pemphigus vulgaris (p. vulgaris) and pemphigus vegetans (p. vegetans)
the blisters are suprabasal.
• In pemphigus foliaceus (p. foliaceus), pemphigus erythematosus (p. erythe­
matosus) and fogo selvagem, the blisters are situated more superficially.
Pemphigus vulgaris is by far the most common variant, accounting for
80% of cases.8,9
In addition to affecting humans, pemphigus has been described in a variety
of animals including dogs, cats, goats, and horses.10
Pemphigus vulgaris
Clinical features
Pemphigus vulgaris (p. vulgaris) particularly affects the middle aged (onset
typically at 40–60 years of age) although occasionally (up to 2.6%) children
are affected.1–7 Self-limiting neonatal disease through transplacental transfer
of maternal autoantibodies has also rarely been documented (see pathogene-
sis).8–11 The disease begins in the mouth (Figs 5.2, 5.3) in 50–70% of patients
with painful erosions or bullae and, after a period of weeks or months, the
Fig. 5.2
Pemphigus vulgaris: painful erosions are present on the buccal mucosa. By courtesy
of R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 5.3
Pemphigus vulgaris: in this patient there is an intact blister on the floor of the
mouth. Pemphigus commonly presents in the mouth. By courtesy of the Institute
of Dermatology, London, UK.
blisters spread to involve the skin.12–15 Oral lesions most commonly affect the
buccal, palatine, and gingival mucosae.1,15–17 Pemphigus vulgaris is only rarely
confined to the skin.18,19
The typical skin lesion is a fragile, flaccid blister, which develops on nor-
mal or erythematous skin, and readily ruptures, leaving a painful, crusted,
raw, bloody erosion (Figs 5.4, 5.5). Lesions are most often seen on the
scalp, face, axillae, and groin, although in some patients they are generalized
(Figs 5.6–5.8).1–3,20 Blisters can be induced by rubbing the adjacent, appar-
ently normal skin with a finger – the Nikolsky sign. Direct pressure applied
to the center of the blister is also followed by lateral extension – the Asboe-
Hansen sign.2 Healing is often accompanied by postinflammatory hyperpig-
mentation but scarring is not a feature.2
Before the introduction of corticosteroid therapy, the lesions usually became
more extensive and in the past often led eventually to death. Treatment with
high doses of corticosteroids, immunosuppressants, such as azathioprine and
more recently biologicals has significantly reduced the mortality to 5–15%
and prolonged remissions without treatment are now being reported.2 A con-
siderable proportion of the deaths that do occur, however, are due to the
side effects of therapy and include staphylococcal infections and, to a lesser
extent, pulmonary embolism.2 Severe opportunistic infections due to a wide
range of organisms including listeria, nocardia, enterococci, herpes virus,
cryptococcus and candida may further complicate the disease.21–27
Fig. 5.4
Pemphigus vulgaris: since the blisters are superficial, erosions are more commonly
encountered. By courtesy of the Institute of Dermatology, London, UK.
Fig. 5.5
Pemphigus vulgaris: extensive erosions and blisters are present on the shin. By
courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 5.6
Pemphigus vulgaris: umbilical lesions showing intact blisters as well as raw
erosions. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 5.7
Pemphigus vulgaris:
extensive trauma-induced
blisters. By courtesy
of the Institute of
Dermatology, London, UK.
Nail involvement seems to be more common than previously reported.
Patients may present with hemorrhagic paronychia, chronic paronychia,
trachyonychia, onycholysis or onychomadesis.17,28 Paronychia and onycho-
madesis are the most common nail changes encountered. Nail involvement is
more common in the nails of digits affected by periungual blisters and also in
patients with large number of skin blisters.29
Occasional modes of presentation include linear lesions and pemphi-
gus arising after surgery, burns, vaccination, and radiation therapy.30–39
Development after exposure to pesticides and a possible association with
cocaine snorting has also been reported.40,41 A very exceptional case has been
described in which blisters were initially confined to melanocytic nevi.42
P. vulgaris may also be rarely induced by a variety of drugs.
In addition to oral and cutaneous involvement, lesions have been described
at a wide variety of sites including the nasopharynx, larynx, ear, esophagus,
eye, external genitalia, urethra, and anal and colonic mucosa.1,43–45 Esophageal
lesions, although originally thought to be rare, have more recently been
Pemphigus 153
Fig. 5.8
Pemphigus vulgaris:
extensive disease can
be very disfiguring. By
courtesy of the Institute of
Dermatology, London, UK.
documented in as many as 63–87% of patients.46,47 Erosions and ulcers are
t­ ypically found and intact blisters are rare. Exceptionally, the whole mucosa
may be affected with subsequent sloughing – esophagitis dissecans superfi-
cialis.48 Ocular lesions are usually restricted to the conjunctiva, presenting as
conjunctivitis or small vesicles that rapidly rupture.2,49,50 Very rarely, scarring
may develop and corneal ulceration with perforation has been described.51
Vulval, vaginal, and cervical lesions are well recognized.52–56 Exceptionally,
the vagina may be the sole site of involvement.57 Penile lesions most com-
monly affect the glans.58 They are not usually followed by any significant
sequelae.
The development of pemphigus may be associated with a variety of dis-
orders including other autoimmune bullous dermatoses, particularly bullous
pemphigoid, lupus erythematosus, thymoma, and myasthenia gravis as
well as Hashimoto's thyroiditis, vitiligo, minimal change nephropathy, and
ulcerative colitis.59–66 It has also been described in a patient with the 1p36
deletion syndrome.67 As in the many other diseases with an immunological
pathogenesis, pemphigus is accompanied by an increased incidence of inter-
nal malignancy including thymoma, lymphoma, and multiple myeloma (see
paraneoplastic pemphigus).68,69 It has also been reported in association with
Kaposi's sarcoma.70
Pathogenesis and histological features
Pemphigus is an immunologically mediated disease.71,72 Examination of per-
ilesional skin by direct immunofluorescent techniques reveals in vivo-bound
immunoglobulin (usually IgG) and often complement (C3) in the intercel-
lular region of the epidermis (Fig. 5.9).73 Abundant antigen in the follicular
outer root sheath and germinal matrix may account for the marked scalp
involvement typical of pemphigus, and plucked hair follicles may serve as an
adequate substrate for direct immunofluorescence analysis.74,75 The in vivo-
bound IgG is mainly of the IgG1 and IgG4 subclasses.76
Indirect immunofluorescent techniques show that the serum of patients
with pemphigus contains an IgG antibody that reacts with the intercellular
region of normal squamous epithelium – the intercellular substance (pemphi-
gus) antibody.77 This antibody is, however, not entirely specific as it may be
found in a variety of other conditions, such as severe burns, penicillin drug
reactions, and following radiation therapy.78–80 Presumably, pemphigus anti-
gens are released into the circulation following such trauma with resultant
antibody production. Circulating antibodies are predominantly of the IgG1
and IgG4 subclasses; IgG3 is i­dentified much less often.81
154 Acantholytic disorders
Fig. 5.9
Pemphigus vulgaris: direct immunofluorescence. By courtesy of the Institute of
Dermatology, London, UK.
Circulating IgG is pathogenic.71,72 The level of the antibody titer closely
parallels the clinical state of the disease.82–85 IgG4 titers diminish during
remission whereas circulating IgG1 may continue to be present.72,83 Relapse is
commonly preceded by rising IgG4 antibody titers.83
P. vulgaris very occasionally may be evident in a neonate born of a mother
with active pemphigus vulgaris.8,86 Such autoantibodies cross the placenta,
inducing disease in the infant. The condition is, however, short lived, with
lesions disappearing, as the maternal antibodies are catabolized. Passive
transfer of IgG4 into neonatal mice results in the development of blisters.87
Purified IgG from pemphigus induces acantholysis in human skin explants
and keratinocyte cultures.88,89
The pemphigus antibody binds to the full thickness of the epidermis.
Compared with p. vulgaris, immunofluorescence studies on the sera of
p. foliaceus patients tend to show more staining in the superficial epidermis,
correlating with the level of the split.90,91 Conversely, the sera from patients
with p. vulgaris show more affinity for the lower epidermis. Despite these
trends, we generally do not base diagnoses on these (often subtle) differences
in immunofluorescence staining distribution.
The p. vulgaris antibody is directed at the extracytoplasmic domain of
the 130-kD epithelial desmosomal cadherin, desmoglein 3 (Dsg3), which
forms a complex with plakoglobin (85 kD).92–98 The p. vulgaris antibody,
however, does not recognize the latter. Many patients also have antibod-
ies that bind to the p. foliaceus antigen, desmoglein 1 (Dsg1), a 160-kD
polypeptide.99,100 Dsg3 is expressed primarily in the oral mucosa and, there-
fore, antibodies directed against this antigen result in mucosal pemphigus.
In contrast, Dsg1 is a cutaneous antigen and, therefore, antibodies directed
against it result in lesions affecting the skin but not the mucosa (cutaneous
pemphigus).90 Anti-Dsg1 antibodies also show cross-reactivity against Dsg4,
a recently identified member of the desmoglein family.101,102 While patient
sera contain antibodies against nonconformational epitopes of Dsg3, active
disease correlates with the presence of antibodies directed against the NH2-
terminal aspect of Dsg3, in particular ectodomains 2–4.103–105 Oral disease is
particularly associated with reactivity to ectodomains 1-4, which is reduced
in cutaneous pemphigus.103
Antibodies reactive to a number of other proteins including desmoplakin,
desmocollins, pemphaxin, and acetylcholine receptor have also been demon-
strated in the sera of p. vulgaris patients.106–110
Sera from patients with pemphigus vulgaris not infrequently contain
additional IgA antibodies, in particular against Dsg1 and Dsg3.111–113
Although the combination of both IgG and IgA antibodies has in some
instances been referred to as IgG/IgA pemphigus in the literature, this
appears to be an ­ill-defined and heterogeneous disease group.111,114 In addi-
tion to ­pemphigus vulgaris, the additional presence of anti-Dsg IgA anti-
bodies has also been demonstrated in pemphigus foliaceus, pemphigus
vegetans, pemphigus ­herpetiformis, and paraneoplastic pemphigus.111,115,116
Furthermore, so-called IgG/IgA pemphigus may show an atypical clinical
presentation, histological features more reminiscent of IgA pemphigus,
and the presence of IgA antibodies against desmocollins in a subset of
patients.114,117–123
The pathogenesis of the acantholysis is uncertain. Direct binding of
antibody to the desmosomal cadherins is of major importance and results
in internalization of Dsg3 and degradation by the endolysosomal path-
way.71,114,124 Plakoglobin has been implicated in mediating intracellular
events following IgG binding to Dsg3.125,126 In particular, the role of pla-
koglobin is signal transduction to the nucleus.125,127 There is also some evi-
dence to suggest that the process may involve, at least secondarily, the
action of local proteolytic enzymes.70 Pemphigus antibody induces expres-
sion of plasminogen activator receptor on the surface of keratinocytes.128
Binding of plasminogen activator to its keratinocyte cell membrane recep-
tor results in plasminogen activation with resultant production of plas-
min.129,130 This latter has non-specific proteolytic activity, which may
be responsible at least in part for the dissolution of the desmosomes.71
P. ­vulgaris antibodies stimulate production of keratinocyte phospholipase
C, inositol 1,4,5-triphosphate, and increase intracellular calcium. Protein
kinase C activation results in release of keratinocyte plasminogen activa-
tor and increased expression of plasminogen activator receptor.131–133 Other
factors, however, must be of greater importance since p. vulgaris IgG can
induce acantholysis in plasminogen activator knockout mice.134 An addi-
tional phenomenon is rapid phosphorylation of heat shock protein 27 and
p38MAPK resulting in reorganization and collapse of the cytoskeleton as
a result of IgG binding to Dsg3.135,136 This process is mediated by upstream
events involving EGF receptor kinase and src.137 Complement appears not
to be essential for acantholysis and it is thought that any involvement is
secondary, perhaps accelerating or extending the process.71 Although it has
been suggested that apoptosis may be induced by p. vulgaris IgG, and that
this mechanism may be important in the pathogenesis of the disease, a
recent study has shown that apoptosis is not a prerequisite for blistering
and may be a secondary phenomenon.138
T cells are also critical to the development of the antibody-mediated
acantholysis.70 CD4+ memory T cells are predominantly involved and both
T-helper 1 (Th1) and Th2 Dsg3-specific subtypes are represented.139,140 Th1
T-cell-derived interferon-γ stimulates production of IgG1, and Th2 cells
produce interleukin (IL)-4 and IL-13 which are responsible for secretion
of B-cell-derived IgG4.141 Both populations are therefore of importance in
stimulating production of p. vulgaris antibody.72 In addition, there is evi-
dence that tumor necrosis factor 1 (TNF-1), Fas-ligand and IL-1 are also of
importance in the development of acantholysis.142 Knockout mice for both
these cytokines show diminished acantholysis in passive antibody transfer
experiments.143
There is considerable evidence of a genetic background influencing suscep-
tibility to pemphigus as shown by strong associations with human leukocyte
antigen (HLA)-DRβ1*0402, HLA-DRβ1*1401 and HLA-DQβ1*0503.144–147
Perhaps surprisingly, however, there are only occasional documented reports
of familial occurrence.148–151
Pemphigus blisters rupture easily. It is therefore essential to biopsy an
early lesion to establish the correct diagnosis. The characteristic acantho-
lysis develops because of damage to the intercellular bridges. Acantholytic
cells are rounded and have intensely eosinophilic cytoplasm, pyknotic
nuclei, and perinuclear halos. An early lesion of p. vulgaris shows a slit-
like ­suprabasal cleft or vesicle containing occasional acantholytic cells. The
established blister contains acantholytic cells in clumps and in isolation
(Figs 5.10 and 5.11). Characteristically, the floor of the cavity is lined by
a single layer of intact basal cells, the so-called ‘tombstone’ pattern (Fig.
5.12).152
The acantholytic process frequently involves the epithelium of the adn-
exae, which can be a useful diagnostic clue in those lesions which lack the
roof of the blister (Fig. 5.13).153 The dermal papillary outline is usually main-
tained and, frequently, the papillae protrude into the blister cavity. Sometimes
the features of eosinophilic spongiosis are seen on biopsy, particularly in
early lesions.154 The blister cavity often contains a few inflammatory cells
(notably eosinophils) and, in the dermis, there is a moderate perivascular

Fig. 5.10
Pemphigus vulgaris: established blister showing marked acantholysis and scattered
neutrophils. The dermal papillae project into the cavity as villi.
Fig. 5.11
Pemphigus vulgaris:
(A) perianal mucosa
showing acantholysis and
B conspicuous villi; (B) high-
power view.
Pemphigus 155
Fig. 5.12
Pemphigus vulgaris: cell-free example showing a linear palisade of intact basal
keratinocytes – the so-called ‘tombstone’ appearance.
Fig. 5.13
Pemphigus vulgaris:
follicular involvement
distinguishes pemphigus
from Hailey-Hailey disease
in which it is not a feature.
chronic inflammatory cell infiltrate with conspicuous eosinophils, although
­sometimes these are scanty or even absent. Mucous membrane lesions show
similar histology.
Ultrastructurally, there is dilatation of the intercellular space with conse-
quent stretching of the desmosomal attachment points (Figs 5.14, 5.15).155
With progression, these separate and eventually disappear, residual cell
membranes often showing a pseudovillous morphology. Hemidesmosomes
are morphologically normal. Immunoelectron microscopy confirms that the
immunoreactants are located within the intercellular space.
Endemic pemphigus vulgaris
Patients with clinical and histological presentation of pemphigus vulgaris
but epidemiological features of fogo selvagem were identified in the Goiania
and Brasilia regions of Brazil, known endemic areas of pemphigus foliaceus.
These patients demonstrate classical mucocutaneous disease and antibodies
to both Dsg1 and Dsg3, but are remarkable for early onset of disease, fre-
quently before the age of 20.156
156 Acantholytic disorders

or without immunofluorescence studies, it may be impossible to establish a

definitive diagnosis. Darier's and Hailey-Hailey diseases are not associated
with immunoreactants.
Dyskeratosis in the form of corps ronds and grains is typical of Darier's dis-
ease, but is rarely seen in Hailey-Hailey disease, and is not a feature of pemphigus.
In Hailey-Hailey disease, the perivesicular epithelium is likened to a dilapidated
brick wall, an effect sometimes seen in p. vulgaris. More frequently, however, the
epithelium overlying and adjacent to the blister is essentially intact.
Acantholysis involving the follicular epithelium is often seen in pemphi-
gus, but usually not in Hailey-Hailey disease. The pemphigus-like variant
of Grover's disease is histologically indistinguishable from pemphigus, but
the clinical history, minute size of the lesions as viewed by the microscope,
and negative immunofluorescence findings make distinction relatively easy.
Extreme degrees of acantholysis in acantholytic solar keratosis may on rare
occasions be confused with the previously mentioned acantholytic disorders.
Similarly, it is important not to misinterpret the trivial finding of incidental
focal acantholytic dyskeratosis in a skin specimen removed or biopsied for an
unrelated finding.

Fig. 5.14
Pemphigus vulgaris: electron photomicrograph of an early lesion showing suprabasal,
intraepidermal vesiculation. Residual cytoplasm of basal keratinocytes lines the floor
of the blister. The lamina densa is clearly visible.
Fig. 5.15
Pemphigus vulgaris: electron photomicrograph of an early lesion showing marked
dilatation of the intercellular space. Cytoplasmic ‘villus’ formation is conspicuous
and only occasional desmosomes are apparent.
Differential diagnosis
The differential diagnosis of p. vulgaris includes a variety of conditions such
as Darier's disease, Hailey-Hailey disease, and transient acantholytic derma-
tosis (Grover's disease) (Table 5.2). In the absence of clinical information
Pemphigus vegetans
Clinical features
Pemphigus vegetans (p. vegetans), a chronic variant of p. vulgaris, has a
somewhat better prognosis than p. vulgaris with occasional cases associated
with spontaneous remission documented.1–3 It accounts for 1–2% of all cases
of pemphigus.1 As with the vulgaris variant, p. vegetans typically presents in
adults. There has, however, been a small number of cases described in child-
hood including a dapsone-responsive IgA-mediated variant.4–7 The lesions,
which present as blisters and erosions, are particularly prolific in the flexures,
especially the axillae, the groin, the inframammary region, the umbilicus and
at the margins of the lips. The scalp is also said to be a site of predilection.8,9
Soon thereafter, patients characteristically develop hypertrophic vegetations
and pustules at the blistered edges (Fig. 5.16).1
The oral cavity is commonly affected and a cerebriform or ‘scrotal’ tongue
is said to be a diagnostic clue in cases of early involvement.10–13 An exceptional
case of the disease restricted to the tongue has been reported.14 Esophageal
involvement presenting as erosions and white plaques has been described in
a number of patients and the nasal mucosa, larynx, vulva, vagina, penis, and
anus may also be affected.7,15–19 Nail involvement including onycholysis and
pustules is sometimes seen.20 Acral involvement can clinically be mistaken for
acrodermatitis continua suppurativa.21 A case has been described developing
after and restricted to a split-thickness skin graft.22 A further exceptional case
developed in association with intranasal heroin abuse and was restricted to the
nasal mucosa.23 Peripheral blood eosinophilia is commonly present.
Two clinical subtypes are recognized:24,25
• In the Neumann variant (the more serious form), lesions usually begin
as described in p. vulgaris, but the ensuing erosions develop vegetations.
The course of this variant is similar to that of p. vulgaris.
• In the Hallopeau variant (‘pyodermite vegetante’), the eruption begins as
pustular lesions that rapidly evolve into verrucous vegetating plaques.2
Bullae are usually not seen. This is a milder variant in which spontaneous
remission is not uncommon.

Table 5.2
Differential diagnosis of suprabasal pemphigus

Pemphigus vulgaris* Darier's disease* Hailey-Hailey disease*

Types of lesion Intraepithelial bullae Suprabasal clefts Intraepithelial bullae
Adjacent epithelium Intact Intact Disintegrating
Involvement of adnexae Yes Yes No
Corps ronds and grains No Yes Rarely
Dermal inflammation Mononuclears, eosinophils Mononuclears Mononuclears
IMF Positive Negative Negative
*The lesions of Grover's disease may histologically mimic any of these and can only be distinguished by immunofluorescence.
 Pemphigus 157

Fig. 5.17
Fig. 5.16 Pemphigus vegetans: the epidermis is hyperplasic and there are scattered abscesses.
Pemphigus vegetans:
axillary ulceration and
vegetative lesions. From
the slide collection of the
late N.P. Smith, MD, The
Institute of Dermatology,
London, UK.

Pathogenesis and histological features

Support for the thesis that p. vegetans is a variant of p. vulgaris is based on
the finding that both subtypes are associated with IgG and C3 deposition in
the epidermal intercellular space on direct immunofluorescence, and circu-
lating ‘pemphigus’ antibody.25 P. vegetans is characterized by an antibody
directed at the desmosomal cadherin, desmoglein 3.26–28 Antibodies against
desmocollins 1 and 2 as well as periplakin have also been documented.29,30
Rarely, additional IgA antibodies to Dsg3 may also be detected.31
Precipitating factors for this variant of pemphigus are largely unknown.
Exceptionally, however, p. vegetans has been linked with the angiotensin-
­converting enzyme (ACE) inhibitors, captopril and enalapril.32,33 Lesions
localized to the nasal mucosa in a patient with longstanding nasal heroin
abuse have been reported and an association with human immunodeficiency
virus (HIV) infection documented.19,34,35 There are few reports relating p. veg-
etans with an underlying malignancy and in one patient a p.vegetans-like
Fig. 5.18
lesion was a manifestation of paraneoplastic pemphigus.33,36–40
Pemphigus vegetans:
Although a variant of p. vulgaris, p. vegetans shows strikingly different follicular involvement is
histological features. Suprabasal acantholysis is present but is often subtle, seen on the right.
being masked by an exuberant proliferation of squamous epithelium which
may sometimes show pseudoepitheliomatous hyperplasia (Fig. 5.17). The
epithelial proliferation involves both the epidermis and the infundibular folli-
­hyperplasia and microabscesses may be confused with p. vegetans. In par-
cular epithelium. Characteristically, there is an intense inflammatory cell infil-
ticular, pyostomatitis vegetans must be excluded in patients presenting with
trate containing numerous eosinophils, and intraepidermal microabscesses
oral involvement. The latter is usually associated with inflammatory bowel
are often seen (Figs 5.18, 5.19). Eosinophilic spongiosis is a feature.41,42 The
disease and although it may mimic p. vegetans clinically and histologically,
inflammatory changes and epithelial proliferation are sometimes so marked
direct immunofluorescence is invariably negative. Halogenoderma may also
that the true nature of the lesions is obscured. Very occasionally, 10–40-μm
show similar histological features.
eosinophilic hexagonal Charcot-Leyden crystals have been described within
the eosinophil-rich microabscesses.32,43 The diagnosis of p. vegetans is eas-
ily overlooked and is made only by the pathologist with a high index of Pemphigus foliaceus
suspicion.
Clinical features
Differential diagnosis Pemphigus foliaceus (p. foliaceus) is considerably more uncommon than
Since early lesions may be similar, or identical, to p. vulgaris, the same differ- p.  vulgaris and although it most often affects the middle aged and elderly,
ential diagnosis as discussed for that variant should be considered. In estab- it has a very variable age of onset, sometimes affecting younger adults and
lished lesions associated with squamous epithelial hyperplasia, the suprabasal even, occasionally, children.1–8 Very exceptionally, maternal antibodies have
cleft formation is often focal and easily overlooked. Infections, ­particularly been known to cross the placenta, resulting in neonatal disease.9–11 In general,
fungal and bacterial, that are associated with ­pseudoepitheliomatous ­nonendemic p. foliaceus in children is relatively benign and of short duration.6
158 Acantholytic disorders

Fig. 5.21
Pemphigus foliaceus:
crusted lesions are evident
Fig. 5.19 on the back of this young
Pemphigus vegetans: male. From the collection
there are numerous of the late N.P. Smith,
eosinophils. Note the MD, The Institute of
acantholysis. Dermatology, London, UK.

The superficial blisters of p. foliaceus are exceedingly fragile and there-

fore much less obvious; erosions and large leafy scales or crusts are often
predominant (Figs 5.20–5.22). The lesions may remain localized to the
scalp, nose, face, and trunk for many months or years, leading to a ­mistaken
diagnosis of seborrheic dermatitis, seborrheic keratosis, or even lupus
­erythematosus. Sometimes the eruption involves the entire surface of the body
or produces a clinical resemblance to exfoliative dermatitis (erythroderma)
(Fig. 5.23).12,13 Mucous membrane involvement is rare.1 Exceptionally,
patients may present with localized disease, typically restricted to the face.14,15
The development of pustular lesions is exceptional.16 P. foliaceus often has
a much more benign course than p. vulgaris, although patients with severe

Fig. 5.20
Pemphigus foliaceus:
multiple erosions
are present with B
background erythema
and postinflammatory Fig. 5.22
hyperpigmentation. Pemphigus foliaceus: (A) there are numerous crusted lesions on the lower
Courtesy of The Institute of abdomen and in the groin, (B) high-power view. From the slide collection of the late
Dermatology, London, UK. N.P. Smith, MD, The Institute of Dermatology, London, UK.

Fig. 5.23
Pemphigus foliaceus: in this patient, there is generalized erosion with scaling
and erythroderma. By courtesy of R.A. Marsden, MD, St George's Hospital,
London, UK.
­ isease, requiring ­corticosteroid and immunosuppressant therapy, still have
d result of an antibody-mediated cellular response rather than purely the result
an appreciable ­mortality. The ­disease may be complicated by Kaposi's vari-
celliform eruption.17
Very occasionally, patients may develop p. foliaceus during or after a pre-
vious episode of p. vulgaris and vice versa.18–20 The development of bullous
pemphigoid following an episode of p. foliaceus has also been described.21,22
This is accompanied by an antigen shift, possibly as a result of intermo-
lecular epitope spreading.19,23–25 A case of a blistering disorder displaying
­features of bullous pemphigoid and pemphigus foliaceus has been described
in ­association with consumption of Spirulina algae.26 The coexistence of both
p. ­vulgaris and p. foliaceus in one patient has also been reported.27 A fur-
ther case of paraneoplastic pemphigus with concomitant clinical features of
­pemphigus foliaceus and the presence of antibodies against desmoglein 1 was
recently reported.28
In addition to idiopathic p. foliaceus, drug-induced variants, notably due
to penicillamine, may also be encountered (Fig. 5.24). A localized form
may also be associated with topical drugs such as imiquimod and has been
reported following radiation therapy.29–32 Pemphigus foliaceus is rarely asso-
ciated with an underlying malignancy including ­non-Hodgkin's lymphoma
and esophageal cancer.33,34
A B
Fig. 5.24
Pemphigus foliaceus: (A) in this patient, the eruption was induced by penicillamine therapy; (B) close-up view of intact blisters, erosions and crusting. By courtesy of R.A.
Marsden, MD, St George's Hospital, London, UK.
Pemphigus 159
Pathogenesis and histological features
Similar to other variants of pemphigus, p. foliaceus is an immunologically medi-
ated disease. Examination of perilesional skin by direct ­immunofluorescent
techniques reveals in vivo-bound immunoglobulin (usually IgG) and often
complement (C3) in the intercellular region of the epidermis.1 Abundant anti-
gen in the follicular outer root sheath and germinal matrix may account for
the marked scalp involvement typical of pemphigus.35
Indirect immunofluorescent techniques show that the sera of patients with
p. foliaceus contain an IgG antibody that reacts with the intercellular region
of normal squamous epithelium.36 IgG4 predominates followed by IgG1.37,38
IgG3 is also sometimes present. This may be of importance since IgG3 is
the most efficient activator of complement.37 Some 60–70% of patients have
­positive indirect immunofluorescence.39
The p. foliaceus antibody binds to a 160-kD desmosomal cadherin, des-
ignated desmoglein 1 (Dsg1).40,41 The sera of p. foliaceus patients bind to
the extracellular amino terminal domain of bovine Dsg1 whereas sera from
both p. vulgaris and p. vegetans patients react with the intracellular domain
of Dsg1.42,43 Compared with p. vulgaris, immunofluorescence studies on the
sera of p. foliaceus tend to show more staining in the superficial epidermis,
correlating with the level of the split.44,45 Conversely, the sera from patients
with p. vulgaris show more affinity for the lower epidermis. Anti-Dsg1 anti-
body is pathogenic.46 Injection of purified anti-Dsg1 antibodies from sera of
patients with p. foliaceus into neonatal mice induces subcorneal acantho-
lysis in a pattern typical of p. foliaceus.47 Acantholysis is thought to be the
of steric hindrance.48 Internalization of nonclustered Dsg1 has been put for-
ward as a possible mechanism resulting in lack of newly formed desmosomes
rather than a disruption of pre-existing structures.49 Increasing evidence sug-
gests that the blistering is the result of the activation of p38 mitogen-acti-
vated protein kinase-dependent signaling by the p. foliaceus IgG antibodies.50
Rarely, patient sera contain additional IgG antibodies directed against des-
moglein 3 (Dsg3) and the presence of additional IgA antibodies against Dsg1
as well as Dsg3 has also been detected.3,51,52 Furthermore, three patients have
been reported with clinical and histological features of p. foliaceus but direct
immunofluorescence findings reminiscent of p. erythematosus. Antibodies
recognizing bullous pemphigoid antigen1 (BP230) as well as a 190-kD
­protein co-migrating with periplakin were detected in these patients in addi-
tion to anti-Dsg1 antibodies.53 The use of D-penicillamine may be associated
with the acquisition of a pemphigus-like antibody and the development of
p. foliaceus.54
Since the blisters of p. foliaceus are superficial, they are therefore fragile
and it is often very difficult to obtain an intact lesion for diagnosis. Patients
commonly have erosions without blisters, and frequently the clinician does
not suspect a bullous disorder. Usually, the cleft or blister lies within the
160 Acantholytic disorders
A B
Fig. 5.25
Pemphigus foliaceus: (A) in this example, there is a cell-free, subcorneal blister; (B) occasional acantholytic cells are present adjacent to the roof.
g­ ranular layer or beneath the stratum corneum (Fig. 5.25). The roof of the
fragile blister is often not present, having sloughed either before or after
biopsy. Acantholysis is frequently difficult to detect, but usually a few acan-
tholytic cells can be found attached to the roof or floor of the blister. In those
cases where the blister is missing, a careful inspection of the hair follicles
may reveal focal acantholysis. Sometimes the blister contains numerous acute
inflammatory cells (Fig. 5.26), particularly neutrophils, which can make dis-
tinction from subcorneal pustular disorders, including bullous impetigo, a
dermatophyte infection, candidiasis, pustular psoriasis, and subcorneal pus-
tular dermatosis especially difficult.55,56 Eosinophilic spongiosis may also be
seen.57
Differential diagnosis
The histological features in the superficial forms of pemphigus may be eas-
ily overlooked and, since bullae are often not appreciated by the clinician,
the unwary pathologist may not consider a bullous disorder when evaluat-
ing the biopsy. A high index of suspicion is therefore critical. The differential
diagnosis of superficial pemphigus includes bullous impetigo, staphylococcal
scalded skin syndrome, IgA pemphigus, and subcorneal pustular dermatosis
(Table 5.3). Distinction depends upon a careful consideration of the clinical
information, the results of bacterial culture, and immunofluorescent studies.
Fig. 5.26
Pemphigus foliaceus: in this example, the blister cavity contains numerous neutrophils.
Acantholytic cells are conspicuous.
Table 5.3
Differential diagnosis of superficial pemphigus: conditions characterized by
subcorneal pustules
Superficial pemphigus
IgA pemphigus
Subcorneal pustular dermatosis
Pustular psoriasis
Reiter's syndrome
Pustular drug reaction
Bullous impetigo
Staphylococcal scalded skin syndrome
Pustular fungal infection
Endemic pemphigus foliaceus (fogo
selvagem)
Clinical features
Fogo selvagem (Brazilian pemphigus foliaceus, ‘wild fire’, endemic pemphigus
foliaceus) is endemic in regions of Brazil and has also been documented in other
areas of Central and South America including Colombia, El Salvador, Paraguay,
Venezuela, and Peru.1–11 An endemic area has also been described in Tunisia.12,13
The condition is associated with poverty and malnutrition and particularly
affects children and young adults. Results from a more recent epidemiological
study demonstrated disease manifestation also in patients of higher socioeco-
nomic class and urban areas.14 There is a striking familial incidence.4 Most cases
are found along major rivers, and people especially at risk include farmers and
workers involved in land clearing and road construction.2 It appears that the
majority of patients live at an altitude of between 500 and 800 meters, and that
their homes are generally within 10–15 kilometers of running fresh water and in
the path of prevailing winds, thus suggesting a likely insect vector.4,15 In support
of this, a case-controlled epidemiological study has provided evidence that bites
by the black fly (family Simuliidae) are a significant risk factor for development
of the disease and it has been proposed that a component of the saliva may trig-
ger an antibody response in susceptible individuals.16–18 Simulium nigrimanum,
which is found in the same areas in which Brazilian fogo selvagem occurs, has
been identified as being the likely species involved.17
The clinical presentation of fogo selvagem has been divided into a number
of categories including localized and generalized forms:2,4
• Localized disease presents in a variety of ways including small blisters
and erosions or violaceous papules and plaques distributed mainly in the
seborrheic areas. Such lesions may be clinically misdiagnosed as discoid
lupus erythematosus.
 Pemphigus 161

Fig. 5.27
Brazilian pemphigus foliaceus: this woman with chronic disease shows very severe
scaling. Blisters are not apparent. By courtesy of S.A. Pecher, MD, Amazonas, Brazil.
were detected.32,33 Patients have circulating CD4+ memory T cells with a Th2
cytokine profile that proliferate in response to the extracellular domain of
Dsg1 and are thought to be of importance in the initiation and progression of
the disease by stimulating B-cell production of autoantibodies.34–36 The sys-
temic kinin system appears to be activated in patients with fogo selvagem but
the significance of this finding and its mechanism of action in blister forma-
tion are unclear.37
Patients often share the HLA phenotype DRB1*0102 and lack DQB1*0201
which is thought to represent a dominant protective gene found in unaffected
persons living in endemic regions.38,39 HLA-DRB1*0404, *1402 and *1406
may also confer susceptibility.4,28,34
The histological changes of fogo selvagem are identical to the other forms
of superficial pemphigus (p. foliaceus and p. erythematosus).40 Since the blis-
ters are superficial, often only nonbullous erosions are present for histologi-
cal examination. It is very difficult to obtain an intact lesion for diagnosis.
Typically, the cleft or blister lies within the granular layer or beneath the stra-
tum corneum. Acantholysis is frequently subtle but usually a few acantho-
lytic cells can be found attached to the floor of the blister. The blister roof is
often missing. Blisters may contain numerous inflammatory cells, particularly
neutrophils. This feature may cause confusion with infection or other sub-
corneal pustular disorders. Eosinophilic spongiosis is also sometimes present,
­particularly if biopsies of early lesions are examined (Figs 5.28, 5.29).

• Generalized presentation includes bullous exfoliative, exfoliative

erythrodermic, and disseminated plaque and nodular (resembling nodular
prurigo) variants (Fig. 5.27).4
With resolution, patients may sometimes develop hyperpigmentation.19
The antibody does not cross the placenta and therefore neonatal disease is
not a feature.20 Patients with fogo selvagem appear to have no increased risk
for other concomitant autoimmune disorders.21
In contrast to Brazilian fogo selvagem, endemic disease in the area of El
Bagre, Colombia, shows several unusual and distinguishing features.22 The dis-
ease affects an older population with a strong male predilection and clinical fea-
tures reminiscent of pemphigus erythematosus. In addition to the more ­classical
presentation, patients develop hyperkeratotic plaques on the face, chest, and
back reminiscent of discoid lupus erythematosus as well as an erythematous
macular lesion in a butterfly-like distribution in the central face.22 Active dis-
ease is also accompanied by conjunctivitis. The disease also shows characteris-
tic immunological and histological changes, which are discussed below.

Pathogenesis and histological features

The immunological features of fogo selvagem are similar to p. foliaceus.
Indirect immunofluorescent techniques show that the sera of patients with Fig. 5.28
Brazilian pemphigus foliaceus: in this example of an early lesion, the features of
fogo selvagem contain an IgG4 antibody that reacts with desmoglein 1.15,23
eosinophilic spongiosis are evident.
Passive transfer of this antibody to BALB/c neonatal mice results in acan-
tholysis and subcorneal blistering clinically indistinguishable from that of
human disease.24–26 Low-titer IgG1 and IgG2 antibodies may also be pres-
ent and nonpathogenic IgG1 antibodies are present in unaffected individuals
and in the preclinical stages of patients from endemic areas.15,24 IgG antibod-
ies may be accompanied by IgM antibodies, a finding seen more frequently
in individuals from rural rather than urban areas. Furthermore, additional
IgM antibodies are detected more frequently associated with fogo selvagem
than pemphigus foliaceus.27 Fogo selvagem is otherwise histologically and by
immunofluorescence indistinguishable from nonendemic foliaceus and, like
the latter, the antibody recognizes epitopes in the ectodomain of Dsg1.28,29
Epitope recognition is conformation specific and calcium dependent, and
recently intramolecular epitope spreading has been implicated in the patho-
genesis of the disease. Epitope spreading appears to be related to onset of dis-
ease as well as disease modulation with remission and relapse.30 Specifically,
it has been shown that sera from patients in the preclinical stage or in remis-
sion recognize epitopes in the COOH-terminal region of the ectodomain of
Dsg1 while antibodies against epitopes in the NH2-terminal region of the
ectodomain are detected at disease onset.15,30 Interestingly, a study has sug-
gested that the presence of serum IgG4 antidesmoglein-1 in asymptomatic
individuals may suggest preclinical disease.31 A subset of patients may also Fig. 5.29
have antibodies to Dsg3, and in up to 36% of sera from individuals from Brazilian pemphigus foliaceus: there is superficial dermal edema and a perivascular
the Terena reservation of Liao Verde, Brazil, additional anti-Dsg3 ­antibodies inflammatory cell infiltrate with conspicuous eosinophils.
162 Acantholytic disorders
The verrucous plaques and nodules seen occasionally in localized or
chronic fogo selvagem show acanthosis, hyperkeratosis, parakeratosis, and
papillomatosis.41 Acantholysis is invariably present.
The hyperpigmentation characteristic of remission is a direct result of
­pigmentary incontinence.
The histological findings in the endemic form described in the El Bagre
area in Colombia are identical to those of fogo selvagem in active disease.
In addition, liquefactive degeneration of the epidermal basal cell layer is
observed in a quarter of biopsies.22 By direct immunofluorescence, a posi-
tive lupus-band test is detected in 40% of patients in addition to IgG depo-
sition on the surface of keratinocytes. Reactive antibodies are of the IgG4
subtype with Dsg1 being the major antigen. Sera from patients also contained
additional antibodies against antibasement membrane zone as well as further
IgG1 anticell-surface antibodies, which may represent desmoplakin1, envo-
plakin, and periplakin.42
Recently, criteria have been proposed to establish a diagnosis of fogo
­selvagem as distinct from nonendemic p. foliaceus:4
• clinical evaluation,
• presence of subcorneal acantholysis,
• positive direct and indirect immunofluorescence and/or
immunoprecipitation or ELISA assays,
• confirmatory epidemiological data.
Differential diagnosis
As with p. foliaceus, the histological features in fogo selvagem may be easily
overlooked and a high index of suspicion is critical to making the diagno-
sis. The differential diagnosis includes p. foliaceus, p. erythematosus, bullous
impetigo, staphylococcal scalded skin syndrome, and subcorneal pustular
dermatosis. Careful clinical correlation, immunofluorescence studies, and
sometimes bacterial culture are necessary to establish a definitive diagnosis.
Pemphigus herpetiformis
Clinical features
Pemphigus herpetiformis (p. herpetiformis, herpetiform pemphigus, acantho-
lytic dermatitis herpetiformis) is a variant of pemphigus which shows clinical
features resembling dermatitis herpetiformis with the histology and immu-
nofluorescent findings of pemphigus.1–6 It is rare, accounting for only up to
7.3% of cases of pemphigus.2 The sexes are affected equally and there is a
wide age range varying from 31 to 83 years.3
Patients typically present with intensely pruritic, grouped, erythematous
papules and plaques, vesicles and blisters, sometimes associated with mucous
membrane involvement.2 Urticaria may also be a presenting feature.7 The
Nikolksy sign is variably present. Although lesions are often generalized,
there is a tendency for the extensor surfaces of the extremities to be par-
ticularly involved. Exceptionally, herpetiform pemphigus may be associated
with psoriasis, systemic lupus erythematous or with an underlying malig-
nancy including prostate and lung cancer (see paraneoplastic pemphigus).8–12
Although in some patients the clinical manifestations remain herpetiform
throughout, in others, the features evolve into more typical p. foliaceus,
fogo selvagem and, less commonly, p. vulgaris.2,4–6 Contrariwise, patients
with typical p. foliaceus and p. vulgaris may go on to develop a herpetiform
eruption.13 IgA pemphigus may also present with herpetiform lesions.14,15 In
­general, p. herpetiformis has a benign course, most patients responding well
to sulfones or steroids.2,3,16
Pathogenesis and histological features
Immunofluorescence testing shows IgG in an intercellular pattern char-
acteristic of the pemphigus group of disorders on both direct and indirect
techniques.1,2,4,16 In most patients, Dsg1 (p. foliaceus antigen) is the tar-
get autoantigen.4,6,17,18 However, in some patients, antibodies against Dsg3
(p. vulgaris antigen) have also been documented.18,19 A single patient has been
reported with both IgG as well as IgA antibodies against Dsg1 in addition to
anti-Dsc (desmocollin) 3 IgG.15 Why antibodies to Dsg1 in patients with
p. herpetiformis often fail to induce appreciable acantholysis compared with
p. foliaceus is uncertain. It is postulated that the p. herpetiformis antibody
t­ argets a different epitope although this has yet to be confirmed. Recently, two
patients with neutrophil-rich histology were shown to co-localize ­pemphigus
antibody and the neutrophil chemoattractant IL-8. In addition, circulating
IgG antibody up-regulated cultured keratinocyte IL-8 expression, thereby
offering an explanation for the neutrophil recruitment.20,21
The biopsy findings are variable and often non-specific. Although eosino-
philic spongiosis is most typical, spongiosis associated with either a mixed
eosinophilic and neutrophilic, or a neutrophil-predominant infiltrate may
also be encountered.4,22 Intraepidermal vesicles and pustules, also of variable
composition, are often present and dermal papillary neutrophil microab-
scesses have been described.2,6,16 Acantholytic cells are usually (but not invari-
ably) identified. A requirement for multiple biopsies before a diagnosis can be
established is a common theme in the literature.
Differential diagnosis
There is both clinical and histological overlap with IgA pemphigus and
­dermatitis herpetiformis. Immunofluorescence allows for distinction between
these entities. It should also be noted that, exceptionally, dermatitis herpeti-
formis may histologically show occasional acantholytic cells in the absence of
any evidence of pemphigus herpetiformis.
In those cases where eosinophilic spongiosis is the predominant histologi-
cal feature, the differential diagnosis also includes hypersensitivity reactions
and infection (bacterial and fungal). Immunofluorescence studies and special
stains for microorganisms will eliminate these possibilities.
Pemphigus erythematosus
Clinical features
Pemphigus erythematosus (p. erythematosus, Senear-Usher syndrome) is
a mild localized form of superficial pemphigus with the histological and
immunofluorescent findings of p. foliaceus combined with features of lupus
­erythematosus.1–6 In general, the latter is subclinical, being suggested only
by laboratory findings, but there are also rare reports of full-blown systemic
disease being present.4 The condition shows a worldwide distribution and a
slight female predominance.5 Exceptionally, it has been described in children
although immunological confirmation of the diagnosis is available in only
one case.7–10
Clinically, it is commonly confined to the head, neck, and upper trunk, and
typically resembles p. foliaceus. Lesions are erythematous, scaly, and crusted,
with or without superficial vesicles, blisters or erosions. Facial ­involvement
often shows a butterfly distribution reminiscent of lupus erythematosus
or seborrheic dermatitis (Fig. 5.30).1 Mucous membrane involvement is
­exceedingly rare.2
Fig. 5.30
Pemphigus erythematosus: there is scaliness and erythema affecting both cheeks.
By courtesy of the Institute of Dermatology, London, UK.
 Pemphigus 163

There are reports of p. erythematosus developing after treatment with a
number of drugs, notably D-penicillamine, and there are also instances attrib-
uted to therapy with propranolol, captopril, pyritinol, thiopronine, ceftaz-
idime, and cefuroxime.11–15 P. erythematosus has also been described as a
complication of heroin abuse.16
P. erythematosus may rarely be associated with thymoma.3,17–19 Typically,
the thymoma precedes the onset of cutaneous lesions, which often present
following thymectomy.18 Most tumors have been benign but one malignant
variant has been documented.19 P. erythematosus may also be a manifestation
of paraneoplastic pemphigus.3
Pathogenesis and histological features
Pemphigus erythematosus, in addition to intercellular staining, also shows
granular deposition of IgG and complement along the basement mem-
brane region (positive lupus band test) (Figs 5.31 and 5.32).2,20,21 Typically
the ­latter deposits are found within sun-exposed skin but in some patients
normal, nonsun-exposed skin may also be positive.2 Pemphigus antibody is
­generally present on indirect immunofluorescence, and antinuclear factor
may also be identified.20,21 Anti-DNA antibodies and antibodies to extract-
able nuclear antigens are negative except in those patients with features of
systemic lupus erythematosus.4 In common with p. foliaceus, the antibody
reacts with Dsg1.22
P. erythematosus has histological changes that are identical to those seen in
p. foliaceus and fogo selvagem. As the blisters are superficial, it is often very
difficult to obtain an intact lesion for diagnosis. Usually, the cleft or blister
lies within the granular layer or beneath the stratum corneum. As with the
other forms of superficial pemphigus, acantholysis is frequently difficult to
detect, but usually a few acantholytic cells can be found attached to the roof
or floor of the blister. The blister may contain numerous acute inflammatory
cells, particularly neutrophils, which can make distinction from subcorneal
pustular disorders especially difficult.

Differential diagnosis
The differential diagnosis includes the other forms of superficial pemphi-
gus (p. foliaceus and fogo selvagem), bullous impetigo, and staphylococ-
cal scalded skin syndrome, in addition to subcorneal pustular dermatosis.
Distinction depends upon a careful consideration of the clinical information,
the results of bacterial culture, and immunofluorescence studies.

Paraneoplastic pemphigus
Clinical features
Paraneoplastic pemphigus is a variant of pemphigus, quite distinct from
p. vulgaris and p. foliaceus.1 Paraneoplastic pemphigus may be associated
with a variety of tumors, such as B-cell lymphoproliferative disorders and
hematopoietic malignancies, Castleman's disease, Waldenström's macro-
globulinemia, thymoma (occasionally with myasthenia gravis), Hodgkin's
Fig. 5.31 lymphoma, carcinomas (e.g., carcinoma of bronchus, pancreas, liver, uterus,
Pemphigus breast, and liver), and sarcomas (including dendritic follicular cell sarcoma,
erythematosus:
round cell liposarcoma, leiomyosarcoma, and inflammatory myofibroblas-
typical intercellular
immunofluorescence with
tic tumor).2–47 We have seen an exceptional association with systemic mas-
granular staining (IgG) at tocytosis. Lymphoma is most often the coexistent neoplasm.1 In a case of
the basement membrane a patient with non-Hodgkin's lymphoma, the disease developed only after
region. By courtesy six cycles of fludarabine, raising the possibility of an association with the
of B. Bhogal, FIMLS, medication.48 In a further exceptional case, a patient presented with a dis-
Institute of Dermatology, ease fulfilling the diagnosis of paraneoplastic pemphigus by histology, immu-
London, UK. noblotting, and immunoprecipitation. However, no neoplasm was found in
8 years of follow-up.49
Paraneoplastic pemphigus has been defined by Sapadin and Anhalt as
follows:50
• painful mucosal erosions and a polymorphous skin eruption in the
context of an occult or confirmed neoplasm (Fig 5.33),
• histopathological changes of keratinocyte necrosis, intraepidermal
acantholysis, and vacuolar-interface dermatitis,
• direct immunofluorescence showing intercellular IgG and complement
accompanied by linear or granular complement at the dermal–epidermal
junction (Fig 5.34),
• indirect immunofluorescence showing circulating antibodies to simple,
columnar, and transitional epithelia in addition to a more typical
pemphigus pattern of binding to skin and mucosa,
• circulating autoantibodies that immunoprecipitate a high molecular
weight complex of polypeptides from keratinocyte extracts weighing
250, 230, 210, 190, and 170 kD.
Although the disease may develop in a wide age range (7–83 years), the
majority of patients have been in the fifth to eighth decades and there is a
male predominance.5 Exceptionally, children may be affected.4,51–54 Lesions
are seen in both the mucosa and the skin. Patients present with refractory,
Fig. 5.32 painful, persistent erosions of the oral mucosa and vermilion border of the
Pemphigus erythematosus: immunoelectron micrograph showing immunoreactant lips. In addition, the tongue, gingiva, floor of mouth, palate, oropharynx,
beneath the lamina densa in addition to occupying the intercellular space. By and nasopharynx can be affected.5 Manifestation confined to the skin or oral
courtesy of B. Bhogal, FIMLS, Institute of Dermatology, London, UK. mucosa is exceptional.22,55,56 Esophageal disease has been described and the
164 Acantholytic disorders
Fig. 5.33
Paraneoplastic pemphigus: there are numerous erosions and crusted lesions.
Courtesy of The Institute of Dermatology, London, UK.
Fig. 5.34
Paraneoplastic pemphigus: IgG is evident in an intercellular distribution.
trachea and bronchi may be affected.57–59 The latter is sometimes accompa-
nied by an invariably fatal bronchiolitis obliterans-like disorder.46,58,59 Colonic
involvement is unusual.60 Frequently, patients also have severe pseudomem-
branous conjunctivitis with symblephara, and eventual blindness may occur.5
The vulva, vagina, and penis are sometimes affected.4 Rarely, the disease is
accompanied by other autoimmune disorders including myasthenia gravis
and alopecia areata.46,56
Cutaneous lesions are typically polymorphic and often present as a pruritic
papulosquamous dermatosis with subsequent blistering. The trunk, proximal
extremities, palms, and soles are characteristically affected.61 Nail involve-
ment may occur. Although the eruption typically resembles p. vulgaris, it may
also mimic p. foliaceus, IgA pemphigus, bullous pemphigoid, linear IgA dis-
ease, lichen planus pemphigoides, erythema multiforme, and toxic epidermal
necrolysis.39,62–67 P. vegetans-like lesions have been described.49 Paraneoplastic
pemphigus is associated with a very high mortality.5
Pathogenesis and histological features
In paraneoplastic pemphigus, circulating antibodies bind to desmosomal and
hemidesmosomal plakin family members including 250-kD (desmoplakin I),
230-kD (bullous pemphigoid antigen), 210-kD (a doublet originally thought
to be desmoplakin II but later determined to represent envoplakin) and a
190-kD antigen (periplakin).68–71 The presence of antibodies to envoplakin
and periplakin (both cornified envelope constituents) is believed to be highly
specific for paraneoplastic pemphigus and the linker domain of plakins may
be of particular significance.72,73 There are also antibodies to an as yet unde-
termined 170-kD antigen.66 Antibodies to Dsg1 and 3 are also usually pres-
ent and plectin (another plakin family member) antibodies may be found.74,75
Anti-Dsg antibodies are thought to be of particular importance in the ini-
tiation of lesions, disrupting the cell membrane and thereby exposing des-
mosomal and hemidesmosomal plakin proteins with resultant autoantibody
formation.68,76
Direct immunofluorescence shows IgG deposition affecting the whole
thickness of the epidermis whereas C3 is found only on the lower layers.68,77–79
Characteristically, the intercellular staining is often focal and faint.77,78
In addition, complement is present along the basement membrane region.
Immunoglobulin deposition in the respiratory epithelium has also been docu-
mented.57–59 Indirect studies confirm the presence of a circulating antibody
although the membrane deposition is often masked by strong cytoplasmic
labeling.68 This latter can be reduced or abolished by serum dilution.68
In paraneoplastic pemphigus, in addition to binding to stratified squamous
epithelium, the antibody labels transitional epithelium, pseudostratified
respiratory epithelium, small and large intestinal mucosa, and thyroid epi-
thelium.78 It also reacts with myocardium and skeletal muscle. Rat bladder
epithelium is said to be highly specific for paraneoplastic pemphigus.79 Up to
25% of cases, however, are negative.80
Recently, there has been accumulating evidence demonstrating consider-
able heterogeneity within disorders designated as paraneoplastic pemphi-
gus in addition to overlap with other immunobullous diseases. Patient sera
frequently contain additional IgA antibodies against Dsg3 and a patient
with IgA antibodies to desmocollins analogous to IgA pemphigus has
recently been reported.66,81 Immunophenotypic variability among paraneo-
plastic pemphigus patients has thus been established. The documentation
of patients displaying p. vulgaris-like or p. foliaceus-like features has led
some authors to suggest that immunobullous disorders arising in association
with malignancy would be best viewed as representing a spectrum rather
than a distinct entity.62 Included within this spectrum are other nonpem-
phigus immunobullous disorders resembling erythema multiforme, graft-
­versus-host disease, and lichen planus. The description of antibodies reactive
with desmoplakin I and II in some patients with erythema multiforme raises
the possibility that these autoantibodies play a pathogenic role in a ­subset
of patients.82 However, further study will be necessary to determine the
­significance of this finding.
Analogous to other forms of pemphigus, recent studies have suggested a
genetic predisposition. HLA typing has identified HLA-Cw*14 as the pre-
disposing allele in a Chinese population while DRB1*03 was identified in a
French study.83,84
The histological findings in paraneoplastic pemphigus are highly variable
but are characterized by an admixture of suprabasal acantholysis, often resem-
bling p. vulgaris, with cleft or vesicle formation (sometimes involving adnexal
epithelium), and interface changes with basal cell liquefactive degeneration,
dyskeratotic keratinocytes, and lymphocytic exocytosis (Figs 5.35–5.37).69,85
Spongiosis is often present.3 A perivascular and lichenoid chronic inflamma-
tory cell infiltrate is typically seen in the superficial dermis.77 In some cases,
the histological features may closely simulate lichen planus. Eosinophils,
however, are rare. Pigmentary incontinence is frequently evident.85
Acantholysis-like change has also been described affecting the bronchial
lining epithelium and brochiolitis obliterans-like features may be seen.57,59
Differential diagnosis
The biopsy findings of admixed acantholysis and interface change appear to
be relatively non-specific. This contention is demonstrated by skin lesions
in patients with typical autoimmune pemphigus without evidence of neo-
plasia that have histological features considered typical of paraneoplastic
pemphigus.79
The differential diagnosis includes mainly interface dermatitides (e.g.,
drug eruption, lichen planus, erythema multiforme, graft-versus-host disease)
rather than other variants of pemphigus. A very high index of suspicion on
the part of the pathologist and clinician alike and confirmatory immunofluo-
rescence studies are prerequisites to achieving a correct diagnosis.
 Pemphigus 165

Fig. 5.35 Fig. 5.37

Paraneoplastic pemphigus: this medium-power view shows suprabasal acantholysis Paraneoplastic pemphigus: note the basal cell hydropic degeneration and cytoid
and interface change. Note the hyperkeratosis and hypergranulosis. Courtesy of bodies. There is an intense lymphohistiocytic infiltrate. A single eosinophil is
N. Brinster, MD, Virginia Commonwealth University Medical Center, Richmond, evident. Courtesy of N. Brinster, MD, Virginia Commonwealth University Medical
Virginia, USA. Center, Richmond, Virginia, USA.

• Patients with SPD-like IgA pemphigus present with superficial flaccid

pustular lesions, often arising on an erythematous base and typically
affecting the trunk and proximal limbs, although the intertriginous sites
are predilected.11 Very uncommonly, there is exclusive involvement of
the oral mucosa and perianal skin.23 Occasionally, there is generalized
skin involvement. Lesions are crusted and progress with peripheral
extension to form ringlike and rosette patterns.15 The features may be
indistinguishable from classical non-IgA-associated SPD.
• Patients with the IEN IgA dermatosis variant present with generalized
pustules and crusts and erythematous macules with peripheral vesicles
forming the so-called sunflower-like configuration (Figs 5.38, 5.39).7
A dermatitis herpetiformis-like presentation with grouped edematous
papules may also be encountered.11,12,15
Pruritus is common and is sometimes severe.8

Fig. 5.36
Paraneoplastic pemphigus: higher-power view of acantholysis with suprabasal
cleft formation. Courtesy of N. Brinster, MD, Virginia Commonwealth University
Medical Center, Richmond, Virginia, USA.

IgA pemphigus
Clinical features
IgA pemphigus is a rare dapsone-responsive variant of pemphigus that, as its
name suggests, is characterized by intercellular IgA deposition and presents
clinically with pustular rather than bullous or vesicular lesions.1–6 This disease
has been described under a number of different names, such as intraepidermal
neutrophilic IgA dermatosis, IgA pemphigus foliaceus, IgA herpetiform pem-
phigus, intraepidermal IgA pustulosis, intercellular IgA dermatosis, and inter-
cellular IgA vesiculopustular dermatosis.7–16 Most patients are middle aged Fig. 5.38
IgA pemphigus:
or elderly but children may also be affected.8,17–21 The sex incidence is equal.
erythematous lesions
There is no racial or geographic predilection.8,11 Drug-induced variants have
and an intact vesicle are
occasionally been documented.22 present. From the slide
IgA pemphigus is divided into two major subtypes: subcorneal pustular collection of the late
dermatosis (SPD) variant (IgA pemphigus foliaceus) and intraepidermal neu- N.P. Smith, MD, The
trophilic IgA dermatosis (IEN) variant (IgA pemphigus vulgaris).7 Other less Institute of Dermatology,
readily classifiable variants may also be encountered. London, UK.
166 Acantholytic disorders

Fig. 5.39 Fig. 5.40

IgA pemphigus: high-power view showing pus-filled intact blisters and an erosion. IgA pemphigus: this biopsy is from the edge of an established blister. Note the
From the slide collection of the late N.P. Smith, MD, The Institute of Dermatology, heavy inflammatory cell infiltrate and focal acantholysis.
London, UK.

The lesions in occasional patients resemble classic p. vulgaris or p.

f­ oliaceus. In one childhood case, a p. vegetans-like presentation associated with
­α1-antitrypsin deficiency was documented.18 Mucous membrane involvement
in either variant is exceptional.17 Nikolsky's sign has been reportedly nega-
tive at least in a subset of patients.2,12,13 IgA pemphigus tends to be a chronic
relapsing but relatively benign disorder.11,12,15
A significant number of patients (approximately 20%) may have an
associated monoclonal gammopathy, usually of the IgA class.11,24–26 Two
documented cases have been benign and the others have represented B-cell
lymphoma or multiple myeloma.11

Pathogenesis and histological features

SPD IgA pemphigus is characterized by intercellular IgA deposition in the
upper epidermis, and circulating IgA antibodies which preferentially bind to
the upper epidermis are typically present.4 In contrast, in the IEN variant, IgA
is deposited preferentially in the lower epidermis, and circulating antibodies
also generally bind to the lower epidermis. In some patients, however, the IgA
antibody binds to the entire thickness of the epithelium. A linear subcorneal
distribution has also been documented.9 Complement is not usually present
and IgG and IgM are absent.7 The antibodies are of the IgA1 subclass and
are usually of low titer.4,17 They have been identified in approximately 50%
of patients.12
By immunoelectron microscopy performed on a limited number of cases,
the immunoglobulin has been identified within the intercellular space, on
the keratinocyte cell membrane, in some cases showing desmosomal accen-
tuation.27–29 In the SPD type, labeling has been predominantly detected
in extracellular spaces between keratinocytes at desmosomes while label-
ing is mainly in intercellular spaces in nondesmosomal areas in the IEN
variant.30
The two subtypes result from autoantibody production to different
­desmosomal proteins.31 Patients with the SPD variant show reactivity with
desmocollin 1.32–35 In contrast, anti-Dsg1 or anti-Dsg3 IgA antibodies are
present in the IEN variant.19,36–38 One patient with the SPD variant showed
both anti-Dsc1 as well as anti-Dsg1 IgA.39 In some patients, however, nei-
ther desmocollins nor desmogleins appear to be involved, suggesting that IgA
pemphigus is a heterogeneous group of conditions.13,18,35,38
Histologically, in the SPD variant, vesicles are typically found in a sub-
corneal location associated with a neutrophil infiltrate. It is thought that the
presence of IgA is responsible for the striking neutrophil response of this dis-
order since IgA is associated with neutrophil chemotaxis and neutrophils bear
IgA receptors.40,41
In the IEN variant, the pustules can be distributed throughout all ­layers of
the epidermis and may also involve the hair follicles (Figs 5.40, Figs 5.41).18
Fig. 5.41
IgA pemphigus: the blister cavity contains neutrophils and eosinophils.
Acantholytic cells are usually (but not always) present. Typically, they are
sparse and, as such, this diagnostic clue may be very easily overlooked.11–13
Prominent dyskeratotic cells have been described in a single case of IgG/IgA
pemphigus.42 Significant numbers of eosinophils may also be seen in occa-
sional IEN cases.20,43 Neutrophil dermal papillary microabscesses have also
been described, sometimes accompanied by neutrophil spongiosis.12,20 A
perivascular infiltrate of neutrophils, lymphocytes, and histiocytes surrounds
the superficial vascular plexus and eosinophils may also sometimes be pres-
ent. In addition to the major variants characterized by pustules, some patients
with IgA pemphigus show histological features typical of classic p. vulgaris,
p. foliaceus or even, exceptionally, p. vegetans.4,18
Differential diagnosis
The differential diagnosis includes subcorneal pustular dermatosis, typical
p. foliaceus, and infections such as bullous impetigo. Although clinically sub-
corneal pustular dermatosis tends to be more restricted to the flexural sites,
absolute distinction from the subcorneal variant of IgA pemphigus depends
upon immunofluorescent studies. Gram stain and a periodic acid-Schiff (PAS)
should always be included in the histological workup to exclude an infective
process.
 Acantholytic dermatoses with dyskeratosis 167

Drug-induced pemphigus
There are at least 25 drugs that have been shown to be associated with the
development of pemphigus.1 Penicillamine and captopril are the most com-
mon offenders; however, enalapril, propranolol, bisoprolol, glibenclamide,
cilazapril, penicillins, cephalosporins, rifampicin, pyrazolon derivatives, and
lisinopril, among others, have also been implicated.1–8 Some drugs such as
penicillamine may elicit either p. foliaceus or p. vulgaris, but the former is
much more common.
Symptoms disappear in most patients following withdrawal of causative
drugs that contain a sulfhydryl group (thiol drugs). Non-thiol drugs are much
less likely to be associated with remission following withdrawal.2
Histologically, drug-induced pemphigus resembles sporadic counterparts
with positive direct immunofluorescence in most, but not all, patients.9 As
expected, given the different variants of pemphigus that drugs may induce,
antibodies against both Dsg1 and Dsg3 have been documented.10 It has been
suggested that a monoclonal antibody against desmogleins 1 and 3 may be
useful in the diagnosis and prognosis of drug-induced pemphigus.11 Staining
with this antibody is usually patchy in idiopathic pemphigus and diffuse in
drug-induced pemphigus. Furthermore, cases of drug-induced pemphigus Fig. 5.42
with diffuse pattern tend to have a poorer prognosis. Hailey-Hailey disease: erythematous and scaly lesions are present in the groin
and on the labia majora. From the slide collection of the late N.P. Smith, MD, The
Institute of Dermatology, London, UK.
Contact pemphigus
as the genitalia, umbilicus, inframammary regions and scalp, may also be
Clinical features affected. Rarely the disease may be generalized.4,5 Nikolsky's sign is some-
There is a growing body of literature documenting contact with topical sub- times positive.3 Vesicles and bullae, arising on normal or erythematous skin,
stances preceding the onset of pemphigus. The pathogenesis is not under- are soon replaced by erosions, crusting and scaly plaques sometimes resem-
stood, but in some cases the exposure is thought somehow to trigger or bling impetigo (Figs 5.43, 5.44).2,6 Healing is accompanied by hyperpig-
induce pemphigus. The term ‘contact pemphigus’ has been proposed as a mentation, but scarring is not a feature.3 Lesions are frequently itchy and
designation for this phenomenon, which has been described in the vulgaris, malodorous. Sometimes pain is a considerable problem, particularly if fissur-
vegetans, foliaceus and erythematosus variants.1,2 Substances that have been ing is present.3 Symptoms often improve with advancing age.1 Superinfection
implicated include nickel, pesticides, chromium sulfate, tincture of benzoin, by Candida albicans, herpes virus, and Staphylococcus aureus are frequent
phenol, diclofenac, dihydrodiphenyltrichlorethane, ketoprofen, feprazone, complications.7,8 Segmental involvement has rarely been reported as a result
and imiquimod.1–14 Clearly, further study is necessary to elucidate the rela- of type 1 or type 2 mosaicism according to the classification by Happle, and it
tionship between exposure to topical agents and contact pemphigus. has now become clear that at least some of the cases of relapsing linear acan-
tholytic dermatosis represent type 2 segmental Hailey-Hailey disease.9–13
Pathogenesis and histological features The development of the lesions is related to mechanical trauma, stress,
Whether this phenomenon relates to systemic absorption, contact allergy or and ultraviolet radiation and exacerbation of the disease has been reported
a direct ‘toxic’ effect on epidermal antigens is as yet unknown. It is interest- due to scabies, contact irritation, and patch testing.14–18 An exceptional case
ing to note that in the majority of documented cases, the patient has been of a patient developing the disease while on efalizumab for psoriasis has been
exposed to the offending agent for a considerable period of time before the reported.19 Symptoms often improve or even disappear during winter, but
onset of the blistering eruption.6 tend to worsen in summer.1,20 Mucosal involvement is unusual. Anogenital
Biopsy of contact pemphigus shows histological features similar to those disease, however, occasionally presents as multiple 3–5-mm diameter warty
of p. vulgaris, although one patient developed features more reminiscent of
pemphigus vegetans. Immunofluorescent studies show intercellular IgG and
sometimes C3.

Differential diagnosis
The main differential diagnosis is with classic pemphigus. Only clinical infor-
mation will allow distinction of contact pemphigus from other members of
the pemphigus family of disorders.

Acantholytic dermatoses with dyskeratosis

Hailey-Hailey disease
Clinical features
Hailey-Hailey disease (benign familial pemphigus) is a rare, episodic, acan-
tholytic disorder with an autosomal dominant mode of inheritance.1,2 In only
about two-thirds of patients, however, is a family history obtained. There is
an equal sex incidence.2,3
Lesions usually present in the second to fourth decades and appear par- Fig. 5.43
ticularly at sites of minor trauma or friction, especially flexural, around the Hailey-Hailey disease: lesions are most often seen in the flexures as a consequence
neck, and in the axillae and groin (Fig. 5.42). However, other sites, such of friction. By courtesy of the Institute of Dermatology, London, UK.
168 Acantholytic disorders

differentiation demonstrate premature expression and reduced levels of invo-

lucrin due to increased mRNA degradation, and it has been proposed that
intact ATP2C1 is necessary for basal cell layer keratinocytes to maintain their
undifferentiated state.56,57 A number of interesting observations have been
made recently in both Hailey-Hailey and Darier's disease that provide further
insight into how the alteration in the calcium gradient affects ATP receptors
and keratin expression.58 In both diseases there is a lower level of calcium in
the basal cell layer of the epidermis compared to normal skin, the ATP recep-
tor P2Y2 is not identified at the cellular membrane in affected cells whereas
P2X27 which is usually not present on the cellular membrane is expressed in
these cells probably mediating apoptosis. Furthermore, both keratins 14 and
10 are expressed in diseased cells whereas these keratins are mutually exclu-
sive in normal keratinocytes.
While early lesions show suprabasilar lacunae, established Hailey-Hailey
disease is characterized by massive acantholysis associated with suprabasal
vesicle or bulla formation.3 Typically, however, the acantholysis is incom-
plete, the cell retaining some connections and giving an appearance often
­likened to a ‘dilapidated brick wall’ (Figs 5.45–5.47). The adnexal epithelium
is usually spared. Occasionally, dyskeratotic cells resembling the corps ronds
Fig. 5.44 and grains of Darier's disease are seen.
Hailey-Hailey disease: close-up view of keratotic warty lesions. By courtesy of the
Institute of Dermatology, London, UK.

papules.21 This occurs most often in females, particularly blacks, and some-
times may be a presenting feature. In such instances there is overlap with
papular acantholytic dyskeratosis of the vulva.22
Asymptomatic white longitudinal bands may be present on the fingernails
in up to 70% of affected patients.1,23 The other nail changes of Darier's dis-
ease are absent.
Significant associated conditions have not been documented with the pos-
sible exception of a bipolar disorder and a patient with affective disorder (see
Darier's disease).24,25 An association with supernumerary nipples has been
documented in one Tunisian family.26
Exceptionally, squamous carcinoma has been documented as a compli-
cation in patients with Hailey-Hailey disease.27 It is likely, however, that
those arising on the vulva have a human papillomavirus-associated basis.28,29
Condylomatous change and evidence of HPV infection has recently been
detected in genital lesions of the disease.30,31
While it has rarely been reported that Darier's disease may coexist with
Hailey-Hailey disease, the available evidence supports the contention that
these two conditions represent completely different entities.32
Fig. 5.45
Pathogenesis and histological features Hailey-Hailey disease: early lesion showing the characteristic ‘dilapidated brick wall’
appearance.
Hailey-Hailey disease is primarily an abnormality of cell adhesion.
Development of this disease has recently been shown to be caused by mul-
tiple mutations in ATP2C1 on chromosome 3q21–24, a gene that encodes the
calcium pump SPCA1.33,34 SPCA1 is a Ca2+/Mn2+ ATPase present within the
membrane of the Golgi apparatus and responsible for the transport of Mn2+
as well as Ca2+ ions into the Golgi.35,36 Over 100 mutations have been identi-
fied spanning the entire ATP2C1 gene including missense, frameshift, splice
site as well as nonsense mutations.37–46 However, no clear genotype–pheno-
type correlation has emerged as yet. Studies have shown that calcium regula-
tion in cultured keratinocytes is impaired.33 In addition, there is evidence that
integrity of intercellular junctions may be dependent on intracellular calcium
stores.47–50 The precise mechanism by which the abnormality in the calcium
pump causes acantholysis is not known. However, the addition of calcium to
monolayers of squamous cells in culture elicits stratification.48 In contrast,
cells grown in low calcium medium fail to stratify.50 It should be noted that
Darier's disease, another disorder showing acantholysis, is also associated
with a mutation in another calcium pump – ATP2A2. That both of these dis-
orders of acantholysis are associated with mutations in a calcium pump is
strong evidence for an important role in maintaining cell–cell cohesion.
Immunohistochemical studies have confirmed that the major desmosomal
proteins and glycoproteins are synthesized in Hailey-Hailey disease and dis-
tributed along the plasma membranes in uninvolved epidermis.51 In lesional Fig. 5.46
skin there is marked cytoplasmic labeling for the desmoplakins (DpI, DpII), Hailey-Hailey disease: in this example, there is marked hyperkeratosis, parakeratosis,
desmogleins (Dsg2, Dsg3) and the desmocollins.51–55 Studies on keratinocyte and acanthosis. Villi project into the blister cavity.

Fig. 5.47
Hailey-Hailey disease:
in contrast to Darier's
disease, dyskeratosis is
usually minimal or even
absent.
Ultrastructural studies have primarily disclosed abnormalities of the des-
mosome-tonofilament units, characterized by diminished numbers of desmo-
somes and clumped tonofilaments.59–62 The latter have a linear distribution in
the basal keratinocytes, but develop a whorled configuration in the suprabasal
layers.60,62 The cell membranes show microvillus formation.59 An electron
microscopic study of artificially induced early lesions suggests the desmo-
somal splitting precedes the tonofilament clumping.61 Dyskeratotic cells are
characterized by condensed tonofilaments surrounding pyknotic nuclei.
Differential diagnosis
The histological features of Hailey-Hailey disease must be distinguished from
those of Darier's disease, p. vulgaris, and Grover's disease. Pemphigus is dis-
tinguished from Hailey-Hailey disease by the presence of relatively intact epi-
thelium in the adjacent epidermis (versus disintegrating ‘dilapidated brick
wall’) and involvement of adnexal structures. In difficult cases, positive
immunofluorescence staining supports a diagnosis of pemphigus. Darier's
disease tends to show prominent suprabasal cleft formation with involve-
ment of adnexae and is associated with numerous corps ronds and grains.
These points of distinction are summarized in Table 5.2.
Immunofluorescence studies for immunoglobulin and complement are
invariably negative, aiding in the distinction from immunobullous disorders.
Distinction from acantholytic dermatosis of the genital area can, however,
be extremely difficult. In fact, the relationship between these disorders is not
well understood. The combination of clinical features of a lesion or lesions
localized to the vulvogenital area and a negative family history favors acan-
tholytic dermatosis of the genital area.
Relapsing linear acantholytic dermatosis
Clinical features
Relapsing linear acantholytic dermatosis (Hailey-Hailey-like epidermal
nevus) is an exceptionally rare nevus-like condition characterized by ery-
thematous plaques with vesicles and erosions arranged in a linear distribu-
tion along Blaschko's lines.1–3 It typically undergoes spontaneous resolution
followed by recurrence and has a chronic course. Insufficient cases have been
documented to precisely determine its relationship to Hailey-Hailey disease.
Recent data, however, demonstrate that at least some of the patients harbor
mutations in the gene responsible for Hailey-Hailey disease, the ATP2C1.
Acantholytic dermatoses with dyskeratosis 169
The disease has been shown to be a type-2 mosaicism according to Happle,
resulting in homozygosity for the mutated gene and pronounced disease in a
segmental distribution superimposed on more classical disease in a heterozy-
gous individual.4–7
Histological features
The features are indistinguishable from Hailey-Hailey disease.
Darier's disease
Clinical features
Darier's disease (keratosis follicularis, morbus Darier), which is character-
ized by abnormal keratinocyte adhesion, is a rare hereditary disorder, usually
transmitted in an autosomal dominant pattern. In a large series, however,
47% of patients had no clear family history of Darier's disease.1 Presumably
these cases represent new mutations or evidence of incomplete penetrance.
Its documented incidence is variable. In Oxfordshire (UK), the incidence is
1:55 000, in the north of England it is 1:36 000, in the west of Scotland it is
1:30 000, whereas in Denmark it is 1:100 000.2–5 The sex incidence is equal,
although males appear to be more severely affected than females. The disease
usually presents in the first or second decade (with a peak around puberty)
and often follows exposure to ultraviolet light.1 Exceptionally, patients may
not present until their sixth or seventh decade.6 Darier's disease is a long-term
illness. Remissions do not occur, although some patients show improvement
with increasing age.6
The lesions are frequently itchy and, less commonly, painful.1,6 They
are characterized by greasy, crusted, keratotic yellow-brown papules and
plaques found particularly on the ‘seborrheic’ areas of the body – the scalp,
forehead, ears, nasolabial folds, upper chest, back, and supraclavicular fos-
sae (Figs 5.48–5.52).1,5 There is mild involvement of the flexures in the
majority of patients although sometimes this distribution predominates.1,6
Lesions may be induced or exacerbated by stress, heat, sweating, and mac-
eration.1,7 In some areas the lesions have a warty appearance, while in the
flexures they are often vegetative, malodorous (a particularly distressing
problem), and often secondarily infected (Figs 5.53, 5.54).6 Bullous lesions
generally following sun exposure can occur, albeit rarely.8–10 Leukodermic
macules in black patients have also been described.11–14 Additional features
including cutaneous horns and hemorrhagic palmar lesions have also been
documented.15–18
Patients with Darier's disease are susceptible to bacterial (particularly
Staphylococcus aureus), dermatophyte, and viral infections.1,19,20 There are
rare case reports of eczema vaccinatum and eczema herpeticum complicating
Fig. 5.48
Darier's disease: in this patient keratotic brown papules are present on the back of
the neck. From the slide collection of the late N.P. Smith, MD, The Institute
of Dermatology, London, UK.
170 Acantholytic disorders
Fig. 5.49
Darier's disease: close-up view of keratotic papules. From the slide collection of the
late N.P. Smith, MD, The Institute of Dermatology, London, UK.
Fig. 5.50
Darier's disease: this patient shows a striking symmetrical distribution. From the
slide collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.
Darier's disease and a patient who developed localized anogenital cowpox
has also been reported.21–23 Life-threatening Kaposi's varicelliform eruption is
a rare but important complication.24–26 No consistent abnormality of immune
function has been found to explain this.27,28 Recently, however, persistence of
intracellular S. aureus small-colony variants in a patient with Darier's disease
has been shown to be of importance in chronic cutaneous infection and resis-
tance to antibiotic therapy.29 Whether this mechanism is involved in other
patients awaits confirmation.
Other cutaneous manifestations of Darier's disease include unilateral, lin-
ear or zosteriform variants, which some regard as acantholytic, dyskeratotic
epidermal nevi rather than true Darier's disease (see below).30,31 It is more
likely that these variants, at least in part, result from genetic mosaicism.32
The hands are affected in 96% of patients.1 Pits and punctate keratoses
with focal disruptions of the skin ridges of the palms and soles are charac-
teristic features (Fig. 5.55).1,6,33 Acrokeratosis verruciformis-like lesions are
common on the backs of the hands.1 Indeed, acrokeratosis verruciformis of
Hopf, a localized disorder of keratinization of distal extremities, is closely
related to Darier's disease and appears to be caused by mutations in the same
gene.34,35
Nail changes are a particularly important diagnostic feature.1,2,6,36,37
Longitudinal white or red streaks (often both), some of which ­terminate
Fig. 5.51
Darier's disease: lesions
may be induced by heat,
sweating, and maceration.
From the slide collection
of the late N.P. Smith,
MD, The Institute of
Dermatology, London, UK.
Fig. 5.52
Darier's disease: close-up view. From the slide collection of the late N.P. Smith, MD,
The Institute of Dermatology, London, UK.
in a small nick on the free margin, are typical findings (Figs 5.56,
5.57).1 Painful splitting and subungual hyperkeratoses are additional
­manifestations.1 The toenails are affected less often (and less severely) than
the ­fingernails.1 Subtle hand and nail manifestations may sometimes be a
­presenting feature.6
The mucous membranes of the mouth, pharynx, larynx, esophagus, and
female genitalia can also be affected.38–41 Oral lesions are present in up to
50% of patients and consist of small white papules on the hard palate.42,43
Large nodular and verrucous plaques are also sometimes present and occa-
sionally there are gingival, buccal mucosal, and tongue lesions.15 Involvement
of the salivary ducts is said to be uncommon and results in ­salivary gland
swelling with obstruction and sialadenitis.44,45 Recently, however, one
series reported an incidence of 30% involvement of the parotid gland.42
Anal ­involvement may present as pruritus ani or less often as ­vegetating
­malodorous plaques.46

Fig. 5.53
Darier's disease: skin
involvement as severe
as this is fortunately
extremely rare. By
courtesy of M. Greaves,
MD, the Institute of
Dermatology, London, UK.
Fig. 5.54
Darier's disease: severe involvement can be very disfiguring and a source of
considerable disability and embarrassment. By courtesy of M. Greaves, MD, the
Institute of Dermatology, London, UK.
Ocular lesions, particularly affecting the cornea, are seen in up to 76%
of patients.47 Peripheral corneal opacities and central epithelial irregularity
are the usual findings. Pannus formation may rarely be present. Lesions are
­typically asymptomatic.
Associated systemic abnormalities are unusual, but include epilepsy,
­pulmonary lesions, bone cysts, low intelligence, and small stature.1 Various
neuropsychiatric problems including depression and bipolar disorder have
been linked with Darier's disease.6,48 There is some evidence to suggest that
there is familial cosegregation of bipolar disorder with Darier's disease, at
least in a proportion of cases.48,49
Rare and likely incidental associations include visceral malignancy, horse-
shoe kidney, hemodialysis, gynecomastia, cutis verticis gyrate, and Fanconi
anemia.50–55
Spontaneous remissions in Darier's disease are rare, and in the majority of
patients the disease persists throughout life.
Acantholytic dermatoses with dyskeratosis 171
Fig. 5.55
Darier's disease: palmar pits are a helpful diagnostic clue. By courtesy of J. Wilkinson,
MD, Wycombe General Hospital, High Wycombe, UK.
Fig. 5.56
Darier's disease:
parallel white and red
longitudinal streaks are
pathognomonic features.
By courtesy of the
Institute of Dermatology,
London, UK.
Pathogenesis and histological features
Positional cloning studies of different families have all shown the gene of
Darier's disease to be located at 12q23-q24.56,57 Mutations in ATP2A2, a
gene that encodes for SERCA2 (type 2 sarcoendoplasmic reticulum CA2+-
ATPase), cause the disease and have been identified in the majority of patients
screened.57 So far, over 100 different mutations have been reported. They are
predominantly missense mutations, but frameshift and splice site mutations
as well as mutations resulting in a premature stop codon have also been iden-
tified.58–67 However, no clear genotype–phenotype correlation has emerged.
The disease is likely a result of haploinsufficiency since only one correct copy
of the ATP2A2 gene is expressed.68 The mutant copy may furthermore lead
to enhanced proteasome-mediated degradation and/or protein dimerization
resulting in complete loss of SERCA2 activity.68,69 The precise mechanism
of how mutations in the ATP2A2 gene lead to disease is unknown although
172 Acantholytic disorders

Fig. 5.58
Fig. 5.57 Darier's disease: very early lesion showing multiple characteristic corps ronds.
Darier's disease: notches
on the free margin of the pyknotic nucleus surrounded by a clear halo enclosed within a basophilic
nail are common findings. or eosinophilic ‘shell’ (Fig. 5.58). Variable amounts of highly irregular
By courtesy of the keratohyalin granules may also be evident.
Institute of Dermatology, • Grains are located within the horny layer and consist of somewhat
London, UK. flattened oval cells with elongated cigar-shaped nuclei and abundant
keratohyalin granules.
In the fully established lesion there is hyperkeratosis and often parakera-
there is emerging evidence to suggest that the integrity of intercellular junc-
tosis, sometimes arranged in a clearly defined tier (Figs 5.59–5.61). The epi-
tions is dependent on the intracellular calcium stores.70 SERCA is a ubiqui-
dermis may appear acanthotic or atrophic and typically shows acantholysis
tously expressed calcium-ATPase and its function is the transport of cytosolic
with suprabasal cleft formation in which the underlying dermal papillae, cov-
calcium ions into the endoplasmic reticulum.68 There are three different genes
ered by a single layer of epithelium, project into the cavity (villus formation).
encoding these proteins, resulting in a total of nine different isoforms. Of the
The roof contains variable numbers of grains and the adjacent epithelium has
different isoforms only SERCA2b appears to be expressed in keratinocytes.71
variable numbers of corps ronds. Occasionally, epithelial proliferation can be
Loss of SERCA2 function can therefore not be compensated for, explaining
marked, resulting in pseudoepitheliomatous hyperplasia. Bullous lesions are
the severe skin manifestations in the absence of further systemic involvement
illustrated in Figures 5.62 and 5.63.
in most patients with Darier's disease.68 Ultimately, intact intracellular cal-
There may be a perivascular chronic inflammatory cell infiltrate in the
cium ion homeostasis has been identified as a major factor in the complex
superficial dermis, although this is not a common finding.
process of desmosome assembly and is necessary for intracellular interactions
The histological features of the oral, pharyngeal, laryngeal, and esopha-
between desmosomal cadherins and intracellular plaque proteins such as pla-
geal lesions are similar to those described in the skin although dyskeratosis
koglobin.68,72 Apoptosis in Darier's disease resulting in dyskeratotic cells is
is said to be less conspicuous.42 Salivary gland lesions show ductal dilata-
likely directly related to the imbalance in calcium homeostasis, and immuno-
tion and squamous metaplasia of the lining epithelium with acantholysis and
histochemical studies have revealed reduced expression of antiapoptotic pro-
dyskeratosis.44,45
teins of the bcl-2 gene family in lesional epidermis.73–75
No single specific ultrastructural abnormality has been identified in
Darier's disease. Changes described have included complete loss of desmo-
somes in foci of acantholysis with formation of cell membrane microvilli,
cytoplasmic vacuolization, cell membrane defects, abnormal tonofilament
aggregation, clumping and distribution, premature and abnormal forma-
tion of keratohyalin granules and membrane coating (Odland) bodies, and
excessive lipid lamellae between the flattened keratinocytes of the stratum
corneum.76–80 Hemidesmosomes and the lamina densa usually appear morpho-
logically normal, although discontinuities of the latter have been described.
Ultrastructurally, corps ronds are characterized by large dense keratohyalin
masses, numerous membrane coating granules, and tonofilament clumps.76
They are distributed particularly around the nucleus, often surrounding a
perinuclear cytoplasmic halo containing distended vesicles. Grains of Darier
are composed of nuclear remnants with surrounding dyskeratotic debris.76
Acantholysis develops as a consequence of desmosomal breakdown and
dissociation of tonofilaments, although which comes first is uncertain.
The histological features of Darier's disease depend upon a variable
­interplay between acantholysis and abnormal keratinization (dyskeratosis),
the acantholysis resulting in suprabasal cleft formation (and rarely vesicles
or even blisters), and the dyskeratosis manifesting as corps ronds and grains
of Darier. Fig. 5.59
• Corps ronds are large structures, usually most conspicuous in the Darier's disease: scanning view through a typical lesion. Note the keratotic tier and
granular layer, and consist of an irregular eccentric and sometimes suprabasal cleft formation.

Fig. 5.60
Darier's disease: higher-power view showing the well-developed vesicle with
suprabasal acantholysis and well-developed corps ronds and grains.
Fig. 5.61
Darier's disease: in this example both corps ronds and grain of Darier are evident.
Fig. 5.62
Darier's disease: bullous variant showing suprabasal acantholysis, epidermal
regeneration and a subcorneal blister.
Acantholytic dermatoses with dyskeratosis 173
Fig. 5.63
Darier's disease: high-power view of Figure 5.62 showing multiple corps ronds.
Corneal lesions are characterized by corneal epithelial edema, subepithe-
lial granular deposits, and basement membrane thickening. Acantholysis and
dyskeratosis are not seen.47
Differential diagnosis
Although warty dyskeratoma, Hailey-Hailey disease, and pemphigus are
­considered in the differential diagnosis of Darier's disease, their distinction is
not challenging when clinical information is considered. Warty dyskeratoma
is a single umbilicated lesion that typically forms more pronounced papillary
structures. Hailey-Hailey disease is characterized by full-thickness epidermal
acantholysis and does not show extensive dyskeratosis. Grover's disease may
be indistinguishable from Darier's disease in a given biopsy, but the lesions are
usually small, spanning only a few rete ridges. The presence of some combina-
tion of spongiosis, and changes mimicking more than one of the ­acantholytic
dermatoses, is characteristic of Grover's disease. In cases that show only Darier-
like changes, clinical information should allow for ­definitive diagnosis.
Linear Darier's disease
Clinical features
Linear Darier's disease (acantholytic dyskeratotic epidermal nevus, unilat-
eral Darier's disease, zosteriform Darier's disease, segmental Darier's disease)
is a rare acquired condition characterized by the development of grouped,
keratotic, sometimes pruritic, yellow-brown papules which affect the trunk,
trunk and limbs, limbs, scalp, vulva, and face in decreasing order of frequency
(Fig 5.64).1–9 Their linear distribution corresponds to the lines of Blaschko.
Lesions may be aggravated by sunlight, heat, and sweating. Although a wide
age range may be affected, the majority of patients are in the third or fourth
decade. There is an equal sex incidence. There is no family history of Darier's
disease. Usually, patients are free from other stigmata of Darier's disease but
there are very occasionally reports of patients with linear lesions associated
with ipsilateral nail changes and palmar pits typical of Darier's disease.10,11
Pathogenesis and histological features
The precise nature of this lesion remains conjectural. Although many authors
prefer to regard it as a variant of epidermal nevus with superimposed acantho-
lytic dyskeratosis, there is an alternative school of thought which believes that
many, if not all, such lesions represent localized or unilateral Darier's disease,
arguing that the condition develops as a consequence of genetic mosaicism.
Certainly, the late age of onset is unlike a typical epidermal nevus, which usu-
ally presents in childhood. The distribution along the lines of Blaschko and
the occasional reports of additional Darier-like features on the ipsilateral side
of the body offers support to a concept of localized Darier's disease. Recently,
174 Acantholytic disorders

Fig. 5.64 Fig. 5.65

Linear Darier's disease: the trunk is a commonly affected site. Note the small papules. Grover's disease:
Courtesy of the Institute of Dermatology, London, UK. innumerable
erythematous papules
ATP2A2 mutations have been identified in lesional tissue but not unaffected are present on the chest
skin patients with linear acantholytic epidermal nevi, confirming the relation- wall. By courtesy of the
ship of these lesions to Darier's disease.12,13 Institute of Dermatology,
London, UK.
Histologically, these lesions are indistinguishable from Darier's disease.

Differential diagnosis
Very rarely, true epidermal nevus may show histological features of acan-
tholysis and dyskeratosis presenting against a background of a verrucous
plaque characterized by marked acanthosis and papillomatosis.14,15 Such
lesions, which are present at birth, would be best classified as epidermal
nevus ­showing acantholysis and dyskeratosis rather than being included in
the spectrum of acantholytic dyskeratotic epidermal nevus.

Transient acantholytic dermatosis

(Grover's disease)
Clinical features
Transient acantholytic dermatosis (persistent acantholytic dermatosis) is a
primary acquired, self-limiting, acantholytic disease of unknown etiology,
seen predominantly in the middle aged or elderly although there are rare
reports of the disorder in children.1–5 Males are affected more often than
females (3:1).2,3 The white races are predominantly affected.5 Cases involv-
ing blacks are exceptionally rare.6 The disease shows a predilection for the
winter months in nonhospitalized patients.7 Although the disease is usu-
ally transient, persistent and recurring variants have also been described
(persistent acantholytic dermatosis) in the literature.8–10 The development
of Kaposi's varicelliform eruption is a rare and unusual complication of
the disease and occult colonization by herpes simplex virus has also been
documented.11,12
The skin lesions are usually rather polymorphic, consisting of 1–3-mm
erythematous, red-brown or flesh-colored papules, vesicles, and eczema-
tous plaques with a predilection for the chest, back, and thighs (Figs 5.65
and 5.66).2 The palms and soles are unaffected. Superimposed excoria-
tions are associated with the intensely pruritic eruption. Pustular, bullous,
nummular, follicular herpetiform, and zosteriform variants have all been
­documented.2,13–16 The mucous membranes, palms, and soles are commonly
spared although there are rare reports of oral, nasal, and laryngeal involve-
ment.2,17,18 Postinflammatory pigmentary changes following resolution of
the acute phase are common. Transient acantholytic dermatosis has been
described in ­association with leukemia and lymphoma in addition to numer-
ous solid tumors including carcinoma of kidney, renal pelvis, bladder, and
prostate.2,19–24 In one study, 25% of patients had some form of malignancy.21
Other rare associations include scabies, renal failure, peritoneal dialysis,
Fig. 5.66
Grover's disease: close-up view. By courtesy of the Institute of Dermatology,
London, UK.
and renal as well as bone marrow transplantation.25–29 It is likely, however,
that the majority of these associations are coincidental. Transient acantho-
lytic ­dermatosis shows a positive correlation with asteatotic eczema, allergic
­contact dermatitis, and atopic dermatitis.3,30,31
Pathogenesis and histological features
The pathogenesis of Grover's disease is incompletely understood. There are,
however, a number of important known etiological factors including:
• sun exposure,
• excessive heat and sweating,
• ionizing radiation,
• adverse reaction to drugs.
Transient acantholytic dermatosis has long been known to be associated
with sun exposure.2,3,32–35 The lesions are photodistributed and the patients
commonly give a history of having recently spent time in the sun.36 There
is also a well-established relationship to excessive heat and sweating.35,37–39
 Acantholytic dermatoses with dyskeratosis 175

Bedridden, febrile patients are particularly at risk and as a result it has

been proposed that the pathogenesis might be analogous to that of miliaria.
Occlusion of sweat ducts and increased sweating resulting in acantholysis
mediated by high concentrations of sweat urea has been proposed, although
this has yet to be proven.40 More recent immunohistochemistry studies have
not generally offered support for this hypothesis although bedridden, febrile
patients may occasionally show prominent involvement of the eccrine duct;
this has been termed sudoriferous acrosyringeal acantholytic disease.21,41,42
Associations with sunlamps, sun parlors, PUVA therapy, steam bath, hot tub,
hot water bottle, and polyester jogging suits have also been documented.1,2,21
Despite these well-recognized associations, there must be other important
predisposing factors, since overexposure to sunlight and excessive sweating
are extremely common yet this disease is rare.
Very occasional reports have described transient acantholytic dermato-
sis developing after radiotherapy for cancer, exceptionally with lesions con-
fined to the area of the port.2,22,43,44 Only a small number of drugs have
been associated (rarely) with the development of transient acantholytic der-
matosis.2 There are reports of lesions following treatment with sulfadox-
ine-pyrimethamine, 2-chlorodeoxyadenosine, D-penicillamine, recombinant
interleukin-4, cetuximab, and induction chemotherapy for allogeneic bone Fig. 5.68
Grover's disease: high-power view showing acantholysis.
marrow transplantation.45–50 The presence of eosinophils in the dermal
inflammatory cell infiltrate has raised the possibility of a hypersensitivity
reaction.21 Occasional cases arising in patients with HIV infection have been
recorded.21
Despite the histological similarity to Darier's and Hailey-Hailey diseases,
there is no evidence of a mutation in the ATP2A2 gene.51
There have been a variety of both direct and indirect immunofluores-
cence observations including lupus erythematosus-like, bullous pemphigoid-
like, and pemphigus-like findings.21,52 These are reviewed in reference 2. They
are the exception rather than the rule and are unlikely to be of any great
significance.
Immunohistochemistry observations have included a reduction or absence
of desmosomal staining with cytoplasmic redistribution of the proteins,
­desmoplakins I and II, plakoglobin, and desmoglein.53–55 Redistribution and
dissolution of desmosomal attachment plaques have been demonstrated as
the first stage in the development of Grover's disease.55
Instead of featuring specific histopathological changes, transient acantholytic
dermatosis mimics three other diseases: Darier's disease, Hailey-Hailey disease,
and pemphigus (p. vulgaris and p. foliaceus) (Figs 5.67–5.70).21 The first is by
far the most commonly encountered. Thus, in the typical case, there is hyperker-
atosis, parakeratosis, acanthosis, and acantholysis ­accompanied by corps ronds
formation and grains of Darier. In the Hailey-Hailey pattern, the acantholy- Fig. 5.69
sis is much more pronounced such that the dilapidated brick wall appearance Grover's disease: this example is indistinguishable from pemphigus vulgaris.
is seen. Follicular involvement may be present. In the ­pemphigus-like ­variant,

Fig. 5.67 Fig. 5.70

Grover's disease: low-power view showing an intact intraepidermal vesicle. Grover's disease: early lesion showing intraepidermal vesiculation.
176 Acantholytic disorders

­ yskeratosis is typically absent. Multiple specimens from any one patient

d
may disclose differing histological variants, and superimposed spongiosis is
often present. Occasional bullae are encountered. A variable dermal mononu-
clear infiltrate is usual and significant numbers of eosinophils are seen in some
cases.21
Patients with sudoriferous acrosyringeal acantholytic disease show, in
addition to typical features of Grover's disease, acantholysis of the ­superficial
portion of the eccrine duct.

Differential diagnosis
Clinically, transient acantholytic dermatosis is easily differentiated from
Darier's disease, Hailey-Hailey disease, and pemphigus. However, the biopsy
findings often mimic these diseases. A histological clue to the diagnosis is the
small size of the lesion. Usually only one or two small discrete lesions that
span a few rete ridges are noted. This is in contrast to other acantholytic­
dermatoses, which tend to involve the entire biopsy. Biopsies from a patient
with Grover's disease often show varying features mimicking more than one
of the acantholytic dermatoses and occasionally a number of patterns are
seen in a single biopsy specimen. Sometimes, a biopsy will show non-spe-
Fig. 5.71
cific features of spongiotic dermatitis. The association of both spongiosis and Warty dyskeratoma: scaly nodule on the scalp, a commonly affected site. By courtesy
acantholysis may be a useful pointer to the diagnosis of Grover's disease (see of the Institute of Dermatology, London, UK.
also Table 5.2).
in the literature.2,3 Although the cutaneous lesions are believed to be of folli-
Acantholytic dermatosis of the cular derivation, histologically similar nodules have been described affecting
the oral and vulval mucosa.8–11 The former occur most often on ­keratinized
genitocrural area mucosa of the palate, alveolar ridge, and gingiva.9 Subungual warty dyskera-
toma-like lesions have also been documented.12
Clinical features
In acantholytic dermatosis of the genitocrural area (papular acantholytic Pathogenesis and histological features
dermatosis of the vulvocrural area) focal dyskeratosis and/or acantho- The etiology of warty dyskeratoma is unknown, although in the past authors
lysis may present as an isolated phenomenon on the vulvocrural region have suggested an effect of actinic radiation or possibly a viral infection.
of young or middle-aged females.1–10 Lesions sometimes extend on to the Neither of these has been substantiated. There is no relationship with Darier's
thigh and perineum.5 Patients present with variably pruritic, multiple, disease. Multiple lesions have been associated with chronic renal disease.5,6
0.1–0.4-mm isolated or groups of white papules, solitary keratotic nod- Warty dyskeratoma is most probably of follicular derivation. Thus, many
ules or, less often, with erythematous or white plaques measuring up to examples appear in continuity with a dilated hair follicle and, less frequently,
1.0 cm in diameter involving the labia majora or inguinal region. More a sebaceous gland may be evident.3,6 The recent observation of positive stain-
recently, cases with histologically similar findings have been described in ing with antibodies directed towards cortex and inner root sheath provides
males, presenting on the penis, scrotum, thigh, perianal region, and in the additional support. Mucosal and subungual variants must have a different
anal canal.11,12 derivation.
Family history is invariably negative for either Darier's or Hailey-Hailey Histologically, warty dyskeratoma is composed of a widely dilated cup-
disease and, by definition, there is no evidence of similar lesions elsewhere on shaped or cystic lesion containing keratinous debris and often associated
the body.4 Two cases have developed in the presence of syringomas.1 with a hair follicle (Fig. 5.72). Superficially, the keratinous debris contains
­conspicuous corps ronds and grains of Darier. The adjacent and deeper
Pathogenesis and histological features ­epithelium shows marked acantholysis and suprabasal villi are a prominent
The pathogenesis is unknown although it is likely that the moist environment feature (Figs 5.73 and 5.74). The underlying dermis is often infiltrated by
of the body folds is of importance. Candida albicans infection has accompa- lymphocytes and histiocytes, and sometimes plasma cells are evident.
nied a number of cases although this may have been coincidental.4,6 With the
exception of one case showing intracellular IgG and C3 staining, immuno-
fluorescence (when performed) has been negative.3–5,8
The lesions show features of hyperkeratosis, parakeratosis, acantho-
sis, and acantholysis, sometimes with dyskeratosis, resembling Darier's or
Hailey-Hailey disease. Warty dyskeratoma-like features associated with fol-
licular involvement may also be encountered.2,4 Typically, minimal or no
inflammation is present.

Warty dyskeratoma
Clinical features
Warty dyskeratoma is a peculiar hyperkeratotic, umbilicated, persistent nodule
that usually presents on the sun-exposed skin of the head and neck of middle-
aged adults, although lesions on the trunk and extremities have ­occasionally
been documented (Fig. 5.71).1–4 Most cases are solitary, but occasional patients
with multiple tumors have been reported, particularly in Japanese patients.3,5–7
Lesions are commonly asymptomatic but ­occasionally discharge and bleeding Fig. 5.72
may be encountered.2 There are conflicting data ­regarding gender distribution Warty dyskeratoma: typical scanning view of a cystic nodule with acantholysis.

Fig. 5.73
Warty dyskeratoma: note
the acantholysis and villi.
Fig. 5.74
Warty dyskeratoma: corps
ronds are conspicuous.
Oral lesions can be morphologically indistinguishable although a num-
ber of cases more likely represent focal acantholytic dyskeratosis arising
in a background of a benign trauma-related keratosis. A single case report
has documented verruciform xanthoma-like features within a typical oral
lesion.13
Differential diagnosis
Although there are histological similarities with familial dyskeratotic come-
dones, Darier's disease, Hailey-Hailey disease, and Grover's disease, deeply
penetrating crateriform lesions with villus formation are not associated with
these entities. In addition, the clinical findings of a solitary umbilicated
Acantholytic dermatoses with dyskeratosis 177
nodule should not be confused with any of the above disorders with the
­possible exception of familial dyskeratotic comedones; however, villi are not
­conspicuous in the latter. There is also considerable overlap with both focal
acantholytic dyskeratosis and acantholytic acanthoma; however, in neither of
these conditions is there a deeply penetrating crateriform lesion.
Familial dyskeratotic comedones
Clinical features
Although thought to be common, familial dyskeratotic comedones have been
extremely rarely documented in the literature. To date, fewer than 10 families
have been reported.1–8 The condition is characterized by an autosomal domi-
nant mode of inheritance. Lesions develop in childhood or adolescence and
are permanent.5 Patients present with 1–3-mm diameter papules containing
small hard keratotic plugs, which on removal leave crateriform lesions resem-
bling comedones (Fig. 5.75). Cutaneous horns may also sometimes be appar-
ent (Fig. 5.76).2 Lesions are often generalized but show a predilection for
the extremities, particularly the forearms and thighs. The face, scalp, palms,
soles, and mucous membranes are typically unaffected. Some patients com-
plain of pruritus or inflammation. There is no evidence of ectodermal dyspla-
sia and systemic lesions are absent.
Histological features
The lesions are characterized by a follicle-like crateriform cystic cavity con-
taining laminated hyperkeratotic and parakeratotic debris and lined by
squamous epithelium showing dyskeratosis and sometimes acantholysis at
the base (Figs 5.77, 5.78).4 Grains of Darier are typically present but corps
ronds are sparse and poorly developed. Villi, as seen in Darier's disease, are
not a feature. Hair shafts and sebaceous glands are absent.
Differential diagnosis
The consistent folliculocentric nature of the eruption and absence of nail and
oral mucosal changes help to distinguish familial dyskeratotic comedones
from Darier's disease. Corps ronds, a characteristic finding in Darier's dis-
ease, are usually not prominent in familial dyskeratotic comedones. Villus
formation and well-developed corps ronds within a solitary lesion distinguish
warty dyskeratoma.
Fig. 5.75
Familial dyskeratotic
comedones: numerous
comedones are present
on the penis and foreskin.
By courtesy of B.J.
Leppard, MD, Royal South
Hants Hospital, UK.
178 Acantholytic disorders
Fig. 5.76
Familial dyskeratotic
comedones: a small
cutaneous horn is seen
arising on the scrotum. By
courtesy of B.J. Leppard,
MD, Royal South Hants
Hospital, UK.
Fig. 5.77
Familial dyskeratotic
comedones: this section
comes from the edge of a
lesion. Note the dell with
associated hyperkeratosis
and parakeratosis. The
acanthosis is in part due
to the oblique angle of the
cut. By courtesy of B.J.
Leppard, MD, Royal South
Hants Hospital, UK.
Diffuse familial comedones differ by the absence of dyskeratosis.9,10
Familial dyskeratotic comedones may also be mistaken for Kyrle's and
Flegel's diseases:
• Kyrle's disease typically presents on the extensor aspect of the lower
extremities and presents in adulthood. There is no familial incidence.
Histolo­gically, it is characterized by transepidermal elimination of
parakeratotic and inflammatory debris. There is no dyskeratosis.
• Flegel's disease typically presents in older adults and is characterized by
epidermal atrophy, interface change, and dyskeratosis. A keratin-filled
crateriform lesion is absent.
Fig. 5.78
Familial dyskeratotic
comedones: note the
superficial dyskeratosis.
By courtesy of B.J.
Leppard, MD, Royal South
Hants Hospital, UK
Perforating folliculitis presents in adults and shows a predilection for the
extremities. It is characterized by a crateriform lesion containing a distorted
and often curled-up hair shaft.
Acantholytic acanthoma
Clinical features
Acantholytic acanthoma is a common entity consisting of a solitary, usually
asymptomatic, keratotic papule or plaque, 0.5–1.5 cm in diameter, often
with overlying scale/crust. It usually presents on the trunk, arm or neck
and is clinically thought to be a seborrheic keratosis or actinic keratosis.1–5
A  case with central umbilication reminiscent of molluscum contagiosum
has also been described.6 Very occasionally multiple lesions have been docu-
mented.7 Some patients report pruritus. Patients are usually elderly (median
age 60 years) and there is a predilection for males (2:1).2,4 Lesions are not
seen about the head, palms, and soles and the mucous membranes appear
to be spared.2
Pathogenesis and histological features
The pathogenesis of this lesion is unknown. Although one case has been doc-
umented in association with immunosuppression, it is likely that this was
coincidental.7
Diagnosis is one of exclusion and depends upon the solitary nature of the
lesion. The histological features are those of hyperkeratosis, acanthosis, and
papillomatosis accompanied by acantholysis affecting all or any layer of the
epidermis (Figs 5.79 and 5.80).1 Dyskeratosis may be evident. A perivascular
lymphohistiocytic chronic inflammatory cell infiltrate, sometimes with occa-
sional eosinophils, may be present in the superficial dermis.
Differential diagnosis
In acantholytic seborrheic keratosis the acantholysis is typically focal and
the lesion elsewhere shows the typical features of horn cysts and squamous
eddies.8 Darier's disease, acantholytic dermatosis of the genitocrural area,
warty dyskeratoma and pemphigus, Hailey-Hailey disease, and Grover's
disease may show similar histological features but are easily ­distinguished
clinically. Acantholytic actinic keratosis also shows dysplasia in addition to
acantholysis.

Fig. 5.79
Acantholytic acanthoma: low-power view showing hyperkeratosis, parakeratosis,
intraepidermal vesiculation, and multiple foci of acantholysis.
Fig. 5.80
Acantholytic acanthoma: high-power view showing acantholysis and dyskeratosis.
Acantholytic dyskeratotic acanthoma
Clinical features
Acantholytic dyskeratotic acanthoma is a recently described entity with
­clinical features similar to acantholytic acanthoma. There is a predilection for
the trunk of middle-aged to elderly adults with an equal gender distribution.1
They are solitary lesions characteristically measuring less than 1 cm with a
clinical impression of basal cell carcinoma, actinic keratosis or squamous cell
carcinoma in situ.1,2
Pathogenesis and histological features
The pathogenesis of acantholytic dyskeratotic acanthoma is unknown.
Acantholytic dermatoses with dyskeratosis 179
Histological characteristics include regular epidermal acanthosis ­showing
acantholytic dyskeratosis with grains and corps ronds.1,2 Acantholytic
acanthosis is typically confluent, affecting varying levels of the epidermis.
Occasionally, it may be confined to the granular and corneal layers or it
may be nonconfluent and multifocal.1 Cup-shaped endophytic growth and
­follicular involvement are not observed.
Differential diagnosis
Acantholytic dyskeratotic acanthoma differs from acantholytic acanthoma by
the presence of marked dyskeratosis. Focal acantholytic dyskeratosis shows
identical histological features but is an incidental finding rather than a clini-
cally distinct lesion. Warty dyskeratoma is characterized by its cup-shaped
and endophytic growth. Pemphigus, Darier's disease, and Grover's disease
differ in their clinical presentation.
Focal acantholytic dyskeratosis
Clinical features
By definition, this is an incidental histological feature without a clinical
correlate.
Pathogenesis and histological features
Focal acantholytic dyskeratosis is a descriptive histopathological term ­referring
to the finding of Darier-like features within the epidermis overlying or adja-
cent to an otherwise unrelated pathological lesion.1,2 The pathogenesis is not
known. The histological features comprise hyperkeratosis, parakeratosis with
suprabasal cleft formation, acantholysis, and dyskeratosis.3 These changes
may be seen in the overlying or adjacent epithelium in a variety of lesions,
such as basal cell carcinoma, melanocytic nevi, chondrodermatitis nodularis
helicis, malignant melanoma, dermatofibroma, and as part of an epidermal
nevus (Fig. 5.81). Focal acantholytic dyskeratosis has recently been described
in a patient with pityriasis rubra pilaris.4 It is important to ­recognize this as
an incidental finding to avoid misdiagnosis as Darier's disease.
Fig. 5.81
Focal acantholytic dyskeratosis: this example showing the changes of Darier's disease
was an incidental finding adjacent to a completely unrelated lesion. There was no
clinical evidence of Darier's disease.
Chapter
Spongiotic, psoriasiform and
6 pustular dermatoses
See
www.expertconsult.com
for references and
additional material

ECZEMATOUS DERMATITIS  180 Actinic prurigo  194 Inflammatory linear verrucous epidermal
Eosinophilic spongiosis  194 nevus  214
Eczema – general considerations  180 Erythroderma  194
Sulzberger-Garbe syndrome  195
Bazex syndrome  215
Endogenous dermatitis  180
Atopic dermatitis  180 Vein graft site dermatitis  195
Papular acrodermatitis of childhood  195 PUSTULAR DERMATOSES  215
Seborrheic dermatitis  182
Discoid dermatitis (nummular eczema)  183 Pityriasis rosea  196 Pustular drug reactions  215
Hand eczema (dyshidrotic eczema, palmoplantar Juvenile plantar dermatosis  199
eczema, pompholyx)  183 Miliaria  199 Subcorneal pustular dermatosis  215
Autosensitization (Id) reaction  184 Fox-Fordyce disease  200 Toxic erythema of the neonate  217
Transient acantholytic dermatosis with prominent
Exogenous dermatitis  184 eccrine ductal involvement  200 Infantile acropustulosis  217
Contact dermatitis  184
Infective dermatitis  186 Transient neonatal pustular melanosis  218
PSORIASIFORM DERMATOSES  201
Asteatotic dermatitis  186 Eosinophilic pustular folliculitis of
Lichen simplex chronicus  188 Psoriasis  201 infancy  218
Nodular prurigo and prurigo nodule  190
Reiter's syndrome  211
Stasis dermatitis and acroangiodermatitis  192
Pityriasis alba  193 Pityriasis rubra pilaris  211

Eczematous dermatitis
This chapter discusses a number of disorders under the rubric eczematous der-
matitis, also called eczema and spongiotic dermatitis. The term eczema refers to
a group of disorders that share similar clinical and histological features but may
have different etiologies. Some object to a diagnosis of eczema since it does not
reflect a specific disease but is a non-specific term that simply can be used for any
clinical lesion that exhibits spongiosis, which clinically manifests as moist, often
‘bubbly’ papules or plaques superimposed on an erythematous base. The patho-
genesis of some forms is poorly understood. The histopathologist usually can-
not render a more specific diagnosis other than ‘spongiotic dermatitis ­consistent
with eczematous dermatitis’ and precise classification within the differential
diagnosis of spongiotic dermatitis is often not possible. For these reasons, this
class of disorders is discussed as a group. Distinguishing clinical, pathogenetic,
and histological features are presented in the appropriate sections.
Eczema – general considerations
Eczema encompasses a number of disorders with variable etiologies and
­clinical manifestations and is one of the most common complaints of patients
visiting dermatology clinics.
The earliest clinical lesions are erythema and aggregates of tiny pruritic ves-
icles, which rupture readily, exuding clear fluid, and later become encrusted
(Fig. 6.1). More chronic lesions become scaly and thickened (lichenification),
resulting in lichen simplex chronicus (Fig. 6.2). Lichenification occurs if the
skin is continually scratched or rubbed as, for example, in atopic dermatitis.
Therefore, the clinical features of dermatitis depend upon the duration of the
lesions, site(s) involved, and the amount of scratching.
For instance, in pompholyx (acute vesicular dermatitis of the hands and
feet), the fluid is trapped beneath the thickened horny layer as small tense
white blisters resembling rice grains. In other regions where the skin is loosely
attached, as on the eyelids, scrotum, and backs of hands, tissue edema is often
marked.
Eczematous dermatitis has two major etiological classifications:
• endogenous dermatitis, related to major constitutional or hereditary
factors,
• exogenous dermatitis, involving environmental factors.
Endogenous dermatitis
Atopic dermatitis
Clinical features
Although atopic (infantile or flexural) dermatitis may begin at any age, it usu-
ally commences from about the sixth week onwards. It is characterized by a
chronic, relapsing course.1 In the infantile phase lesions are present mainly
on the head, face, neck, napkin area, and extensor aspects of the limbs (Fig.
6.3). As the patient grows older and enters childhood, the eruption shifts to
the flexural aspects of the limbs. Chronic atopic cheilitis may also be evident.1
Pruritus is intense and constant scratching and rubbing leads to lichenifica-
tion and frequent bouts of secondary bacterial infection (Fig. 6.4).2,3 Atopic
eczema is commonly associated with dry skin (xerosis). Vesiculation is uncom-
mon. There is an increased risk of dermatophyte and viral infections.1

Fig. 6.1
Eczema: this is a plaque of discoid eczema. Small vesicles are present at the edge
of the lesion. By courtesy of the Institute of Dermatology, London, UK.
Fig. 6.2
Lichenification: pronounced pebbly lichenification on the dorsum of the hand of a
patient with atopic dermatitis. Bizarre forms, as seen here, are not uncommon in
black children. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
The disease improves during childhood and, in over 50% of cases, clears
completely by the early teens. Approximately 75% of patients with atopic
dermatitis have a family history of atopy and up to 50% have associated
asthma or hay fever.4,5 The condition typically worsens in the winter months.
It is associated with an increased incidence of contact dermatitis, ­particularly
affecting the hand.6 Other features that may be seen include ichthyosis
(50%), nipple eczema, conjunctivitis, keratoconus, bilateral anterior cata-
racts, sweat-associated itching, wool intolerance, perifollicular accentuation,
food intolerance and white dermatographism.5 Infraorbital folds (Dennie-
Morgan folds) are said to be characteristic of atopic dermatitis, particularly
when double.1
Pathogenesis
Atopy is defined as a genetically determined disorder encompassing dermati-
tis, asthma, and hay fever. It is associated with excess immunoglobulin E (IgE)
antibody formation in response to common environmental antigens. A subset
of patients with ‘intrinsic atopic dermatitis’ represents perhaps 10–30% of
Endogenous dermatitis 181
Fig. 6.3
Atopic dermatitis: lesions on the face and trunk are particularly seen in infants and
young children. This child has bilateral involvement of the cheeks. By courtesy of
J. Dayrit, MD, Manila, The Philippines.
Fig. 6.4
Atopic dermatitis: these crusted, exudative and infected lesions with lichenification are
characteristic. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
patients with atopy; this does not appear to be due to a response to an envi-
ronmental antigen.7 Atopic dermatitis is a multifactorial disease. Its pathogen-
esis is complex and, despite recent advances, only incompletely understood.
In addition to a genetic susceptibility, the main elements responsible for the
initiation and maintenance of the disease state include abnormal skin barrier
function, abnormal activity of the innate and adaptive immune systems, as
well as environmental factors and infectious agents.7–15
Since patients with atopic dermatitis often have a personal or family his-
tory of asthma or allergies, a genetic predisposition to the disease has long
been suspected. Recent studies have demonstrated that loss-of-function
­mutations in the FLG gene, encoding the cornified envelope protein pro-
filaggrin, are present in a significant subset of patients with atopic derma-
titis and represent the highest risk factor for development of the disease.16
Together with involucrin and loricrin, filaggrin is a major constituent of the
cornified envelope during terminal keratinocyte differentiation responsible
for intact epidermal barrier function. Disruption of the skin barrier function
appears to be of particular significance in the initiation and early stages of
the disease. Nevertheless, 40% of patients with FLG mutations never develop
atopic ­dermatitis and FLG mutations have been identified in only 14–56%
of patients, indicating that other factors may also play an important role in
the pathogenesis of the disease. In addition to the cornified envelope, epider-
mal barrier function is maintained also by other factors such as proteases
and protease inhibitors as well as direct keratinocyte–keratinocyte interac-
tion. Increased expression of kallikrein-related peptidases has been observed
in the stratum corneum in atopic dermatitis and in one study a 4-bp ­insertion
182 Spongiotic, psoriasiform and pustular dermatoses

into the 3′ untranslated region of KLF7 leading to increased levels of this with atopic dermatitis is colonized with Staphylococcus aureus. In contrast,
protease was identified in patients with atopic dermatitis.13,17,18 However, this S. aureus is found on the skin of only a minority of control subjects.33 Disease
finding has not been substantiated in further studies.13 Linkage has also been severity has been shown to correlate with the presence of toxigenic S. aureus.34
demonstrated to the gene SPINK5, encoding the serine protease inhibitor It is thought that staphylococcal superantigens SEA and SEB (staphylococcal
LEKTI. LEKTI, expressed at the granular cell layer, is an important inhibi- enterotoxins A and B, respectively) activate T cells.34–37 In a study of children
tor of the kallikrein-related peptidases KLK5 and KLK7 and is responsible with atopic dermatitis, there was a correlation of disease severity and pres-
for controlling desquamation. Linkage to SPINK5 is, however, significantly ence of SEA and SEB antibodies.35 Recently, application of SEB was shown to
weaker than to profilaggrin.13 A further mechanism involved in skin barrier be associated with T-cell activation in both normal and atopic patients.38 In
function is the presence of intercellular junctions, and recent data have dem- summary, there is mounting evidence that staphylococcal superantigens play
onstrated reduced expression of the tight junction protein claudin-1 in atopic a role in the symptomatology of atopic dermatitis. Whether superantigens
dermatitis.15 play a key role in the development of disease or simply exacerbate symptoms
Many lines of evidence also implicate an abnormal immune response as in atopic patients requires further study.
pivotal in the pathogenesis of atopy. It is interesting to note that atopy is cured
by bone marrow transplantation in patients with Wiskott-Aldrich syndrome,
an immunological disorder characterized by susceptibility to infection and
Seborrheic dermatitis
thrombocytopenia, in addition to eczematous dermatitis.19 Wiskott-Aldrich
syndrome shows an X-linked recessive pattern of inheritance and is charac- Clinical features
terized by depletion of nodal and circulating T lymphocytes. Contrariwise, Seborrheic dermatitis is a common dermatosis which affects up to 1–3% of
patients without a prior history of atopy may develop atopic disease follow- the population.39–41 There is a male predominance. It presents in infants, with
ing transplantation of bone marrow from an atopic individual.20 a second peak affecting adults.42 There is often a family history of the disease.
Patients with atopic dermatitis have an abnormal immune reaction to a It particularly affects those areas where sebaceous glands are most numerous,
variety of environmental antigens leading to production of IgE antibodies i.e., the scalp, forehead, eyebrows, eyelids, ears, cheeks, presternal and inter-
and a T-cell response.9,21–23 There is evidence that certain subpopulations of scapular areas (Figs 6.5, 6.6).43 Occasionally, the flexural regions are affected
T cells selectively circulate to and perform immune surveillance for the skin (intertrigo). Often the lesions of seborrheic dermatitis are sharply margin-
and lymph nodes that drain cutaneous sites.9,23 This subset of lymphocytes ated, dull red or yellowish, and covered by a greasy scale.43 They are therefore
is characterized by a unique immunophenotype and is defined by expression easily confused with psoriasis.
of cutaneous lymphocyte antigen (CLA). In patients with atopic dermatitis, Dandruff and cradle cap are also sometimes included within the spectrum
antigens such as dust mites and bacteria activate CLA T cells, resulting in the of seborrheic dermatitis.
production of cytokines, which stimulate eosinophils to produce IgE, which, Seborrheic dermatitis is one of the most common dermatoses seen in
in turn, promotes mast cells and basophils to release cytokines and chemot- patients with acquired immunodeficiency syndrome (AIDS). Seborrheic der-
actic factors in what has been termed the intermediate-phase response.8 The matitis has also been associated with stress and neurological disorders includ-
so-called late-phase reaction is characterized by migration of eosinophils, ing Parkinson's disease, syringomyelia, and trigeminal nerve injury.44
lymphocytes, histiocytes, and neutrophils from the circulation into the der-
mis and epidermis. Pathogenesis
Factors released by the various cells present in the dermis certainly play
The precise pathogenesis of this condition is unknown. Surprisingly, and in
a role in the generation of the clinical appearance and induction of pruritus,
spite of the distribution (and the name) of the disease, sebaceous gland activ-
leading to scratching and rubbing. In the early phase, mechanical trauma and
ity and sebum composition appear to be normal.44
skin barrier disruption lead to release of proinflammatory cytokines (IL-1α,
Seborrheic dermatitis is associated with heavy colonization of the skin by
IL-1β, TNF-α, GM-CSF) which activate cellular signaling and induce expres-
the lipophilic yeast Malassezia furfur (Pityrosporum ovale) while more recent
sion of vascular endothelial cell adhesion molecules after receptor binding
data have identified a predominance of Malassezia restricta and Malassezia
to endothelial cells.15,24,25 These steps subsequently initiate transvascular
globosa.41,45–50 Although many workers in the field believe this to be of etio-
migration of inflammatory cells.8,26 Chemokines released by inflammatory
logical importance, an almost equal number are unconvinced. The body of
cells attract a more directed cellular immune response. In particular, CCL27,
evidence favoring a significant relationship relates to the successful treatment
CCL22, and CCL17 are increased in patients with atopic dermatitis and levels
correlate with disease activity.14,25 Disease onset is related to TH2 cytokines
IL-4, IL-13, and IL-31 while disease maintenance (chronic phase) is associate
dwith TH1 cytokines. Other T cells, such as Treg and TH17, are also present
in cutaneous lesions but their precise role is uncertain.14 The demonstration
that squamous cells in patients with atopic dermatitis show increased produc-
tion of GM-CSF, a cytokine thought to play a role in Langerhans/dendritic
cell function, further suggests that a keratinocyte defect may be involved in
the pathogenesis of atopy.27
Another area of interest has been the role of superantigens in the patho-
genesis of atopy as well as other immunologically mediated cutaneous and
noncutaneous disorders.28–33 Although superantigens have been implicated in
the pathogenesis of psoriasis and Kawasaki's disease, in addition to atopic
dermatitis, their precise role in these and other diseases is not well understood
and is controversial.29,30 Further research is necessary to clarify the role of
superantigens in immunologically mediated diseases.
Superantigens are microbiological (viral, bacterial, fungal) toxins that
­stimulate CD4+ T cells. They bind to T-cell receptors and to the class II major
histocompatibility complex (MHC), thus stimulating lymphocyte prolifer-
ation, activation and release of cytokines, as well as T-cell-mediated tissue
damage. They may also stimulate B cell activation. Superantigens are power-
ful mediators of the immune system by virtue of their ability to stimulate a Fig. 6.5
large population of T cells in a non-specific manner. Staphylococcal superan- Seborrheic dermatitis: there is diffuse erythema and scaling of the scalp. By
tigens have, in particular, been an area of research.32 The skin of most patients courtesy of B. Al Mahmoud, MD, Doha, Qatar.
 Endogenous dermatitis 183

Fig. 6.6 Fig. 6.8

Seborrheic dermatitis: note the marked scaling. By courtesy of the Institute of Discoid eczema: the lesion is sharply defined and there is a pronounced scale.
Dermatology, London, UK. By courtesy of the Institute of Dermatology, London, UK.

of seborrheic dermatitis with antifungal therapy.39,40,51 Whether this implies a

causal relationship or merely an exacerbating factor is, however, uncertain.

Discoid dermatitis (nummular eczema)

Clinical features
The presence of single or multiple pruritic, coin-shaped, erythematous
plaques with vesiculation, particularly involving the lower legs, forearms,
and backs of hands (Figs 6.7–6.9) characterize this chronic form of derma-
titis.52 The absence of a raised border clinically distinguishes it from ring-
worm.52 There are two peak ages of onset: it affects young women (15–30
years of age) and middle-aged adults of both sexes. The disease tends to
chronicity.

Fig. 6.9
Discoid eczema: there is
extensive involvement
of the leg. A sharply
demarcated erythematous
and scaly circular lesion
is present just below the
knee. By courtesy of R.A.
Marsden, St George's
Hospital, London, UK.

Pathogenesis
The pathogenesis is poorly understood. A participatory role for organisms in
the pathogenesis has been suggested but not been widely accepted.53 Discoid
dermatitis may follow irritants such as soap, acids or alkalis (Fig. 6.10).52
Sometimes it may be a manifestation of atopy and, occasionally, it develops
as a consequence of nickel, chromate or cobalt allergy.54,55 Generalized dis-
ease has also been documented in the setting of interferon alpha-2b plus riba-
virin treatment for hepatitis C infection.56
Fig. 6.7
Discoid eczema:
circumscribed,
Hand eczema (dyshidrotic eczema,
erythematous lesions palmoplantar eczema, pompholyx)
on the forearm, a
characteristic site. By
courtesy of the Institute
Clinical features
of Dermatology, London, Hand eczema is characterized by a recurrent pruritic vesicular eruption of
UK. the palms, soles or digits. Because of the increased thickness of the keratin
184 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.10
Discoid eczema: lesions localized to the fingers most often represent a contact
irritant reaction. By courtesy of R.A. Marsden, St George's Hospital, London, UK.
Fig. 6.11
Hand eczema: tense yellow vesicles are present. By courtesy of B. Al Mahmoud, MD,
Doha, Qatar.
layer at these sites, the vesicles appear as small pale papules before rupturing
(Figs 6.11, 6.12). Occasionally, frank bullae can form. With the passage of
time, the affected parts may show scaling and cracking. The nails sometimes
become dystrophic, with discoloration and transverse ridging.57 In the major-
ity of cases the cause is unknown, although heat or psychological stress may
precipitate an attack.57 In some patients there is a personal or family history
of atopy or coexisting tinea pedis. Rubber, latex, chromium, cobalt or nickel
sensitivity may be the trigger.58–62 The condition can be exacerbated by heat
and, rarely, it is photoinduced.63
Pompholyx is often associated with hyperhidrosis.58 Females are affected
slightly more often than males and patients are predominantly in the second
to fifth decades.59 A familial autosomal dominant form has been reported
where the candidate gene has been mapped to chromosome 18q22.1-
18q22.3.64
Pathogenesis
The pathogenesis is obscure. It has been noted that serum IgE levels are often
raised.58
Fig. 6.12
Hand eczema: more chronic example showing marked scaling. From the collection
of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Autosensitization (Id) reaction
Clinical features
On occasion, patients will develop generalized spongiotic dermatitis in
response to a dermatosis or infection at a distant site. The eczematous derma-
titis resolves if the underlying infection or specific dermatosis is successfully
treated. This phenomenon has also been designated an autoeczematization
or Id reaction. The lesions that characterize the Id reaction may be a local-
ized pompholyx-like eczematous dermatitis of the hands and feet or scattered
papules on the trunk and limbs.65–69 Disorders that may be associated with
the Id reaction include fungal infection (e.g., dermatophyte infection), scabies
infestation, molluscum contagiosum, tick bite, pediculosis capitis, and bacte-
rial and mycobacterial infections.65–69 A generalized nummular dermatitis has
been reported in association with localized dental infection.70
Pathogenesis
The pathogenesis of the Id reaction is poorly understood but some data sug-
gest that an abnormal T-cell-mediated immune response directed against skin
antigens is responsible for this curious disorder.71
Exogenous dermatitis
Contact dermatitis
This form of dermatitis is due to external agents and is divided into two vari-
ants: allergic contact and irritant contact.
Allergic contact dermatitis
Allergic contact dermatitis is an idiosyncratic cell-mediated immunologi-
cal reaction to an environmental allergen, which may be present in very
low concentration. Common examples seen in clinical practice include
sensitivity to nickel (found in items such as jewelry, buttons, watches,
and suspenders), constituents of synthetic rubber (e.g., thiuram in rubber
gloves), primula, poison ivy, topical medicaments (e.g., neomycin, anti-
histamines, local anesthetics), and chromates found in cement and leather
(Figs 6.13–6.15).72–82
Dinitrochlorobenzene (DNCB) is a potent contact sensitizer and this is
used as a test of cell-mediated immunity.83,84
A growing understanding of allergic contact dermatitis has emerged over
the last decade with the preponderance of evidence pointing to a T-cell-
mediated hypersensitivity reaction.3,85–88 It is thought that antigens causing
allergic contact dermatitis are often unstable (haptens) and need to bind to

Fig. 6.13
Contact dermatitis: this early erythematous predominantly macular eruption
developed as a reaction to fabric softener. By courtesy of J. Dayrit, MD, Manila,
The Philippines.
Fig. 6.14
Contact dermatitis: bilateral involvement in a patient using a watch on the right
wrist and a leather bracelet on the left wrist. From the collection of the late N.P.
Smith, MD, the Institute of Dermatology, London, UK.
epidermal host proteins.3,85 These hapten–protein interactions are formed via
covalent binding of electrophilic residues of the chemical with amino acids,
especially cysteine.89–91 In contrast, metal ions, such as nickel, are thought
to form noncovalent protein–metal chelate complexes.89 In the sensitization/
initiation phase of the disease, hapten-specific T cells are generated in lymph
nodes after the initial contact of the skin with a potent hapten.91 Langerhans
cells in skin and dendritic cells in lymph nodes process antigen and stimulate
appropriate naive CLA T cells. CLA-positive T cells are a subset of T cells
that express a skin-selective homing receptor and perform immune surveil-
lance for the skin and lymph nodes that drain cutaneous sites.92 CLA-positive
T cells proliferate when stimulated by the appropriate antigen or antigen–
protein complex. The number of CLA-positive memory T cells increases with
repeated exposures to its antigen.3,85 When the patient is exposed to the anti-
gen, the elicitation phase, the CLA-positive T cells are activated and release
cytokines which lead to the immune reaction responsible for the clinical and
histological features associated with allergic contact dermatitis.87 CD8+ T cells
appear to be the main effector cell in the elicitation phase.89 Keratinocytes
are also thought to play a role through the release of cytokines after hapten
exposure and binding.88
Exogenous dermatitis 185
Fig. 6.15
Contact dermatitis: a
severe reaction to poison
ivy. From the collection
of the late N.P. Smith,
MD, the Institute of
Dermatology, London,
UK.
Occasionally, exposure to strong haptens may result in the development
of allergic contact dermatitis in previously unsensitized individuals (primary
allergic contact dermatitis).89
Ingested or inhaled allergens in a person who has been previously sen-
sitized by cutaneous absorption may result in a clinical picture similar to
allergic contact dermatitis (e.g., ingested nickel, chromium or cobalt may
result in the appearances of hand eczema).93 Much less commonly, systemic
allergic contact dermatitis may be histologically associated with an erythema
­multiforme-like eruption, vasculitis or urticarial morphology.93 This is thought
to result from systemic exposure of a hapten via hematogenous transport to
the skin.94 It may occur with or without prior sensitization, and a large num-
ber of drugs have been implicated in the pathogenesis.94
Irritant contact dermatitis
Irritant contact dermatitis, which is much more common than allergic con-
tact dermatitis, follows exposure to physical or chemical substances capable
of direct damage to the skin. Mechanisms of damage are variable and include
keratin denaturation, removal of surface lipids and water-holding substances,
damage to cell membranes, and/or direct cytotoxic effects.95 Acute irritant
dermatitis usually results from a relatively short single exposure to a potent
irritant, such as strong acid or alkali, whereas chronic cumulative insult or
‘wear and tear’ dermatitis is due to more prolonged contact with one or more
weaker irritants, for example, soap and water, detergents or industrial oil and
plants (Fig. 6.16).96–100
Most forms of occupational dermatitis of the hands, including ‘house-
wives’ and ‘wedding ring’ dermatitis are of the irritant contact type. A diag-
nosis of contact dermatitis is made from the history and distribution of
lesions and, in the case of allergic dermatitis, is confirmed by patch testing
to the suspected allergen. Although both forms of contact dermatitis tend to
be confined to exposed areas, the reaction may eventually spread to involve
nonexposed sites and can persist even when the causative agent is removed
from the environment.
Similar to atopic dermatitis, loss-of-function mutation in the FLG gene,
encoding filaggrin, may confer an increased susceptibility to chronic irritant
contact dermatitis evoking an underlying skin barrier defect in the pathogen-
esis of the disease.101
186 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.16
Contact dermatitis: there is a superimposed pustular element due to an infection
in this patient with a contact reaction to a domestic antiseptic. By courtesy of B. Al
Mahmoud, MD, Doha, Qatar.
Infective dermatitis
Infective dermatitis is a severe chronic and recurrent eczematous dermati-
tis showing pronounced exudation and crusting and presenting in children
with human T-cell lymphotropic virus type 1 (HTLV-1) infection.102–105 Adult
onset is exceptional.106,107 The disease has a predilection for the scalp, flex-
ures, the ears and feet, and sometimes around wounds and ulcers (Fig. 6.17),
and is frequently associated with Staphylococcus aureus and beta-hemolytic
Streptococcus infection of the skin and nasal vestibule. It occurs in regions
where HTLV-1 is endemic. It has frequently been reported in Jamaica, while
presentation in Japan appears relatively rare.108 Development of the disease
may be associated with a defective immune system and may be a risk factor
for the development of other HTLV-1-related diseases such as adult T-cell leu-
kemia and tropical spastic paraparesis.109,110
Asteatotic dermatitis
Commonly seen in the elderly, particularly in winter and in those with minor
degrees of ichthyosis, asteatotic dermatitis (eczema craquelé) may be precipi-
tated by excessive washing, exposure to detergents, cold winds or low humid-
Fig. 6.17
Infective dermatitis: lesions affecting the foot web spaces are often due to
staphylococci or streptococci and are associated with excess sweating. By
courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 6.18
Asteatotic dermatitis: these typical appearances are the result of scaling and
fissuring. By courtesy of B. Al Mahmoud, MD, Doha, Qatar.
ity, all of which tend to dry the skin.111 The affected regions are inflamed and
criss-crossed by scaly lines and superficial fissures (Fig. 6.18). Asteatotic der-
matitis may be associated with internal malignancy, including lymphoprolif-
erative disorders and solid tumors.112–115
Pathogenesis and histological features
The histopathological features of spongiotic dermatitis include both dermal
and epidermal changes. Their relative proportions vary to some extent with
the subtype, but perhaps more importantly, with the stage of evolution of the
disease. It is essential not to consider the changes of spongiotic dermatitis as
static: different features are seen at different stages.116–118 Attempting to dis-
tinguish the various clinical subtypes based on histological features alone is
generally futile. Instead, once the disorder has been recognized as spongiotic
in nature, clinical examination is a much more satisfactory method of deter-
mining the particular variant.
The histological hallmark of spongiotic dermatitis is the presence of inter-
cellular edema or spongiosis (L., Gr. spongia, sponge). Slight degrees of intra-
cellular edema may also be evident but may easily be overlooked. In the early
stages of development, spongiosis results in widening of the intercellular
spaces, rendering the intercellular bridges conspicuous (Fig. 6.19). Further
accumulation of fluid leads to the eventual development of an intraepidermal
vesicle. A common finding in association with the intercellular edema is lym-
phocytic infiltration of the epidermis (exocytosis). In severe contact irritant
dermatitis, the epidermis may be infiltrated by large numbers of neutrophil
polymorphs in association with necrotic keratinocytes.119 In addition, such
reactions may be accompanied by dermoepidermal separation resulting in a
vesicle or blister. The lesions very often become traumatized and may show
marked crusting.
Spongiotic dermatitides not uncommonly become infected with bacterial
or fungal organisms. Superimposed infection may dramatically alter the his-
tological picture by causing marked acute inflammation with subepidermal,
intraepidermal, and subcorneal pustules. Such changes may dominate the his-
tological picture and obscure the underlying spongiotic dermatitis. Use of
stains for organisms – Gram, periodic acid-Schiff (PAS) – or cultures are nec-
essary to evaluate for infection.
Concomitant with these changes are varying degrees of epithelial prolif-
eration, ranging from mild acanthosis in early acute dermatitis to marked
psoriasiform epidermal hyperplasia in chronic variants. Parakeratosis is
frequently seen overlying spongiotic foci, while hyperkeratosis is a usual
accompaniment of chronic spongiotic dermatitis that has been scratched or
rubbed (lichenification).
The dermis is often congested and edema is usually marked in active
lesions. The vessels of the superficial vascular plexus are surrounded by a
 Exogenous dermatitis 187

Fig. 6.19
Dermatitis: the earliest visible manifestation of intercellular edema is widening of
the intercellular spaces with accentuation of the intercellular bridges.
Fig. 6.21
Acute dermatitis:
the vesicle contains
mixed inflammatory cell infiltrate composed of lymphocytes, histiocytes, and lymphocytes and
occasional eosinophils or neutrophils. The degree and composition of der- occasional eosinophils.
mal inflammation is highly variable. Eosinophils may be numerous in allergic
contact dermatitis.119
Traditionally, spongiotic dermatitis is subclassified histologically into
acute, subacute, and chronic variants:
• In acute lesions, vesiculation and blister formation may be seen (Figs
6.20–6.22).
• Acanthosis and spongiosis, often with vesiculation, also characterize
subacute spongiotic dermatitis (Fig. 6.23).
• In chronic spongiotic dermatitis, although spongiosis is evident, it may be
subtle, and vesicles are uncommon. Epithelial acanthosis is marked and
often shows a psoriasiform pattern (Fig. 6.24).
Systemic contact dermatitis may be associated with the features of vascu-
litis or erythema multiforme.120 As with other forms of spongiotic dermatitis
the histological appearances can be divided into acute, subacute, and chronic
forms. Spongiosis is more conspicuous in the acute phase although it is never
marked. In contrast, the epidermal hyperplasia becomes more conspicuous
and psoriasiform towards the chronic end of the spectrum.

Fig. 6.22
Acute dermatitis: in contact reactions, Langerhans cell-rich vesicles are often
present, as shown in this picture. These should not be mistaken for the Pautrier
microabscesses of mycosis fungoides.

The features of seborrheic dermatitis are often non-specific and subtle. It

is characterized by hyperkeratosis and parakeratosis, the latter particularly
related to hair follicles and typically associated with neutrophil exocytosis
(Figs 6.25, 6.26). Yeasts may sometimes be found in the stratum corneum
particularly if PAS stained sections are examined. Epidermal acanthosis with
thickened rete ridges is present and often marked in chronic lesions. It is,
however, somewhat irregular in contrast to the uniform hyperplasia charac-
teristic of psoriasis. Variable spongiosis with lymphocyte exocytosis is com-
mon. The dermis may be edematous and mild vascular dilatation is usually
seen. A mixed inflammatory cell infiltrate consisting of lymphocytes, histio-
Fig. 6.20 cytes, and small numbers of eosinophils surrounds the superficial vascular
Acute dermatitis: fluid-filled vesicle due to intense spongiosis. plexus.
188 Spongiotic, psoriasiform and pustular dermatoses

Fig. 6.23
Subacute dermatitis showing patchy parakeratosis, crusting, marked acanthosis Fig. 6.25
with considerable elongation (and fusion) of the epidermal ridges, and focal Seborrheic dermatitis:
spongiotic vesiculation. The dermis contains an intense lymphocytic infiltrate. in this field, there is
perifollicular psoriasiform
hyperplasia. Parakeratosis
is present on either side
of the follicular ostium.

Fig. 6.24
Chronic dermatitis (lichenification): there is hyperkeratosis with hypergranulosis
and psoriasiform hyperplasia. The papillary dermis is fibrosed and there is a patchy
chronic inflammatory cell infiltrate.

Differential diagnosis
Although spongiosis is a characteristic feature of spongiotic dermatitis, it
is also encountered in many other inflammatory dermatoses (Table 6.1),
particularly superficial dermatophytoses. A diagnosis of spongiotic der-
matitis should never be made until a stain for fungus (e.g., PAS reaction)
has been performed to exclude this possibility. This is especially impor-
tant since the common treatment of spongiotic dermatitides – topical
corticosteroids – would exacerbate a fungal infection (tinea incognito)
(Figs 6.27–6.29).
Lichen simplex chronicus
Clinical features
The term lichen simplex chronicus (circumscribed neurodermatitis) refers to
the development of localized areas of thickened scaly skin complicating pro-
longed and severe scratching in a patient with no underlying dermatological
Fig. 6.26
Seborrheic dermatitis:
there is parakeratosis, and
occasional neutrophils are
present.
condition (Fig. 6.30).1 Lichenification is an identical process in which an
underlying intensely pruritic dermatosis such as atopic eczema is present.2
Dermatophyte infections, stasis dermatitis, and chronic allergic contact
dermatitis may also predispose to lichenification. Picker's nodules and nodu-
lar prurigo are related conditions (see below).3
Patients present with profound pruritus and localized scaly plaques with
accentuated skin markings described as resembling tree bark. There is a pre-
dilection for females, and young to middle-aged adults are predominantly
 Exogenous dermatitis 189

Table 6.1
Conditions featuring spongiosis

• Pityriasis rosea
• Superficial fungal infections
• Herpes gestationis (early lesions)
• Polymorphic eruption of pregnancy
• Erythema multiforme
• Miliaria rubra
• Erythema annulare centrifugum
• Guttate parapsoriasis
• Acral papular eruption of childhood
• Eczema
• Lichen striatus
• Insect-bite reaction
• Prurigo nodularis

Fig. 6.29
Spongiotic superficial dermatophyte infection: numerous fungal hyphae are seen in
this PAS-stained section.

Fig. 6.27
Spongiotic superficial dermatophyte infection: there is marked subcorneal
vesiculation.

Fig. 6.30
Lichen simplex chronicus:
thick, scaly erythematous
plaques are present on
the shins, a commonly
affected site. By courtesy
of R.A. Marsden, MD,
St George's Hospital,
London, UK.

Histological features and pathogenesis

Fig. 6.28
Spongiotic superficial dermatophyte infection: higher-power view.
affected. Accessible skin is particularly affected and the nape and sides of the
neck, the thighs, the lower legs and ankles, vulva, and scrotum are sites gen-
erally involved.2
Pebbly lichenification refers to a distinct variant in which lichenoid
papules follow intense scratching in patients with inflammatory dermatoses
such as atopic eczema.2
Although the etiology and pathogenesis of lichen simplex chronicus remains
elusive, psychological factors may play an important role.4,5 Recent data fur-
ther suggest that an underlying neuropathy may be of importance in at least
a subset of patients.6
Histologically, lichen simplex chronicus is characterized by marked hyperk-
eratosis, sometimes with small foci of parakeratosis, and a usually prominent
granular cell layer (Fig. 6.31).7 The epidermal ridges are elongated and irregu-
larly thickened. Mild spongiosis is variably present depending upon the cause.
A perivascular and sometimes interstitial inflammatory cell infiltrate consisting
of lymphocytes, histiocytes, and small numbers of eosinophils is present in the
superficial dermis. Enlarged, angulated myofibroblasts are sometimes evident
and, as in many other chronic skin conditions, scattered small, multinucleated
cells, so-called Montgomery giant cells, are identified. Papillary dermal fibrosis is
190 Spongiotic, psoriasiform and pustular dermatoses

Fig. 6.33
Fig. 6.31 Nodular prurigo: typical
Lichen simplex chronicus: there is hyperkeratosis, patchy parakeratosis, and globular nodules; the
elongation of the rete ridges. intervening skin appears
normal. From the
collection of the late N.P.
Smith, MD, the Institute
of Dermatology, London,
UK.

Fig. 6.32
Lichen simplex chronicus:
there is hypergranulosis.
Note the vertically
orientated collagen fibers,
a characteristic feature. Fig. 6.34
Nodular prurigo: there are scattered, excoriated discrete nodules on the buttocks
and thighs. Note the postinflammatory hyperpigmentation. By courtesy of R.A.
a characteristic feature and in some cases nerve hyperplasia is seen (Fig. 6.32).3 Marsden, MD, St George's Hospital, London, UK.
In our experience, however, the latter feature is distinctively uncommon.

Nodular prurigo (prurigo nodularis) and
prurigo nodule (picker's nodule)
Clinical features
Nodular prurigo is characterized by the development of chronic, intensely
pruritic, lichenified, and excoriated nodules.1,2 It occurs over a wide age
range, from 5 to 75 years, with a mean of 40 years. Rarely, children are
affected.3 Disease duration ranges from 6 months to 33 years, with a mean
of 9 years. Nodular prurigo occurs equally in men and women. It shows
significant overlap with lichen simplex chronicus, although this is not uni-
formly accepted.1,2
Individual lesions are often described as globular with a warty and excori-
ated surface and may measure up to 2 cm in diameter (Fig. 6.33).2 They are
often grouped, symmetrical, and occur predominantly on extensor aspects
of the (distal) limbs (Figs 6.34, 6.35).1 The trunk may also be affected.2
Occasional disseminated cases have been described.2 The palms and soles are
typically uninvolved.2 The intervening skin usually appears normal. Similar-
looking lesions are sometimes seen in patients with eczema (see below).
The majority of patients with nodular prurigo are perfectly well and inves-
tigations are unhelpful; however, occasionally nodular prurigo is found in
patients with gluten enteropathy.4 Psychosocial disorders have been reported
in a high proportion of patients.5 In some cases the eruption occurs after an
insect bite, but subsequent lesions develop spontaneously.5
 Exogenous dermatitis 191

Fig. 6.35
Nodular prurigo: in this Fig. 6.36
patient there is very Nodular prurigo: there is hyperkeratosis, hypergranulosis, and
severe involvement of pseudoepitheliomatous hyperplasia. The dermis is scarred and there is a
the shins and dorsal perivascular and interstitial chronic inflammatory cell infiltrate.
surface of the feet. By
courtesy of the Institute
of Dermatology, London,
UK.

The pruritus is episodic and may be precipitated or aggravated by heat and

anxiety.5 Significant laboratory abnormalities may include anemia, eosino-
philia, and raised serum IgE levels.5
Nodular prurigo (eczema) is defined as lesions of nodular prurigo arising
on a background of overt eczema.5 While this distinction is of academic inter-
est it has no clinical or prognostic importance.
A prurigo nodule is a solitary variant that develops as a consequence of
localized scratching and picking.
On occasion, nodular prurigo is accompanied by the features of bullous
pemphigoid (pemphigoid nodularis).6

Pathogenesis and histological features

Classical nodular prurigo, which is focal and characterized by hyperplasia,
has recently been related particularly to follicular epithelium.2,7 In the epider-
mis this manifests as orthohyperkeratosis, hypergranulosis and acanthosis, Fig. 6.37
sometimes to the degree of pseudoepitheliomatous hyperplasia (Figs 6.36, Nodular prurigo: higher-power view.
6.37).8 Superficial mild spongiosis and focal parakeratosis is occasionally
present and the features may resemble chronic eczema.5 Subepidermal fibrin
deposition is sometimes a feature.9
In the dermis there is vascular hyperplasia, with dilated vessels in both the
papillary and reticular dermis. New vessel formation is apparent and there
is a surrounding perivascular mild inflammatory cell infiltrate, consisting
mainly of lymphocytes and some histiocytes, plasma cells, occasional eosino-
phils and scattered, superficial, small multinucleated cells (Montgomery giant
cells) (Fig. 6.38).8 Mast cells are present in normal numbers.1 The infiltrate
has been described as having an inverted triangular configuration extending
from the superficial dermis.2 This has not been the present author's experi-
ence. Occasionally, the dermal features include lymphoid follicles with germi-
nal center formation, thereby resembling a persistent insect bite reaction.5 An
additional finding is the presence of fibrosis of the papillary dermis.8
With light microscopy the nerves may appear normal, increased in number
or occasionally hyperplastic (Fig. 6.39).1,5 Special neural stains or S-100 pro-
tein immunocytochemistry may accentuate mild proliferative changes. Nerve
changes, however, do not appear to be essential for the diagnosis.1 Studies
have shown no evidence of true neuroma formation and it is thought by some
authors that the neural changes are secondary to chronic trauma and scratch-
ing of the intensely pruritic nodules.1,5,7 This intense pruritus may have been Fig. 6.38
partly responsible for the large amount of attention given to ­neural changes in Nodular prurigo: note the conspicuous eosinophils.
192 Spongiotic, psoriasiform and pustular dermatoses

Acroangiodermatitis (pseudo-Kaposi's sarcoma, congenital dysplastic

angiopathy, arteriovenous malformation with angiodermatitis) refers to the
clinical manifestation of purple macules, nodules, and sometimes verrucous
plaques typically developing on the dorsal aspects of the feet and toes in
patients with severe and longstanding venous insufficiency.7 Varicose veins
are often present. The condition is of particular importance in that it may
be clinically mistaken for Kaposi's sarcoma.8 Identical lesions have been
described complicating Klippel-Trénaunay, Stewart-Bluefarb, and Prader-
Willi syndromes, surgical arteriovenous fistulae as seen for example in hemo-
dialysis patients, complicating poorly fitting suction socket prostheses on
amputation stumps and on paralysed limbs.9–22

Pathogenesis and histological features

The pathogenesis of stasis dermatitis and acroangiodermatitis is unknown
although it may be related to the tissue anoxia that typically results from
increased venous pressure or circulatory disturbance.13
Stasis dermatitis shows, in addition to the epithelial changes of spongiotic
dermatitis, marked hemosiderin deposition in the dermis accompanied by fibro-
sis and a characteristic lobular pattern of superficial and/or deep dermal neo-
Fig. 6.39
Nodular prurigo: in our experience, nerve hyperplasia is an uncommon observation.
vascularization (Figs 6.41–6.45). Inflammatory cells – including lymphocytes,
histiocytes, and variable numbers of plasma cells – are often numerous, and
erythrocyte extravasation is usually prominent.
nodular prurigo in the past. Very rarely, however, hyperplastic nerve trunks are
associated with Schwann cell proliferation, giving rise to small neuromata.10
Electron microscopy has shown vacuolation of Schwann cell cytoplasm,
together with loss of definition of internal structure of the mitochondria.5,10,11

Stasis dermatitis and acroangiodermatitis

Clinical features
Stasis (varicose) dermatitis usually involves the medial aspect of the lower leg
or ankle, but may be more widespread, and develops as a complication of
impaired venous return from the lower limbs.1 Superficial varicose veins are a
frequent predisposing factor. The lesion appears as an itchy, scaly, often swol-
len and hyperpigmented area. Such changes are often seen around chronic
stasis ulcers (Fig. 6.40). Malignant tumors (both squamous and basal cell car-
cinomas) may occasionally develop at the edge of these ulcers.2–5 Furthermore,
in the early stages of the disease, the lesion may present singly and can be clini-
cally mistaken for a cutaneous malignancy, i.e., squamous cell carcinoma.6

Fig. 6.41
Stasis dermatitis: there is hyperkeratosis, focal parakeratosis and marked epidermal
hyperplasia. The dermis is chronically inflamed and scarred.

Fig. 6.40
Stasis dermatitis: there is
vesiculation, exudation,
and crusting on the lower
leg around a stasis ulcer,
which was precipitated
by allergy to the antibiotic
dressing. By courtesy
of R.A. Marsden, MD,
St George's Hospital, Fig. 6.42
London, UK. Stasis dermatitis: note the increased vascularity.
 Exogenous dermatitis 193

Fig. 6.43 Fig. 6.46

Stasis dermatitis: there is marked mural fibrin deposition. The features often overlap Acroangiodermatitis showing lobular capillary proliferation, red cell extravasation,
with atrophie blanche. and a chronic inflammatory cell infiltrate.

In acroangiodermatitis, the vascular proliferation is often so exuberant that

it may mimic a vascular neoplasm, most often Kaposi's sarcoma (Fig. 6.46).23

Differential diagnosis
Acroangiodermatitis differs from Kaposi's sarcoma by the absence of a spin-
dle cell population or irregular lymphatic-like vascular channels dissecting
the dermal collagen. In addition, the promontory sign (tumor vessels partially
surrounding normal vessels and the adnexae) is absent. In acroangiodermati-
tis, the hallmark is the presence of lobular capillary proliferation.
In cases where the diagnosis is in doubt, CD34 immunocytochemistry is of
value. The spindle cells in Kaposi's sarcoma express this antigen whereas those
in acroangiodermatitis do not.24 Smooth muscle actin emphasizes the pericytes in
acroangiodermatitis and a reticulin stain can be used to highlight the lobularity.

Pityriasis alba
Clinical features
Fig. 6.44
Pityriasis alba is a very common form of chronic dermatitis usually affecting
Stasis dermatitis: in this view, there is marked new blood vessel formation and
abundant hemosiderin is present. preadolescent children of either sex.1 In the United States, the prevalence is
1.9% in a healthy population.2 The lesions are seen on the face in particu-
lar, but the shoulders, upper extremities, and legs may also be involved (Figs
6.47–6.49).1,3 Early lesions present as slightly scaly, mildly pruritic, round to
oval pink plaques measuring from 0.5 to 5.0 cm or more in diameter, which
later appear as scaly hypopigmented lesions.1 The races are equally affected
although lesions are more prominent in dark-skinned persons.1,4 The condi-
tion usually resolves spontaneously after months or years.

Pathogenesis and histological features

The etiology is unknown although some authors believe it may be a form
of atopic dermatitis since many patients also have features of classic
atopic dermatitis or a family history of atopy.5 However, some patients
with pityriasis alba lack typical features of atopy. An association with
xerosis has also been postulated and the condition has also been linked to
copper deficiency.6,7
The histological features of the early stage include follicular dilatation and
plugging with infundibular spongiosis, parafollicular parakeratosis, and seba-
ceous gland atrophy accompanied by a superficial perivascular lymphocytic
infiltrate and edema.8 In the later stages, the changes are those of chronic
non-specific dermatitis including hyperkeratosis, parakeratosis sometimes
Fig. 6.45 accompanied by mild acanthosis, and slight spongiosis.8–10 There is variable
Stasis dermatitis: the hemosiderin can be highlighted with a Prussian blue reaction hypo- and hyperpigmentation of the basal keratinocytes with reduced or nor-
for iron. mal numbers of melanocytes and pigmentary incontinence.8,11
194 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.47
Pityriasis alba: there are
multiple hypopigmented,
scaly patches on the
arms. Lesions are more
obvious in the colored
races. By courtesy of C.
Furlonge, MD, Port of
Spain, Trinidad.
Fig. 6.48
Pityriasis alba: there is
striking leukoderma on
the cheek and chin, which
are commonly affected
sites. By courtesy of R.A.
Marsden, MD, St George's
Hospital, London, UK.
Actinic prurigo
Clinical features
Actinic prurigo is a rare familial photodermatitis with a female predilection
and disease onset in childhood (4–5 years of age) although disease manifesta-
tion has also been documented in adulthood.1–4 The disease is most commonly
observed in Native Americans as well as Latin Americans. Caucasians, Asians,
and Australians are less frequently affected.1,2,4,5 The clinical presentation is varied.
Patients typically present with intense pruritus and an erythematous papular
Fig. 6.49
Pityriasis alba: lesions in white-skinned patients are much more subtle. By courtesy
of the Institute of Dermatology, London, UK.
eruption. Lesions may form nodules and plaques and there may be evidence of
lichenification and excoriation due to repeated scratching and postinflamma-
tory scarring.1–3 Sun-exposed areas of the face, neck, upper chest, forearms, and
hands are predominantly involved. The lips and conjunctiva are also frequently
affected.1,3 Associated cheilitis particularly affecting the lower lip is characterized
by edema, fissuring, ulceration, and chronic dry scaling and may be the sole mani-
festation.6 Conjunctival involvement results in photophobia, hyperemia, and for-
mation of a pseudopterygium.1,3 The disease course of actinic prurigo is chronic
with significant adverse impact on the quality of life.7 Remission may be observed
in the winter months in patients living in geographic areas with significant varia-
tion of sunlight throughout the year.1,3 In a subset of patients with childhood onset,
symptoms will improve in adulthood with occasional spontaneous remission.3
Pathogenesis and histological features
Using phototesting, the majority of patients show increased sensitivity to a
broad spectrum of UVA as well as UVB radiation.1,2 The disease has strong
associations with HLA haplotypes, in particular DRB1*0407 (60–70% of
patients) and DRB1*0401 (20% of patients).3
The histological features are often nondiagnostic and areas of excoriation
are frequently biopsied. In late lesions changes include regular epidermal acan-
thosis with overlying hyperparakeratosis and some degree of hypergranulosis.
There is an associated marked superficial to mid-dermal perivascular chronic
inflammatory cell infiltrate composed predominantly of lymphocytes. In the pap-
illary dermis focal fibrosis may be seen and there is often pigment incontinence.
Lymphoid follicles can be present especially in areas of ulceration, particu-
larly in lesions on the lip. Eosinophils are frequently noted. Biopsies from the
lip show similar epidermal features in addition to spongiosis and basal cell
vacuolar change. Dermal edema and prominent telangiectatic vessels are fur-
ther characteristic features. An associated lymphoplasmacytic infiltrate may
be bandlike or show lymphoid follicles with germinal centers. The latter is
mainly seen in conjunctional biopsies.
Eosinophilic spongiosis
Eosinophilic spongiosis is the histopathological term used to describe spon-
giosis in which eosinophils are the predominant cell type.1–5 Eosinophilic
spongiosis is a non-specific finding with which a considerable number of der-
matoses may be associated. Table 6.2 lists dermatoses in which eosinophilic
spongiosis is commonly encountered. Detailed discussion of each of these dis-
orders is found in the appropriate chapters.
Erythroderma
Spongiotic dermatitis is one of the causes of erythroderma. Sometimes incor-
rectly called exfoliative dermatitis, erythroderma is applicable only when the

Table 6.2
Diseases featuring eosinophilic spongiosis
• Incontinentia pigmenti
• Pemphigus
• Bullous pemphigoid
• Linear IgA disease
• Pemphigoid (herpes) gestationis and polymorphic eruption of
pregnancy
• Insect-bite reactions
• Atopic eczema
• Contact dermatitis
• Grover's disease
• Drug reactions
Fig. 6.50
Erythroderma: the entire skin surface is erythematous and slightly scaly. The
appearances are relatively non-specific and give no indication of the cause. By
courtesy of the Institute of Dermatology, London, UK.
entire skin surface is inflamed, erythematous, and scaly (Fig. 6.50).1–5 The clini-
cal features are remarkably consistent irrespective of the underlying disease and
therefore often pose a diagnostic challenge. Pruritus is variable, being particu-
larly severe in the Sézary syndrome and in mycosis fungoides. Lymphadenopathy
is usually present (dermatopathic lymphadenopathy). Prolonged erythroderma,
particularly in the elderly, may be complicated by cardiac failure, peripheral
circulatory collapse, hypothermia, and infection. Patients with erythroderma
are frequently biopsied since the clinical examination findings are often non-
specific. Diagnosis without clinical information is often not possible.1 Table
6.3 lists the various causes of erythroderma. The specific diseases that cause
­erythroderma are discussed in detail in the appropriate chapters.
Sulzberger-Garbe syndrome
Clinical features
Sulzberger-Garbe syndrome (distinctive exudative discoid and lichenoid
chronic dermatosis) was originally described as a widespread pruritic eruption
associated with discoid lesions in middle-aged Jewish males.1–3 Involvement
of the penis was said to be characteristic. Transformation from eczematous
Exogenous dermatitis 195
Table 6.3
Causes of erythroderma
• Dermatitis
• Lymphoma (mycosis fungoides, T-cell leukemia, Hodgkin's lymphoma)
• Drugs (gold, penicillin, etc.)
• Psoriasis
• Pityriasis rubra pilaris
• Ichthyosiform erythroderma
• Scabies
• Lichen planus
to lichenoid lesions and vice versa is also thought to be a typical feature. The
lesions are chronic, lasting from months to years, but eventually resolving.
Pathogenesis and histological features
The existence of Sulzberger-Garbe syndrome as a distinctive entity is contro-
versial. Some authors consider patients classified under this designation as
having nummular dermatitis.3
Biopsy of exudative lesions shows a non-specific spongiotic dermatitis.
Biopsy of lichenoid lesions is characterized by a bandlike lymphocytic infil-
trate. Variable numbers of eosinophils may be present.
Vein graft site dermatitis
Occasionally, patients undergoing coronary artery bypass develop an eczema-
tous dermatitis in the region of the scar from the saphenous vein donor site.1,
2 The pathogenesis is unclear. Since patients often have objective evidence of
neuropathy, some authors believe that the neuralgia may play a pathogenic
role.1 It is also possible that stasis changes play a role in this disorder.
Biopsy shows non-specific spongiotic dermatitis.
Papular acrodermatitis of childhood
Clinical features
Papular acrodermatitis of childhood (Gianotti-Crosti syndrome, infantile
papular acrodermatitis) is a rare disease representing a cutaneous response to
a number of viral infections. It is characterized by the acute onset of mono-
morphic, symmetrical flat-topped papules or papulovesicles, 1–10 mm across,
which range in color from pink to red or brown and are located primarily
on the face (particularly the cheeks), buttocks, and extensor surfaces of the
forearms and legs, with the trunk typically being spared (Figs 6.51–6.53).1–4
Lesions are usually blanchable although petechial and hemorrhagic variants
can be rarely encountered.4 A positive Koebner phenomenon is sometimes
elicited.4 The lesions are occasionally pruritic and are self-limiting, lasting
up to 3 weeks. Mucous membranes are not affected. Infants and children are
predominantly affected although there are occasional reports of the condition
developing in adults.4–9
Systemic signs include hepatosplenomegaly and axillary and inguinal
lymphadenopathy. Sometimes a fever is evident. There may be an anicteric
acute hepatitis and occasionally patients progress to chronic liver disease.
Pathogenesis and histological features
In the original and early reports, Gianotti-Crosti syndrome was documented
following infection with hepatitis B virus.10–12 More recently cases have been
reported in association with hepatitis A virus, coxsackievirus, influenza virus,
Epstein-Barr virus, cytomegalovirus, parainfluenza virus, human herpesvi-
rus-6 (HHV-6), poxvirus, parvovirus, and rotavirus.13–25 In addition, the dis-
ease had been associated with HIV infection.26 Gianotti-Crosti syndrome has
also been reported following Mycoplasma infection, Lyme borreliosis, and
immunization.27–35 The pathogenesis is unknown although viral antigenemia
and immune complex-mediated mechanisms have been proposed.36
Biopsies of skin lesions show entirely non-specific histological features.
The epidermis often appears normal or it may be mildly acanthotic with
­parakeratosis. Lymphocytic exocytosis is usually present.3 The upper dermis
contains a lymphohistiocytic infiltrate in a perivascular distribution and there
196 Spongiotic, psoriasiform and pustular dermatoses

Fig. 6.53
Gianotti-Crosti syndrome: the papules are very uniform. A viral etiology is often
identified. By courtesy of C. Gelmetti, MD, Milan University, Italy.

In cases with hepatitis, the appearances are those of an acute viral hepa-
titis, which usually resolves over a period of up to 6 months. Rarely, chronic
disease ensues.

Fig. 6.51 Pityriasis rosea

Gianotti-Crosti syndrome: the eruption is present on the face and arms, there is
sparing of the trunk. By courtesy of C. Gelmetti, MD, Milan University, Italy.
Clinical features
Pityriasis rosea (‘rose-colored scale’) presents as an acute inflammatory der-
matosis characterized by self-limiting oval papulosquamous lesions on the
trunk and extremities.1–3 The disease appears to be more common in females,
and 75% of cases occur between the ages of 10 and 35 years.4 It is character-
ized by seasonal variation, being most common in the months of December to
February.5 Although pityriasis rosea typically presents as a solitary episode,
recurrent disease may occur in up to 2% of patients.6,7
In the majority of cases the disease first manifests itself with the appear-
ance of a ‘herald patch’, a single red scaly lesion that increases in size over
48 hours up to 2–10 cm in diameter (Fig. 6.54).8 A significant proportion of
patients report symptoms, including pyrexia, headache, malaise, arthralgia,
chills, vomiting, diarrhea, and lymphadenopathy, up to 2–3 weeks before the
onset of the eruption.9
After the appearance of the herald patch there is a ‘secondary incu-
bation period’ of 7–14 days before the generalized eruption of pink to
salmon-colored elliptical scaly lesions (Fig. 6.55).10 The latter are approxi-
mately 1 cm in length and their longest axes occur along the Blaschko skin
tension lines, producing the characteristic ‘fir’ or ‘Christmas tree’ effect.
There is usually an erythematous center, the periphery of the macule being
Fig. 6.52 slightly brown and scaly. In dark-skinned patients the macules tend to be
Gianotti-Crosti syndrome: darker than the surrounding skin (Fig. 6.56). The lesions spread from the
note the widespread chest to the abdomen, thighs, arms, and back, generally within 2 weeks,
erythematous papules persist for 2—4 weeks, and fade over a further 2 weeks. Pityriasis rosea
on the cheeks of this may be pruritic.
young girl. By courtesy of Oral lesions have been described in up to 16% of patients.4 They may take
C. Gelmetti, MD, Milan
the form of a single large erythematous plaque, bullae, multiple hemorrhagic
University, Italy.
puncta, round erythematous macules and plaques or erythematous annular
lesions.4,11–14
is also swelling of endothelial cells sometimes accompanied by marked papil- Several morphological variants may occur: a papular variant is seen in
lary dermal edema.31 Scattered eosinophils may be present.36 Occasionally, a young children, pregnant women and those of Afro-Caribbean descent; a
more lichenoid pattern of inflammation is encountered. There is no evidence vesicular or bullous variant may occur in infants and children; and an urti-
of vasculitis. carial form has also been noted.5,14,15 Occasionally, pityriasis rosea has a pur-
Direct immunofluorescence is negative.3 puric, hemorrhagic component.5,14,16 Localized and unilateral forms, and
By immunohistochemistry, the infiltrate consists of an admixture of CD4+ an ‘inverse’ form presenting on the face and extremities, have also been
helper T cells and CD8+ cytotoxic T cells.19,36,37 documented.17
 Exogenous dermatitis 197

A B

Fig. 6.54
Pityriasis rosea: (A) the ‘herald patch’ which marks the onset of this dermatosis, is marked by an arrow; (B) close-up view. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.

Pathogenesis and histological features
The exact etiology of pityriasis rosea is unknown; however, most of the evi-
dence points to an infectious, probably viral, cause. It sometimes complicates
an upper respiratory tract infection.18 The herald patch may develop at the
site of an insect bite, particularly fleas, but patches have also occurred in areas
of old trauma and scars, suggesting an isomorphic (Koebner's) response.17
Atypical pityriasis rosea has also been described in bone marrow transplant
recipients and following treatment with interferon-alpha (IFN-α) as well as
Hodgkin's disease, and a pityriasis rosea-like eruption has been documented
due to drugs such as imatinib mesylate, ACE inhibitors, and hydrochlorothi-

A B

Fig. 6.55
Pityriasis rosea: (A) the secondary rash presents as small pink slightly scaly macules; (B) close-up view. From the collection of the late N.P. Smith, MD, the Institute of
Dermatology, London, UK.
198 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.56
Pityriasis rosea: in pigmented skin, there is often postinflammatory
hyperpigmentation and the erythematous nature of the eruption is not apparent. By
courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
azide.19–23 Case clustering in establishments with communal living supports an
infectious etiology. Recently, HHV-7, as well as HHV-6 and HHV-8, has been
identified in peripheral blood mononuclear cells in addition to plasma and
skin of patients with pityriasis rosea, and herpes virus-like particles have been
identified in cutaneous lesions of pityriasis rosea by electron microscopy.24–33
Other workers, however, have failed to confirm this observation.28,34,35 Rarely,
a pityriasis rosea-like eruption may be a manifestation of HIV/AIDS.36
The histopathological features are those of a non-specific subacute or
chronic dermatitis and comprise focal hyperkeratosis and angulated paraker-
atosis with slight acanthosis (Figs 6.57–6.60).37 The granular cell layer may
be absent beneath the foci of parakeratosis. Intraepidermal cytoid bodies are
present in as many as 50% of cases.38,39 Focal acantholytic dyskeratosis has
occasionally been documented.40 A lymphohistiocytic infiltrate surrounds the
vessels of the superficial vascular plexus and there is slight spongiosis. Rarely,
spongiotic vesiculation may be evident.5 Occasionally, scattered eosinophils
are present. Red cell extravasation is a not infrequent feature and occasional
erythrocytes may be seen within the epidermis.
Immunocytochemical staining has demonstrated that the dermal infiltrate
consists mainly of T cells, including helper and suppressor cells, together with
Fig. 6.57
Pityriasis rosea: low-power view showing multiple foci of scale with psoriasiform
hyperplasia.
Fig. 6.58
Pityriasis rosea: small foci of parakeratotic scale are a characteristic finding. The
epidermis shows mild spongiosis.
large numbers of Langerhans cells.41 Human leukocyte antigen DR (HLA-DR,
Ia-like antigen) has been demonstrated on the surface of keratinocytes, and
this has been interpreted as showing that they are taking an active role in cel-
lular immunity.42–44 HLA-DR antigen may also be expressed on the surface of
the T-helper cells.43
Differential diagnosis
Guttate psoriasis shows considerable overlap with pityriasis rosea. The presence
of neutrophils within the parakeratotic mounds favors a diagnosis of psoriasis.
A wide range of drugs has been associated with a pityriasis rosea-like erup-
tion including barbiturates, ketotifen, clonidine, captopril, isotretinoin, gold,
bismuth, arsenic, organic mercurials, methoxypromazine, D-penicillamine,
tripelennamine hydrochloride, metronidazole, and salvarsan.15,17 In such cases,
the distinction depends upon clinicopathological correlation. The presence of
large numbers of eosinophils is a clue to a hypersensitivity reaction.
Acute and subacute eczematous dermatitis may also be confused with
pityriasis rosea. The presence of lens-shaped parakeratosis and limited spon-
giosis favors pityriasis rosea. Again, clinical findings should help make this
distinction.
Fig. 6.59
Pityriasis rosea: there
is spongiosis and a
perivascular lymphocytic
infiltrate. The angulated
tier of parakeratosis
(teapot lid sign) is
characteristic.
 Exogenous dermatitis 199

Fig. 6.60 Fig. 6.62

Pityriasis rosea: in this field, there is red cell extravasation. Juvenile plantar
dermatosis: close-up
view showing scaling
Pityriasis lichenoides chronica is characterized by interface change and and fissuring. By
vacuolar degeneration of the basal layer of the epidermis, features not seen courtesy of the Institute
in pityriasis rosea. of Dermatology, London,
A PAS stain is mandatory in all cases to exclude a dermatophyte infection. UK.

Juvenile plantar dermatosis
Clinical features
Scaly palms and soles with loss of a normal epidermal rete pattern charac-
terize juvenile plantar dermatosis. The affected area often has a shiny red
appearance with fissures (Figs 6.61, 6.62).1–4 As its name suggests, the dis-
ease is seen in prepubertal children with a mean age of 9.6 years.1 The most
common sites affected are the volar aspect of the great toe and the ball of
the foot.1 The hand is only rarely affected. Patients often have a personal or
family history of atopy.2,4 The disorder usually lasts for 6 months to several
years before resolving.1,3 However, many patients develop features of classic
eczema of the hands later in life.2
Pathogenesis and histological features
The pathogenesis of this disorder is not understood; however, it has been sug-
gested that synthetic footwear may play a role in its development.3
Biopsy shows epidermal acanthosis and subacute to chronic spongiosis.1
Variable parakeratosis and hypogranulosis may be seen. A lymphocytic infil-
trate centered on the eccrine duct is said to be characteristic.1
Differential diagnosis
The histological changes are probably non-specific but the presence of chronic
inflammation centered on the sweat duct should suggest juvenile plantar derma-
tosis in the appropriate clinical setting and allow distinction from other spongi-
otic dermatitides, which typically spare the acrosyringium. One group could not
identify PAS-positive material occluding sweat ducts in multiple histological sec-
tions of juvenile plantar dermatosis (compare with miliaria).1 A PAS stain with
diastase digestion should also be performed to evaluate for fungal infection.

Miliaria
Clinical features
This common disorder, although most often seen in children, may affect any
age group but congenital presentation is rare.1 It develops as a consequence
of obstruction to the outflow tract of the intraepidermal component of the
eccrine sweat duct and is associated with excessive sweating and exposure to
high humidity. Traditionally, the condition is subdivided into three subtypes:
miliaria crystallina, miliaria rubra, and miliaria profunda.2,3
• In miliaria crystallina the level of obstruction is within the stratum
corneum, and results in the formation of small, clear vesicles, located
Fig. 6.61 particularly on the trunk (Fig. 6.63). There are accompanying symptoms
Juvenile plantar
of a high fever and pronounced sweating.
dermatosis: multiple
erythematous lesions
• Miliaria rubra (prickly heat) is particularly common in hot, humid
are present on the climates and is due to obstruction within the prickle cell layer, resulting
soles of the feet. By in erythematous papules and vesicles, usually located about the
courtesy of the Institute trunk and intertriginous regions (Fig. 6.64). This form of miliaria is
of Dermatology, London, particularly common in infants. The term miliaria pustulosa has been
UK. applied to the above subtypes when pustules develop. Miliaria rubra
200 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.63
Miliaria crystallina: tiny vesicles resembling water droplets are scattered over the
abdomen of this young male. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
Fig. 6.64
Miliaria rubra: the characteristic appearance is of large numbers of minute papules
and vesicles. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK.
and its pustular variant have also been found in association with
pseudohypoaldesteronism, type I.4,5,6
• In miliaria profunda, also typically seen in tropical climates, the
obstruction is at level of the sweat duct. Small papules are seen on the
trunk and occasionally the extremities.
Pathogenesis and histological features
The pathogenesis of miliaria is poorly understood. It has been suggested that
bacteria play a role in the development of the disease. There is evidence that
extracellular polysaccharide substance (EPS), a PAS-positive material pro-
duced by some strains of Staphylococcus epidermidis, obstructs the sweat duct
and causes the disease.7 Normal controls who had S. epidermidis swabbed on
to the volar aspect of their forearms followed by occlusion and heat devel-
oped miliaria. These results have not been replicated with other bacteria.7
Biopsy revealed EPS in lesions from several patients.
A subcorneal vesicle containing a few neutrophils characterizes miliaria
crystallina, while rubra involves an intraepidermal spongiotic vesicle. In
both variants the lesions can be seen to be centered upon an intraepider-
mal eccrine sweat duct. Miliaria pustulosa is characterized by features of
miliaria in addition to an intraepidermal or subcorneal pustule. Miliaria
profunda is characterized by spongiosis of the dermal portion of the eccrine
duct, often associated with dermal chronic inflammation adjacent to the
affected duct.
Fox-Fordyce disease
Clinical features
Fox-Fordyce disease (apocrine miliaria, chronic itching papular eruption of
the axillae and pubic region) presents as a chronic papular eruption, associ-
ated with pruritus, and located in areas containing apocrine sweat glands
(i.e., the axillae, the pubic area, the vulval labia, the perineum, and areola)
(Fig. 6.65).1–3 The papules are discrete, firm, and flesh-colored or pigmented.
Associated hair loss is often present.
The disease is uncommon and over 90% of reported cases have occurred
in women, usually aged 13–35 years. Rarely, prepubescent and postmeno-
pausal patients have been described.4,5
Pathogenesis and histological features
Patients with Fox-Fordyce disease have apocrine anhidrosis. Although eccrine
sweating is normal, apocrine sweating does not occur due to the keratotic
plugging of the apocrine duct orifice. The continued secretion of sweat, how-
ever, causes the duct to rupture and an apocrine sweat retention cyst forms
in the epithelium. The exact cause of the follicular plugging is unknown,
but a hormonal link has been postulated. Occasional instances of coexistent
hidradenitis suppurativa have been recorded.6
Follicular infundibular plugging is present in association with acanthosis,
parakeratosis, spongiosis, and an underlying non-specific chronic inflamma-
tory cell infiltrate. Dilation of the apocrine glands may be present and the
presence of perifollicular foamy histiocytes is a frequent and diagnostically
helpful feature.7–9 Further reported findings include vacuolar change, dysker-
atosis, and parakeratotic lamellae affecting the follicular infundibulum.10 The
keratinous obstruction prevents the outflow of apocrine secretion and leads
to the diagnostic feature of an intrafollicular sweat retention vesicle; serial
sections may be needed to demonstrate this lesion.11,12
Transient acantholytic dermatosis with
prominent eccrine ductal involvement
Grover's disease (transient acantholytic dermatoses) is discussed more com-
prehensively elsewhere; however, since it is commonly associated with spongi-
osis (often in the absence of acantholysis), it deserves mention in this chapter.
Recent studies of Grover's disease have shown a strong correlation with high
temperature and sweating and it has been suggested that its pathogenesis may
be analogous to that of miliaria.1–3 Supporting this concept is the development
of Grover's disease in bed-ridden and febrile patients. The lesions are usually
present on the back. These patients often have prominent involvement of
the eccrine duct and the lesions have been termed sudoriferous acrosyringeal
acantholytic disease (sudoriferous Grover's disease).4 Biopsies taken from
patients with sudoriferous acrosyringeal acantholytic disease often show, in
addition to typical features of Grover's disease, acantholysis of the superfi-
cial portion of the eccrine duct. When acantholysis is present and a clinical
history is provided, the diagnosis is usually straightforward. However, not
uncommonly, biopsies taken from patients with Grover's disease show spon-
giosis only (often eosinophilic spongiosis). In these patients, a diagnosis of
Grover's disease may still be made in the appropriate clinical setting.
It is important to note that myriad cutaneous disorders may show some
degree of spongiosis. For example, such disparate conditions as mycosis fun-
goides and psoriasis are not uncommonly associated with a degree of spon-
giosis. In this chapter, we have focused our discussion on entities for which
spongiosis is a dominant and fairly consistent histological finding. Other enti-
ties that may occasionally be associated with some degree of spongiosis are
discussed in the appropriate chapters.
 Psoriasis 201

Fig. 6.65
Fox-Fordyce disease: (A) there are numerous white
papules. The axilla is a characteristic site; (B) close-up
A B view. By courtesy of the Institute of Dermatology,
London, UK.

Psoriasiform dermatoses
The psoriasiform reaction pattern is defined by the presence of epidermal
hyperplasia with fairly uniform and marked enlargement of the rete ridges.
Although confluent parakeratosis with neutrophil exocytosis is characteris-
tic of psoriasis (the prototype of this group of conditions), this feature is not
included within the definition, which would otherwise become too restrictive.
Diseases in addition to psoriasis which may manifest a psoriasiform pattern
include Reiter's syndrome, pityriasis rubra pilaris, lichen simplex chronicus,
psoriasiform drug reactions, subacute and chronic spongiotic dermatitis,
parapsoriasis, and pityriasis rosea (herald patch). Other conditions in which
psoriasiform hyperplasia may sometimes be a feature include dermatophyte
infections and candidiasis, secondary syphilis, scabies infestation, inflamma-
tory linear verrucous epidermal nevus, necrolytic migratory erythema, acro-
dermatitis enteropathica, and pellagra. Neoplastic conditions such as Bowen's
disease and mycosis fungoides, which often show marked epidermal hyper-
plasia, are not included in this definition.
(Fig. 6.69). The scalp, the extensor surfaces (mainly the knees and elbows),
the lower back, and around the umbilicus are particularly affected. The clini-
cal features, however, show regional variation: scalp involvement often shows
very marked plaque formation, whereas on the penis scaling is commonly
minimal and the features may be mistaken for Bowen's disease (Figs 6.70–
6.72). Linear lesions (linear psoriasis) follow previous trauma (koebneriza-
tion) (Fig. 6.73).
Psoriasis may manifest in a variety of other ways.
• Guttate (eruptive) psoriasis presents as small (0.5–1.5 cm in diameter)
papules over the upper trunk and proximal extremities, typically in
younger patients (Figs 6.74–6.76).

Psoriasis
Clinical features
Psoriasis is a chronic relapsing and remitting disease of the skin that may
affect any site.1 It is one of the commonest of all skin diseases, with a reported
incidence of 1–2% in Caucasians.2,3 It is rare among blacks, Japanese, and
native North and South American populations.4 Males and females are
affected equally. Although psoriasis may occur at any age, it most frequently
presents in the teens and in early adult life (type I psoriasis).5 A second peak
in which the disease is often milder appears around the sixth decade (type II
psoriasis).5
The classic cutaneous lesion of psoriasis vulgaris (plaque psoriasis),
developing in about 85–90% of patients with psoriasis, is raised, sharply
demarcated, with a silvery scaly surface (Figs 6.66–6.68).6,7 The underly-
ing skin has a glossy, erythematous appearance. If the parakeratotic scales Fig. 6.66
are removed with the fingernail, small droplets of blood may appear on the Psoriasis: typical plaque disease showing bilateral and fairly symmetrical
surface (Auspitz's sign); this is diagnostic. Plaques, when multiple, are often distribution. In this example, the silvery scale is well demonstrated. From the
symmetrical and annular lesions due to central clearing are a common finding collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
202 Spongiotic, psoriasiform and pustular dermatoses

Fig. 6.67 Fig. 6.69

Plaque psoriasis: note the symmetry of these lesions. By courtesy of R.A. Annular psoriasis: central clearing of plaques results in annular lesions. By courtesy
Marsden, MD, St George's Hospital, London, UK. of R.A. Marsden, MD, St George's Hospital, London, UK.

• Psoriasis inversa is characterized by the development of plaques in the

flexures (Fig. 6.77).
• Generalized pustular psoriasis (von Zumbusch) is an acute variant,
characterized by fever of several days' duration, together with the
sudden appearance of sterile pustules, 2–3 mm across, over the trunk
and extremities (Fig. 6.78).8 The surrounding skin is erythematous
and confluence may result in a generalized erythroderma (Fig. 6.79).
Usually, recurrent episodes of fever occur, followed by fresh outbreaks
of pustules (Fig. 6.80). Systemic signs include weight loss, weakness,
and hypocalcemia, with a raised white cell count and high erythrocyte
sedimentation rate (ESR). Although the precipitating factor is often
unknown, pustular psoriasis may follow a streptococcal or viral
infection. Withdrawal of systemic steroid therapy is also a known
predisposing cause.9 Treatment with systemic steroids or intensive
topical regimens has also been incriminated.10 Other risk factors for
developing a pustular episode include drugs, pregnancy, hypocalcemia,

Fig. 6.70
Plaque psoriasis: the scalp is a commonly affected site. By courtesy of the Institute
of Dermatology, London, UK.

Fig. 6.71
Plaque psoriasis: in this
extreme case, the initial
Fig. 6.68 diagnosis was Norwegian
Plaque psoriasis: close-up scabies. Surprisingly,
view showing the thick alopecia is an uncommon
scale. From the collection complication. By courtesy
of the late N.P. Smith, of R.A. Marsden, MD,
MD, the Institute of St George's Hospital,
Dermatology, London, UK. London, UK.
 Psoriasis 203

Fig. 6.74
Guttate psoriasis: this infant shows a characteristic distribution over the trunk.
By courtesy of M. Liang, MD, Children's Hospital, Boston, USA.

Fig. 6.72
Psoriasis: penile lesion showing a sharply demarcated, erythematous, eroded,
slightly scaly plaque. By courtesy of C. Furlonge, MD, Port of Spain, Trinidad.

Fig. 6.75
Guttate psoriasis: this close-up view shows the erythema and scaling.
By courtesy of the Institute of Dermatology, London, UK.

Fig. 6.73
Plaque psoriasis: linear involvement is a manifestation of koebnerization following
trauma. By courtesy of the Institute of Dermatology, London, UK.

and sunlight or phototherapy.11 Uncommon variants of pustular

psoriasis include an annular form, exanthematous pustular psoriasis,
juvenile and infantile pustular psoriasis.12,13 The annular variant is
a somewhat less serious variant in which, due to central clearing,
lesions develop an annular or gyrate morphology.11 Often, the systemic
manifestations are less florid. The exanthematous variant, which tends
to develop de novo, may sometimes follow an infection or represent
a pustular drug reaction.11 Impetigo herpetiformis most probably
represents pustular psoriasis of pregnancy although some authors
classify it as a separate entity.14
• In psoriatic erythroderma, there is an intense generalized erythema
affecting the entire skin surface, associated with desquamation (Fig.
6.81). Ectropion may be present and scalp involvement is sometimes
followed by hair loss. Erythroderma may be precipitated in patients
with psoriasis vulgaris by infection with Staphylococcus aureus, abrupt Fig. 6.76
curtailment of steroid or methotrexate therapy, and sunburn.11 Systemic Guttate psoriasis: as with plaque disease, guttate psoriasis is associated with a
symptoms including fever, chills, shortness of breath, fatigue, and Koebner phenomenon. By courtesy of the Institute of Dermatology, London, UK.
204 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.77
Flexural (inverse)
psoriasis: this is a rare
variant in which the
lesions develop on
flexural skin.
Fig. 6.78
Pustular psoriasis (von Zumbusch): note the extreme generalized erythema and
pustulation. This variant is rare and may sometimes prove fatal. By courtesy of R.A.
Marsden, St George's Hospital, London, UK.
myalgia are commonly present.11 Biochemical abnormalities include
hypoalbuminemia, anemia, and dehydration.15 High-output cardiac
failure is an important complication.
• Localized (mixed) pustular psoriasis represents the development of
pustules on pre-existent plaques.9 This variant most often develops in
acute flares of psoriasis or following treatment.11 It sometimes represents
a harbinger of a more generalized process.
• Palmoplantar pustular psoriasis of Barber (pustulosis palmaris et
plantaris) refers to a chronic recurrent pustular dermatosis localized to
the palms and soles (Figs 6.82, 6.83). It shows a strong predilection
for females (9:1) in the fourth to fifth decade of life and the disease is
associated with a history of smoking.6,16,17 In about 25% of patients there
is coexistent chronic plaque psoriasis.6
• Acrodermatitis continua (acropustulosis) of Hallopeau is a rare sterile
pustular eruption of the fingers or toes, involving the nails and slowly
extending proximally (Figs 6.84, 6.85).
Fig. 6.79
Pustular psoriasis: early
stage showing intense
erythema. By courtesy
of the Institute of
Dermatology, London, UK.
Fig. 6.80
Pustular psoriasis: close-up view showing typical pustules arising on a background
of intense erythema. By courtesy of the Institute of Dermatology, London, UK.
The nail is frequently affected in psoriasis; lesions may include pitting,
discoloration, onycholysis, subungual hyperkeratosis, nail grooving, splinter
hemorrhages and complete loss in pustular psoriasis.18
Patients with psoriasis have a higher incidence of certain comorbidities
including, depression, obesity, type 2 diabetes mellitus, hyperlipidemia,
hypertension, metabolic syndrome, cardiovascular disease, Crohn's disease,
and multiple sclerosis, as well as cutaneous and visceral malignancies.6,19
Psoriatic arthritis
Psoriatic arthritis has a prevalence of 0.02–7% but more recent data suggest
that it could be as high as 30%.20 It may take a number of different forms
(Fig. 6.86):21
• The most common is an asymmetrical involvement of a few joints of the
fingers or toes; this accounts for over 70% of cases.
• In 15% of cases a symmetrical polyarthritis, clinically indistinguishable
from rheumatoid arthritis, but seronegative, is seen.
 Psoriasis 205

Fig. 6.83
Palmoplantar pustular psoriasis: close-up view of palmar pustules.
By courtesy of the Institute of Dermatology, London, UK.

Fig. 6.81
Psoriatic erythroderma: there is generalized erythema. Patients are at risk of
dehydration, hypoalbuminemia, and anemia. By courtesy of R.A. Marsden,
St George's Hospital, London, UK.

Fig. 6.84
Acropustulosis continua: there is pustulation with erythema and scaling, the nail
has been shed, and there is damage to the nail plate. By courtesy of R.A. Marsden,
St George's Hospital, London, UK.

Fig. 6.82
Palmoplantar pustular
psoriasis: there is intense
erythema, scaling, and
numerous pustules. By Fig. 6.85
courtesy of the Institute of Acropustulosis continua: a particularly severe example. By courtesy of S. Dalziel,
Dermatology, London, UK. MD, University Hospital, Nottingham, UK.
206 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.86
Psoriatic arthropathy: joint involvement is a rare manifestation. Lesions of the
interphalangeal joints, while said to be characteristic, are an uncommon finding.
In this patient there is gross deformity. By courtesy of R.A. Marsden, St George's
Hospital, London, UK.
Fig. 6.87
Psoriatic arthropathy:
classic type. Note the
destruction of the distal
interphalangeal joint
of the first finger. By
courtesy of the Institute
of Dermatology, London,
UK.
• In approximately 5% of cases the distal interphalangeal joints are
involved, the classical picture of psoriatic arthropathy (Fig. 6.87).
• A further 5% have a destructive and severely deforming arthritis,
arthritis mutilans.
• The remaining cases have ankylosing spondylitis, with or without
peripheral joint involvement (Fig. 6.88).
Psoriatic arthritis is associated with a high incidence of mitral valve pro-
lapse with resultant incompetence.22 The peak age of onset is 36–45 years
of age, although the destructive form may occur earlier. A high incidence of
immunoglobulin gene polymorphism has been identified in patients with pso-
riatic arthritis, suggesting an inherited predisposition.23
Psoriatic arthritis in children, although uncommon, is of importance
because frequently the arthritis precedes the onset of the skin lesions. A care-
ful examination for nail changes and questioning about a family history may
be of value in establishing the diagnosis.
Pathogenesis and histological features
Although the etiology of psoriasis remains incompletely understood, consid-
erable advances have been made in the past two decades to unravel the com-
plex mechanisms involved in the pathogenesis of this common dermatosis.
For many years psoriasis was considered to represent a primary epidermal
hyperproliferative disorder. More recent studies, however, have shown that
a T-lymphocyte-driven immune process is central to the development of the
psoriatic plaque and, in fact, may represent the earliest stage in its evolution.
Other important factors include genetic influences, the environment, and the
contribution of keratinocyte-derived mediators of the inflammatory process.
Fig. 6.88
Psoriatic arthropathy: sacroiliitis. Note the virtual obliteration of the sacroiliac joints.
By courtesy of R.A. Marsden, St George's Hospital, London, UK.
The inherited predisposition to develop psoriasis has long been known.
A positive family history is common. Documented prevalence rates in first-
degree relatives have ranged from 7.8% to 17.6%.24,25 Monozygotic twins
have a concordance of 64–70% while that of dizygotic twins is in the order of
14–23%.26 Linkage analysis has identified at least nine separate loci (PSORS1–
9).6,7,27–30 PSORS1 shows the strongest genetic susceptibility, being implicated
in 35–50% of familial psoriasis. 6,7,31,32 The locus is present on chromosome
6p within the major histocompatibility complex and more recent data have
demonstrated HLA-Cw6 as the susceptibility allele on PSORS1.31,32
Genetically, psoriasis is a heterogeneous disease at the level of PSORS1
and two distinct types have been identified:5
• Type I disease which affects young adults and includes guttate psoriasis is
characterized by a familial segregation involving HLA-Cw6.5,33
• Type II disease includes psoriasis vulgaris presenting at an older age
(over 50 years) as well as palmoplantar pustulosis and shows no familial
segregation and no association with the PSORS1 locus.4,33,34 Patients with
pustular psoriasis have a higher incidence of HLA-B27, as do those with
psoriasis and peripheral arthritis, and this is most marked if spondylitis
is present.35 Further genes related to increased genetic susceptibility for
psoriasis include the interleukin-23 receptor gene on chromosome 1p,
the interleukin-12B gene on chromosome 5q, zinc finger protein 313 on
chromosome 20q, the CDKAL1 gene on chromosome 6p, the PTPN22
gene on chromosome 18p, the IL-4–IL-13 cytokine gene cluster on
chromosome 5q, the LCE3B/3C gene on 1q, and the PSORS2 locus on
chromosome 17q.7
The IL-23 receptor is of interest as it is also associated with ankolysing
spondylitis and psoriatic arthritis while the CDKAL1 gene has also been
­associated with Crohn's disease and type-2 diabetes mellitus.7
Certain factors are known to induce psoriasis in a person who is geneti-
cally predisposed. There is a tendency for lesions to develop at sites of previ-
ous skin trauma (e.g., mechanical friction, sunburn or childhood illnesses such
as varicella); this is termed the isomorphic or Koebner's phenomenon.36–38
Infections are well known as predisposing factors in the onset of psoriasis.
In children in particular, upper respiratory tract infections frequently trig-
ger psoriasis, while infections with Streptococcus pyogenes are implicated in
the development of acute guttate psoriasis, together with an exacerbation of
other forms of psoriasis.39–42 Specific streptococcal serotypes, however, do not
appear to be implicated.
Other factors known to exacerbate psoriasis include stress, bereavement,
HIV/AIDS, withdrawal of corticosteroids after prolonged use, and treatment

with a number of drugs including lithium, antimalarials, and beta-blocking
agents.6,43
The development of the psoriatic plaque results from a complex interplay
between keratinocyte hyperproliferation with loss of differentiation, changes
in the superficial dermal vasculature, and a T-lymphocyte-mediated inflam-
matory component.44 The relative roles of keratinocyte hyperplasia, vascular
changes, and immunological reactions have been the subject of much discus-
sion in the recent literature.45 Most recently, the focus has been particularly
directed towards the importance of the innate as well as adaptive immune
systems.7
In the skin there is an increased epidermal proliferation rate: the transit
time of keratinocytes through the epidermis in normal skin is 56 days; in pso-
riatic skin it is shortened to 7 days.46,47 The epidermal cell cycle is probably
shortened, and there is a large increase in the number of proliferating genera-
tive cells in the basal layers, where up to three layers of proliferating cells may
be seen compared with only one in normal resting epidermis.
Vascular proliferation predominantly affecting the postcapillary venules
of the dermal papillae appears to be one of the earliest manifestations of
psoriasis.48 This is mediated by upregulation of αVβ3 integrin and vascular
endothelial growth factor (VEGF).49–51
The current weight of evidence suggests that a T-cell-mediated immune
reaction is central to the pathogenesis of psoriasis.44,52 Clinical studies sup-
porting this hypothesis include the response to antilymphocyte therapies
such as ciclosporin.53 More recently, remission in patients with severe pso-
riasis has resulted from treatment with an activated T-lymphocyte selective
toxin DAB389 IL-2 that interacts with the receptor-binding domain of IL-2.54
Successful responses to therapy with monoclonal anti-CD3 and anti-CD4
antibodies adds further support.55,56 Additional evidence has come from bone
marrow transplantation studies. Unaffected patients develop psoriasis follow-
ing a transplant from an affected donor whereas patients are cured of their
disease following transplantation from an unaffected donor.57 In vitro stud-
ies in which intradermal injection of T-helper lymphocytes from an affected
patient into severe combined immunodeficient mice results in the development
of typical psoriasis further supports a T-lymphocyte-driven pathogenesis.58
The innate immune system appears to play an important part in the early
stages of the disease and increased numbers of activated plasmacytoid den-
dritic cells are present in early psoriatic lesions.59 Production of interferon
alpha by plasmacytoid dendritic cells and TNF-α and INF-γ by natural killer
cells leads to activation of myeloid dendritic cells and subsequent prolifera-
tion of T cells through IL-12 and IL-23 release.7,60
Although CD4 T-helper (Th) lymphocytes are probably of importance in
the earliest stages of plaque development, the major population is charac-
terized by CD8 expression. The immunophenotype of the T cells includes
CD45RO+, HLADR+, CD25+ and CLA+, indicating activated skin-specific
memory cells.61 The lymphocyte cytokine profile, which includes IL-2, IL-17,
interferon gamma (IFN-γ), and absence of IL-4, IL-10, and tumor necrosis
factor alpha (TNF-α), reflects a predominantly Th1-mediated inflammatory
reaction as well as IL-17-A producing type 17 helper T (Th17) cells.7,62–64
Th17 cells are of particular importance for epithelial immunosurveillance
and produce IL-22, a molecule involved in keratinocyte differentiation and
proliferation.65,66 IFN-γ is central to the development of the plaque. In vitro
studies have shown that the keratinocyte proliferation is IFN-γ dependent.67
Also, IFN-γ injection in normal human skin results in epidermal prolifera-
tion.68 In addition to the lymphocyte-derived cytokines discussed above, the
keratinocytes themselves are a rich source of inflammatory mediators, which
are likely to be of importance in initiating the inflammatory reaction and
the development and maintenance of the psoriasiform plaque.69 In particular,
keratinocytes secrete IL-1α, IL-1β, and TNF-α. These cytokines play a major
role in angiogenesis, in recruitment of circulating lymphocytes, and induc-
ing expression of a number of endothelial cell adhesion molecules includ-
ing E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell
adhesion molecule-1 (VCAM-1).69–71 These last are of particular importance
in facilitating the extravasation of lymphocytes through the endothelium.52
Keratinocytes are also a valuable source of chemokines including IL-8, mela-
noma growth stimulatory activity alpha (MGS/GRO-α), gamma inducible
protein 10 (IP-10), and molecule chemoattractant protein 1 (MCP-1).69 IL-8
is of importance in both neutrophil and T-lymphocyte chemotaxis.72 It also
Psoriasis 207
promotes keratinocyte proliferation and induces angiogenesis.73,74 IL-8 is pre-
dominantly derived from superficial keratinocytes and the associated neu-
trophils within the psoriatic plaque. MGS/GRO-α is an additional powerful
neutrophil chemoattractant.69
The pathogenesis of psoriasis therefore involves interaction between
injured keratinocytes and activated lymphocytes through the release of vari-
ous cytokines developing in a background of genetic predisposition.71 The
precise relationship between the T-cell-driven immune reaction and epider-
mal hyperplasia, however, remains unclear. Similarly, the initiator(s) of this
process are uncertain. Although autoantigens and bacterial superantigens are
currently favored, the possibility of a direct consequence of lymphocyte–kera-
tinocyte interaction has not yet been disproved.74
In biopsies of the early lesions, the histological features consist primarily
of dermal changes.75–79 The evolution of the psoriatic plaque consists initially
of the development of tortuous, dilated, and frequently congested capillaries
in the superficial papillary dermis accompanied by edema and a perivascu-
lar mononuclear cell infiltrate (Fig. 6.89).75 This vascular change is common
to all forms of psoriasis and may even be seen in biopsies from clinically
resolved lesions following treatment.78 Lymphocytes then migrate into the
lower epidermis, which becomes spongiotic. Subsequently, the upper epider-
mis shows focal vacuolation and eventual loss of the granular cell layer with
the resultant formation of parakeratotic mounds. Migration of neutrophils
from capillaries in the dermal papillae through gaps in the epidermal base-
ment membrane and hence to the stratum corneum completes the process.
Psoriasiform hyperplasia of the affected epidermis then follows.
Classical plaque psoriatic lesions show marked and characteristic acan-
thosis of the epidermal ridges, which are evenly elongated and club-shaped at
their bases, alternating with long edematous papillae, which are club-shaped
at their tips (Figs 6.90–6.93). Fusion of adjacent ridges is commonly pres-
ent in established lesions. The suprapapillary plate is typically thinned and
the epidermal surface is covered by confluent parakeratosis associated with
diminution or loss of the granular cell layer. The lower suprabasal layers of
the epidermis can frequently be seen to be actively dividing. Large tortuous
capillaries are present in the papillary dermis and there is a slight perivascular
lymphocytic infiltrate in the subpapillary dermis. Palmar and plantar lesions
may sometimes cause diagnostic difficulty as spongiosis can be marked, and
occasionally vesiculation is evident.78
The diagnostic features of active lesions include the ‘Munro microab-
scess’ and ‘spongiform pustule of Kogoj’. Munro microabscesses represent
an accumulation of polymorphs within the parakeratotic stratum corneum.
Spongiform pustules are seen beneath the keratin layer and consist of small
accumulations of neutrophils and occasional lymphocytes intermingled with
the epidermal cells in foci of spongiosis.
Fig. 6.89
Evolving psoriasis: in the early stages, there is capillary dilatation, with spongiosis,
as shown in this field. A small parakeratotic mound is also demonstrated.
208 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.90
Plaque psoriasis: scanning view showing extensive parakeratosis, regular
acanthosis, club-shaped epidermal ridges, and ridge fusion.
Fig. 6.91
Plaque psoriasis: closer view showing parakeratosis with neutrophil aggregates
(Munro microabscess). There is marked dilatation and tortuosity of the capillaries
within the dermal papillae. Spongiosis is also present.
Fig. 6.92
Plaque psoriasis: Munro microabscess, spongiform degeneration, and parakeratosis.
Fig. 6.93
Plaque psoriasis: tortuous and dilated capillaries.
In guttate psoriasis, the histological features overlap with those of evolv-
ing disease.78 Parakeratosis associated with loss or diminution of the granular
cell layer is limited to small foci contrasting with a background of orthokera-
tosis (Figs 6.94, 6.95). Neutrophils are seen surmounting the parakeratotic
tiers. Acanthosis is much less marked than in fully established plaque disease.
Neutrophils and lymphocytes are commonly present in the superficial papil-
lary dermis and mild spongiosis is often a feature, particularly if biopsies of
early lesions are examined.80
In generalized pustular psoriasis and its three variants the histological pic-
ture is slightly different in that the spongiform pustule occurs as a macropus-
tule and is the characteristic lesion (Figs 6.96, 6.97).79 As the spongiform
pustule increases in size, the epidermal cells die, with resulting central cavita-
tion. At the edges, a shell of thinned epidermal cells remains. Eventually there
is migration of neutrophils into the horny layer and the picture resembles that
of a large Munro abscess. Although the epidermal and dermal features may
be similar to those of psoriasis vulgaris, particularly if the pustule has devel-
oped against a background of plaque-type disease, more often the features
are much less well developed (Fig. 6.98). Frequently, therefore, there is no or
only minimal epidermal hyperplasia although tortuous and dilated capillaries
accompanied by a lymphocytic or mixed lymphocytic and neutrophil infiltrate
are usually seen.11
Fig. 6.94
Guttate psoriasis: the multiple discrete, parakeratotic mounds are characteristic.
Hyperplasia is not as well developed as in plaque disease.
 Psoriasis 209

Fig. 6.95 Fig. 6.98

Guttate psoriasis: close-up view. Pustular psoriasis: in this patient, the lesions developed dramatically in the absence of
significant plaque disease. There is only mild hyperplasia of the underlying epidermis.

In palmar/plantar pustular lesions, the initial changes are those of spon-

Fig. 6.96
Pustular psoriasis: a macropustule is present. Typical psoriasiform hyperplasia with
parakeratosis is seen in the adjacent epidermis.
giosis with lymphocytic exocytosis in the lower epidermis.80 As the lesion
­progresses, neutrophils infiltrate the epidermis and a macropustule develops.
In psoriatic erythroderma the histological features are variable but in the
majority of cases a positive diagnosis can be established.81 Most commonly,
the features are those of evolving psoriasis similar to guttate psoriasis, i.e.,
slight epidermal hyperplasia, focal diminution or loss of the granular cell
layer, and mild spongiosis (Fig. 6.99). Parakeratosis is often limited to slight
change overlying the hyperplastic epithelium and neutrophils are variably
present (Fig. 6.100). A lymphohistiocytic infiltrate is present in an edema-
tous papillary dermis and dilated, tortuous, spiraling vessels are regularly
evident. Extravasated red blood cells are a constant finding. Less commonly,
the features are those of psoriasis vulgaris and sometimes the changes overlap
regressing psoriasis.
In resolving lesions, foci of hyperkeratosis overlying hypergranulosis are
scattered through the parakeratotic scale and the epidermal hyperplasia is less
marked (Fig. 6.101).
Current treatment for severe widespread plaque psoriasis may include
the use of PUVA therapy. Over the recent years it has been shown that this
is associated with an increased risk (albeit low) of cutaneous squamous
cell carcinoma and dysplastic keratoses.82–85 Patients at most risk include

Fig. 6.99
Fig. 6.97 Psoriatic erythroderma: there is only very focal parakeratosis with scattered
Pustular psoriasis: close-up view. neutrophils. The epidermal hyperplasia is only slight.
210 Spongiotic, psoriasiform and pustular dermatoses

Fig. 6.100 Fig. 6.102

Psoriatic erythroderma: close-up view of parakeratosis and neutrophil karyorrhectic Bullous pemphigoid and pustular psoriasis: on the left is a subcorneal pustule while
debris. on the right is a subepidermal blister.

Fig. 6.101 Fig. 6.103

Resolving psoriasis: newly formed basket-weave orthokeratin is seen underlying Bullous pemphigoid and pustular psoriasis: higher-power view of the blister.
focal residual parakeratosis.

those who have had more than 200 PUVA treatments and/or a cumula-
tive dose in excess of 1000 J/cm2. There is some evidence to suggest that
these tumors behave in a low-grade fashion, with little risk of metastatic
spread.85
Psoriasis may rarely coexist with a number of autoimmune bullous
dermatoses including bullous pemphigoid, pemphigus vulgaris, linear IgA
disease, and epidermolysis bullosa acquisita.86–92 Although not in all cases,
there is often a relationship to treatment, particularly with PUVA ther-
apy. In some instances, the histology may show features of both conditions
(Figs 6.102–6.104).

Differential diagnosis
The differential diagnosis of psoriatic lesions includes a number of
conditions:
• Pityriasis rubra pilaris differs from psoriasis by the presence of
alternating parakeratosis and hyperkeratosis in both vertical and
horizontal directions (spotty parakeratosis). Neutrophil infiltration of the
stratum corneum is not a feature of pityriasis rubra pilaris unless there is Fig. 6.104
secondary infection. Bullous pemphigoid and pustular psoriasis: higher-power view of the pustule.
 Pityriasis rubra pilaris 211

• Lichen simplex chronicus typically shows scarring of the dermal papillae

due to persistent rubbing, and there is no thinning of the suprapapillary
plate. Hyperkeratosis and hypergranulosis are often marked and there is
minimal parakeratosis unless there is a background of spongiosis.
• Papulosquamous drug eruptions (e.g., due to lithium or propranolol)
may appear similar to psoriasis, but a moderate to high number of
eosinophils is usually present in the infiltrate.
• Seborrheic dermatitis typically shows psoriasiform hyperplasia and
corneal neutrophil infiltration may sometimes be a feature. It differs from
psoriasis by the presence of a more conspicuous spongiotic component,
which in psoriasis only occurs in early lesions and is usually not marked.
In those cases where the distinction is not possible, the term ‘sebo-
psoriasis’ is sometimes used.
• Pustular psoriasis and its variants are all similar; they must be
distinguished from other pustular eruptions, including conditions such
as pustular dermatophytoses, bacterial impetigo, and pustular drug
eruptions. Pustular psoriasis may be differentiated from subcorneal
pustular dermatosis by the absence of spongiform change or degeneration
in the latter condition. Gram and PAS stains and culture will exclude Fig. 6.105
infective conditions. Superficial pemphigus can be distinguished by Pityriasis rubra pilaris: there is characteristic hyperkeratosis and surrounding
the presence of acantholysis and the usual absence of psoriasiform erythema. At the edges individual follicular lesions are evident. By courtesy of M.M.
hyperplasia. In IgA pemphigus, acantholytic cells are usually, but not Black, MD, Institute of Dermatology, London, UK.
always, present and this diagnostic clue may be very easily overlooked,
but should allow distinction from psoriasis. In lesions of IgA pemphigus
that lack acantholytic cells, immunofluorescence studies may be
necessary to make the distinction from pustular psoriasis if the clinical
diagnosis is in doubt.

Reiter's syndrome
The skin lesions of Reiter's syndrome typically show psoriasiform hyperpla-
sia with parakeratosis. The epidermis is markedly acanthotic with elonga-
tion and hypertrophy of the epidermal ridges. The suprapapillary plates are
thinned and there is infiltration of the epidermis by neutrophils, associated
with the formation of spongiform pustules, microabscesses, and ultimately
macropustules indistinguishable from pustular psoriasis. A perivascular lym-
phohistiocytic infiltrate with neutrophils is seen in the upper dermis.

Pityriasis rubra pilaris

Clinical features
Pityriasis rubra pilaris is an erythematous papulosquamous disorder character-
ized by follicular plugging (often best seen on the dorsal aspects of the hands
and feet), perifollicular erythema that becomes confluent, palmoplantar hyper-
keratosis, and pityriasis capitis.1–3 It is an uncommon disease, accounting for
approximately one of every 5000 new dermatological referrals in the United
Kingdom.3 Males and females are affected equally and the age distribution
tends to peak in the first and fifth decades.3 Although the majority of cases doc-
umented have affected Caucasian patients, occasional reports describing pityri-
asis rubra pilaris in black African patients have recently been published.4
Pityriasis rubra pilaris has been classified clinically into five types:3
• Type I, classical adult pityriasis rubra pilaris, is seen in over 50% of
patients. Initially, a single erythematous patch appears on the upper
half of the body (typically the face and scalp) and gradually spreads as
large areas of sometimes pruritic or burning follicular hyperkeratosis
with erythematous perifollicular halos (Fig. 6.105).4 The erythematous
areas coalesce and many patients develop generalized erythroderma
(Fig. 6.106). Characteristically, occasional islands of unaffected skin
are present (Fig. 6.107). Follicular papules on the dorsal aspects of
the fingers and extensor surfaces of the wrists, arms, and thighs are
said to be characteristic.5 Fine and powdery scaling occurs on the face
and scalp, with coarser scaling on the lower body (Fig. 6.108). The
erythema has an orange–yellow tint, which is more noticeable on the
palms and soles, together with marked hyperkeratosis (Fig. 6.109).
Fig. 6.106
Pityriasis rubra pilaris:
confluence of lesions
leads to extensive
erythroderma.
By courtesy of the
Institute of Dermatology,
London, UK.
The nails are also affected, showing distal yellow–brown discoloration,
subungual hyperkeratosis, nail thickening, and splinter hemorrhages.6
Ectropion is often present,7 and there may be diffuse alopecia.8 Oral
lesions are uncommon and include diffuse hyperkeratosis and macular
erythema with white streaks reminiscent of lichen planus.5 Prognosis for
patients in this group is good, with up to 80% resolving within 3 years.
• Type II, atypical adult pityriasis rubra pilaris, occurs in approximately
5% of patients and is manifested by atypical morphological features
and a lengthy duration, often up to 20 years. The scaling is more
ichthyosiform and there are often areas of eczematous change. The
prognosis in this group is poor, with only 20% resolving within 3 years.
• Type III, classical juvenile pityriasis rubra pilaris, resembles the classical
adult form except for its age distribution; it affects children up to 2 years
of age, accounting for approximately 10% of patients (Fig. 6.110). More
often, however, the eruption commences on the lower half of the body.
212 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.107
Pityriasis rubra pilaris: characteristic, scattered islands of unaffected skin are evident.
By courtesy of the Institute of Dermatology, London, UK.
Fig. 6.108
Pityriasis rubra pilaris: in this patient, the scale is conspicuous.
By courtesy of the Institute of Dermatology, London, UK.
Fig. 6.109
Pityriasis rubra pilaris:
palmar and plantar
erythema with
hyperkeratosis are
frequent manifestations.
Sometimes, there is an
orange–yellow tint, as
seen in this patient. By
courtesy of the Institute
of Dermatology, London,
UK.
Fig. 6.110
Pityriasis rubra pilaris:
classical juvenile type.
Note the very extensive
distribution of the lesions.
By courtesy of M.M.
Black, MD, Institute of
Dermatology, London, UK.
The prognosis in this group is good, most patients clearing within 1 year
but a recurrence rate of up to 17% has been reported.9
• Type IV, circumscribed pityriasis rubra pilaris, affects 25% of patients
and presents in prepubertal children. Sharply defined areas of follicular
hyperkeratosis and erythema are seen on the knees and elbows, together
with occasional scaly erythematous patches on the rest of the body and
palmoplantar hyperkeratosis.10
• Type V, atypical juvenile pityriasis rubra pilaris, accounts for approximately
5% of patients; presentation occurs early in life and this type has a lengthy
duration. Characteristic follicular hyperkeratosis is present, together with a
mild erythema. Ichthyosiform features are sometimes seen.5 The skin of the
feet and hands may become thickened and scleroderma-like.
Familial variants, which account for 0–6.5% of cases, mostly present with atyp-
ical features as described in type V pityriasis rubra pilaris.5 In most families, inheri-
tance has been via an autosomal dominant mechanism with variable expression
and reduced penetrance although a recessive form has also been postulated.11
Pityriasis rubra pilaris has been reported in association with HIV
­infection.12,13 Nodulocystic acneiform or furuncle-like lesions and lichen
spinulosus may also be present. This is a particularly severe variant, which
responds poorly to therapy.13 Further associations include rheumatological
disease, in particular arthritis, dermatomyositis, and underlying malignancy
possibly representing a paraneoplastic phenomenon.14–25
Pathogenesis and histological features
The etiology of pityriasis rubra pilaris is largely unknown. It has been associ-
ated with abnormal vitamin A metabolism but there is little evidence in sup-
port for this other than a frequent response to vitamin A or retinoid therapy.5
Linkage to autoimmune disease, immune dysfunction, internal malignancy,
infections and, particularly in recent years, to human immunodeficiency
virus, have also been described.5,13,26,27 In the majority of cases, however, there
is no preceding or associated condition. Pityriasis rubra pilaris is associated
with an increased rate of epidermopoiesis.28–32
Fully developed follicular papules show characteristic features comprising
conical follicular plugging, with marked uniform acanthosis of the epidermis
and broad epidermal ridges and dermal papillae (Fig. 6.111).28,29,33 There is
hyperkeratosis, with foci of parafollicular parakeratosis. In the dermis there
is a mild to moderate inflammatory cell infiltrate and sebaceous atrophy.
Although the histological features may be non-specific, biopsies from
established, nonfollicular lesions comprise alternating orthokeratosis and
parakeratosis in both vertical and horizontal directions, focal or confluent
hypergranulosis, thick suprapapillary plates, broad epidermal ridges, narrow
 Pityriasis rubra pilaris 213

Fig. 6.113
Fig. 6.111 Pityriasis rubra pilaris: alternating hyperkeratosis and parakeratosis.
Pityriasis rubra pilaris:
follicular lesion showing
the conical keratin plug.
Parakeratosis is present
above the adjacent
epithelium.

dermal papillae, and a perivascular lymphocytic infiltrate in the superficial

dermis (Figs 6.112–6.114).34 Small numbers of plasma cells and eosinophils
are sometimes present.26 Superficial blood vessels may appear slightly dilated.
Occasionally there is also mild spongiosis with scattered intraepidermal lym-
phocytes.27 Neutrophil infiltration as seen in psoriasis is not usually a feature
of pityriasis rubra pilaris and its presence may indicate a bacterial or fungal
superinfection. Acantholysis with or without dyskeratosis involving follicular
and interfollicular epithelium has recently been emphasized, and exception-
ally a lichenoid infiltrate has been documented.26,35–38
In early lesions, the diagnosis is often problematical. Parakeratosis is usu-
ally poorly developed and lamellar orthohyperkeratosis predominates.34
Hypergranulosis is present and the rete ridges are broadened and slightly
elongated. The suprapapillary plates may be mildly thickened.
In erythrodermic lesions, the keratin layer may be thinned or lost and the
granular cell layer diminished.34
Palmar and plantar lesions show hyperkeratosis, focal parakeratosis, and
mild acanthosis (Fig. 6.115).

Fig. 6.114
Pityriasis rubra pilaris:
close-up view.

Fig. 6.115
Pityriasis rubra pilaris:
plantar lesion showing
hyperkeratosis, focal
Fig. 6.112 parakeratosis, and regular
Pityriasis rubra pilaris: there is hyperkeratosis with focal parakeratosis and acanthosis with a rounded
psoriasiform hyperplasia. lower border.
214 Spongiotic, psoriasiform and pustular dermatoses Inflammatory linear verrucous epidermal nevus

Differential diagnosis
Pityriasis rubra pilaris may be confused both clinically and histologically
with psoriasis. Features in favor of pityriasis rubra pilaris include follicular
plugging with parakeratosis of the adjacent epithelium, focal parakeratosis,
broad rete ridges, thickened suprapapillary plates, increased granular cell
layer, and an absence of tortuous dilated capillaries immediately adjacent to
the epidermis. In psoriasis the acanthosis is typically more marked and often
strikingly regular, the rete ridges are thin and often fused, the suprapapillary
plate is thinned, parakeratosis is usually confluent, and characteristic collec-
tions of neutrophils are seen in the overlying parakeratotic stratum corneum
in association with spongiform degeneration of the underlying superficial
epidermis.

Inflammatory linear verrucous

epidermal nevus
Clinical features
Fig. 6.117
Inflammatory linear verrucous epidermal nevus (ILVEN) is an uncommon
Inflammatory linear verrucous epidermal nevus (ILVEN): in this view there is marked
condition which usually presents in infants or young children as an intensely psoriasiform epidermal hyperplasia with massive hyperkeratosis. Mild chronic
pruritic, persistent, scaly, unilateral, linear erythematous lesion following inflammation is seen in the superficial dermis.
the lines of Blaschko.1 Individual lesions are discrete, scaly papules, which
coalesce to form plaques.2 Superimposed lichenification and excoriations are
commonly present. Although lesions may be widely distributed, the leg, thigh,
and buttock are sites of predilection (Fig. 6.116).1,3 Females are more often
affected than males (4:1).2 The left side of the body is most often involved.2,4,5
Much less commonly, the disorder is bilateral and, exceptionally, the condi-
tion is generalized.6–8 Familial cases have been documented and adults may
sometimes be affected.7–11 Occasionally inflammatory linear verrucous epi-
dermal nevus coexists with psoriasis and rarely it presents as part of the epi-
dermal nevus syndrome.12,13 Exceptionally, the condition is associated with
arthritis.14

Histological features
Histologically, the nevus is characterized by sharply demarcated, alternating
parakeratosis and orthohyperkeratosis (Figs 6.117–6.119).2,5,15 The epider-
mis shows papillomatosis with psoriasiform hyperplasia and absence of the

Fig. 6.118
Inflammatory linear verrucous epidermal nevus (ILVEN): alternating hyperkeratosis
and parakeratosis is characteristic.

Fig. 6.116
Inflammatory linear
verrucous epidermal
nevus (ILVEN): patients
present with scaly,
erythematous, itchy
papules and plaques
in a linear distribution,
showing a predilection
for the legs. From the
collection of the late N.P.
Smith, MD, the Institute
of Dermatology, London, Fig. 6.119
UK. Inflammatory linear verrucous epidermal nevus (ILVEN): close-up view.
 Subcorneal pustular dermatosis 215

granular layer below the foci of parakeratosis contrasting with a thickened

granular cell layer underneath the orthohyperkeratosis. Occasionally, Munro
microabscesses are a feature. The rete ridges are elongated and thickened.
Focal slight spongiosis is present, accompanied by lymphocytic exocytosis.
A mild perivascular lymphocytic infiltrate is seen in the superficial dermis.

Differential diagnosis
ILVEN must be distinguished from linear psoriasis.16 In ILVEN, parakera-
tosis alternates with orthohyperkeratosis in contrast with psoriasis where
the parakeratosis is confluent. Similarly, the thickened rete ridges of ILVEN
contrast with the thinned ones of psoriasis. By immunocytochemistry, in
ILVEN, involucrin expression is markedly diminished in the epithelium deep
to the parakeratosis, while it is increased in the epithelium underlying the
hyperkeratosis.17 In psoriasis, there is a general increase in involucrin expres-
sion throughout the entire lesion.
Rare cases of ILVEN showing histiocyte infiltration of the underlying
­dermis reminiscent of verruciform xanthoma have been documented.18–21

Bazex syndrome (acrokeratosis Fig. 6.120

paraneoplastica) Bazex syndrome: note the
violaceous discoloration
Clinical features of the ear. By courtesy of
J.L. Bolognia, MD, Yale
Bazex syndrome denotes an acral psoriasiform dermatosis in association Medical School, CT, USA.
with internal malignancy.1–3 Elderly patients, usually males, present with
a symmetric erythematous or violaceous, scaly eruption affecting the ears,
nose, fingers, and toes (Fig. 6.120).1 The knees and elbows may some-
times be involved. Vesicles and bullae are less common manifestations.4
In patients with black or dark-brown skin, the lesions can present with
hyperpigmentation.2 Palmoplantar lesions are keratodermatous and nail
involvement ranges from paronychia, horizontal or vertical ridging, yellow
discoloration and thickening to onycholysis and subungual keratotic debris
(Fig. 6.121).1
Patients with Bazex syndrome invariably have an associated systemic malig-
nancy, most often affecting the oropharynx, larynx, esophagus, and lung, in
descending order of frequency.1 Cervical lymph node metastases are com-
monly present. Persistence of the cutaneous lesions is rare and they commonly
regress following successful treatment of the underlying malignancy.2,5

Histological features
Histologically, there is considerable overlap with psoriasis and chronic spon-
giotic dermatitis, the epidermis showing hyperkeratosis, parakeratosis, and
acanthosis. In addition however, dyskeratosis and interface changes reminis-
cent of lichen planus are also commonly present.1 A perivascular or less com-
monly lichenoid chronic inflammatory cell infiltrate is present in the superficial Fig. 6.121
dermis. Bazex syndrome: keratoderma. By courtesy of J.L. Bolognia, MD, Yale Medical
Bullous lesions may be subepidermal or, less often, intraepidermal.1,6 School, CT, USA.

Pustular dermatoses

Pustular drug reactions
This topic is discussed in the chapter on adverse reactions to drugs.
Subcorneal pustular dermatosis
Clinical features
Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) is a rare
chronic, relapsing, and apparently noninfective eruption of unknown eti-
ology.1,2 It predominantly affects females (4:1) and is usually diagnosed
during the middle years of life. Pediatric cases have, however, occasion-
ally been described.3,4 It may be associated with a benign or malignant IgA
paraproteinemia (up to 40% of cases) or multiple myeloma, and sometimes
pyoderma gangrenosum is also present.5–15 Other associations include rheu-
matoid arthritis, systemic lupus erythematosus, hyperthyroidism, Crohn's
disease, multiple sclerosis, IgG cryoglobulinemia, bullous pemphigoid, mor-
phea, diffuse scleroderma, Sjögren syndrome, marginal zone lymphoma,
chronic lymphocytic leukemia, squamous carcinoma of the bronchus, and
metastatic gastrinoma, although it is doubtful whether these are of any great
significance.15–26
Clinically, patients present with waves of superficial flaccid pustules in
circinate or serpiginous groups and sheets, particularly in the folds of the
body, such as the axillae (Figs 6.122, 6.123) and groins, beneath the breasts,
216 Spongiotic, psoriasiform and pustular dermatoses

Fig. 6.122
Subcorneal pustular
dermatosis: typical
example showing a
Fig. 6.123
succession of pustules
Subcorneal pustular dermatosis: close-up view of early lesions characterized by
spreading outwards from
numerous pustules arising on an erythematous background. By courtesy of R.A.
the axilla. At the periphery
Marsden, MD, St George's Hospital, London, UK.
the lesions are healing
with crust formation. By
courtesy of R.A. Marsden,
MD, St George's Hospital,
London, UK.

and on the abdomen. Fluid levels are sometimes evident. Typically, the
mucous membranes, face, scalp, and peripheries are spared. Healing is rapid,
usually within a few days or weeks, and the condition responds to dapsone,
although not as dramatically as dermatitis herpetiformis. Postinflammatory
hyperpigmentation is common.
Canine subcorneal pustular dermatosis, particularly affecting Miniature
Schnauzers, has been reported.27

Pathogenesis and histological features

The etiology of subcorneal pustular dermatosis is unknown. Intercellular
IgA deposits have been identified in a significant number of cases by direct
immunofluorescence and many patients have a circulating IgA pemphigus
antibody. These cases have been documented in the literature as IgA pemphi- Fig. 6.124
gus.28–33 Subcorneal pustular dermatosis should be restricted to the immuno- Subcorneal pustular dermatosis: situated immediately below the stratum corneum
fluorescence-negative group. is a blister cavity containing edema fluid and numerous neutrophils. The epidermis
The characteristic lesion is a subcorneal pustule, which appears to sit on shows neutrophils in transit. Within the papillary dermis is a neutrophil and
the skin surface (Fig. 6.124). The contents of the pustules are predominantly lymphocytic infiltrate.
neutrophils, although an occasional eosinophil may be identified. The epi-
dermis beneath the pustule shows surprisingly little change except for poly-
morphs in transit and perhaps slight intercellular edema (Fig. 6.125).
Older lesions may contain acantholytic cells (Fig. 6.126). In the dermis,
superficial blood vessels are surrounded by a non-specific mixed inflamma-
tory cell infiltrate consisting of neutrophil polymorphs and mononuclear
cells.

Differential diagnosis
The histological features of subcorneal pustular dermatosis cannot be reli-
ably distinguished from those of bullous impetigo, staphylococcal scalded
skin syndrome, pemphigus foliaceus, and IgA pemphigus. Impetigo is, how-
ever, a disease of young children and, although a Gram stain is often negative,
cultures should grow staphylococci or streptococci.
The staphylococcal scalded skin syndrome (Ritter's disease) is predomi-
nantly a disease of infants, but rarely it may present in adults. Clinically it
is different from subcorneal pustular dermatosis, being characterized by the
development of large flaccid blisters, which rupture, leaving extensive areas
of denuded skin.
Although acantholysis is typical of the pemphigus group of diseases, it Fig. 6.125
may occasionally be seen in impetigo, staphylococcal scalded skin syndrome, Subcorneal pustular dermatosis: close-up view.

Fig. 6.126
Subcorneal pustular
dermatosis: in addition
to neutrophils there are
scattered acantholytic
keratinocytes.
These features are
indistinguishable from
those of pemphigus
foliaceus.
subcorneal pustular dermatosis, and pustular psoriasis. In difficult cases the
demonstration of positive immunofluorescence will establish the diagnosis of
pemphigus (however, see IgA pemphigus).
There has been considerable controversy in earlier literature concerning
the relationship between subcorneal pustular dermatosis and pustular psoria-
sis, with some authors claiming them to be one and the same condition and
others equally determined that they are quite different. In our view, these are
two distinct diseases. Thus, in subcorneal pustular dermatosis, there is no
family history and there is no evidence of more typical psoriasiform lesions
elsewhere. Subcorneal pustular dermatosis responds to dapsone in the vast
majority of cases and histologically spongiform change deep to the pustule
(typical of psoriasis) is characteristically absent. Psoriasis is not associated
with monoclonal gammopathy or multiple myeloma.
Toxic erythema of the neonate
Clinical features
Toxic erythema of the neonate (erythema toxicum neonatorum, erythema neo-
natorum) is a very common self-limiting disorder affecting from 48% to 72%
of all newborn infants.1–7 There is no racial predilection but males appear
more commonly affected.2,8 It presents as an asymptomatic erythematous mac-
ular rash usually in the first 3 days of life.1,9 Occasionally, it may be evident
at birth and, exceptionally, the onset is delayed until the second week after
birth.5,6,10 Sometimes there are papules and vesicles and, in some patients, pus-
tule formation is evident. The condition most often affects the forehead, face,
chest, trunk, and extremities.1 The palms and soles are typically uninvolved.
The eruption is asymptomatic and very typically transient, with lesions often
lasting only a number of hours or days.1 Full resolution is usually achieved by
1–5 days although recurrences may occur in up to 11% of neonates.2 Toxic
erythema of the neonate is frequently associated with a peripheral blood
eosinophilia.
Pathogenesis and histological features
The etiology of this condition is completely unknown.2 While an acute graft-
versus-host type of reaction resulting from transfer of maternal lymphocytes
Infantile acropustulosis 217
during delivery was initially thought to be of pathogenetic importance, more
recent data favor an immunological response to the initial colonization of the
skin by commensal microorganisms.11–16
Early erythematous lesions show a somewhat nondescript perivascular
inflammatory cell infiltrate with conspicuous eosinophils, which may be seen
penetrating the epidermis in close proximity to hair follicles. In an established
lesion, the pustules are follicular, lie subcorneally, and contain large numbers
of eosinophils and occasional neutrophils.17 The external root sheath of the
infundibulum may also be affected.
Differential diagnosis
Toxic erythema of the neonate must be distinguished from incontinentia pig-
menti. The latter, however, is characterized by eosinophilic spongiosis, a fea-
ture not seen in toxic erythema. In miliaria rubra the vesicles are related to
sweat ducts rather than hair follicles and typically contain mononuclear cells
rather than eosinophils. Toxic erythema of the neonate must also be distin-
guished from infantile acropustulosis, transient neonatal pustular melanosis,
and infantile eosinophilic pustular folliculitis (see below).
Infantile acropustulosis
Clinical features
This uncommon condition usually presents in the first year of life and is
sometimes evident at birth.1–4 There is a marked male predilection. Although
it is most often seen in black children, it has occasionally been reported in
Asians and whites.5–8
The disorder presents as crops of intensely itchy, erythematous papules
1–5 mm in diameter, vesicles, and pustules, which are found most often on the
palms and soles, but the volar surfaces of the wrists, the ankles, the face, and
scalp may occasionally be affected (Fig. 6.127).6 The mucous membranes
are spared.1 Lesions are often present for 1–2 weeks and tend to recur every
2–4 weeks. With progression, the duration of the eruption diminishes and the
remission lasts for gradually increasing periods of time. Spontaneous resolu-
tion has usually occurred by 2–3 years of age.
Pathogenesis and histological features
The etiology and pathogenesis of this condition are unknown. However, infan-
tile acropustulosis may be associated with atopy and hypereosinophilia.6,9–11
Sometimes, a history of prior or concurrent scabies infection is present but
whether this is causal is uncertain.4
Fig. 6.127
Infantile acropustulosis: typical small pustules centered about the base of the
thumb. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
218 Spongiotic, psoriasiform and pustular dermatoses
Histology reveals a subcorneal pustule containing predominantly
­ eutrophils, although occasionally small numbers of mononuclears and
n Eosinophilic pustular folliculitis of infancy
eosinophils are evident. Eosinophil-rich pustules have also been described but
with hindsight most such cases probably represent eosinophilic pustular fol-
liculitis.11 Slight acantholysis of the adjacent epidermis has been described.12
The underlying dermis often contains a perivascular chronic inflammatory
cell infiltrate, sometimes with scattered neutrophils and eosinophils. Direct
and indirect immunofluorescence tests are negative.
Differential diagnosis
The diagnosis of infantile acropustulosis depends upon careful clinicopatho-
logical correlation. Conditions that may enter the differential diagnosis
include scabies, pompholyx, Candida and dermatophytosis, herpes simplex,
juvenile dermatitis herpetiformis, toxic erythema of the neonate, bullous
impetigo, eosinophilic pustular folliculitis occurring in infancy, and transient
neonatal pustular melanosis.
Transient neonatal pustular melanosis
Clinical features
Transient neonatal pustular melanosis is an uncommon condition which pres-
ents with vesicles and pustules on the forehead, under the chin, on the nape of
the neck, chest, back, and buttocks.1–4 In contrast to eosinophilic pustular follic-
ulitis of infancy, the scalp is rarely involved. It affects 4–5% of black infants and
0.1–0.3% of white infants.2 There is no sex predilection.3 Lesions, which present
at birth or during the first day of life, heal rapidly to leave small brown macules
with a peripheral scale, and have usually disappeared by 3 months of age.3
Histological features
Histologically, the features are identical to those of infantile acropustulosis:
i.e., a subcorneal neutrophil-rich pustule sometimes accompanied by small
numbers of eosinophils.1
Clinical features
Eosinophilic pustular folliculitis (Ofuji's disease), which is largely a con-
dition of adults and presents as recurrent episodes of itchy follicular pap-
ules and pustules on the face, trunk, and extremities, may rarely develop
in infants.1–6 There is a predilection for males.1 In the infantile form,
lesions, which may be present at birth or develop during the first 24
hours, are found particularly on the scalp, hands, and feet.1,7–10 The trunk
and limbs can also be affected.2 Patients present with 1–3-mm white
to yellow crusted pustules arising on an erythematous base.1,2 A blood
eosinophilia is often present.7,11 The condition persists from 3 months to
up to 5 years.2
Pathogenesis and histological features
The etiology is unknown, although in a small number of cases an associa-
tion with atopy has been documented.12 In contrast to the adult disease, HIV
infection is very rarely present.13
The histological features are those of an eosinophil-rich ‘spongiotic’ pus-
tule related to the outer root sheath of the hair follicle from the stratum
corneum to the level of insertion of the sebaceous duct.14–18 A heavy inflam-
matory cell infiltrate consisting of eosinophils, lymphocytes, and histiocytes
is present in the adjacent dermis. The reported histological features are, how-
ever, less distinctive and specific compared to classic, adult-type, eosinophilic
pustular folliculitis.10,19
Numerous other pustular dermatoses may be encountered including
superficial pemphigus, particularly IgA pemphigus, pustular drug reac-
tions, bullous impetigo and staphylococcal scalded skin syndrome, pustu-
lar dermatophyte infections, pustular lesions in pyoderma gangrenosum,
and necrolytic migratory erythema. These are discussed elsewhere in this
book.
 Lichenoid and interface Chapter

See
www.expertconsult.com
for references and
additional material
dermatitis
Wei-Lien Wang and Alexander Lazar
7
Lichenoid dermatoses  219 Interface dermatoses  237 Rothmund-Thomson syndrome  246
Lichen planus  219 Erythema multiforme  238 Blooms' syndrome  247
Lichen nitidus  229 Toxic epidermal necrolysis and Stevens-Johnson Cockayne's syndrome  248
Lichenoid keratosis  231 syndrome  241 Dyskeratosis congenita  248
Lichen striatus  232 Paraneoplastic pemphigus  245 Graft-versus-host disease  249
Adult Blaschkitis  233 Poikiloderma  245 Pityriasis lichenoides  255
Keratosis lichenoides chronica  234 Poikiloderma of Civatte  245
Erythema dyschromicum perstans  236 Mitochondrial DNA syndrome-associated
Lichenoid and granulomatous dermatitis  236 poikiloderma  246

The term ‘lichenoid’ refers to inflammatory dermatoses which are character-
ized by a bandlike lymphohistiocytic infiltrate in the upper dermis, hugging
and often obscuring the dermoepidermal interface. Lichen planus is the proto-
typic lichenoid dermatitis (Box 7.1). Interface dermatitis refers to the presence
of basal cell vacuolization (hydropic degeneration) and is often accompanied
by single-cell keratinocyte apoptosis (Box 7.2). These two terms are by no
means mutually exclusive as most lichenoid infiltrates are accompanied by
interface change. However, some dermatoses are characterized primarily by
interface change without a lichenoid infiltrate such as lupus erythematosus
and erythema multiforme.
Lichenoid dermatoses
Lichen planus
Clinical features
Lichen planus (Gr. leichen, tree moss) is a common, usually intensely pruritic,
symmetrical, papulosquamous dermatosis.1,2 Its prevalence in the general
population is approximately 1%, and it most often presents in the fourth to
sixth decades with a slight female predominance.3,4 It is uncommon in child-
hood.5,6 Occasional familial cases have been reported.7,8
The disease is characterized by small, smooth, shiny, flat-topped polygonal
papules measuring several millimeters to 1 cm in diameter and often having a
violaceous color (Fig. 7.1). Delicate white lines known as Wickham's striae
typically cross the slightly scaly surface (Fig. 7.2). The lesions are found
most commonly on the flexor aspect of the wrists, the forearms, the exten-
sor aspect of the hands and ankles, the lumbar area and the glans penis (Fig
7.3). Lichen planus is associated with a positive Koebner's phenomenon. It is
a usually self-limiting although sometimes protracted disorder, patients clear-
ing of lesions within weeks to 1 or 2 years.
Oral involvement, which is very common (affecting up to 60% of
patients with cutaneous disease), shows a marked female preponderance
and presents most often in the seventh decade. It may sometimes be the sole
manifestation (an estimated 15–35% of patients with oral lichen planus
never develop skin lesions).9–14 The buccal mucosa, vestibule, tongue, and
gingivae are most often affected, in decreasing order of frequency.12 Patients
frequently present with a white lacelike pattern, but papules, plaques and
erosions, ulcerated, atrophic, and bullous variants may also be found (Figs
7.4–7.6).1,15 Lesions are usually asymptomatic, although erosions and bul-
lae are sometimes tender and painful. Chronic ulcerated oral lichen planus
is of particular importance because it has been related to an increased risk,
albeit low, of developing squamous cell carcinoma (Fig 7.7). The risk of
developing malignancy is debated, with current literature suggesting that
0–12.5% of affected patients will develop an oral malignancy.12,16–22 Oral
involvement in lichen planus and its relationship to cutaneous squamous
cell carcinoma is discussed in greater depth elsewhere. Involvement of the
gums may present as desquamative gingivitis.1 Other mucous membranes
that may be involved include those of the pharynx, larynx, esophagus,
nose, anus, and genitalia.23 Familial cases of lichen planus limited to oral
involvement are noted.24
Ocular involvement is rare and may include eyelid lesions, blephari-
tis, conjunctivitis, keratitis, punctate corneal opacities, iridocyclitis, and
chorioretinitis.25,26
Esophageal involvement, although rare, is an important potential
cause of morbidity, and is the most frequently involved gastrointestinal
site.27 Concomitant oral lesions are invariably present. To date, middle-
aged or elderly females are typically affected.28–31 Complications include
chronic dysphagia and stricture formation affecting the mid or upper
esophagus.28,32–35 Patients with esophageal lichen planus may have a
risk of developing squamous cell carcinoma. The role of surveillance is
uncertain.27,28,30,31,36,37
Genital lesions in lichen planus are common (particularly in males),
being present in up to 25% of patients, and sometimes adopting an annu-
lar configuration (Fig. 7.8).1 Similar annular lichen planus may be found
elsewhere on the body, including intertriginous areas.38 Occasionally, penile
lesions are the sole expression of the disease.39 Vulval lesions may be found
in up to 51% of females with cutaneous involvement.40 Sometimes gingi-
val and female genital lesions may coexist as a variant of erosive lichen
planus, the so-called vulvovaginal-gingival syndrome.41–44 Patients present
with dyspareunia and intense burning vulval pain. The vulva appears con-
gested and there may be erosions, which are often surrounded by a white
reticulate border. Vaginal involvement similarly presents as dyspareunia
220 Lichenoid and interface dermatitis

Box 7.1
Causes of lichenoid dermatitis

• Lichen planus
• Lichenoid graft-versus-host disease
• Lichen nitidus
• Lichenoid keratosis
• Lichenoid drug reaction
• Fixed drug reaction
• Lichen planopilaris
• Lichen striatus
• Adult Blaschkitis
• Lichen aureus
• Lichenoid mycosis fungoides
• Ashy dermatoses
• Lichenoid and granulomatous dermatitis

Box 7.2 A
Causes of interface dermatitis

• Lichenoid dermatoses (see Box 1.)

• Erythema multiforme
• Stevens-Johnson syndrome/toxic epidermal necrolysis
• Connective tissue disorders: lupus erythematosus, dermatomyositis,
and mixed connective tissue disorders
• Graft-versus-host disease
• Poikiloderma including those related to rare inherited disorders
• Interface drug reactions
• Interface viral exanthem
• Pityriasis lichenoides

and often postcoital bleeding due to inflammatory, desquamative, and ero-

sive changes. More typical features of lichen planus may be encountered
elsewhere on the body. Squamous carcinoma is an important complication
of chronic vulval lichen planus.45 The development of penile cancer is rare.46
Genital involvement in lichen planus is discussed elsewhere. B
The nails are affected in about 10% of patients with lichen planus; mani-
festations include thinning of the nail plate, longitudinal ridging, striations, Fig. 7.2
pterygium formation, subungual hyperkeratosis and, very rarely, complete Lichen planus: (A) note the characteristic Wickham's striae at the edge of these
destruction of the nail (Figs 7.9).1 Although nail involvement in children is pigmented lesions; (B) Wickham's striae are evident on these lesions, which have
said to be rare, some authors regard twenty-nail dystrophy of childhood as a arisen on the back, an uncommonly affected site. (A) From the collection of the late N.P.
Smith, MD, the Institute of Dermatology, London, UK. (B) Courtesy of J. Dayrit, MD,
variant of localized lichen planus, although not all accept this hypothesis.47–51
Manila, The Philippines.

Fig. 7.1 Fig. 7.3

Lichen planus: there are typical flat-topped polygonal papules on dorsum of the Lichen planus: there is extensive bilateral involvement of the flexor aspect of
hand. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, the forearms. From the collection of the late N.P. Smith, MD, the Institute of
London, UK. Dermatology, London, UK.

Fig. 7.4
Lichen planus: this lace-like pattern is characteristic. From the collection of the late
N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig. 7.5
Lichen planus: there
is extensive ulceration
of the buccal mucosa.
By courtesy of
R.A. Marsden, MD,
St George's Hospital,
London, UK.
Most lesions of lichen planus heal within 6–18 months of onset. However,
oral and hypertrophic variants and lichen planopilaris tend to have a chronic
course. Postinflammatory hyperpigmentation, which may be very disfiguring,
is not uncommon, particularly in colored races (Fig. 7.10).
A number of variants of lichen planus merit specific mention:
• Lichen planopilaris (follicular lichen planus), presents as single or
multiple plaques of scarring alopecia associated with a spectrum of
lesions including typical lichenoid papules involving the scalp to brown
or violaceous keratotic follicular papules affecting the trunk and
extremities (Figs 7.11–7.13).52–55 Nonscarring plaques with prominent
follicular papules may also be present. Linear lesions have rarely been
described.56–58 Some authors suggest that scalp lichen planus represents
pseudopélade of Brocq.59,60 Children can also be affected. 61
• Atrophic lichen planus, the clinical features of which merely reflect
resolution of the more typical active phase.
Lichenoid dermatoses 221
Fig 7.6
Lichen planus: the tongue
is commonly affected. By
courtesy of M. Blanes,
MD, Alicante, Spain
Fig. 7.7
Lichen planus: there is an ulcerated squamous carcinoma on the lower lip. By
courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
• Lichen planus actinicus (lichen planus subtropicus, summertime actinic
lichenoid eruption (SALE)), develops in patients with prolonged exposure
to sunlight and, therefore, usually manifests in spring or summer,62–66
with improvement or remission in the autumn or winter. It occurs
particularly in the Middle East (especially Egypt) and the Far East and
affects younger people, with a maximum incidence in the second and
third decades and a slight female predominance (Fig 7.14). Affected sites
include the lateral aspects of the forehead, the dorsum of the hands, the
forearms, face, and neck. The eruption can include a mixture of lichen
planus-like and lichen nitidus-like lesions, whereas in others, the lesions
appear as purely one or the other (see actinic lichen nitidus, below).
Typically, the lichen planus lesions have an annular configuration with a
bluish-brown, rather atrophic center and slightly raised border. They may
sometimes coalesce to form circinate plaques. Occasionally, a melasma-
like appearance has been documented.66 There is usually little pruritus
and Koebner's phenomenon is commonly absent. The nails are often
unaffected.
222 Lichenoid and interface dermatitis
B Fig. 7.10
Fig. 7.8
Lichen planus: (A) typical papules are present on the shaft of the penis; (B) note the
erythematous erosions around the vulval introitus and labia minora. (A) From the
collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK;
(B) By courtesy of S. Neill, MD, Institute of Dermatology, London, UK.
• Lichen planus pigmentosus, most commonly encountered in the tropics
in dark-skinned patients, is characterized by the development of variably
pruritic pigmented dark-brown macules predominantly affecting exposed
skin and the flexures (Figs 7.15, 7.16). The most common affected sites
include the face and neck.67–72 There is no sex predilection. The disorder
is characterized by periods of exacerbation and remission.4 Exceptionally,
involvement of the oral mucosa has been documented.5
• Hypertrophic lichen planus, which represents superimposed lichen
simplex chronicus, commonly affects the lower limbs, particularly the
shins, and manifests as highly pigmented warty plaques (Fig. 7.17).73
Familial lichen planus shows an increased incidence of this variant.74
The lesions are intensely itchy and very persistent. There may be an
attendant (albeit very slight) risk of neoplastic transformation although
the evidence is weak and based largely on case reports.75
Fig. 7.9
Lichen planus: there is longitudinal ridging and striation affecting the thumbnail,
with inflammatory changes in the nail folds. From the collection of the late N.P.
Smith, MD, the Institute of Dermatology, London, UK.
Lichen planus: postinflammatory hyperpigmentation is a common manifestation.
By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
• Ulcerative lichen planus, a chronic variant affecting the fingers, hands,
soles, and toes, is often associated with permanent loss of the nails (Figs
7.18, 7.19). Squamous cell carcinoma may complicate this variant of
lichen planus.76
Other variants include lichen planus linearis, which occurs predominantly
in children, and the rare vesicular or bullous variants, which must be distin-
guished from lichen planus pemphigoides. Bullous lichen planus implies the
development of vesicles or bullae on pre-existent lichenoid lesions as a con-
sequence of severe basal cell hydropic degeneration. It is more often a histo-
logical finding rather than a clinical observation. In contrast, lichen planus
pemphigoides is characterized by the development of large tense bullae aris-
ing on normal or erythematous skin in a patient with typical lichen planus
elsewhere. It represents the combined expression of lichen planus and bullous
pemphigoid.77
Childhood lichen planus shows a modest male predominance (2:1).5,6,61,78
Although mucosal involvement is said to be rare, recent series report a fre-
quency of 14–39%.6,61,78 Hypertrophic lesions may be seen in up to 26%
of cases.6
 Lichenoid dermatoses 223

Fig. 7.13
Lichen planopilaris: follicular lichenoid papules are clearly seen in this patient. By
courtesy of the Institute of Dermatology, London, UK.

Fig. 7.11
Lichen planopilaris: there are characteristic hyperpigmented follicular papules, which
are confluent in some areas. The limbs are commonly affected. By courtesy of R.A.
Marsden, MD, St George's Hospital, London, UK.

Fig. 7.14
Lichen planus actinicus: there is marked facial hyperpigmentation representing
postinflammatory changes. From the collection of the late N.P. Smith, MD, the
Institute of Dermatology, London, UK.

Fig. 7.12
Lichen planopilaris: marked inflammatory changes with scarring and secondary hair
loss. These changes are difficult to distinguish from those of pseudopélade and
chronic discoid lupus erythematosus. From the collection of the late N.P. Smith,
MD, the Institute of Dermatology, London, UK.

Pathogenesis and histological features

The etiology of lichen planus is unknown. Theories of infectious (bacterial
and viral), autoimmune, metabolic, psychosomatic, and genetic causes have
all had their proponents. Currently, however, it is thought that lichen planus
represents an abnormal delayed hypersensitivity reaction to an as yet undeter-
mined epidermal neoantigen, possibly to a combination of an external anti- Fig. 7.15
gen coupled with an internal self-antigen.79,80 The association of lichen planus Lichen planus pigmentosus: there are coalescent pigmented papules. From the
with a number of viral infections including hepatitis B and C and human collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
224 Lichenoid and interface dermatitis
Fig 7.16
Lichen planus pigmentosus: the face is a commonly affected site. From the
collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig. 7.17
Hypertrophic lichen planus: raised, warty, violaceous plaques on the shin of an
elderly man. These lesions had been present for 30 years. By courtesy of R.A.
Marsden, MD, St George's Hospital, London, UK.
Fig. 7.18
Ulcerative lichen planus: there is marked atrophy of the skin around this crusted
ulcer. By courtesy of the Institute of Dermatology, London, UK.
Fig. 7.19
Ulcerative lichen planus: the digits are often affected. This variant is associated with
a slightly increased risk of squamous cell carcinoma. By courtesy of R.A. Marsden,
MD, St George's Hospital, London, UK.
­immunodeficiency virus (HIV), combined with the well-recognized relationship
to numerous drugs, adds support to this hypothesis.81–83
Lichen planus is associated with a variety of liver cell abnormalities including
aberrant liver function tests and serology.84,85 An increased incidence of chronic
active hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis has
also been recorded.86–91 Not all documented series, however, have confirmed
these observations, suggesting that the reported relationship may be dependent
upon the background level of hepatitis B virus infection.89 Lichen planus has
also followed hepatitis B vaccination.92–95 More recently, lichen planus (particu-
larly oral disease) has been linked to hepatitis C virus and chronic liver disease.
The incidence of hepatitis C virus in patients with lichen planus is, however,
very variable, ranging from effectively zero in some populations, including the
United Kingdom, India, and Slovenia, to as high as 100% in Japan.96–101
Evidence of other disorders including thyroid disease, dyslipidemia, and
impaired carbohydrate metabolism including overt diabetes mellitus has also
been documented in lichen planus, particularly the oral variant.102–110 A recent
study from Japan suggests a possible association of hepatitis C infection with
both diabetes and lichen planus.109
A significant association between lichen planus and human leukocyte anti-
gen (HLA)-DR1 and HLA-DQ1 has been noted by a number of authors.111–117
This association pertains to patients with or without mucosal lesions but does
not extend to patients with the drug-induced variant. It is suggested that this
association relates to antigen presentation by HLA-DR1+ cells to T-helper
cells with the resultant development of an autoimmune response.111
Although it is generally accepted that the pathogenesis of the basal cell
damage in lichen planus primarily involves the cellular immune response, the
precise mechanism(s) require further elucidation. It is unlikely that autoan-
tibody and immune complex-mediated damage have a significant role in the
lichenoid tissue reaction.79,80
The initial event in the evolution of the lichen planus papule is destruction
of the basal epidermal layer (keratinocytes and melanocytes).118,119 In the ear-
liest stage of development, increased numbers of Langerhans cells are present
within the epidermis and it is believed that these cells process modified epi-
dermal antigens for presentation to T lymphocytes.120 Keratinocytes express
HLA-DR and this is likely to be of pathogenetic importance. Subsequent
migration with resultant CD8+ T-cell activation results in basal keratinocyte
death due to the combined effects of interferon-gamma (IFN-γ), interleukin
(IL)-6, granulocyte-macrophage colony stimulating factor (GM-CSF), and
tumor necrosis factor alpha (TNF-α).81–83,121 The expression of FasR/FasL by
the basal keratinocytes suggests that apoptosis is an important mode of cell
death in lichen planus.122 The dermal infiltrate consists predominantly of Ia+,
CD4+ lymphocytes.120,123 CD8+ lymphocytes are also present in close appo-
sition to the dermoepidermal junction adjacent to foci of basal keratinocyte
necrosis and are said to predominate in early lesions.121,123–125 B lymphocytes
are scarce and plasma cells are characteristically absent in cutaneous lesions,
except in the hypertrophic variant.
 Lichenoid dermatoses 225

Development of the typical papule appears to be due to a combination

of continued keratinocyte destruction and regenerative activity, with the lat-
ter depending upon the migration of epithelium from the edge of the lesion
and from adjacent eccrine ducts, rather than from increased mitotic activ-
ity. There is little uptake of tritiated thymidine at the site of basal cell dam-
age, but conspicuous uptake at the edges of the lesion and, as a reflection
of regeneration, keratin 17 expression is also up-regulated in the suprabasal
epithelium.126 The typical features of lichen planus therefore depend upon a
variable interplay between basal cell liquefactive degeneration and irregular
epidermal regeneration.
The earliest identifiable change in lichen planus is the presence of cytoid
bodies and associated pigmentary incontinence. Cytoid bodies (colloid or
Civatte bodies) are round or oval, homogeneous, eosinophilic bodies identifi-
able within the basal epithelium and the papillary dermis (Fig. 7.20). They
display diastase-resistant periodic acid-Schiff (PAS) positivity, and may be
identified within papules, perilesional skin, and even apparently uninvolved
skin. Although they may be seen in a variety of dermatoses (including lupus
erythematosus, graft-versus-host disease, and poikiloderma) and seemingly
normal skin, where their presence, if either in large numbers or in a cluster,
suggests lichen planus. Fig. 7.21
Lichen planus: this scanning view is characteristic and highlights the hyperkeratosis,
Ultrastructurally, cytoid bodies are composed of tightly arranged aggre-
hypergranulosis, and irregular acanthosis. Note the typical bandlike inflammatory
gates of filaments 6–8 nm in diameter; immunocytochemically they are com-
cell infiltrate and pigment incontinence.
posed of keratin.
Characteristic histological features of an established papule can usually
be recognized at scanning magnification (Fig. 7.21). They comprise hyper-
keratosis, typically wedge-shaped hypergranulosis (clinically presenting as
Wickham's striae) related to the intraepidermal components of sweat ducts
and hair follicles, and irregular acanthosis (Figs 7.22, 7.23). The acantho-
sis often has a saw-toothed appearance (Figs 7.24, 7.25). The presence of
prominent parakeratosis argues strongly against a diagnosis of lichen planus.
Lymphocytes and histiocytes may sometimes be seen in the epidermis and
very occasionally satellite cell necrosis is a feature. Liquefactive degeneration
of the basal layer of the epithelium is characteristic and often subepidermal
clefts are present (Max Joseph spaces). Pigmentary incontinence is common
(Fig. 7.26). A lymphohistiocytic bandlike infiltrate occupies the upper dermis
and obscures the dermoepidermal junction. Hyperkeratosis persists in resolv-
ing lichen planus, but the acanthosis regresses, leaving a flattened epidermis
(Fig. 7.27); there may be focal scarring and the dermal infiltrate is less con-
spicuous (Fig. 7.28).
Lesions may become completely atrophic and histologically there is flat-
tening of the epidermis, variable number of colloid bodies, and pigment
incontinence with almost no inflammation. If colloid bodies are rare, distinc-
tion from poikiloderma may be very difficult. Fig. 7.22
Lichen planus: note the hyperkeratosis, hypergranulosis, and irregular acanthosis.

Fig. 7.20 Fig. 7.23

Lichen planus: this view shows characteristic eosinophilic cytoid bodies associated Lichen planus: the hypergranulosis is clearly related to the acrosyringium. There is
with basal cell liquefactive degeneration and a lymphohistiocytic infiltrate. marked basal cell liquefactive degeneration. Note the fibrin deposition.
226 Lichenoid and interface dermatitis

Fig. 7.24 Fig. 7.27

Lichen planus: the acanthosis is irregular and often has a saw-toothed appearance. Atrophic (resolving) lichen planus: there is hyperkeratosis, epidermal flattening, and
a slight residual lymphohistiocytic infiltrate.

Fig. 7.25
Lichen planus: close-up view of Figure 7.24 showing basal cell liquefactive
degeneration and cytoid bodies.
Fig. 7.28
Atrophic (resolving) lichen planus: in addition to the lymphohistiocytic infiltrate,
there are excessive numbers of fibroblasts and increased papillary dermal collagen.

In lesions of annular lichen planus the typical histologic features are only
seen in the periphery at the advancing edge of the lesion.
In micropapular lichen planus the changes are so focal that the diagnosis
may be missed if serial sections are not examined.
Lichen planopilaris in its early stages shows an infiltrate surrounding the
lower hair follicle and papilla, follicular dilatation, and keratin plugging (Fig.
7.29).52,54 The adjacent interfollicular epithelium may or may not show a typ-
ical lichenoid infiltrate (Fig. 7.30). Basal cell hydropic degeneration, cytoid
body formation, and pigmentary incontinence are also sometimes evident. In
advanced scalp lesions, the hair follicles are destroyed and replaced by ver-
tically orientated fibrous scars, reminiscent of the fibrous streamers seen in
pseudopélade of Brocq.
Lichen planoporitis represents a rare variant in which lichenoid/interface
changes are centered on the acrosyringium and eccrine sweat duct as it enters
the epidermis. Squamous metaplasia of the ductal lining epithelium may be
a feature.127
Fig. 7.26 In lichen planus actinicus, the annular borders of the macules show typi-
Lichen planus: melanin pigment is present within macrophages (pigmentary cal features of lichen planus. In the center of the lesions, however, the epithe-
incontinence). lium is atrophic, thin, and flattened, although the lymphohistiocytic infiltrate
 Lichenoid dermatoses 227

A B

Fig. 7.29
Lichen planopilaris: (A, B) there is marked follicular dilatation and plugging accompanied by a bandlike folliculocentric infiltrate. This patient presented with scarring alopecia
and typical lichen planus lesions elsewhere.

B
A

Fig. 7.30
Lichen planopilaris: (A, B) there is a strikingly folliculocentric bandlike infiltrate associated with keratin plugging. The interfollicular epidermis is unaffected.

remains. Foci of parakeratosis and eczematization within the follicular epi-

thelium have also been described. Lichen nitidus-like lesions may sometimes
be seen (see below).
Lichen planus pigmentosus is characterized by epidermal thinning accom-
panied by basal cell vacuolization, pigmentary incontinence, and a superficial
dermal lichenoid lymphohistiocytic infiltrate.4
Hypertrophic lichen planus is characterized by more marked hyperkera-
tosis and acanthosis, with the epithelium sometimes showing pseudoepithe-
liomatous hyperplasia such that misdiagnosis as squamous cell carcinoma is
a distinct possibility, particularly if clinical information is not available (Figs
7.31–7.33).73 A number of changes not seen in ordinary lichen planus may be
observed and include parakeratosis, spongiosis, necrotic keratinocytes above
the basal cell layer, and eosinophils and plasma cells in the dermal infiltrate.
These changes may raise the possibility of a lichenoid drug eruption. The dif-
ferential diagnosis is not difficult, as lichenoid drug eruptions tend to be more
generalized and are not usually associated with hypertrophic changes.
The oral lesions of lichen planus, although often displaying the classical
features, may show parakeratosis; occasionally, alternate foci of both are Fig. 7.31
evident. In contrast to the cutaneous lesions, the epithelium is sometimes Hypertrophic lichen planus: note the hyperkeratosis, focal wedge-shaped hypergranulosis,
rather thin and the saw-toothed pattern indistinct. There is typically basal very marked irregular acanthosis, and superficial dense bandlike infiltrate.
228 Lichenoid and interface dermatitis
Fig. 7.32
Hypertrophic lichen planus: there is very marked irregular acanthosis. Note the
hypergranulosis.
Fig. 7.33
Hypertrophic lichen
planus: there is basal cell
liquefactive degeneration
with cytoid bodies.
cell hydropic degeneration. Basement membrane thickening due to the depo-
sition of fibrin-rich eosinophilic amorphous material is commonly present.
The cellular infiltrate, in addition to lymphocytes and histiocytes, frequently
contains plasma cells. Dysplasia may be seen.
Unlike skin involvement, esophageal lesions show parakeratosis. Variable
epithelial atrophy and/or mild thickening are usually seen and the saw-toothed
pattern of acanthosis is not a feature.28,32–34 As with oral lesions, plasma cells
often accompany the lymphocytic infiltrate.
Vesicular or bullous lesions are subepidermal and occur due to excessive
edema developing in association with the basement membrane zone damage
complicating basal cell hydropic degeneration (Fig. 7.34).
Fig. 7.34
Bullous lichen planus: oral lesion showing separation of the squamous epithelium
from the lamina propria. Note the bandlike infiltrate.
Fig. 7.35
Lichen planus: brilliant
green fluorescence
indicates the presence
of fibrin. By courtesy
of the Department of
Immunofluorescence,
Institute of Dermatology,
London, UK.
Direct immunofluorescence studies on skin biopsies from patients with
lichen planus usually reveal a linear fibrillar band of fibrin at the dermoepi-
dermal junction (Fig. 7.35). The cytoid bodies may be highlighted non-
­specifically by the use of antisera, mainly to IgM, but also to IgG, IgA and C3
(Fig. 7.36). A lichen planus ‘specific antigen’, which is present in the prickle
cell and granular cell layers, has been demonstrated by indirect immunofluo-
rescence of patients' serum with fetal skin.128 Whether this is of pathogenetic
significance is unknown. Direct immunofluorescence of lichen planopilaris
reveals follicular, linear basement membrane zone labeling with immunoglob-
ulin (primarily IgG or IgA).129 Fibrin may also be present. The nosological
implications of this observation are uncertain. Indirect immunofluorescence
for circulating antibasement membrane zone antibodies is negative.
 Lichenoid dermatoses 229

i­nterferon-alpha therapy.8,9 Occasionally, papules may be encountered on the

palms and soles.3–12 Familial cases have been rarely described.13,14 Lichen niti-
dus can spontaneously resolve within a few months or persist indefinitely.2
Mucous membrane involvement presenting as grayish-yellow papules has
also been described.4 Nail involvement, which is extremely rare, presents as
thickening with ridges, rippling, terminal splitting, striations, and pits.2,4
Keratodermic, vesicular, hemorrhagic, purpuric, and perforating variants
may rarely be encountered.2,15–19 Perforating lichen nitidus shows a predilec-
tion for the forearms and fingers and may be trauma related.17,20
Actinic lichen nitidus refers to the development of lichen nitidus on sun-
exposed sites, usually during the summer months. In some cases, involvement
is predominantly facial and it may present in black patients.21 It shows con-
siderable overlap with actinic lichen planus (see above).22,23

Fig. 7.36
Lichen planus: cytoid
bodies labeled positively
for IgM. By courtesy
of the Department of
Immunofluorescence,
Institute of Dermatology,
London, UK.

Differential diagnosis
Lichen planus should be differentiated from other diseases showing a
lichenoid infiltrate and hydropic degeneration of the basal layer of the epi-
thelium.130 Thus lichen planus may be indistinguishable from lichenoid Fig. 7.37
keratosis and their distinction is entirely dependent on clinicopathological Lichen nitidus: numerous tiny papules are present on the chest of a young child.
correlation. In many cases of lichenoid keratoses, there are other associated By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
changes including focal spongiosis and parakeratosis. Atrophic lesions may
be confused with poikiloderma and chronic discoid lupus erythematosus. A
lichen planus-like morphology is typical of the early stages of chronic graft-
versus-host disease (GVHD).
Poikiloderma shows epidermal atrophy, with loss of the ridge pattern and
no tendency to a saw-toothed appearance. In those examples associated with
mycosis fungoides, the lichenoid infiltrate contains variable numbers of atypi-
cal lymphocytes and mycosis fungoides cells.
Chronic discoid lupus erythematosus is associated with epidermal atro-
phy and follicular plugging. The inflammatory cell infiltrate is patchy with a
tendency to periappendageal location. A positive lupus band test is a helpful
discriminator.
Lichen planus may easily be mistaken for a lichenoid drug reaction, par-
ticularly in the absence of clinical information. Histological features favoring
the latter include high-level cytoid bodies and eosinophils within the dermal
infiltrate.

Lichen nitidus
Clinical features
Lichen nitidus is a rare but distinctive dermatosis, which shows an equal sex
incidence.1 Children and young adults are predominantly affected. It presents Fig. 7.38
clinically as an eruption of pinhead-sized, flesh-colored, shiny, flat-topped Lichen nitidus: numerous
tiny papules are present
or dome-shaped papules and shows a predilection for the arms, chest, abdo-
on the penis. The genitalia
men, and genitalia (Figs 7.37, 7.38).1–5 A positive Koebner's phenomenon are commonly affected.
is typically present.5 The condition is usually localized and asymptomatic, From the collection of the
although occasionally there may be mild or even intense pruritus.2 Rarely, late N.P. Smith, MD, the
generalized lesions have been described.2,6,7 An association with generalized Institute of Dermatology,
lesions and Down's syndrome has been documented, as has been a case after London, UK.
230 Lichenoid and interface dermatitis

Histological features
Lichen nitidus is recognizable by a characteristic histology in many cases. The
classic papule is sharply circumscribed and occupies the space of only four
or five dermal papillae. It is often depressed in the center and composed of
atrophic epidermis, frequently covered by a parakeratotic tier and overlying
a cellular infiltrate (Figs 7.39–7.42). Clawlike extensions of epidermal ridges
mark the lateral boundaries of the lesion. The epithelium shows basal cell
hydropic degeneration, and cytoid bodies may be a feature. The inflamma-
tory component consists of lymphocytes, histiocytes, and variable numbers
of epithelioid cells. Giant cells are sometimes a feature and true granulomata
may occasionally be found, although caseation is never present.24 In addition
to red blood cell extravasation, purpuric variants may show increased vascu-
larity with vessel wall thickening and hyalinization.18 In rare cases, a promi-
nent lymphocytic inflammatory infiltrate can extend down the hair follicle
and eccrine glands, making the distinction from lichen striatus challenging.24
A follicular variant of lichen nitidus may be seen and mimics lichen spinulo-
sus histologically.25 However, rarely, lichen nitidus and lichen spinulosus may
coexist clinically.26
Fig. 7.41
Lichen nitidus: the infiltrate consists of lymphocytes, histiocytes, and epithelioid
cells. Ill-defined noncaseating granulomata are not uncommon.

Fig. 7.39
Lichen nitidus: scanning view showing a typical small, circumscribed lesion occupying
only a couple of dermal papillae. Note the clawlike epidermal lateral borders.
Fig. 7.42
Lichen nitidus: there are multiple lesions of lichen nitidus with an associated
granulomatous component. The patient also had typical lichen planus lesions. By
courtesy of R. Margolis, MD, St Elizabeth's Hospital, Boston, USA.

Palmar lesions may be identical to those seen elsewhere or show a more

diffuse bandlike upper dermal lymphohistiocytic infiltrate with associated
giant cells and focal parakeratosis.3,10–12,27
Fibrin can be detected at the basement membrane zone by immunoflu-
orescent techniques, but immunoglobulin deposition is not a feature.28,29
Immunophenotypic studies show that there is a marked excess of CD4+
cells (helper/inducer T cells) over CD8+ cells (cytotoxic/suppressor T cells).28
Langerhans cells are conspicuous.30 These findings are similar to those
described for lichen planus.
Ultrastructural examination reveals rather non-specific findings includ-
ing epidermal intercellular edema, subepidermal edema, colloid bodies,
decreased numbers of desmosomes, and disruption or reduplication of the
lamina densa.31–33 Perivascular electron-dense deposits (the nature of which is
unknown) have been described in purpuric variants.8

Comment
Lichen nitidus may coexist with lichen planus or predate it and lichen niti-
Fig. 7.40 dus-like lesions may be found in patients with typical lichen planus, but it is
Lichen nitidus: note the parakeratosis and bandlike infiltrate. unlikely that the conditions are closely related.34,35 Wickham's striae are not
 Lichenoid dermatoses 231

a feature of lichen nitidus and mucosal involvement is exceptional.2,4 Lichen
nitidus is associated with parakeratosis and epidermal atrophy, in contrast
to the orthohyperkeratosis and acanthosis seen in lichen planus. The saw-
toothed appearance of the lower border of the epidermis seen in lichen planus
is not a feature of lichen nitidus and immunofluorescence for immunogloblins
is negative. Epithelioid cells and giant cells are characteristic of lichen nitidus
and are not typically a feature of lichen planus. Three patients with Crohn's
disease were reported to develop lichen niditus; however it remains to be
seen if lichen nitidus is truly an extragastrointestinal finding of this disease.36
Another patient developed lichen nitidus after hepatitis B vaccine injection.37
The significance of this is uncertain.
Lichenoid keratosis
Clinical features
Lichenoid keratosis (benign lichenoid keratosis, lichen planus-like keratosis,
solitary lichen planus) is not uncommon and usually presents as a solitary,
0.3–2-cm diameter, sharply demarcated, erythematous, violaceous, tan or
brown papule or plaque (Fig. 7.43).1,2 Occasionally, multiple lesions may
be present.2,3 It is usually of short duration and shows a predilection for the
face (particularly the cheeks and nose), neck, upper trunk (especially the pre-
sternal area), forearm, and dorsum of the hand.2,4–8 The surface is often scaly.
Lesions are commonly asymptomatic, but mild pruritus has sometimes been
documented.8 Patients are frequently Caucasian, but occasionally blacks are
affected.2,7,8 Females develop these lesions more commonly than males, usu-
ally in their fourth to seventh decades.2,5
Lichenoid keratosis is often clinically misdiagnosed as a seborrheic ­keratosis,
superficial basal cell carcinoma, squamous cell carcinoma, actinic keratosis or
Bowen's disease.5
expression, suggesting the absence of localized antigenic stimulation as seen
in lichen planus.2,12 These studies suggest that lichenoid keratosis is an entity
distinct from lichen planus despite the similarities in histology.
Despite this, histologically, as its name suggests, the features are similar to
those of lichen planus. Thus there is hyperkeratosis, wedge-shaped hypergran-
ulosis, variable acanthosis, and basal cell liquefactive degeneration sometimes
accompanied by lymphocytic exocytosis (Figs. 7.44, 7.45).2,3,5 Foci of parak-
eratosis are also frequently seen.1,2 Although the saw-toothed acanthosis of
lichen planus is sometimes evident, more often the epithelium merely shows
broadened, widened, and irregular epidermal ridges.4 The basal epidermal
layers may sometimes show very minor degrees of cytological atypia, includ-
ing cellular and nuclear enlargement with conspicuous nucleoli, but these
changes represent regenerative phenomena.3 Dysplasia as seen in lichenoid
actinic keratosis is not a feature of a lichenoid keratosis. Colloid bodies are
usually conspicuous in both the epidermis and dermis and pigmentary incon-
tinence is often marked (Figs 7.46–7.48).1,2,7 Apoptotic keratinocytes can
be prominent and may be associated with inatraepidermal blister formation
with subepidermal vesiculation. Epidermal pallor and dermal edema can be
seen in cases with only slight or no acanthosis and an interface population of
lymphocytes along the junction with vacuolar degeneration. Foci of atrophy
can be occasionally encountered.2 In some cases a combination of lichenoid
and spongiotic changes may be seen.

Pathogenesis and histological features

The precise nature of lichenoid keratosis is uncertain. In the past, it was
regarded as a solitary lesion of lichen planus or thought to have an actinic
pathogenesis.9–11 It was also proposed to represent an immunological or regres-
sive response to a pre-existent epidermal lesion similar to the phenomenon
encountered with a ‘halo’ nevus.2 The frequent association of solar lentigines
or, less commonly, seborrheic keratoses in the adjacent epithelium has been
cited as evidence in favor of this hypothesis.4–6,8 Recent studies have shown
that the lymphocytic infiltrate in lichenoid keratosis to be immunophenotypi-
cally distinct from lichen planus. The lymphocytes in lichenoid keratosis are
predominantly CD8-reactive in contrast to lichen planus. More CD20-positive
B cells are usually seen in lichenoid keratosis. Furthermore, the lymphocyte Fig. 7.44
infiltrate in lichenoid keratosis lacks the cutaneous ­lymphocyte antigen (CLA) Lichenoid keratosis: scanning view showing hyperkeratosis, hypergranulosis,
irregular acanthosis, and a bandlike chronic inflammatory infiltrate.

Fig. 7.43 Fig. 7.45

Lichenoid keratosis: there is scaling overlying a slightly raised erythematous plaque. Lichenoid keratosis: in this field there is basal cell liquefactive degeneration. Cytoid
By courtesy of the Institute of Dermatology, London. bodies are present.
232 Lichenoid and interface dermatitis
A dense chronic inflammatory cell infiltrate is typically present in the
superficial dermis. Although this characteristically has a lichenoid distri-
bution, on some occasions it may be more discrete and predominantly
perivascular in location.4,7 The infiltrate consists largely of lymphocytes and
histiocytes, but small numbers of plasma cells and eosinophils are occasion-
ally present. Exceptionally, a few atypical lymphocytes (enlarged with hyper-
chromatic, irregular, contoured nuclei) which are CD30 and CD3 reactive
can be also seen.2 The adjacent dermis sometimes shows lentigo and solar
elastosis, which is usually mild if present. Features suggestive of mycoses
fungoides such as Pautrier abscesses, dermal–epidermal tagging and mild
lymphocytic atypia have been rarely noted in benign lichenoid keratosis.13
Clinicopathological correlation and careful follow-up are essential in such
cases to avoid misdiagnosis.
Immunofluorescence findings, which are similar to those of lichen planus,
comprise deposits of IgM and, less commonly, IgG outlining cytoid bodies.5
Differential diagnosis
Many conditions show lichenoid histology and therefore come into the differ-
ential diagnosis. Most prominently, these include lichen planus and lichenoid
drug reactions.
If clinical information is available, differentiation from lichen planus
should present little difficulty. Lichen planus is characterized by large num-
bers of lesions in contradistinction to the single papule or plaque of lichenoid
Fig. 7.46
Lichenoid keratosis: in this early lesion, there is more uniform acanthosis.
Fig. 7.47
Lichenoid keratosis: there is interface change with cytoid bodies.
Fig. 7.48
Lichenoid keratosis: basal cell liquefactive degeneration is evident in addition to
cytoid bodies. Note the parakeratosis.
keratosis. In addition, lichen planus is usually itchy. Parakeratosis and dermal
plasma cells with eosinophils are not a feature of lichen planus, but are typi-
cal of lichenoid keratosis.7
Both actinic keratoses and squamous cell carcinoma in situ may some-
times show a lichenoid inflammatory cell reaction. Dysplasia by definition
is not a feature of lichenoid keratosis.1,2 Inflamed seborrheic keratosis and
porokeratosis can have a prominent lichenoid reaction. The absence of
horn cyst formation, squamous epidermal eddies, and laminated stratum
corneum keratin helps distinguish these lesions from seborrheic keratosis,
while the absence of cornoid lamella excludes porokeratosis. Melanocytic
lesions with halo phenomenon can become a diagnostic consideration and
require examination of the dermis and dermoepidermal junction for mel-
anocytic nests. In difficult cases, additional step sections or S-100 protein
immunohistochemical study can prove useful. Finally, the presence of scat-
tered CD30-positive lymphocytes in some cases of lichenoid keratosis may
raise the histological differential diagnosis of lymphomatoid papulosis.
However, the paucity of these enlarged CD30-positive cells, the absence of
a deep infiltrate, and the clinically history of a solitary lesion is reassuring
for lichenoid keratosis.2
Lichen striatus
Clinical features
Lichen striatus (Blaschko linear acquired inflammatory skin eruption
(BLAISE)) is an uncommon, usually asymptomatic, dermatosis of unknown
etiology, affecting the limbs or neck in which lesions typically follow Blaschko's
lines.1–8 Infrequently, the condition is pruritic.6–9 It is self-limiting, normally
disappearing within months to a year of onset. It shows a female predomi-
nance (2–3:1) and, although it may occur at any age, it most often presents
in children aged 5–15 years.2,5,7,8 Rarely, lichen striatus has been described
in adults (adult Blaschkitis, see below).4,10,11 Occurrence during pregnancy is
very rare.12 A family history is rarely encountered, suggesting a genetic pre-
disposition and/or a common environmental etiology in such cases.2,6,8,13,14 It
is associated with seasonal variation with most series reporting the majority
of patients presenting in spring and summer,2,7 with the exception of one large
series where the majority of patients presented in the winter 8,13 Case cluster-
ing has been documented.2
Lesions, usually solitary and unilateral, present as erythematous or flesh-
colored lichenoid or sometimes psoriasiform scaly papules, which coalesce
into a continuous or interrupted linear or curved band, 1–3 cm wide and
often covering the whole length of a limb, either lower or upper extremi-
ties (Figs 7.49, 7.50).2,8 Occasionally, multiple lesions have been recorded,
as has bilaterality.8,15,16 Presentation at two different sites and at multiple
 Lichenoid dermatoses 233

sites may exceptionally occur.17 Nail changes, which may affect a single nail,
include onycholysis, longitudinal ridging, splitting, and nail loss.8,1,18,19 An
exceptional case of lichen striatus with bilateral nail dystrophy has been
described.20 Lichen striatus is not associated with Koebner's phenomenon.
Hypo- or hyperpigmentation sometimes follows resolution, which may be
marked in people with pigmented skin.8 Lichen striatus is associated with
atopy in up to 60% of patients.1,6–8

Pathogenesis and histological features

The etiology of this condition is unknown although case cluster-
ing and seasonality raises the possibility of an environmental or infec-
tive basis in conjunction with an abnormal host response.2,21 The
development of lesions along Blaschko's lines also raises the possi-
bility of a cell-mediated autoimmune reaction to an abnormal clone
of cells. Blaschko's lines are believed to represent the direction along
which epidermal growth centers expand during early skin develop-
ment.1 It has been suggested that the distribution of lesions in lichen
striatus may reflect a postzygotic abnormality such as somatic mutation
affecting localized stem cells.1 An intriguing case following trauma in
an adult has been reported.22 Further exceptional cases associated with
solarium use, varicella infection, and hepatitis B vaccine have been
described.23–25
The histological features of lichen striatus may be non-specific and show
changes of mild chronic non-specific dermatitis.26 In an established lesion,
however, the changes often consist of an admixture of spongiotic dermatitis
with lichenoid and interface features (Fig. 7.51).27 Thus, there is often par-
akeratosis with a normal or slightly acanthotic epidermis accompanied by Fig. 7.50
intercellular edema, lymphocytic exocytosis, and keratinocyte necrosis (Figs Lichen striatus: the arms
are sometimes affected.
7.52–7.54). Satellite cell necrosis may sometimes be a feature and transepi-
The condition most often
dermal elimination of keratinocyte debris (perforating lichen striatus) has presents in children. By
occasionally been documented.4,28 Intraepidermal Langerhans cell vesicles courtesy of the Institute
have exceptionally been described.27 A heavy lymphohistiocytic infiltrate is of Dermatology, London,
present in the superficial dermis and also surrounds the vessels of the superfi- UK.
cial and deep vascular plexuses and sometimes also the cutaneous adnexae.4,27
Eosinophils and plasma cells are uncommon.27

Some biopsies may be indistinguishable from lichen planus. In those

cases where there is follicular involvement, the features can resemble
those of lichen planopilaris, and old lesions sometimes simulate lichen
nitidus.
By immunohistochemistry, the majority of the intraepidermal lympho-
cytes are of a CD8+ cytotoxic phenotype.4,27 The dermal lymphocytes
consist of an admixture of CD4+ and CD8+ subtypes. CD7 is typically
conserved.25 Intraepidermal Langerhans cells may be normal, increased or
decreased.27
Nail changes include slight spongiosis with exocytosis, focal hyper-
granulosis, dyskeratosis, and a bandlike lymphohistiocytic infiltrate
affecting the proximal nail fold, nail bed, and nail matrix dermis.18

Adult Blaschkitis
Clinical features
Adult Blaschkitis (acquired relapsing self-healing Blaschko dermatitis) is a
rare, relapsing linear eruption with a mean age of onset of 40 years, predomi-
nantly affecting males.1–14 Lesions, which are pruritic papules and vesicles,
Fig. 7.49 affect multiple sites, particularly the trunk, following Blaschko's lines and
Lichen striatus: a typically resolve in days or weeks.1 The condition, which may be unilateral or
linear band of scaly more commonly bilateral, recurs over the ensuing months or years.
hyperpigmented papules
is present on the inner Pathogenesis and histological features
aspect of the leg, a
commonly affected
The etiology is unknown. Abnormalities in chromosome 18 in cells from
site. By courtesy of involved skin in comparison to normal-appearing skin has been described
R.A. Marsden, MD, in a female patient with adult Blaschkitis, supporting a link with cutaneous
St George's Hospital, genetic mosaicism.13 Association with a drug has been cited in one case and
London, UK. emotional stress has been reported to precede relapses.11,12
234 Lichenoid and interface dermatitis

Fig. 7.51 Fig. 7.53

Lichen striatus: scanning view showing hyperkeratosis, focal parakeratosis, and Lichen striatus: there is
irregular acanthosis. A heavy inflammatory cell infiltrate is present in the upper spongiosis and marked
dermis. There is conspicuous pigmentary incontinence. Case courtesy of S. Lyle, lymphocytic exocytosis.
MD, Beth Israel Deaconess Medical Center, Boston, USA. Case courtesy of S.
Lyle, MD, Beth Israel
Deaconess Medical
Center, Boston, USA.

Fig. 7.52 Fig. 7.54

Lichen striatus: note the
Lichen striatus: in this field, there is parakeratosis, hyperkeratosis, spongiosis, and
spongiosis, basal cell
interface change. Note the pigment incontinence and intense chronic inflammatory
liquefactive degeneration,
cell infiltrate. Case courtesy of S. Lyle, MD, Beth Israel Deaconess Medical Center,
and pigmentary
Boston, USA.
incontinence. Case
courtesy of S. Lyle, MD,
Beth Israel Deaconess
Medical Center, Boston,
USA.

Histologically, adult Blaschkitis is characterized by spongiotic changes;

lichenoid features are absent and no deep involvement of adnexal structures
is seen.6,8 A rare case with interface changes has been reported.10
Differential diagnosis
It resembles lichen striatus and it has been suggested that there is no justifi-
cation for separating the two entities.15 However, it differs clinically by the
presence of vesicles, its truncal distribution, and relatively rapid resolution.
Relapsing courses are typical. Pruritus is rare in lichen striatus. Lichen stria-
tus predominantly affects young children although rare cases similar to adult
Blaschkitis but affecting children have been described.
Keratosis lichenoides chronica
Clinical features
Keratosis lichenoides chronica (Nekam's disease, lichen ruber verrucosus et
reticularis) is a very rare, chronic inflammatory dermatosis that combines
the features of a seborrheic dermatitis-like eruption of the scalp and face
with a progressive lichenoid papulonodular dermatosis affecting the trunk,
buttocks, and limbs.1–6 Patients usually present in the third to fifth decades
although exceptionally reports of pediatric involvement have been docu-
mented, some with possible familial association.7–9 It is usually persistent and
 Lichenoid dermatoses 235

typically does not respond to treatment although improvement in the summer

may sometimes be seen.5
Facial and scalp lesions are erythematous, greasy and scaly, and bear no
resemblance to those found on the trunk and extremities, which are ery-
thematous or violaceous lichenoid scaly papules in a confluent, reticulate,
or linear distribution. The latter may suggest Koebner's phenomenon (Figs
7.55, 7.56). Papulonodular and infiltrated plaques are sometimes also pres-
ent. Lesions are typically bilateral, symmetrical, and usually asymptomatic
although rarely pruritus may be intense. Scarring is not a feature. Associated
features include oral papules and ulceration, ocular lesions (blepharitis, con-
junctivitis, anterior uveitis, and iridocyclitis), laryngeal nodules, palmoplantar
keratoderma, and nail changes including yellow discoloration and dystro-
phy (longitudinal ridging, nail plate thickening, onycholysis, and paronychia)
(Fig. 7.57).1,10–14 Genital involvement including penile and scrotal papules,
chronic balanitis, and phimosis has been documented.6,10,11
Keratosis lichenoides chronica has been described in association with a
number of systemic diseases including chronic infections (toxoplasmosis,
tuberculosis, and viral hepatitis), kidney disease, and lymphoma.3,15–17

Pathogenesis and histological features

Although the precise nature of keratosis lichenoides chronica is uncertain,
some authors regard it as a variant of hypertrophic lichen planus.10,18
Histologically, the lichenoid eruption is characterized by hyperkeratosis
and parakeratosis, variable acanthosis, and epidermal atrophy associated
with a bandlike lymphohistiocytic infiltrate in the superficial dermis, often
with conspicuous melanophages.11 Neutrophils may be prominent in the
stratum corneum. Perifollicular/acrosyringotropic and perivascular chronic
inflammation may also be evident. Epidermal basal keratinocytes show Fig. 7.56
hydropic degeneration, and cytoid body formation has been described.11,18 Keratosis lichenoides chronica: close-up view of solitary lichenoid papules and a
confluent plaque. By courtesy of R.A. Marsden, MD, St George's Hospital,
Many necrotic keratinocytes are present.1 Exceptionally, amyloid deposition
London, UK.
has been documented.19
The dermal infiltrate consists of lymphocytes, histiocytes, and variable
plasma cells and eosinophils.11
Direct immunofluorescence highlights the cytoid bodies.18
The scalp and facial lesions show the features of a chronic dermatitis,
namely spongiosis with exocytosis and patchy parakeratosis. A perivascular
chronic inflammatory cell infiltrate of lymphocytes, histiocytes, and plasma
cells may be present in the upper dermis.5

Fig. 7.55
Keratosis lichenoides
chronica: there
are erythematous
hyperkeratotic lichenoid
lesions in a linear and
reticular distribution. By Fig. 7.57
courtesy of R.A. Marsden, Keratosis lichenoides chronica: plantar involvement showing disfiguring exophytic,
MD, St George's Hospital, hyperkeratotic verrucous plaques. By courtesy of R.A. Marsden, MD, St George's
London, UK. Hospital, London, UK.
236 Lichenoid and interface dermatitis

Erythema dyschromicum perstans

Clinical features
Erythema dyschromicum perstans (dermatosis cenicienta, ashy dermatosis) is
an acquired, usually asymptomatic, disfiguring dermatosis which occurs par-
ticularly in Latin American (especially Mexican) populations and in Asians.1–7
It was originally named dermatosis cenicienta after the clinical appearance of
affected patients – los cenicientos (the ash-colored ones).1 However, white-
skinned races may rarely be affected.8 It is of unknown etiology, shows a
female predilection, and can develop at any age although the majority of
patients are in their first three decades.2,9 Presentation in infancy has been
documented.10
Patients develop oval, irregular or polycyclic, gray macules with ery-
thematous, indurated, inflammatory borders of 1–2 mm. The lesions extend
peripherally, show a tendency to coalesce, and often affect large areas of the
integument (Figs 7.58–7.60). With progression, the eruption develops a gray-
blue color and loses the erythematous border, which is sometimes replaced by
a hypopigmented periphery. It is usually symmetrical, and particularly affects
the trunk, proximal extremities and, to a lesser extent, the face and neck.2 Fig. 7.58
Erythema dyschromicum
The palms and soles, scalp, nails, and mucous membranes do not appear to
perstans: this patient
be involved.6 shows irregularly
distributed gray
macules. By courtesy
Pathogenesis and histological features of R.A. Marsden, MD,
The etiology is unknown. Cases have followed HIV infection and there is a St George's Hospital,
report of simultaneous development of vitiligo and erythema dyschromicum London, UK.
perstans. The significance of these observations is doubtful.11,12 Increased sus-
ceptibility with HLA-DRB1*0407 in Mexican patients has been reported.13
Sections from the inflammatory border show hyperkeratosis and an epi-
dermis of normal thickness or somewhat atrophic, accompanied by basal cell
hydropic degeneration and cytoid body formation (Fig. 7.61). Pigmentary
incontinence is marked and a mild perivascular or lichenoid inflamma-
tory cell infiltrate is present in the superficial dermis (Fig. 7.62). Sections
from the central gray area show epidermal atrophy, follicular hyperkera-
tosis, and pigmentary incontinence. The dermal inflammatory infiltrate is
composed of both CD4 and CD8 T cells, usually with CD8 forms slightly
predominating.14
Direct immunofluorescence reveals non-specific staining of the cytoid
bodies with IgG, IgM, and C3.15–17 Fibrinogen may be present at the der-
moepidermal junction.16 The immunocytochemical studies are therefore simi-
lar to lichen planus. The epidermal keratinocytes express Ia antigen and the
­lymphocytic population comprises both helper/inducer and suppressor/cyto-
toxic phenotypes similar to lichen planus.17,18
Ultrastructural findings are non-specific, comprising intra- and interepi-
dermal edema with cytoplasmic vacuolation, separation of keratinocytes,
retraction of desmosomes, cytoid body formation, focal gaps in the kera-
tinocyte basal lamina, and pigment-laden histiocytes in the papillary
dermis.16,19,20

Differential diagnosis
The precise relationship of erythema dyschromicum perstans to lichen
planus is uncertain. The histological, immunological, and ultrastructural
findings certainly suggest that they are closely related.15,16 Typical lichen Fig. 7.59
Erythema dyschromicum perstans: in this patient there is extensive involvement of
planus may precede the development of erythema dyschromicum per-
the face, neck, and trunk. By courtesy of J. Tschen, MD, Baylor College of Medicine,
stans and sometimes the two conditions have presented simultaneously, Houston, USA.
although some of the documented cases may have represented lichen
planus pigmentosus.21,22

Lichenoid and granulomatous dermatitis
Clinical features
These lesions were described in 2000 by Magro and Crowson to have features
of both lichenoid and granulomatous dermatitis.1 There is a slight female
predominance (21:15) affecting a broad range of ages (5–86 years old).
The extremities and trunk are most often involved, followed by the head and
neck region. Clinically, the lesions present as lichenoid papules
Pathogenesis and histology
Various etiologic agents included drug, coexisting medical illnesses, and
infections have been implicated. Similar to any lichenoid disorder, there is a
 Interface dermatoses 237

Fig. 7.60
Erythema dyschromicum
perstans: in this patient
with more advanced
Fig. 7.62
disease, there is a
Erythema dyschromicum
generalized bluish
perstans: note the
discoloration. By
hydropic degeneration,
courtesy of the Institute
cytoid body, and pigment
of Dermatology, London,
incontinence.
UK.

Fig. 7.61
Erythema dyschromicum perstans: there is hyperkeratosis and marked pigmentary
incontinence.
bandlike infiltrate of lymphocytes and histiocytes. The histiocytes are vari-
ably described as loosely aggregated and superficially located, cohesive gran-
ulomata, diffuse interstitial granulomatous inflammation, scattered solitary
giant cells, and granulomatous vasculitis.1 Cases associated with drugs also
may display parakeratosis, keratinocyte necrosis, acrosyrinogeal accentua-
tion, red cell extravasation, granulomatous vasculitis, eosinophils, and plas-
macellular infiltrate sparing the deep dermis.1,2 Lymphocyte atypia may also
be a feature in examples associated with cutaneous lymphoma or lymphoma-
tous drug reactions.1
Interface dermatoses
Definitions
There is such considerable variation in the literature as to the exact defini-
tions and interrelationships between erythema multiforme (particularly the
‘major’ variant), Stevens-Johnson syndrome, and toxic epidermal necroly-
sis that it is often difficult or impossible to be certain to which disease the
authors are actually referring!1–5 The consensus paper published in 1993 by
Bastuji-Garin is used as a basis for classification since the authorship included
most of the major players at that time in this difficult subject.1
Classification of an individual patient depends upon the precise morphol-
ogy and pattern of individual lesions and the extent of skin involvement
(detached and detachable epidermis) as a percentage of total body surface
area at the worst stage of the illness.
• Target lesions are defined as sharply demarcated and round, less than
3.0 cm in diameter and comprising three distinct zones, namely a central
erythematous or purpuric disc with or without a blister, surrounded
by a raised edematous ring, in turn bordered by an erythematous rim
(Fig. 7.63).1 Target lesions are typically distributed in an acral location,
are often seen following a herpetic infection, and are characteristic of
erythema multiforme. Typical target lesions are not seen in patients with
widespread epidermal detachment.
• Raised atypical target lesions are ill-defined, round, palpable lesions
with only two zones including a central raised edematous area with an
erythematous border.
• Flat, atypical target lesions are ill-defined, round lesions with only two
nonpalpable zones. The center may be blistered (Fig. 7.64).
• Macules with or without blisters are defined as nonpalpable,
erythematous or purpuric macules with irregular shape and size and
often confluent. Blisters often occur on all or part of the macule.
This lesion is characteristically seen in patients with widespread
epidermal detachment who have a history of drug ingestion.
Working on this basis, the following definitions have been proposed:1
• Bullous erythema multiforme is characterized by < 10% detachment,
typical target lesions, and sometimes raised atypical target lesions.
238 Lichenoid and interface dermatitis
Fig. 7.63
Target lesion: characterized by a central blister surrounded by an edematous ring
and an outer erythematous border. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
• Stevens-Johnson syndrome is characterized by > 10% detachment, flat
atypical target lesions, and erythematous macules in addition to blisters
and erosions affecting one or more mucous membranes.
• Overlap Stevens-Johnson syndrome/toxic epidermal necrolysis is
characterized by 10–30% detachment, atypical target lesions, and flat
erythematous macules.
• Toxic epidermal necrolysis is characterized by > 30% detachment with
flat atypical target lesions and/or erythematous macules. Rarely, toxic
epidermal necrolysis may develop as large epidermal sheets in the absence
of erythematous macules.
Erythema multiforme
Clinical features
Erythema multiforme is a relatively common condition, which predominantly
affects younger individuals (particularly in their second to fourth decades),
Fig. 7.64
Flat atypical target lesion: characterized by only two components, a central
edematous area or blister surrounded by a zone of erythema, these lesions may
be seen in erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal
necrolysis. By courtesy of the Institute of Dermatology, London.
including children, and shows a slight male predilection.1–8 All races may
be affected. It is self-limiting and commonly recurrent (recurrent erythema
multiforme), although rarely continuous episodes of erythema multiforme
have been described (persistent erythema multiforme).9–13 Very occasionally,
­epidemics are seen, as for example in military camps.4 The eruption shows
seasonal variation with many patients developing the condition in spring and
summer.
It presents as symmetrically distributed, fixed, discrete erythematous
round maculopapules 1–2 cm in diameter which appear in crops on the
acral regions, particularly the elbows, the knees, and extensor aspects of
the extremities (Figs 7.65–7.67). Sometimes, the face, palms and soles,
flexural extremities, and perineum (Fig. 7.68) are affected.2 The scalp is
rarely involved.14 Typically, the center of the lesions becomes ischemic to
produce a bluish discoloration (the classic iris or target lesion) which may
eventually blister. Although lesions are often present for up to 7 days, the
entire episode is usually over by 6 weeks or less.14 Lesions often number
a hundred or more. Resolution may be associated with postinflammatory
hyperpigmentation.
Oral lesions are common and are usually mild, typically presenting as mul-
tiple ulcers, which may involve the entire oral cavity, or predominantly affect
the buccal mucosa and tongue (Figs 7.69, 7.70).15 Target lesions on the lips
may also be encountered.
In many patients, episodes of erythema multiforme are recurrent, develop-
ing as often as five times each year. Such cases are almost invariably due to
herpes simplex infection. Particular clinical features of this variant include a
positive Koebner's phenomenon, photodistribution, grouping of lesions over
the elbows and knees, and nail fold involvement.8
In the older literature, a variant of erythema multiforme was recognized
(erythema multiforme major) in which patients developed severe mucosal dis-
ease including oral, ocular, and anogenital lesions. In keeping with the current
thinking on this complex topic, such cases are now included in the spectrum
of Stevens-Johnson syndrome.1,2
Rarely, patients (usually females) may develop erythema multiforme in asso-
ciation with discoid or systemic lupus erythematosus – Rowell syndrome.
Pathogenesis and histological features
The etiology in the overwhelming majority of cases is past or present infec-
tion with herpes simplex virus (HSV) types I and II. In many patients, dis-
ease is subclinical. In some studies the relationship is strongest in patients
with recurrent disease. Occasionally, Mycoplasma infection is of etiological
importance. Although many other viral and bacterial infections have also
Fig. 7.65
Erythema multiforme: multiple lesions on the hand, a typical site of presentation.
From the collection of the late N.P. Smith, MD, the Institute of Dermatology,
London, UK.
 Interface dermatoses 239

Fig. 7.66 Fig. 7.68

Erythema multiforme: multiple ulcerated lesions on the hands. From the collection Erythema multiforme: note the presence of erythema and erosion on the labium
of the late N.P. Smith, MD, the Institute of Dermatology, London, UK. minus. By courtesy of P. Morgan, MD, London, UK.

Fig. 7.69
Erythema multiforme: multiple erosions are present on the labial mucosa. By
courtesy of P. Morgan, MD, London, UK.

Fig. 7.67
Erythema multiforme: more extensive involvement in an adult with large
erythematous lesions. The blisters have ruptured. By courtesy of the Institute of
Dermatology, London.

been implicated including orf, cowpox, Epstein-Barr virus, streptococcus,

meningococcus, Histoplasma, and various childhood illness immunizations,
it is uncertain whether these truly represent erythema multiforme or whether
they might be better classified as some other dermatosis, including Stevens-
Johnson syndrome.4,14,16 Erythema multiforme has also been described as
a side effect of a number of drugs including sulfonamides, trimethoprim-
sulfamethoxazole combinations, penicillin, barbiturates, the oral con-
traceptive pill, TNF-α antagonists, bortezomib, sorafenib, and anti- Fig. 7.70
retroviral drugs in HIV patients.4,1,17–20 An interesting association with Erythema multiforme: there is a large ulcer on the buccal mucosa. By courtesy of
ciprofloxacin after alcohol ingestion has been described.21 The antineoplastic P. Morgan, MD, London, UK.
240 Lichenoid and interface dermatitis

drug ­paclitaxel has not only been associated with erythema multiforme but
may ­trigger a photosensitive variant of the disease.22 Furthermore, the erup-
tion has also been associated with photocontact dermatitis to ketoprofen.23
A single association with HPV vaccination has been reported.24 A localized
contact dermatitis to a henna tattoo has also triggered the disease.25 Erythema
multiforme has also been associated with internal malignancy, including
lymphoma, and may follow radiotherapy.26,27
Although cultures of skin lesions in erythema multiforme are generally
negative for herpes simplex, viral DNA has been identified within the epi-
dermis of skin lesions by polymerase chain reaction (PCR); in situ hybrid-
ization and immunohistochemistry detecting viral components are often
positive.13,16,28–35 Viral DNA is absent from healed lesions.31 Viral gene
expression correlates with lesion development.29 Since there is no evidence
of a viremia, it is thought that viral DNA is transported to the skin within
circulating lymphocytes rather than directly through the bloodstream or
via centrifugal neuronal spread.31,34 Why it localizes to specific sites in the
skin is unknown but this may be related to ultraviolet (UV) exposure. It is
likely that an episode of erythema multiforme develops as a delayed hyper-
sensitivity (and/or cytotoxic) reaction to herpes viral antigens including
DNA polymerase expressed on the surface of keratinocytes. The identifi- Fig. 7.71
Erythema multiforme: early lesion showing hyperkeratosis, basal cell hydropic
cation of IFN-γ in active skin lesions suggests a delayed hypersensitivity
degeneration, and occasional cytoid bodies.
reaction with involvement of variable cytokines recruiting additional lym-
phocytes and macrophages to amplify the inflammatory reaction.35,36 It
has been postulated that HSV DNA polymerase might also be associated
with increased expression of transforming growth factor-beta (TGF-β) and
p21waf, thereby accounting for cell growth arrest and apoptosis.37 Viral
antigens do not persist in lesional skin after resolution of the eruption and
therefore in patients with recurrent disease, repeat transportation of viral
DNA to the skin must occur.
Erythema multiforme is associated with an increased incidence of
HLA-B15 (B62), HLA-B35, and HLA-DR53, particularly in recurrent
disease.38–41 Patients with limited mucosal involvement show an increased
frequency of HLA-DQB1*0302 compared with patients in whom
mucosal lesions predominate, when HLA-DQB1*0402 is more com-
monly identified.41
Erythema multiforme is characterized by a combination of basal cell
hydropic degeneration and keratinocyte apoptosis accompanied by a heavy
superficial dermal lymphohistiocytic infiltrate associated with lymphocytic
exocytosis and satellite cell necrosis.16,42–46 An exceptional case in which the
predominant cells were histiocytes mimicking Kikuchi's disease has been
described.47
Apoptotic keratinocytes are rounded, intensely eosinophilic, and often
anucleate, although residual pyknotic forms may be present (Figs 7.71, Fig. 7.72
7.72). Their distribution may be focal, involving only an occasional and often Erythema multiforme: close-up view of basal cell hydropic degeneration.
basally located keratinocyte, or it can affect the entire epidermis, thereby
resembling toxic epidermal necrolysis (Lyell's syndrome) (Fig. 7.73). Marked
basal cell hydropic degeneration sometimes results in subepidermal clefting
or vesiculation (Fig. 7.74). Intra- and intercellular intraepidermal edema is
evident and spongiotic vesiculation can be a feature (Fig. 7.75).
In biopsies from early lesions, the changes may be predominantly dermal
with marked edema of the papillary dermis accompanied by a chronic inflam-
matory cell infiltrate and red cell extravasation (Fig. 7.76), thereby account-
ing for the clinical appearance of purpura.
The inflammatory cell infiltrate in erythema multiforme usually comprises
lymphocytes and histiocytes; neutrophils are sparse or absent. Eosinophils
may sometimes also be present.48 Leukocytoclasis is not seen.
Histological features, similar to those of the skin lesions, typify involve-
ment of the mucous membranes with spongiosis and intracellular edema.
These lesions tend to be more obvious and, therefore, intraepithelial blisters
are sometimes conspicuous.
With immunohistochemistry, the infiltrate consists predominantly of
helper (CD4+ Vβ2+) lymphocytes with a lesser number of cytotoxic lym-
phocytes and admixed macrophages.49,50 Keratinocytes express intracellu-
lar adhesion molecule-1 (ICAM-1) and HLA-DR, the latter thought to be
induced by IFN-γ of activated CD4+ T-helper 1 (Th1) cell derivation.49,51
TNF-α is not expressed in HSV-associated lesions.37 Circulating soluble Fas is Fig. 7.73
thought to be an mediator of apoptosis, as in toxic epidermal necrolysis and Erythema multiforme: marked apoptosis has resulted in intraepidermal vesiculation.
 Interface dermatoses 241

S­ tevens-Johnson syndrome. Autantibodies to desmoplakin 1 and 2 may also

play a role in erythema multiforme major.16

Differential diagnosis
Erythema multiforme shows considerable overlap with Steven-Johnson
syndrome and toxic epidermal necrolysis. In erythema multiforme, how-
ever, there are commonly more marked inflammatory changes than seen in
Stevens-Johnson syndrome and toxic epidermal necrolysis in which the epi-
dermal changes of widespread apoptosis are the predominant feature.
Erythema multiforme may also on occasion be confused with fixed drug
eruption, acute graft-versus-host disease (GVHD), and connective tissue
diseases such as systemic or subacute cutaneous lupus erythematosus and
dermatomyositis. Presence of mucin and evidence of chronicity such as hyper-
keratosis and parakeratosis are useful clues for connective tissue disease. The
presence of conspicuous eosinophils would be in favor of a drug reaction.
Focal interface change combined with an absence of significant eosinophils
and follicular involvement is thought helpful for distinguishing between
GVHD and erythema multiforme. None of the findings is considered abso-
lutely pathognomonic of any entity and clinicopathological correlation will Fig. 7.76
most often ensure their distinction with ease. Erythema multiforme: early lesion showing interface change and marked upper
dermal edema.

Toxic epidermal necrolysis and

Stevens-Johnson syndrome
The original description of toxic epidermal necrolysis included two unrelated
conditions:1
• the scalded skin syndrome seen in infants and young children and due to
staphylococcal infection with toxin production,
• a drug hypersensitivity reaction, predominantly affecting adults, now
regarded as the sole representative of this entity.

Clinical features
Classification of a blistering disorder as toxic epidermal necrolysis (Lyell's
syndrome) or Stevens-Johnson syndrome is based upon the extent of detached
or detachable skin at the worst stage of the illness.2 In the former condition,
30% or more skin is involved whereas in the latter less than 10% is affected
(Figs 7.77, 7.78). An intermediate category where 10–30% of the skin is
involved has also been recognized.3–5
Toxic epidermal necrolysis and Stevens-Johnson syndrome are very rare
conditions, with reported incidences ranging from 0.93 to 1.3 cases per mil-
Fig. 7.74
Erythema multiforme: in this example, subepidermal vesiculation is present. lion population in Europe and 0.5 in the United States.6–9 They represent
severe drug hypersensitivity reactions except for those instances in which
GVHD develops a toxic epidermal necrolysis-like appearance.7,10 While prior
studies have shown there is no racial predilection, there is some evidence
of genetic susceptibility to this condition. Patients with HLA-B*1502 and
HLA-B*5801 are associated with carbamazepine-induced Stevens-Johnson
syndrome and allopurinol-induced Stevens-Johnson syndrome among the
Han Chinese, respectively. 5,11,12 The elderly are predominantly affected, but
the condition may present at any age, including children, infants, and the
newborn.13–15 In the last group, mucosal lesions may sometimes be the sole
manifestation of the disease.16 Prior studies have shown that females are
affected more often than males (2:1) but more recent reports suggest that this
may be changing, with more male and HIV/AIDS patients being reported.4,15
In children the sex ratio is equal.
Patients typically present with a short prodromal illness of pyrexia, sore
throat, muscle ache, headache, anorexia, nausea, vomiting, and burning
eyes, soon followed by the development of a painful rash most often start-
ing on the face, neck, and shoulders before becoming more generalized with
trunk and proximal limb accentuation.4,5,15–18 The eruption consists of irregu-
lar, erythematous, and sometimes purpuric or necrotic, flat, atypical target
lesions. In some patients, an exanthematous, morbilliform eruption is initially
Fig. 7.75 seen.19 Occasionally, typical target lesions overlapping with erythema multi-
Erythema multiforme: early lesion showing spongiosis, lymphocytic exocytosis, and forme may be a feature.9 In any event, this early stage is soon followed by the
cytoid bodies. development of flaccid, fluid-filled bullae (Fig. 7.79). These rapidly ulcerate,
242 Lichenoid and interface dermatitis
Fig. 7.77
Stevens-Johnson syndrome: this patient developed Stevens-Johnson syndrome
following sulfonamide therapy. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
Fig. 7.78
Stevens-Johnson syndrome: this condition is distinguished from toxic epidermal
necrolysis by there being less than 10% of the skin involved. Note the tense
blisters. By courtesy of the Institute of Dermatology, London, UK.
l­eaving painful raw erosions similar to scalding (Figs 7.80–7.83). Nikolsky's
sign is positive. Eventually, the whole body, with the exception of the hair-
bearing scalp, may become affected.
Toxic epidermal necrolysis/Stevens-Johnson syndrome is a multisystem
disease. The mucous membranes are affected in all patients and sometimes
represent the presenting manifestation.17 The oropharynx, eyes, genitalia,
and anus show particular involvement, in descending order of frequency.4,5,19
Ocular lesions are especially important, as they are a cause of significant long-
term morbidity in 40–50% of survivors.4,20 Patients may manifest conjunctivi-
tis, synechiae, the sicca syndrome, trichiasis, and keratitis.19 Gastrointestinal
Fig. 7.79
Toxic epidermal necrolysis: early stage showing multiple large fluid-filled blisters.
By courtesy of R. Reynolds, MD, Harvard Medical School, Boston, USA.
Fig. 7.80
Toxic epidermal necrolysis: there is widespread erythema and numerous blisters
are evident. By courtesy of I. Zaki, MD, and S. Dalziel, MD, University Hospital,
Queen's Medical Centre, Nottingham, UK.
lesions, esophageal stricture, hepatitis, and pancreatitis are occasional man-
ifestations.21–23 Tracheobronchial involvement is fairly common and adult
respiratory distress syndrome is an important and potentially life-threatening
complication.17 Anemia and leukopenia are typically seen.
The mortality of Stevens-Johnson syndrome is approximately 5%, whereas
the more extensive skin involvement in toxic epidermal necrolysis is reflected
in a higher mortality of up to 40%.17,22,24–26 Causes of death include sepsis
(particularly due to Staphylococcus aureus and Pseudomonas aeruginosa),
heart failure, pulmonary embolism, septic shock, disseminated intravascular
coagulation, and gastrointestinal bleeding.19 Increased age, a high proportion
of skin loss, deteriorating renal function,22 and extensive involvement of the
bronchial epithelium4 are all associated with a poor prognosis.

Fig. 7.81
Toxic epidermal necrolysis: note the generalized blistering resembling scalding.
By courtesy of I. Zaki, MD, and S. Dalziel, MD, University Hospital, Queen's Medical
Centre, Nottingham, UK.
Fig. 7.82
Toxic epidermal necrolysis: this is a serious potentially life-threatening condition.
This is a particularly severe example. From the collection of the late N.P. Smith, MD,
the Institute of Dermatology, London, UK.
Pathogenesis and histological features
Toxic epidermal necrolysis/Stevens-Johnson syndrome almost always represents
an adverse drug reaction.13,17,27 However, in children, infection with Mycoplasma
pneumoniae has sometimes been implicated in the latter condition.5,16 Etiological
agents include sulfonamides, anticonvulsants (phenytoin, barbiturates, and
carbamazepine), antibiotics (aminopenicillins, quinolones, and cephalosporins),
nonsteroidal antiinflammatory agents (phenylbutazone, oxyphenbutazone,
isoxicam, and piroxicam), and allopurinol.17,19 HIV antiretroviral agents have also
been implicated.28 Patients with such adverse reactions may show a positive patch test
to the offending drug and lymphocyte transformation may be demonstrable.27,29
Interface dermatoses 243
Fig. 7.83
Toxic epidermal necrolysis: healing is commonly followed by postinflammatory
hyperpigmentation. From the collection of the late N.P. Smith, MD, the Institute of
Dermatology, London, UK.
Toxic epidermal necrolysis may also evolve in the setting of acute
GVHD. Although some of these cases are undoubtedly due to an adverse
drug reaction, a proportion represents a specific and severe manifestation
of acute GVHD. This is associated with a very poor outlook and high
mortality.10,30
Toxic epidermal necrolysis/Stevens-Johnson syndrome is an important
complication of HIV infection and is seen in up to 1 in 1000 acquired immu-
nodeficiency syndrome (AIDS) patients per year.31 The high incidence relates
in part to the frequent use of sulfonamides in these patients.32 Patients with
systemic lupus erythematosus are also particularly at risk.15
Exceptionally, toxic epidermal necrolysis has been documented in adults fol-
lowing an infection including hepatitis A and Mycoplasma pneumoniae.4,33,34
The precise mechanisms involved in the pathogenesis of toxic epidermal
necrolysis are unclear. Affected patients in sulfonamide-related cases are com-
monly slow acetylators, and detoxification of resultant reactive drug metabo-
lites is impaired.17,35,36 Although the condition may result from a direct action
in some cases, it is thought to be more likely that drug metabolites function
as haptens and induce an indirect cellular immune reaction to keratinocytes.
Patients with AIDS are deficient in glutathione and, as a result, persistence of
such reactive metabolites may explain the increased incidence of this disease
in these patients.36
Toxic epidermal necrolysis is associated with an increased incidence of
HLA-B12: 50% compared with 26% in the normal population.37 As men-
tioned above, specific HLA types are associated with Stevens-Johnson syn-
drome in certain racial populations.
Although the exact pathogenesis of the disease is not clear, it has been
demonstrated that the inflammatory cells in the blisters are cytotoxic T lym-
phocytes and natural killer cells.38 The main cytotoxic protein expressed is
granulysin and this protein seems to be a major player in the induction of
disseminated keratinocyte necrosis. When the protein is injected into the skin
of mice, blisters closely simulating those seen in toxic epidermal necrolysis/
Stevens-Johnson syndrome develop.38
The histological features are those of variable epidermal apoptosis associ-
ated with basal cell hydropic degeneration or subepidermal vesiculation (Figs
7.84–7.87).39,40 Lymphocytic exocytosis may be present and satellite cell
necrosis is sometimes apparent.41,42 Sweat duct epithelium is also involved,
and hair follicles may also be affected, although much less often (Fig. 7.88).13
A light, predominantly perivascular infiltrate of lymphocytes, macrophages,
and melanophages is present in the superficial dermis, which also is com-
monly edematous (Figs 7.89, 7.90). Small numbers of eosinophils may be
present.
244 Lichenoid and interface dermatitis

With immunohistochemistry, the dermal infiltrate consists predomi-

nantly of CD4+ T-helper cells, whereas in the epidermis CD8+ cells are most
numerous.41,43,44 Histiocytes may be conspicuous.45 Langerhans cells are
depleted. Keratinocytes express HLA-DR. Keratinocyte cell death is thought
to result from the combined effects of cytolytic enzymes including perforin
and cytokines such as soluble TNF-α and IL-6.18,39,45–47 Fas ligand-mediated
apoptosis is believed to be of major importance in the final development of
necrolysis.4,5,18,39,45–47

Differential diagnosis
Staphylococcal scalded skin syndrome is an important clinical differential
diagnosis. The typical histological finding of a subcorneal pustule in this con-
dition makes the distinction easy. In addition, staphylococcal scale skin syn-
drome does not demonstrate full-thickness necrosis.
Toxic epidermal necrolysis/Stevens-Johnson syndrome may sometimes be
indistinguishable from severe erythema multiforme. Marked lymphocytic
exocytosis, apoptosis predominantly affecting the lower epidermis, intense,
lichenoid dermal chronic inflammation with extension along the superficial
and deep vascular plexuses, and prominent erythrocyte extravasation are
Fig. 7.86
more in favor of erythema multiforme.40,48 This histological distinction is also Toxic epidermal necrolysis: this field shows the floor of the blister. There are no
mirrored to some extent by the etiology. Thus, those cases that result from an inflammatory cells in this example.

Fig. 7.87
Toxic epidermal necrolysis: medium-power view showing necrosis of the full
Fig. 7.84 thickness of the roof of the blister.
Toxic epidermal necrolysis: low-power view showing subepidermal blistering.

Fig. 7.88
Fig. 7.85 Toxic epidermal necrolysis: follicular involvement showing basal cell hydropic
Toxic epidermal necrolysis: the roof of the blister is completely necrotic. degeneration and apoptosis.
 Interface dermatoses 245

poikiloderma. Histologically, poikiloderma is characterized by hyperkerato-

sis, epidermal atrophy with basal cell liquefactive degeneration, pigmentary
incontinence, telangiectasia, and a variable superficial dermal lymphohistio-
cytic infiltrate (Figs 7.91, 7.92).

Poikiloderma of Civatte
Poikiloderma of Civatte (poikiloderma of head and neck, Derbyshire neck) refers
to a fairly common progressive and irreversible disorder in which typical poiki-
loderma presents in a photodistribution, predominantly affecting the sides of the
face and neck and the ‘V’ of the chest (Fig. 7.93).1–4 Middle-aged and elderly
women, menopausal females, are predominantly affected. Possible etiological
factors include hormonal effects, phototoxicity or photoallergy possibly due to
perfumes or fragrances.4–6 Recently, familial cases have been documented.4

Histological features
In addition to the typical features of poikiloderma, solar elastosis is often very
marked.3 In some biopsies, however, the appearances can be very non-specific.
Fig. 7.89
Toxic epidermal necrolysis: there is a perivascular lymphohistiocytic infiltrate.

Fig. 7.91
Poikiloderma: there is basal cell hydropic degeneration and a very light perivascular
Fig. 7.90 lymphohistiocytic infiltrate.
Toxic epidermal necrolysis: note the apoptosis and pigment incontinence.

infection tend to be more inflammatory than those that represent an adverse

drug reaction, in which the changes are predominantly epidermal.48 The pres-
ence of eosinophils does not seem to distinguish between drug- and infection-
related causes within this histological spectrum.40
Toxic epidermal necrolysis resulting from an adverse drug effect and that
presenting in a background of severe GVHD are indistinguishable.

Paraneoplastic pemphigus
Erythema multiforme-like histological features are an integral feature of para-
neoplastic pemphigus.

Poikiloderma
Poikiloderma (Gr. poikilos, spotted, mottled, varied) is a clinical descriptive
term applied to skin showing slight scaling, atrophy, variable pigmentation,
and telangiectasia. It is a feature of a number of conditions including lupus
erythematosus, dermatomyositis, large plaque parapsoriasis, poikiloderma
of Civatte, poikiloderma congenitale, Bloom's syndrome, Cockayne's syn- Fig. 7.92
drome, dyskeratosis congenita, and DNA mitochondrial syndrome-associated Poikiloderma: close-up view.
246 Lichenoid and interface dermatitis

Mitochondrial DNA syndrome-associated
poikiloderma
Photodistributed poikiloderma has been documented in a number of mito-
chondrial DNA syndromes, particularly Pearson's syndrome, which also
includes failure to thrive, exocrine pancreas insufficiency, severe renal tubule
dysfunction, and bone marrow suppression.1 Other dermatological manifes-
tations of mitochondrial DNA syndromes include acrocyanosis, dry brittle
hair, vitiligo, hyperpigmentation, and anhidrosis.2–7
hands.6 While occasionally reported, mental retardation is not usually a fea-
ture of this syndrome.1 The disease is associated with the development of
cutaneous squamous cell carcinoma and more rarely basal cell carcinoma.2,4
Bowen's disease has also been described.7
There is also an increased risk of internal malignancies, particularly tib-
ial osteosarcoma and multicentric osteosarcoma (7–32%).1,2,8–10 An associa-
tion with duodenal stenosis and annular pancreas has been described in one
patient.11 The life span of the patient, however, is generally normal.

Rothmund-Thomson syndrome
Clinical features
This rare syndrome, which has been described in Asians and blacks as well as
Caucasians, has an autosomal recessive mode of inheritance. In contrast to the
earlier finding of an equal sex incidence, the more recent literature suggests a
predilection for males (2:1).1,2 It usually presents between the third and sixth
months of life (hence the term ‘poikiloderma congenitale’) as a reticulated,
erythematous rash – sometimes described as marmoreal (L. marmor, marble) –
on the face, which eventually spreads to involve the extremities and the but-
tocks (Figs 7.94–7.96).2 The trunk and flexural aspects are usually spared.1
Affected infants are photosensitive and, therefore, there is often a history of
sun exposure before the development of skin lesions.3,4 This is later replaced
by reticular, linear, or punctate foci of atrophy.4 Telangiectasia is present and
areas of hypo- and hyperpigmentation may be noted. The poikilodermatous
change is seen most frequently at sun-exposed sites.1
Fig. 7.94
A variety of other manifestations may be observed, including variable alo- Rothmund-Thomson
pecia particularly involving the scalp, eyebrows and eyelashes, and seen most syndrome: there is
often in females. This is present in up to 80% of patients.1 Gastrointestinal a marked mottled
problems including chronic emesis and diarrhea may be seen in infancy.2 hyperpigmentation
Juvenile, subcapsular (unilateral or bilateral) cataracts are common and skel- predominantly affecting
etal abnormalities include short stature, osteopenia, pathological fractures, the peripheries. By
dislocations, irregular metaphyses, abnormal trabeculation, and stippled ossi- courtesy of the Institute
fication of the patellae.2 Small hands with shortened digits are frequently of Dermatology, London,
seen.5 Frontal bossing, saddle nose, and prognathism are characteristic.1 UK.
Absent or malformed radii are seen in 10–20% of patients and bifid or absent
thumb may also be present.1,2,6 Nail dystrophy, dental abnormalities (par-
ticularly conical-shaped teeth with caries), and hypogonadism may also be
detected. Hyperkeratotic warty or verrucous lesions sometimes develop on
the extensor surfaces, particularly overlying joints and especially the feet and

Fig. 7.95
Rothmund-Thomson
syndrome: there is
symmetrical involvement
of the legs. By courtesy
Fig. 7.93 of the Institute of
Poikiloderma of Civatte: note the mottled hyperpigmentation in a characteristic Dermatology, London,
distribution. By courtesy of the Institute of Dermatology, London, UK. UK.

Fig. 7.96
Rothmund-Thomson syndrome: there is atrophy in addition to hyperpigmentation.
By courtesy of the Institute of Dermatology, London, UK.
Pathogenesis and histological features
Rothmund-Thomson syndrome, in some patients at least, has been shown
to be associated with a mutation in the RECQL4 gene, a member of the
DNA helicase family (see Bloom's syndrome).9,12–15 Cytogenetic analysis has
revealed mosaicism in a subpopulation including trisomy 8.2 The underlying
defect in Rothmund-Thomson syndrome is unknown. While most investiga-
tions have failed to demonstrate abnormal sensitivity to UVA or UVB, there
have been occasional recent reports of reduced unscheduled DNA synthesis
following irradiation of cultured fibroblasts with UVB and UVC.3,16 More
recent studies suggest a role for RECQL4 in repairing DNA induced by UV
irradiation.17 Other investigations have demonstrated that RECQL4 is also
involved in DNA replication.18–20
No recognized diagnostic test for this disorder is available and diagnosis
is based primarily on the polioderma rash.15 Mutational screening for the
RECQL4 gene is possible and can correlate with certain aspects of the syn-
drome, but additional genes may also be involved.21
The histological features of poikiloderma include hyperkeratosis, epi-
dermal atrophy, liquefactive degeneration of the basal epidermal cells, and
telangiectasia. Pigmentary incontinence may be present and a perivascular
chronic inflammatory cell infiltrate is sometimes evident in the superficial
dermis. The latter sometimes also shows elastic tissue fragmentation and
depletion or absence of cutaneous appendages.1 The squamous cell carcino-
mas show typical features.
An examination of scalp has revealed hypopigmented vellus hairs without
cortices.6
Bloom's syndrome
This rare chromosomal instability syndrome (also known as congenital
telangiectatic erythema with dwarfism) has an autosomal recessive mode of
inheritance and is particularly seen in East European (Ashkenazi) Jews. When
found in non-Jews, there is a high incidence of parental consanguinity. It rep-
resents a genetically homogenous single locus disease unassociated with any
apparent heterogeneity.1
Clinical features
There is a characteristic appearance with microcephaly, dolichocephaly, and
small, narrow ‘pinched’ facies, and stunted growth leading to severe dwarf-
ism.2,3 An erythematous rash with telangiectasia develops predominantly on
the face (in particular the ‘butterfly’ area) and is exacerbated by sunlight
(Fig. 7.97).4 The rash may also affect the backs of the hands and forearms
Interface dermatoses 247
and typically develops in infancy. Café-au-lait spots are a common manifes-
tation and discrete areas of hypopigmentation are usual.3 A peculiar high-
pitched, squeaky (so-called '’Mickey Mouse’) voice is sometimes a feature.5
Male infertility is common.3 Patients may suffer impaired concentration,
short-term memory, and general mental organizational disability.5
Bloom's syndrome is typified by an inherent propensity to chromosomal
abnormalities, in particular, sister chromatid exchange. There is an associ-
ated increased incidence of most malignancies, especially acute leukemia,
non-Hodgkin's lymphoma, colon carcinoma, breast carcinoma, and cutane-
ous squamous cell carcinoma. Patients are prone to develop multiple primary
tumors, which often develop at an early age (third decade). As a result, death
by age 30 usually occurs due to cancer.4,6 They may also suffer immunode-
ficiency (diminished IgG, IgA, IgM) and are therefore at an increased risk
of childhood infections, pulmonary infections, and chronic lung disease.5,7
There is also an elevated risk of adult onset-like diabetes mellitus.8
Pathogenesis and histological features
The gene for Bloom's syndrome, BLM, which has been mapped to 15q21.3,
is a member of the RecQ helicase protein family, responsible for unwinding
DNA and RNA.9–15 It has been identified as representing part of the BRCA1-
associated genome surveillance complex, which is mutated in families with
hereditary breast cancer.16 The protein functions as a 3′-5′ DNA helicase and
may be involved specifically in allowing sister chromatid separation during
mitosis.12,17 DNA helicases have essential roles in genetic recombination,
transcription, DNA replication, and repair.15 Mutation of the BLM gene
results in genomic instability. Bloom's syndrome is associated with increased
sensitivity to alkylating agents, increased spontaneous chromosome breakages,
increased interchromatid exchange (including sister chromatid exchange,
6–10-fold), increased somatic cell mutation frequency, and reduced replication
fork elongation rate.4,11 Mutations include missense, nonsense, frameshift,
and genomic deletions, most of which result in premature translation
terminations and resultant defective Bloom's syndrome protein with impaired
function.14 Multiple defective nuclear enzymes including DNA ligase I have
been identified.18 Monosomy 7 and deletions of the long arm of chromosome
7 are found in the majority of patients with myeloid leukemia.19 A mouse
model recapitulates many aspects of the human disease syndrome, including
hematopoietic malignancies.20
Fig. 7.97
Bloom's syndrome:
characteristic facies
includes ‘pinched’
features. Marbled
erythema of the cheek
and crusted lesions
involving the lower
lip. By courtesy of D.
Atherton, MD, Institute
of Dermatology and
Children's Hospital at
Great Ormond Street,
London, UK.
248 Lichenoid and interface dermatitis

The cutaneous lesions are typified by a lupus erythematosus-like histol-

ogy. There is epidermal atrophy accompanied by liquefactive degeneration
of the basal layer with cytoid body formation. A lymphohistiocytic infil-
trate is present in the superficial dermis. Telangiectatic blood vessels are
evident.

Cockayne's syndrome
This is a very rare disorder with an autosomal recessive mode of inheritance
and a male predominance (4:1) with the majority of cases reported to be of
British ancestry. It is a multisystem disease associated with premature aging and
particularly affects the skin, teeth, eyes, skeleton, and central nervous system.1

Clinical features
Children appear to be normal at birth and have an unremarkable early devel-
opment. However, usually in the second year of life, they show photosensi-
tivity and acquire a ‘butterfly’ rash (as in lupus erythematosus) on the malar
region, which with time is associated with scarring and hyperpigmentary
changes. These features, in association with prognathism, sunken eyes, loss of
subcutaneous fat, and nasal atrophy (‘beaked’ nose), give the children a char-
acteristic progeria-like or bird-headed appearance (Fig. 7.98).2–4 Fine hair
and anhidrosis may also be evident.1
Ocular lesions include corneal opacity, cataract, retinal degeneration, and
optic atrophy with resultant blindness.1 ‘Salt and pepper’ pigmentation of the
fundus is characteristic.2
Patients usually suffer from progressive sensorineural deafness.1 The patients
are dwarfs and have disproportionately long limbs with enlarged hands and
feet.2 Microcephaly is common and radiological examination reveals thick-
ening of the skull bones. Kyphosis, ankylosis, and flexion contractures are
frequent complications, and dental abnormalities include malocclusions and
caries. Involvement of the central nervous system presents as microcephaly,
normal pressure hydrocephalus, mental subnormality, ataxia, choreoatheto-
sis, spasticity, myoclonus, and gait disturbance.1,2,5 Renal function is usually
impaired.6
Patients with Cockayne's syndrome have an increased incidence of infec-
tions and usually die within the third decade.
An unusually severe form with early onset and quick death associated with
abnormal thymidine dimer repair (and hence showing overlap with xero-
derma pigmentosum) has recently been described.5,7
Prenatal diagnosis of Cockayne's syndrome is now possible.8
Pathogenesis and histological features
The two genes responsible for Cockayne's syndrome (CSA and CSB) have
been cloned, with most cases due to mutations in CSB.9–11 CSA encodes a
WD (Trp-Asp) protein, which interacts with a number of proteins including
p44 protein, a subunit of transcription/DNA repair factor IIH (TFIIH).12 CSB
belongs to the yeast SNF2/SW12 protein family, which is of importance in
gene transcriptional activation.12 Unlike CSA, CSB is devoid of helicase activ-
ity. CSB protein interacts with CSA and excision repair enzyme XPG. It may
also have a role in response to hypoxic injury and in chromatin structure.11
A mouse model of this syndrome has been developed.13
Patients with Cockayne's syndrome have an impaired DNA excision/
repair mechanism and are hypersensitive to the effects of UV radiation with
an inability to promote normal levels of DNA and RNA synthesis following
UV irradiation.14–17 The specific defect resides within repair of mutations in
transcriptionally active genes rather than in excision/repair mechanisms in
general.18,19 There are five complementation groups identifiable by cell fusion
studies: CSA, CSB, XPB, XPD, and XPG.5,11 XPB, XPD, and XPG differ from
groups CSA and CSB by showing an increased incidence of skin cancer.12
Cockayne's syndrome may also coexist with trichothiodystrophy.20
Biopsy of the malar rash shows epidermal atrophy associated with basal
cell hydropic degeneration. A chronic inflammatory cell infiltrate is present
in the superficial dermis.
Fig. 7.98
Cockayne's syndrome: the features include prominent ears, prognathism, a
‘beaked’ nose, and flexion contractures.By courtesy of D. Atherton, MD, Institute of
Dermatology and Children's Hospital at Great Ormond Street, London, UK.
The cerebral lesions are characterized by loss of white matter, cerebellar cor-
tical atrophy, hydrocephalus, and widespread calcification.5,21 Histologically,
there is demyelination and gliosis. Iron-laden neurons, neurofibrillary tan-
gles, and giant, bizarre astrocytes have also been reported.21,22 Severe athero-
sclerosis resulting in occasional strokes can occur. 21
The kidney shows global sclerosis due to marked basement membrane (type
IV) collagen deposition associated with tubular atrophy and interstitial fibrosis.6
Dyskeratosis congenita
Clinical features
This is a rare, but important, systemic illness with poor prognosis and high
mortality. It has a predominantly X-linked recessive mode of inheritance
and occurs mainly in males (6:1), although both autosomal dominant
and recessive variants are also recognized.1–5 The condition consists
predominantly of a complex triad of skin pigmentation, nail, and mucosa
abnormalities. There is also an increased incidence of malignancy including
hematological and solid tumors.1,2,6
The skin acquires a widespread reticular pigmentation with associated
poikiloderma, which at first appears most prominently on the face, neck,
and the ‘V’ neck region of the upper chest, but later becomes generalized
(Fig. 7.99).1,4 During childhood the nails become dystrophic and are often
lost (Fig. 7.100). There may also be palmoplantar hyperkeratosis associated
with hyperhidrosis, development of epiphora, early loss of dentition, caries,
poor growth, sparse hair, bullous eruptions, lacrimal duct stenosis, and men-
tal subnormality.1–3,7 A reduced diffusion capacity develops from pulmonary
fibrosis.2
Premalignant leukoplakia involving particularly the mouth and anus is an
important complication, with a significant risk of squamous cell carcinoma
developing in these lesions.2,5 The urethra and vagina may also be affected.
Hematological manifestations include thrombocytopenia, aplastic anemia,
pancytopenia, myelodysplasia, and acute myeloid leukemia.7–9

The grave outlook of dyskeratosis congenita relates particularly to the
development of infections complicating aplastic anemia, malignancy, and
pulmonary complications.2,10
The clinical features of this disease are most severe in males with the
X-linked variant. There is considerable variation in autosomal variants and
in some of these patients symptoms may be very mild, allowing a normal life
expectancy.2
Pathogenesis and histological features
Dykeratosis congenita is characterized by mutations in genes involved in
telomere function, with the effected gene depending on the mode of inheri-
tance.6 X-linked recessive dyskeratosis congenita is due to mutations of the
DKC1 gene, which has been mapped to Xq28.11 The mutations, which are
predominantly missense, result in single amino acid substitutions in dyskerin,
a nucleolar protein believed to be responsible for site-specific pseudouridy-
lation of ribosomal RNA. It is also associated with mutations in the TERC,
TERT, NOP10, and NHP2 genes involved in telomere function.12,13 Not all
cases have a known genetic cause. There is marked chromosomal ­instability
Fig. 7.99
Dyskeratosis congenita: typical poikilodermatous pigmentation on the neck. By
courtesy of D. Atherton, MD, Institute of Dermatology and Children's Hospital at
Great Ormond Street, London, UK.
Fig. 7.100
Dyskeratosis congenita: there is dystrophy of the nails with marked atrophy of the
surrounding skin. By courtesy of D. Atherton, MD, Institute of Dermatology and
Children's Hospital at Great Ormond Street, London, UK.
Interface dermatoses 249
with a striking predisposition to develop rearrangements.2,14 Dyskeratosis
congenita therefore appears to result from defective telomerase activity with
resultant impaired stem cell turnover or proliferative activity.4,15 This is sup-
ported by the finding that telomeres are markedly shortened and that this
develops at an early age.6,16
The autosomal dominant variant has similarly recently been shown to be
associated with a mutation of the RNA component of telomerase TERC,
telomerase enzyme TERT – both part of the shelterin telomere protection
complex TIN2.4,6
Finally, the autosomal recessive variant has been associated with mutation
in the NOP10/NHP2 genes that regulate telomerase.6
The histological features of the pigmentary changes are non-specific, show-
ing only pigmentary incontinence.
Biopsies of the mucosal lesions show an acanthotic epithelium with or
without dysplastic changes. In the latter case, great care must be taken to
exclude the presence of squamous cell carcinoma.
Graft-versus-host disease
Clinical features
Graft-versus-host disease (GVHD) represents a complex multisystem major
complication of organ transplantation, usually bone marrow, that particu-
larly affects the skin, intestine, and liver. It develops when transplanted immu-
nocompetent donor T lymphocytes are activated, proliferate, and respond
to foreign host major histocompatibility complex (MHC)-histoincompatible
antigens in a background of recipient immunosuppression.1–9 In the context
of identical class I HLA antigens, as may be seen in sibling donors, class II
HLA antigens (HLA-DR, -DP, and -DQ) and minor histocompatibility anti-
gens are of major pathogenetic significance.1,2 These latter HLA antigens are
expressed on host epithelial cells following pregraft irradiation or chemother-
apy, thereby focusing the donor lymphocyte immune response on the skin,
liver, and intestinal tract.1,10,11
GVHD is a very serious complication of allogeneic bone marrow trans-
plantation and morbidity and mortality is very high.12 It may also follow
solid organ transplantation, develop in severely immunodepressed patients
after transfusion of nonirradiated blood or blood products, or complicate
transplacental transfer of maternal lymphocytes into an immunodeficient
fetus.13–15
The clinical features of GVHD develop as a consequence of donor
T lymphocyte-mediated reactions to host tissues. Successful bone marrow
transplantation is dependent upon compatibility of the ABO system blood
groups and histocompatibility antigens (HLA). The D locus (HLA class II)
is of particular importance; successful transplantation has occurred in the
presence of identical D loci with dissimilarities at the A and B loci. However,
the development of GVHD is not totally dependent upon HLA incompatibility
as it can develop in 35% of cases with identical A, B, and D loci, suggesting the
additional importance of the minor histocompatibility antigens (miH).2,16
Development of acute GVHD appears to be a consequence of HLA dis-
parity, sex mismatch, increasing patient age, and the presence of infection.7
While the skin is a major target organ in GVHD and one of the first involved
organs, the liver and gastrointestinal tract are also affected.9,17 Manifestations
include malaise, nausea and vomiting, diarrhea, malabsorption, and abnor-
mal liver function. Additionally, patients with GVHD have an increased risk
of opportunistic infections, which are an important cause of morbidity and
mortality.
Historically, GVHD was conventionally subdivided into two subgroups by
time after transplantation:
• Acute GVHD occurs within the first 3 months following transplantation
(most often presenting between 2 and 6 weeks).2,17–19
• Chronic GVHD presents after the third month.
However, changing transplantation practices have resulted in delayed
and even atypical presentations of GVHD. In 2005, the National Institutes
of Health Consensus Development Project on Criteria for Clinical Trials in
Chronic Graft-versus-Host Disease proposed new criteria to standardize the
diagnosis of chronic GVHD and also account for these new GVHD presenta-
tions, dividing it into four groups:17,19–21
250 Lichenoid and interface dermatitis

• Classic acute GVHD: acute GVHD presenting within 100 days after
HCT or donor leukocyte infusion,
• Persistent, recurrent or late onset acute GVHD: acute GVHD occurring
more than 100 days after transplation without chronic GVHD
symptoms,
• Classic chronic GVHD: chronic GVHD without features of acute GHVD
regardless of timing from transplantation,
• Overlap syndromes: both acute and chronic GVHD features present
regardless of timing from transplantation.
The classical features of acute and chronic GVHD are presented below.
The other two categories show similar features and are defined by the clinical
context in which they occur, that is their timing relative to transplantation.

Acute GVHD
Acute GVHD develops in between 6% and 90% of patients who undergo
bone marrow transplantation.22 The incidence relates particularly to HLA
mismatch, the age of the patient, and the conditioning regimen protocols
used.1,2 Additional risk factors of importance include sex mismatch, i.e., when
the donor is a female (particularly if multiparous) and the recipient is male,
use of radiation and/or high dosage chemotherapy prior to transplantation,
prior blood transfusions, prior splenectomy, viral infections, and inadequate
immunosuppression.2
It presents with the sudden onset of fever and malaise, which are rap-
idly followed by cutaneous signs including facial erythema and a gener-
alized morbilliform, maculopapular rash characteristically affecting the
palms and soles (Figs 7.101, 7.102). Mucosal lesions may also be a feature Fig. 7.101
(Fig. 7.103). The skin lesions particularly affect the upper half of the body Acute graft-versus-host disease: chest and arm showing widespread macular
and the back of the neck; ears and shoulders are sites of predilection.1,7,18,19 erythema with fine telangiectasia and mild scaling. By courtesy of R. Touraine, MD,
Lichen planus-like features may sometimes supervene. Additional cutane- Hôpital Henri Mondor, Paris, France.
ous lesions include purpura, petechiae, desquamation, and a folliculitis-like
appearance.7,19
More severe variants include erythroderma or even a toxic epidermal
necrolysis-like reaction. The latter has a poor prognosis and may be a mani-
festation of a drug reaction or represent a true component of acute GVHD.
It usually affects a large surface area, shows mucosal involvement, and is
associated with severe liver and gastrointestinal lesions.23,24 Mortality is very
high (50% and higher, especially if untreated), related to the effects of ther-
apy in addition to the lesions themselves.12,25 In the event of survival of acute
GVHD, the rash may resolve completely or merge into the features of chronic
GVHD. It is often difficult on clinical grounds (and histologically) to dif-
ferentiate between acute GVHD, viral disorders, and cytotoxic/adverse drug
reactions.
The clinical manifestations of acute GVHD are traditionally divided into
four stages:1,2,17,18
• Stage I: Maculopapular eruption affecting up to 25% of surface area.
Bilirubin levels of 2–3 mg/dL and diarrhea in excess of 500 mL/day.
• Stage II: Maculopapular erythema affecting 25–50% of surface area.
Bilirubin levels of 3–6 mg/dL and diarrhea in excess of 1000 mL/day.
• Stage III: Generalized erythroderma. Bilirubin levels of 6–15 mg/dL and
diarrhea in excess of 1500 mL/day. Fig. 7.102
• Stage IV: Toxic epidermal necrolysis. Bilirubin levels of 15 mg/dL or more Acute graft-versus-host disease: this vivid palmar erythema is characteristic.
and diarrhea exceeding 1500 mL/day. By courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris, France.

Chronic GVHD
Chronic GVHD develops in 10% of all patients undergoing allogeneic bone
marrow transplantation and in 30–70% of all long-term survivors.26 Systems
involved include the skin, eyes, mouth and esophagus, liver, genitalia, muscle,
and peripheral and central nervous systems.7 Virtually all chronic GVHD
patients exhibit skin manifestations and 90% develop oral lesions.2 Some
develop chronic GVHD de novo (30%); others show a gradual progression
of continuous acute GVHD into the chronic variant (32%).2 Occasionally,
chronic GVHD may follow a period of resolution of acute GVHD, after an
interval of quiescence (36%).2 Chronic GVHD can occur as a lichen planus-
like eruption or show features of a poikilodermatous or sclerodermatous reac-
tion.27–29 A discoid lupus erythematosus-like reaction is rare. Polymyositis and
fasciitis have also been described.30–32 In addition, a variety of presentations
have been reported which can be subtle, especially in the early phase. These
include xerosis, ichthyosis, follicular prominence, pityriasiform, eczematous,
psoriasiform lesions, annular lesions similar to urticaria or erthyema annu-
lare centrifigum, a morbilliform papulosquamous rash, and even erythro-
derma.33 Risk factors for developing chronic GVHD include prior episode of
acute GVHD, increasing age, sex mismatch, i.e., when the donor is a female
(particularly if multiparous) and the recipient is male, and use of non-T-cell
depleted bone marrow.2,34
Although early in chronic GVHD the lesions are typically lichenoid and later
sclerodermatous, in some patients these features may appear ­simultaneously.2
 Interface dermatoses 251

Fig. 7.103 Fig. 7.104

Acute graft-versus-host disease: note the erosions on the buccal mucosa. By Early chronic graft-versus-host disease: there are widespread, almost confluent
courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris, France. hyperpigmented lichenoid papules. Associated erosion of the epidermis gives an
appearance similar to toxic epidermal necrolysis (Lyell's syndrome). By courtesy of
R. Touraine, MD, Hôpital Henri Mondor, Paris, France.

UV irradiation, trauma, and infection with herpes zoster virus or Borrelia can
precipitate chronic GVHD.2
The early chronic GVHD lesion commonly has a classic lichenoid appear-
ance with typical erythematous or violaceous polygonal papules sometimes
showing Wickham's striae (Fig. 7.104). The periorbital region, ears, palms,
and soles are sites of predilection.2 Oral mucosal lesions include typical net-like
lacy white lesions, and ulcerated areas may also develop (Figs 7.105–7.107).
The cheeks, tongue, palate, and lips are sites of predilection.2 Symptoms of
Sjögren's syndrome are also often present. Onycholysis and cicatricial alope-
cia may be features. The rash is sometimes less typical, appearing as a desqua-
mative active dermatitis or as follicular hyperkeratosis. As mentioned above,
the findings can sometimes be subtle, such as xerosis.33
The late phase of chronic GVHD is typically sclerodermatous and usu-
ally presents 8–18 months after transplantation (Figs 7.108–7.110). The
development of a poikilodermatous rash is followed by induration, atro-
phy, and sclerosis.30 The resultant features resemble morphea or systemic
sclerosis; chronic ulceration, particularly involving pressure points, can
be an unpleasant complication. Blisters may occasionally develop.30 The
development of cutaneous squamous cell carcinoma has occasionally been
documented.31,32
Chronic GVHD has a mortality of up to 40%. Causes of death include Fig. 7.105
Early chronic graft-versus-host disease: there are diffuse widespread lichenoid
infection, cachexia, and liver failure.2
changes of the lips. By courtesy of R. Touraine, MD, Hôpital Henri Mondor,
Systemic features include chronic hepatitis, diarrhea with malabsorption,
Paris, France.
bronchiolitis obliterans, peripheral entrapment neuropathy, and polymyosi-
tis.2 Opportunistic infections are also of major importance.

Pathogenesis and histological features
GVHD is mediated by the combined effects of donor T lymphocytes (CD4+
T cells responding to MHC class II antigens and CD8+ T cells to class I anti-
gens) and cytokines including IL-1, TNF-α, IFN-γ and GM-CSF.1,2,11,35–43 The
development of acute GVHD depends upon a complex interplay between
host immunosuppression, tissue damage as a result of pregraft induction
therapy, and donor lymphocyte proliferation and activation with consequent
injury and death of susceptible host tissues.1
The lymphocytes may be of CD4+ or CD8+ immunophenotype and com-
monly there is an admixture. Both Th1 and Th2 CD4+ subtypes are rep-
resented. The former produce IL-2 and IFN-γ and are thought to promote
GVHD, the latter produce IL-4, IL-6 and IL-10 and are believed to be pro-
tective, although this has been contested.44 Natural killer (NK) cells may also
be of importance although their presence appears to be variable.45 B cells are
absent. Activated keratinocytes following induction chemotherapy or irradia-
tion produce TNF-α and IL-1 and express ICAM-1 and HLA-DR.46 This may
result in increased recognition of histoincompatible MHC antigens by donor
T-cells.1 The superficial dermal endothelial cells express E-selectin, α4β1
integrin, αLβ2 integrin, ICAM-1, platelet endothelial cell adhesion mole-
cule-1 (PECAM-1), and vascular cell adhesion molecule-1 (VCAM-1) which
mediate lymphocyte adhesion to the endothelium and facilitate recogni-
tion, activation, and response to MHC molecules.1,47–49 The mechanisms
of cell injury and death result from both cytotoxic T cell and possibly NK
cell-mediated cytotoxic effects and the actions of cytokines. The former
includes cytolytic actions mediated by perforin and granzyme B, and apop-
tosis through the Fas-Fas ligand pathway.50,51 IL-1, IL-2, IL-6 and TNF-α are
thought to be of particular importance in mediating cytotoxicity.1 Raised
serum TNF-α correlates with GVHD and antibodies to TNF-α or its recep-
tor protect against the disease.1,52–54 Recently, regulatory T cells (Treg) have
been postulated to play a role in GVHD. Treg are decreased in patients with
GVHD and their role remains to be elucidated.17 Studies suggest a role for
B cells in GVHD.55
252 Lichenoid and interface dermatitis
Fig. 7.106
Early chronic graft-versus-host disease: florid reticulate white striae on the buccal
mucosa are evident. By courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris,
France.
Fig. 7.107
Early chronic graft-versus-host disease: there are erosive changes on the tongue.
By courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris, France.
Deposition of IgM and C3 at the dermoepidermal junction and around
the superficial vasculature in up to 39% of patients with acute GVHD sug-
gests that humoral responses play a significant role in the pathogenesis of
GVHD.56
The development of chronic GVHD is dependent on a variety of factors
including, antihost tissue activity of donor T cells and the development of
autoimmunity.2,57 The infiltrate consists predominantly of CD8+ T cells; NK
cells are usually absent.2 As with acute GVHD, TNF-α and IL-1 are the major
cytokines implicated.2
Fig. 7.108
Late chronic graft-versus-host disease: note the grossly hyperpigmented sclerotic
limb. By courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris, France.
Fig. 7.109
Late chronic graft-versus-host disease: hyperpigmented sclerotic plaques are present
on the back. By courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris, France.
The acute lesion of GVHD is characterized by focal or diffuse basal cell
hydropic change (Figs 7.111–7.114).58 Apoptotic and dyskeratotic ­keratinocytes,
at all levels of the epidermis and associated with adjacent lymphocytes (satellite
cell necrosis), are characteristic.17,59,60 Isolated cytoid bodies are also frequently
evident. Lymphocytic exocytosis is invariably present and spongiosis is sometimes
a feature. Microvesiculation at the dermoepidermal ­junction occasionally occurs.
Follicular involvement is a common feature and the hair bulge region is typically
affected.61,60 Langerhans cells are often reduced in number. Vascular changes include
endothelial cell swelling with sloughing, and intimal and ­perivascular lymphocytic
 Interface dermatoses 253

Fig. 7.110 Fig. 7.112

Late chronic graft-versus-host disease: there is mottled hypo- and hyperpigmentation Acute graft-versus-host disease: high-power view showing basal cell liquefactive
with gross atrophy and scaling. By courtesy of R. Touraine, MD, Hôpital Henri degeneration. Diagnosis is entirely dependent on the clinical history.
Mondor, Paris, France.

infiltration. Blood vessel proliferation has also been described. Perivascular edema
and nuclear dust may additionally be present and mast cells are also conspicu-
ous.62,63 Eosinophils are sometimes present and this finding does not necessarily
indicate a drug reaction. Therefore, the histologic presentation of GVHD is broad
and no finding can be considered pathognomonic for GVHD.12,19
The toxic epidermal necrolysis-like lesions are characterized by severe
epidermal necrosis in association with subepidermal vesiculation. Evidence
of sweat gland involvement is commonly present.64,65 Keratinous plugging
of the acrosyringium may therefore be seen and the excretory ducts often
show cytopathic-degenerative and proliferative changes.65 The former com-
prises basal cell hydropic degeneration, lymphocytic infiltration, and apop-
tosis. Follicular involvement is a not uncommon additional manifestation.66
The histological features of acute GVHD may be subdivided into four stages,
which have prognostic significance (Table 7.1).66–68
The histology of chronic GVHD is typically lichenoid in appearance and is
indistinguishable from idiopathic lichen planus (Fig. 7.115). These features
are hyperkeratosis, hypergranulosis, irregular acanthosis, basal cell hydropic
degeneration, cytoid body formation, pigmentary incontinence, and a ban- Fig. 7.113
Acute graft-versus-host disease: high-power view lesion showing parakeratosis,
basal cell hydropic degeneration, and apoptosis.

Fig. 7.111
Acute graft-versus-host disease: evolving lesion showing basal cell hydropic Fig. 7.114
degeneration and scattered apoptotic keratinocytes. The dermis contains dilated Acute graft-versus-host disease: high-power view showing parakeratosis, apoptosis,
blood vessels and a light perivascular chronic inflammatory cell infiltrate. and satellite cell necrosis.
254 Lichenoid and interface dermatitis
Table 7.1
Grading of acute graft-versus-host disease
Grade Feature
I Focal or diffuse vacuolar alteration of basal cells
II Vacuolar alteration of basal cells; spongiosis and
dyskeratosis of epidermal cells
III Formation of subepidermal cleft in association with
dyskeratosis and spongiosis
IV Complete loss of epidermis
Reproduced with permission from Lerner et al. (1974) Transplantation Proceedings, 6,
367–371.
Fig. 7.115
Early chronic graft-versus-host disease: the hyperkeratosis, hypergranulosis,
irregular acanthosis, and basal cell hydropic degeneration are indistinguishable from
idiopathic lichen planus.
dlike lymphohistiocytic infiltrate obscuring the dermoepidermal interface.
In contrast to idiopathic lichen planus, satellite cell necrosis is often present
in the early phase of chronic GVHD and the infiltrate sometimes contains
plasma cells and eosinophils. Squamous metaplasia of the eccrine sweat ducts
has been described.60,65
The late stage of chronic GVHD is characterized by epidermal atrophy
with abolition of the ridge pattern and scarring of the superficial and deep
dermis, with loss of the adnexal structures (Fig. 7.116) imparting a scle-
rodermoid feature including eosinophilic fasciitis, panniculitis, morphea-like
changes, and lichen sclerosus.60,69,70 Features of the early stage of chronic
GVHD, i.e., hydropic basal cell degeneration, cytoid body formation, and
a chronic inflammatory cell infiltrate, may or may not be evident. Dermal
mucin deposition has also been documented.71
Hepatic changes include bile duct atypia with necrosis, periportal inflam-
mation, focal hepatocyte necrosis, and cholestasis.9 Gastrointestinal lesions
show individual crypt cell necrosis accompanied by a mild chronic inflamma-
tory cell infiltrate.60,72,73
Differential diagnosis
The features of acute GVHD can be reproduced by cytotoxic drugs such as
cyclophosphamide and by radiotherapy. Viral infections also enter the dif-
ferential diagnosis, as does an adverse drug reaction, for example, to anti-
biotic therapy. Although the presence of conspicuous eosinophils argues to
Fig. 7.116
Late chronic graft-versus-
host disease: there is
dense fibrosis of the
dermis with tethering of
the subcutaneous fat.
Appendages are absent.
These appearances
are reminiscent of
scleroderma.
some extent in favor of an adverse drug reaction, in reality there are no real
discriminators between adverse drug reactions and acute GVHD.74 In short,
the regular practice of skin biopsy to differentiate between GVHD, drug reac-
tions, chemotherapy effect, and viral infection is extremely difficult and of
dubious clinical value in some cases.
Acute GVHD may be indistinguishable from erythema multiforme and,
in more severely affected patients, toxic epidermal necrolysis. Recently,
the intriguing report of bile pigment deposition in the stratum corneum in
patients with GVHD offers a possible line of approach to making this impor-
tant distinction.75
The early changes of chronic GVHD may be indistinguishable from lichen
planus. However, the dermal infiltrate is usually less conspicuous than that
in lichen planus and sometimes contains plasma cells and eosinophils. The
presence of satellite cell necrosis may be a diagnostic pointer towards chronic
GVHD.
In the absence of clinical information it is usually not possible to dis-
tinguish the features of late chronic GVHD from morphea or systemic
sclerosis.
The histological features of the eruption of lymphocyte recovery are indis-
tinguishable from acute GVHD. The differential diagnosis of acute GVHD
includes engraftment syndrome. This syndrome can occur 10–14 days after
transplantation but before peripheral lymphocytes are seen. It presents with
a fever, hepatitis, intestinal symptoms, and an erythmatous maculopapular
eruption similar to acute GVHD. Some also require the presence of weight
gain and pulmonary edema. Whether or not this represents a hypoacute
GVHD is uncertain. The etiology is unknown although it is postulated that
the damage may be caused by cytokines released from recovering and degran-
ulating neutrophils. G-CSF, GM-CSF, female gender, breast cancer, and other
hematopoietic and drugs have been implicated as risk factors for developing
this condition.17,76
In summary, no histological feature is pathognomonic for graft-versus-
host disease and clinical correlation is essential. Therefore, in the appropri-
ate clinical population, a positive biopsy can be very predictive despite subtle
­non-specific histologic findings. A negative biopsy is less reassuring. Some
have advocated the use of a four-tier diagnostic system of no GVHD, possible
GVHD, consistent with GVHD, and definite GVHD, a practical proposal
that reflects the realities of daily practice.60
 Interface dermatoses 255

Pityriasis lichenoides orrhagic and ultimately develop necrosis and ulceration (Fig. 7.120).
Healing is usually associated with the development of superficial varioli-
form scars. Postinflammatory hyper- or hypopigmentation is not uncommon
Clinical features (Fig. 7.121).9,11 The rash is often polymorphic, individual patients having
Pityriasis lichenoides (Gr. pityron, bran + iasis; lichen; Gr. eidos, form) lesions at varying stages of evolution. Patients may be pyrexic and sometimes
is an uncommon dermatosis of unknown etiology, although a hypersen- lymphadenopathy is present.1
sitivity reaction to a number of infectious agents including adenovirus, The chronic lesions are typified by numerous, lichenoid, brownish-red,
toxoplasmosis, Epstein-Barr virus, and Mycobacterium pneumoniae have scaly papules, 3–10 mm across, the scale being most noticeable peripher-
been proposed.1–4 The condition has also been documented in association ally, sometimes referred to as the mica scale (Figs 7.122, 7.123). These
with a range of autoimmune conditions such as rheumatoid arthritis, hypo- lesions usually heal without scarring, but are sometimes associated with
thyroidism, and pernicious anemia.3,4 Two cases of pityriasis lichenoides hypopigmentation, which may be the most prominent feature in dark-
chronica (PLC) associated with adalimumab therapy for Crohn's disease skinned races.
and a case induced by infliximab have been described.5,6 The term includes
a spectrum of disease manifestations, ranging from the acute ulcerone-
crotic lesions of pityriasis lichenoides et varioliformis acuta (PLEVA, also
known as Mucha-Haberman disease or acute guttate parapsoriasis) to the
more chronic scaly papules of pityriasis lichenoides chronica (chronic gut-
tate parapsoriasis); there is often clinical overlap.7–10 In addition, a febrile,
ulceronecrotic variant (febrile ulceronecrotic Mucha-Habermann disease)
is recognized.3–8
Pityriasis lichenoides in more recent studies lacks strong sex ­predominance
in adults. However, some studies have shown more of a male predominance in
pediatric populations.11–14 It most often occurs in childhood (5–10 years of
age) and early adulthood, second or third decade.11–14
Lesions show a propensity to involve the arms, legs, trunk, and buttocks
(Fig. 7.117). The upper limbs appear to be involved more often than the
lower and the flexor more commonly than the extensor surfaces. They can
begin as small macules that progress to papules. PLC is typically asymp-
tomatic while PLEVA is associated with burning and pruritis.9 The onset
is usually insidious and the course fluctuating and episodic, patients expe-
riencing recurrent crops of lesions, with the exception of the ulcronecrotic
variant which is rapid. Duration of the rash is quite variable: although
many patients are free of lesions by 3–6 months, others show great per-
sistence of the disease, often for many years.11 The disease shows some
seasonal variation, with lesions worsening in winter and showing improve- Fig. 7.118
ment in sunlight. Although pityriasis lichenoides is traditionally divided Pityriasis lichenoides acuta: typical lesions with pustulation are present on the arm,
into acute and chronic variants, not uncommonly both types of lesions can a commonly affected site. By courtesy of the Institute of Dermatology, London, UK.
be seen in the same patient, indicating a possible connection between PLC
and PLEVA.9
In the more acute form of the disease, the initial lesions are crops of
pink papules (Figs 7.118, 7.119). These may become vesicular or hem-

Fig. 7.119
Pityriasis lichenoides
acuta: early lesions
are erythematous and
Fig. 7.117 papular. By courtesy
Pityriasis lichenoides acuta: erythematous papules and crusted lesions are present of the Institute of
on the buttocks and thighs. In severe cases, lesions may be very extensive. Dermatology, London,
By courtesy of the Institute of Dermatology, London, UK. UK.
256 Lichenoid and interface dermatitis

Fig. 7.121
Pityriasis lichenoides acuta: healed lesion showing scarring and hypopigmentation.
By courtesy of the Institute of Dermatology, London, UK.

Fig. 7.122
Pityriasis lichenoides chronica: widespread scaly papules are present on the
chest and arms. From the collection of the late N.P. Smith, MD, the Institute of
B Dermatology, London, UK.

Fig. 7.120
Pityriasis lichenoides acuta: (A) necrotic and ulcerated lesions are present;
(B) close-up view. By courtesy of the Institute of Dermatology, London, UK.

Although there are case reports of lymphoma (mycosis fungoides) devel-

oping in patients with pityriasis lichenoides, this is a rare event; however, see
below.15–17
The rare febrile ulceronecrotic variant is associated systemic features
including fever, muscle weakness and pain, malaise, lymphadenopathy, arthri-
tis, myocardial involvement, and neuropsychiatric manifestations.3–8,11,18,19
Widespread cutaneous manifestations include large 2–6-cm ulceronecrotic
lesions, hemorrhagic and necrotic papules, and erythema multiforme-like
lesions.3,4,11

Pathogenesis and histological features

Immunofluorescence examination of biopsies from fresh purpuric lesions
commonly detects IgM and C3 in the walls of the superficial dermal blood
vessels and along the dermoepidermal junction in both the acute and chronic Fig. 7.123
forms of the disease.20–22 A high proportion of patients have elevated cir- Pityriasis lichenoides chronica: the characteristic mica scale. By courtesy of the
culating immune complexes.23,24 Cytotoxic suppressor T cells constitute the Institute of Dermatology, London, UK.
 Interface dermatoses 257

majority of the infiltrate in pityriasis lichenoides acuta et varioliformis.25,26

Lesser numbers are seen in pityriasis lichenoides chronica. These (and the
overlying keratinocytes in addition to nearby endothelial cells) have been
shown to express HLA-DR.26 In contrast to lymphomatoid papulosis, the
Ki-1 (CD30) activation antigen is generally not expressed in pityriasis
lichenoides acuta except perhaps in overlap cases.27 Macrophages are also
numerous. Langerhans cells are diminished in number. Clonal T-cell receptor
gene ­rearrangements have been described in small numbers of patients with
pityriasis lichenoides acuta raising the possibility of overlap with cutaneous
T-cell lymphoma.28,29 Exceptionally, pityriasis lichenoides acuta may progress
to cutaneous T-cell lymphoma.11,30,31 As a result, some have suggested that
PLEVA may represent a host response to a developing T-cell lymphoprolifera-
tive disorder in some cases.11
The histopathological features of pityriasis lichenoides are similar in both
variants, although in the acute form the changes are usually more severe.
Both are characterized by varying proportions of epidermal and dermal
changes.32–35
The chronic lesions of pityriasis lichenoides are characterized by par-
akeratosis in which there are sometimes small collections of lymphocytes
reminiscent of the Munro microabscesses of psoriasis (Figs 7.124, 7.125). Fig. 7.125
Pityriasis lichenoides chronica: note the parakeratosis, acanthosis, and perivascular
The epidermis may show slight acanthosis and usually small numbers of
and interstitial chronic inflammatory cell infiltrate.
necrotic keratinocytes are present accompanied by a hint of interface change
(Fig. 7.126). Spongiosis is often a feature. There is a perivascular chronic
­inflammatory cell infiltrate in the superficial dermis (Fig 7.127). Red cell
extravasation is often present but is usually not marked.
The acute lesions of pityriasis lichenoides show similar epidermal features,
but on a much exaggerated scale. Marked inter- and intracellular edema
accompanied by keratinocyte necrosis and interface change frequently result
in vesiculation and ulceration (Figs 7.128, 7.129). Exocytosis is usually
prominent and intraepidermal red blood cells are characteristic. The upper
dermis is edematous and contains a chronic inflammatory cell infiltrate (Fig.
7.130). This is usually perivascular and varies from sparse to dense; typically,
it has a wedge-shaped appearance, extending deeply into the reticular
dermis, although this is only seen in biopsies from established lesions. The
infiltrate consists of lymphocytes with an admixture of histiocytes. Red cell
extravasation is usually conspicuous. The blood vessels of the superficial
dermis are dilated and congested. Although the endothelial cells are often
blurred or swollen, fibrinoid necrosis indicating necrotizing vasculitis is
rarely seen (Fig 7.131).

Fig. 7.126
Pityriasis lichenoides chronica: high-power view showing basal cell hydropic
degeneration.

Fig. 7.124 Fig. 7.127

Pityriasis lichenoides chronica: scanning view showing hyperkeratosis with Pityriasis lichenoides chronica: in this high-power view there is a lymphohistiocytic
parakeratosis and acanthosis. infiltrate and melanophages are present.
258 Lichenoid and interface dermatitis
Fig. 7.128
Pityriasis lichenoides acuta: this low-power view shows an ulcerated papule with
overlying crust.
Fig. 7.129
Pityriasis lichenoides acuta: there is basal cell hydropic degeneration and apoptosis.
In febrile ulceronecrotic Mucha-Habermann disease, the features are those
of very severe pityriasis lichenoides acuta and are often accompanied by the
changes of leukocytoclastic vasculitis.11,36–38
In the earlier literature, patients having clinical and histological features
of both pityriasis lichenoides et varioliformis acuta and ­lymphomatoid
Fig. 7.130
Pityriasis lichenoides acuta: this high-power view shows a lymphohistiocytic
infiltrate. Red cell extravasation can also be seen.
Fig. 7.131
Pityriasis lichenoides acuta: high-power view showing fibrinoid necrosis affecting
the dermal vasculature.
papulosis were documented.2 In the light of our current understanding of
these two conditions, it is now apparent that such patients clearly were suf-
fering from lymphomatoid papulosis.
 Superficial and deep perivascular Chapter

See
www.expertconsult.com
for references and
additional material
inflammatory dermatoses
8
Chronic superficial dermatitis  259 Tumid lupus erythematosus  269 Pregnancy prurigo  277
Toxic erythema  261 Perniosis  270 Urticarial vasculitis  278
Erythema annulare centrifugum  261 Chilblain lupus erythematosus  272 Tumor necrosis factor receptor-associated
periodic syndrome  280
Erythema gyratum repens  263 Pigmented purpuric dermatoses  273
Eosinophilic, polymorphic and pruritic
Lymphocytic infiltrate of the skin  264 Lichen aureus  275
eruption associated with radiotherapy  280
Reticular erythematous mucinosis  265 Pruritic urticarial papules and plaques of
Viral exanthemata  280
pregnancy  276
Polymorphous light eruption  267

Chronic superficial dermatitis

Clinical features
Chronic superficial dermatitis (digitate dermatosis, superficial scaly ­dermatitis,
small-plaque parapsoriasis, persistent superficial dermatitis) is a not uncom-
mon condition, which presents as erythematous scaly persistent patches,
showing a predilection for the limbs and trunk. While the lesions may be
round or oval, they often have a finger-like appearance, hence the alternative
designation of digitate dermatosis (Figs 8.1, 8.2).1 The patches are ­usually
a few centimeters in greatest dimension, but may sometimes be much larger.
They are associated with a fine ‘cigarette-paper’ scale that often has a pale
white, tan or yellowish color (Fig. 8.3). The disorder is most commonly
encountered in middle-aged adults and shows a predilection for men. The
patient is usually otherwise asymptomatic. Coexistence with ulcerative colitis
has been reported in one patient.2 Lesions tend to chronicity, often persisting
for many years. While development of mycosis fungoides has been reported
in a patient with chronic superficial dermatitis, it is most likely that these
­represent separate disease processes rather than disease progression.3
Fig. 8.1
Chronic superficial dermatitis: this patient shows digitate erythematous lesions in a
Histological features characteristic distribution. By courtesy of the Institute of Dermatology, London, UK.
Biopsy shows a superficial perivascular lymphocytic infiltrate (Figs 8.4, 8.5).
The infiltrate is of variable density but is often very sparse. Cytological aty-
the changes described above do not represent chronic ­superficial ­dermatitis.
pia is absent. The epidermis often shows foci of spongiosis. A confluent lin-
Delayed-type hypersensitivity reactions are more ­commonly ­associated with
ear band of parakeratosis spanning multiple rete ridges is a characteristic
these histological appearances. Many other ­diseases ­similarly cause such
finding.
non-specific biopsy findings including viral exanthems and ­connective tissue
The infiltrate is largely composed of CD4+ T lymphocytes with a minor
­disease. Therefore, clinical correlation is necessary to e­ stablish the diagnosis.
population of CD8+ T-suppressor cells (Fig. 8.6).2 In a small series, the CD4
The main clinical differential diagnosis is with mycosis fungoides and,
to CD8 ratio ranged from 2 to 4.4. The T cells are generally reactive for
accordingly, most biopsies are obtained to exclude this possibility. The
CD2, CD3, and CD5 (Fig. 8.7). CD7 expression is variable and may be
patches in chronic superficial dermatitis tend to be uniform in size, shape, and
absent. Scattered CD68 reactive macrophages and CD1+ Langerhans cells
color, contrasting vividly with the greater variability of those of mycosis fun-
can be seen.
goides. The presence of spongiosis favors a diagnosis of chronic superficial
dermatitis; however, mycosis fungoides may also be associated with signifi-
Differential diagnosis cant spongiosis and this feature does not reliably distinguish these disorders.
The histological features in chronic superficial dermatitis are entirely ­non-­specific. In Diagnostic pointers favoring early mycosis fungoides include the presence of
fact, the constellation of histological findings is among the most often encountered atypical lymphocytes, epidermotropism, and lymphocytes aligned along the
by the dermatopathologist. Certainly, the vast ­majority of biopsies that show basal cell layer of the epidermis (‘tagging’).
260 Superficial and deep perivascular inflammatory dermatoses
Fig. 8.2
Chronic superficial
dermatitis: these uniform,
linear lesions had been
present for many years.
By courtesy of the
Institute of Dermatology,
London, UK.
Fig. 8.3
Chronic superficial dermatitis: closer examination shows that the lesions appear
somewhat wrinkled and have a fine scale. By courtesy of R.A. Marsden, MD,
St George's Hospital, London, UK.
Immunohistochemistry should be viewed with caution. Loss of T-cell
expression may support a diagnosis of mycosis fungoides provided there
are histological features in favor of the diagnosis and if the clinical con-
text is appropriate. Loss of CD7 expression, however, may be seen in reac-
tive conditions and this feature is therefore not reliable. Occasionally, only
careful review of the clinical information, taken in conjunction with the
histological features of previous biopsies (if available) allows for defini-
tive diagnosis. It is important to note that some investigators have dem-
onstrated cases of chronic superficial dermatitis with clonal T-cell gene
rearrangements by polymerase chain reaction (PCR).4 One case with a
clonal T-cell population resolved, underscoring the growing appreciation
that clonality and malignancy are not necessarily synonymous.4 Therefore,
it appears that demonstration of a clonal T-cell population may not suf-
fice to reliably distinguish chronic superficial dermatosis from early myco-
sis fungoides in all cases. In the past, others have concluded that chronic
Fig. 8.4
Chronic superficial dermatitis: there is parakeratosis, acanthosis, and a superficial
perivascular infiltrate.
Fig. 8.5
Chronic superficial
dermatitis: there is very
slight intercellular edema.
The infiltrate consists
of lymphocytes and
histiocytes.
superficial dermatitis is mycosis fungoides.5 The observation that chronic
superficial dermatitis rarely, if ever, evolves into (or declares itself as) frank
mycosis fungoides has led some authors to cast doubt on this view.6 More
recent publications have asserted that chronic persistent dermatitis does
not progress to mycosis fungoides.7 It is perhaps more likely that some
cases of very early mycosis fungoides cannot be reliably distinguished from
chronic superficial dermatitis. Recently, clonal T-cell gene rearrangements
have been demonstrated in circulating lymphocytes in blood but not in skin
of patients with digitate dermatitis.8 Clearly, long-term follow-up studies
are necessary to resolve the significance of clonality in putative cases of
chronic superficial dermatitis.
Pityriasis lichenoides may also be confused with chronic superficial der-
matitis. Spongiosis without interface changes favors the latter. Pityriasis
lichenoides is associated with either vacuolar or lichenoid interface changes
in the absence of spongiosis.9

Fig. 8.6
Chronic superficial
dermatitis: the infiltrate is
composed predominantly
of CD4+ T-helper cells.
Fig. 8.7
Chronic superficial
dermatitis: in this
example, there is no
significant loss of CD7
expression.
Toxic erythema
Toxic erythema, annular erythema, and gyrate erythema are terms used by
dermatologists to describe a number of diseases that share common clinical
and histological appearances. Clinically, the terms imply annular erythema-
tous lesions. Pathologists often also use these same terms (particularly gyrate
erythema) in a generic manner to describe an inflammatory lesion with a
‘cuffed’ perivascular lymphocytic infiltrate. Although such nomenclature
may be used as a descriptor (as one might use terms such as ‘lichenoid’, for
­example), it should not be taken to imply a specific disease. It is likely that the
Toxic erythema 261
earlier literature frequently classified different diseases together under these
appellations.1 Therefore, to avoid confusion, it is encouraged that these terms
are not used in referring to specific diseases.
Erythema annulare centrifugum
Clinical features
Erythema annulare centrifugum has an incidence of 1 per 100 000 and may
be associated with certain underlying factors, including:
• Connective tissue disorders, e.g., Sjögren's syndrome,1,2
• Drugs, e.g., penicillin, salicylates, amytriptyline, etizolam, gold, sodium
thiomoalate, hydroxychloroquine sulfate, piroxicam, finasteride,
hydrochlorothiazide and thiacetazone,3–11
• Bacterial infections, e.g., Mycobacteria, Streptococcus, Escherichia coli,12
• Viral infection, e.g., Epstein-Barr virus, HIV, herpes simplex and zoster,
molluscum contagiosum,13–16
• Fungal infection, e.g., dermatophytoses, Candida,17–19
• Parasites, e.g., helminthes,20
• Arthropods,21
• Sarcoidosis,22
• Hypereosinophilic syndrome,23
• Bullous dermatosis, e.g., linear IgA dermatosis,24,25
• Autoimmune disease, e.g., polyglandular autoimmune disease type 1 as well
as autoimmune progesterone dermatitis and autoimmune hepatitis,26–28
• Pregnancy.29,30
Many of these associations are likely to be coincidental and, in most
cases, no underlying etiology is identified.31–35 It is unclear whether erythema
annulare centrifugum is a distinctive entity or simply represents the clinical
expression of a number of inflammatory dermatoses such as hypersensitivity
reactions sharing common histological features.36
Mahood and colleagues emphasized that many earlier reports of neopla-
sia associated with erythema annulare centrifugum are questionable since
different subtypes of annular erythemas were often classified together.31,37,38
However, more recent cases have documented erythema annulare cen-
trifugum in patients with underlying malignancy, once again raising the issue
of an association with neoplasia. Erythema annulare centrifugum in patients
with non-small cell lung carcinoma, carcinoma of breast, colon and prostate,
chronic lymphocytic leukemia, and Hodgkin's lymphoma have been reported
in the last decade.14,39–44 In a recent large series, carcinoma was present in 6
of 66 (13%) patients.45 Of these, two had leukemia (acute myelogenous and
acute lymphoblastic); one patient had non-Hodgkin's lymphoma; and three
cases were associated with carcinoma (lung, rectal, and hepatocellular).45
Erythema annulare centrifugum has been reported in all age groups, includ-
ing infants and neonates, but is most commonly seen in young adults.46,47 A
recent large series found that the lower extremities, particularly the thighs,
were the most frequent site of involvement.45 Nearly 50% of patients in this
series had lower extremity involvement. The trunk was affected in 28% of
patients and the upper extremity in 16%. The hands, feet, and face are usu-
ally spared. Head and neck involvement was seen in only 8% of patients.
Laboratory investigation sometimes reveals a peripheral eosinophilia.31
Although individual lesions persist for weeks to a few months before resolv-
ing, a course of relapses and remissions over months to years is common and
an annually and seasonally recurring form has recently been reported.48 Kim
et al. found that lesions lasted from 3 days to 18 years with a mean duration
of 2.8 years.45
The lesions take the form of annular erythematous bands, which may
spread outwards or remain stationary (Figs. 8.8, 8.9). They are well cir-
cumscribed with raised edges, and slight scaling that tends to trail behind the
advancing margin.49 With time, central clearing is seen. Arcuate and polycy-
clic variants are therefore occasionally evident.31 Lesions may be mildly pru-
ritic. Vesiculation is rare.32
Some authors have divided the disease into two distinct subtypes: superfi-
cial and deep gyrate erythema.45
• The superficial variant is associated with pruritus and has a trailing scale.
• The deep variant is characterized by erythematous annular lesions with
indurated borders but lack a scale.
262 Superficial and deep perivascular inflammatory dermatoses
Fig. 8.8
Erythema annulare centrifugum: bilateral annular lesions are present on the
buttocks. From the collection of the late N.P. Smith, MD, The Institute of
Dermatology, London, UK.
Fig. 8.9
Erythema annulare centrifugum: close-up view. From the collection of the late N.P.
Smith, MD, The Institute of Dermatology, London, UK.
Histological features
A spectrum of non-specific histological findings is seen in erythema annulare
centrifugum. As noted above, deep and superficial variants are recognized.45
In the superficial variant, a well-demarcated perivascular infiltrate of
lymphocytes and histiocytes, often described as having a ‘coat sleeve'’ or
­‘pipe-stem’ appearance, is confined to the superficial dermis (Figs 8.10, 8.11).
The overlying epidermis often may be normal; however, epidermal changes
including mild spongiosis, slight and focal basal layer vacuolar degeneration,
mounds of parakeratosis or hyperkeratosis are encountered in approximately
50% of patients.14,45
In the deep subtype of erythema annulare centrifugum, the perivascular
infiltrate involves both the superficial and deep plexuses.14,32–34,45 Epidermal
changes are usually absent or minimal.
In both variants, the degree of inflammation is variable; however, the
­density of inflammation tends to be greater in the deep variant. The vast
majority of cells are lymphocytes; however, a minor component of histiocytes
and eosinophils may be seen.
Fig. 8.10
Erythema annulare
centrifugum: the
superficial and deep
vasculature is surrounded
by a dense infiltrate.
Fig. 8.11
Erythema annulare centrifugum: the infiltrate is composed of mature lymphocytes
and histiocytes.
Differential diagnosis
Given that the histological features of erythema annulare centrifugum are not
distinctive, it is critical to correlate the biopsy and clinical findings. Clinical
information is necessary to distinguish this disorder from other gyrate
­erythemas, pityriasis rosea, hypersensitivity reactions, lupus erythematosus,
viral exanthemata, and Jessner's lymphocytic infiltrate. In cases with significant
­epidermal changes, a silver stain to exclude a fungal infection is also advised.
Clinically, erythema annulare centrifugum may resemble psoriasis. The presence
of ­parakeratotic mounds associated with neutrophils would favor a diagnosis
of psoriasis. In contrast to cutaneous lupus erythematosus, interface changes
are not usually well developed and immunofluorescence studies are negative.
Erythema chronicum migrans also enters the differential diagnosis. The ­presence
of plasma cells would be in favor of the latter condition. Histochemical stains
for spirochetes may be positive but are cumbersome and difficult to interpret.
PCR is a more realiable and easy test to confirm the diagnosis.
 Toxic erythema 263

Erythema gyratum repens

Clinical features
Erythema gyratum repens (L. repens, to crawl or creep) is an extremely rare
and clinically distinctive figurate eruption usually associated with an under-
lying malignancy. The most commonly associated neoplasm is carcinoma
of the lung; other affiliated tumors include carcinoma of the uterus and
­cervix, esophagus, stomach, kidney, and breast as well as essential thrombo-
cythemia.1–11 Treatment of the cancer may be associated with remission of the
cutaneous eruption, while tumor recurrence or metastases can be accompa-
nied by a relapse.2 Rarely, the condition develops in the absence of an under-
lying malignancy.12–17 It may disclose underlying pulmonary tuberculosis. In
one patient with no evidence of malignancy, the rash resolved a few days after
removal of a cavitary tuberculoid lung lesion.14
Ichthyosis may accompany erythema gyratum repens.18 A report of a
patient with transitional cell carcinoma of the kidney who developed erythema
gyratum repens and ichthyosis comes as no surprise since both conditions are
associated with malignancy. The combination of ichthyosis, palmoplantar
keratosis, and erythema gyratum repens, in the absence of malignancy, has Fig. 8.13
also been reported.19 Erythema gyratum repens: the eruption may sometimes have a bizarre appearance.
Erythema gyratum repens-like eruptions have also been described in the By courtesy of R. Cerio, MD, The London Hospital, London, UK.
presence of connective tissue diseases. Typical erythema gyratum repens devel-
oped in a patient with cutaneous subacute lupus ­erythematosus ­following are usually spared.33 Postinflammatory hyperpigmentation may be a feature.1
hydroxychloroquine treatment.20,21 The authors of this report ­concluded that Hyperkeratosis of the palms and soles is also sometimes present.3,12 Males are
the patient's rash represented a peculiar pattern of involvement by ­subacute affected twice as commonly as females.3 Patients are usually in their seventh
lupus which they designated subacute lupus gyratum repens. An erythema gyra- decade.20
tum repens-like eruption has also been described in association with Sjögren's
syndrome, neutrophilic dermatosis, leukocytoclastic ­vasculitis, in patients with Pathogenesis and histological features
lupus erythematosus, and in the setting of u­ rticarial vasculitis.22–25 Erythema gyratum repens may have an immunological pathogenesis, since
Caputo et al. reported linear IgA dermatosis, erythema, and an erup- granular deposits of IgG and C3 have been found at the basement mem-
tion resembling erythema gyratum repens in a patient without malignancy.26 brane zone of both involved and uninvolved skin in a patient with associ-
Bullous pemphigoid may be associated with erythema gyratum repens and ated bronchial carcinoma and in involved non-sun-exposed skin in another
an erythema gyratum repens-like eruption has been documented in a patient unassociated with neoplasia.16,34–36 In a separate patient, although basement
with treated and resolving psoriasis and with epidermolysis bullosa acquisita membrane zone immunofluorescence was negative, epidermal nuclear label-
accompanied by ulcerative colitis.27–31 ing was identified.37 Caux et al. reported one patient with squamous cell car-
Erythema gyratum repens has been described in patients with hypereo- cinoma of the lung who had immunoreactants at the basement membrane of
sinophilic syndrome, also with no evidence of neoplasia.32 involved and normal non-sun-exposed skin. In addition, this patient showed
The eruption, which may precede the malignancy by months, takes the staining of IgG, IgM, and C3 along the basement membrane of the bron-
form of concentric bands of erythema in an annular or gyrate arrange- chus.35 However, the immunoreactants did not localize to the tumor.
ment (Figs 8.12, 8.13). These bands have been described as having a ‘tim- The appearances in erythema gyratum repens are not diagnostic. They
ber grain’ or ‘zebra-like’ pattern and they move (up to about 1 cm) daily.33 include hyperkeratosis, parakeratosis, acanthosis, and spongiosis, together
Scaling occurs and there may be pruritus. Lesions often commence on the with a superficial perivascular lymphohistiocytic infiltrate in the papillary
arms and legs, but frequently become generalized.1 The hands, feet, and face dermis (Figs 8.14, 8.15).2

Fig. 8.12
Erythema gyratum repens:
the presence of annular
erythematous parallel
bands with scaling is
characteristic. From the
collection of the late N.P.
Smith, MD, The Institute Fig. 8.14
of Dermatology, London, Erythema gyratum repens: there is hyperkeratosis, acanthosis and a mild perivascular
UK. chronic inflammatory cell infiltrate.
264 Superficial and deep perivascular inflammatory dermatoses
Fig. 8.15
Erythema gyratum repens: spongiosis is present.
Differential diagnosis
As noted above, the histological features are non-specific and vary from
patient to patient. Fortunately, the clinical features are so distinctive that con-
fusion with other disorders is unlikely. Obviously, any patient with features
of erythema gyratum repens should be very carefully evaluated for an under-
lying neoplasm.
Lymphocytic infiltrate of the skin (Jessner)
Clinical features
Jessner's lymphocytic infiltrate of the skin is an uncommon dermatosis of
unknown etiology, although a relationship with sun exposure, at least in the
early stages, is occasionally documented.1 Lesions, which may be single or
more often multiple, occur most often on the face, neck, back, and upper
chest, and present as 1–2-cm diameter, asymptomatic, discoid or annular, ery-
thematous or brownish papules or plaques that often show central clearing to
produce circinate lesions (Figs 8.16, 8.17).1–4 Familial cases have occasion-
ally been documented.5–8
In contrast to discoid lupus erythematosus, with which it is sometimes
confused, there is no hyperkeratosis, telangiectases or follicular plugging,
and scarring is not a feature. Rarely, however, the two diseases appear to
Fig. 8.16
Jessner's lymphocytic infiltrate: there are multiple erythematous plaques on this
young man's cheek. By courtesy of the Institute of Dermatology, London, UK.
Fig. 8.17
Jessner's lymphocytic infiltrate: central clearing has resulted in this circinate lesion.
By courtesy of the Institute of Dermatology, London, UK.
coexist.1 The disease tends to affect adults, particularly in the third to fifth
decades. Although some authors have found a predilection for males, 54%
of patients in a large series were female and the overall gender distribution
appears to be equal.1,3 Rarely, the condition presents in children.9–11 Lesions
often resolve within weeks or months, but relapses are not uncommon and, in
many patients, the disorder persists for years. The eruption is not character-
ized by seasonal variation. The evidence available suggests that lymphocytic
infiltrate of the skin is a distinctive dermatosis. It does not evolve into lupus
erythematosus, polymorphous light eruption or lymphoma.1
Pathogenesis and histological features
The etiology of this curious condition is unknown. Although some patients
notice a relationship with sun exposure, many do not, and lesions not uncom-
monly develop on covered sites.
Braddock and coauthors found that natural killer cell lytic activity and anti-
body-dependent cell-mediated cytotoxicity was decreased.10 This same group
identified increased levels of circulating immune complexes in patients with
lymphocytic infiltrate of skin. In two patients immune complexes decreased
to normal levels following treatment but became elevated during recurrence
of disease following treatment.10,11 Based on these observations, these inves-
tigators concluded that immune defects might be important in the pathogen-
esis of Jessner's lymphocytic infiltrate. Of interest, similar findings have been
observed in patients with reticular erythematous mucinosis. Clearly, further
study is necessary to determine the pathogenesis of this disease.
The epidermis is typically unaffected. Within the superficial and mid der-
mis is a perivascular and, much less commonly, a perifollicular infiltrate of
mature lymphocytes (Figs 8.18, 8.19). Occasional histiocytes and scattered
plasma cells may also be present and sometimes there is an increase in dermal
ground substance.12 Lymphoid follicles are not a feature.
The infiltrate consists predominantly of T cells, most often of the CD4+
helper subtype (Fig. 8.20). Occasionally, however, CD8+ suppressor T cells
constitute the majority of cells.3,13–16 Leu 8 is commonly expressed but human
leukocyte antigen (HLA)-DR is not present. B cells are relatively sparse in
number or are absent.
Differential diagnosis
Lymphocytic infiltrate of the skin differs from discoid lupus erythematosus
by the absence of epidermal changes, scarring, and a negative lupus band
test. Immunohistochemistry may sometimes be helpful. The infiltrate in lym-
phocytic infiltrate is HLA-DR negative in contrast to discoid lupus erythe-
matosus in which the lymphocytes and often the keratinocytes are HLA-DR
positive.17 Leu 8 (immunoregulatory T-cell) expression is also more frequently
seen in lymphocytic infiltrate.13,18 In one study, the average percentage of Leu
 Reticular erythematous mucinosis 265

8 ­positive lymphocytes was 65% in lymphocytic infiltrate of skin and only

15% in discoid lupus erythematosus.18 The presence of CD20+ B cells favors
lupus erythematosus, which tends to be composed of a mixture of B and T
cells. In contrast, T cells predominate in lymphocytic infiltrate of skin.14,19,20
One group of investigators has suggested that the presence of plasmacytoid
monocytes favors a diagnosis of lymphocytic infiltrate of skin over lupus ery-
thematosus. They found plasmacytoid monocytes to be present in 58% of
patients with lymphocytic infiltrate of skin but only in 7% of patients with
discoid lupus erythematosus.21 Others, however, have not been able to cor-
roborate this finding.19 The presence of significant dermal mucin would sup-
port lupus erythematosus. Reliable distinction between lymphocytic infiltrate
of the skin and tumid lupus erythematosus may be difficult and frequently
impossible since lymphocytic infiltrate may sometimes be accompanied by
excess dermal mucin. It has therefore been speculated that these entities rep-
resent a continuous disease spectrum rather than different diseases.22 The
finding that a subset of patients with lymphocytic infiltrate of the skin also
had a confirmed diagnosis of lupus erythematosus lead one group to specu-
late whether lymphocytic infiltrate of the skin could represent a variant of
lupus erythematosus.4
Fig. 8.18 Epidermal Langerhans cells are often increased in lymphocytic infil-
Lymphocytic infiltrate of Jessner: a heavy chronic inflammatory cell infiltrate cuffs
trate whereas they are frequently reduced in number in discoid lupus
the vessels in the superficial and mid dermis.
erythematosus.13
Lymphocytic infiltrate may often be distinguished from chronic lympho-
cytic leukemia/lymphocytic lymphoma by careful evaluation of cellular mor-
phology. The benign lymphocytic infiltrate is composed of non-neoplastic
lymphocytes with small, regular, and hyperchromatic nuclei. In chronic lym-
phocytic leukemia/lymphocytic lymphoma the nuclei are larger, irregular, and
paler staining, and a nucleolus may be visible. Regardless of these subtle cyto-
logical differences, if the possibility of low-grade lymphoma exists, immuno-
histochemical studies should be performed. Most often, well-differentiated
lymphomas are of B-cell lineage.
Lymphocytic infiltrate is usually histologically indistinguishable from poly-
morphous light eruption although early lesions of the latter may show edema
of the papillary dermis. It should be noted, however, that sometimes the two
conditions may coexist. In cases where the diagnosis is in doubt, phototesting
may be necessary. One group of investigators has found the presence of plas-
macytoid monocytes to favor lymphocytic infiltrate of the skin over polymor-
phous light eruption.21 However, this has not been confirmed (see above).
Histologically, lymphocytic infiltration of Jessner also shows some over-
lap with reticular erythematous mucinosis. Mucin deposition, however, is
not generally a feature of lymphocytic infiltrate of the skin, although it may
Fig. 8.19 be evident. Furthermore, the infiltrate in reticular erythematous mucinosis is
Lymphocytic infiltrate of Jessner: the infiltrate is composed almost entirely of small usually mild.
lymphocytes.

Reticular erythematous mucinosis

Clinical features
This rare chronic dermatosis, which shows a female predominance (2:1), has
been described worldwide.1 Although it may affect a wide age range, it most
frequently develops in the second to fourth decades.2 Rarely, it is encoun-
tered in children.2 Familial presentation is exceptional.3 It usually presents
as a persistent, reticulate, urticated, macular, and sometimes papular, ery-
thema with an irregular, but well-defined border. The lesions typically occur
on the central chest and upper back (Figs 8.21–8.23).4–6 Less commonly,
they can be found on the face, arms, abdomen, and groins, but the peripher-
ies are spared.1,7,8 Patients frequently notice an exacerbation in the sun, but
the relationship between sunlight and the disease (if any) is not well under-
stood.2,6–11 Although patients are usually asymptomatic, some report pruritus
or burning following exposure to sunlight. There is no evidence of systemic
involvement.
Occasional patients have more infiltrated papules and plaques; this was
originally described as plaquelike cutaneous mucinosis, but is now accepted
as a variant of reticular erythematous mucinosis.12,13 Of particular interest,
Fig. 8.20 the plaquelike form of the disease has been documented in association with
Lymphocytic infiltrate of Jessner: the majority of lymphocytes express CD4 (T-helper carcinoma of the breast and colon and one patient suffered from essential
cells). thrombocytosis in addition to carcinoma of the lung.13,14
266 Superficial and deep perivascular inflammatory dermatoses
Fig. 8.21
Reticular erythematous mucinosis: erythematous reticular eruption in a characteristic
distribution in a young woman. By courtesy of the Institute of Dermatology, London, UK.
Fig 8.22
Reticular erythematous mucinosis: location in the lower back is unusual. From the
collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.
Patients with this condition have an increased risk of thyroid disease,
arthritis, and diabetes mellitus.2 In a series of nine patients, one patient
had evidence of Hashimoto's disease while another had hyperthyroidism.13
A patient with reticular erythematous mucinosis and myxedema in the setting
of Hashimoto's thyroiditis has also been described.15
Reticular erythematous mucinosis in patients with human immuno-
deficiency virus (HIV) infection has also been documented.16,17 Of inter-
est, other cutaneous mucinoses that have been described in association
with HIV infection include scleredema and lichen myxedematosus.17
Furthermore, deposition of mucin in the bone marrow of patients with
acquired immunodeficiency syndrome (AIDS) is a common finding.18 The
pathogenetic ­relationship between these various forms of mucin deposition,
Fig. 8.23
Reticular erythematous mucinosis: closer view of previous figure. Macular elements
predominate. From the collection of the late N.P. Smith, MD, The Institute of
Dermatology, London, UK.
if any, has not been defined. It is, of course, tempting to postulate that they
are related but data to support such a conclusion are not yet established.
The presence of monoclonal IgG (kappa) paraproteinemia has been
reported in one patient.19
Pathogenesis and histological features
The pathogenesis of reticular erythematous mucinosis is not well understood.
Phototoxicity likely plays some role in the disease, either directly or indi-
rectly. Braddock and coauthors found that natural killer cell lytic activity
and antibody-dependent cell-mediated cytotoxicity were decreased.20 This
same group found increased levels of circulating immune complexes. Of
interest, two patients were observed to have circulating immune complexes
that decreased with treatment only to become elevated during recurrence of
disease following treatment.20 Based on these observations, the investigators
concluded that immune defects may be of importance in the pathogenesis. Of
interest, similar findings have been observed in patients with Jessner's lym-
phocytic infiltrate (see above). Clearly, further study is necessary regarding
the precise pathogenetic basis of this disease.
The epidermis may be slightly flattened or appear normal. Within the der-
mis there is moderate vascular dilatation associated with a marked mono-
nuclear perivascular and often perifollicular infiltrate composed mainly of
T-helper lymphocytes (Figs 8.24, 8.25).6,13,20–22 Excess mucin (predominantly
hyaluronic acid) is usually present in the upper dermis but in more chronic
lesions it is sometimes absent (Fig. 8.26). The mucin stains positively with
Alcian blue (pH 2.5) and colloidal iron, but is usually not metachromatic with
toluidine blue. The collagen fibers are separated, but appear morphologically
normal. Fragmentation of elastic fibers is sometimes a feature.7 There is no
evidence of fibroblastic proliferation, but by immunohistochemistry increased
numbers of factor XIIIa-positive dermal dendrocytes have been identified.23
A few cases with positive direct immunofluorescence have been reported.
IgM-reactive papillary dermal cytoid bodies were documented in one case.20
Rare examples show staining for IgM along the dermal–epidermal junc-
tion.2,10,24 The significance of these findings is unclear but may be further
­evidence of an immunological basis for the pathogenesis of this condition.24
 Polymorphous light eruption (including juvenile spring eruption and lambing ears) 267

Ultrastructural studies are largely unhelpful. Other than demonstrating

conspicuous and dilated rough endoplasmic reticulum within dermal fibro-
blasts, electron microscopy merely serves to confirm the light microscopic
observation of widely separated fascicles of collagen fibers.21 In a number
of reports tubuloreticular structures were identified within the cytoplasm of
endothelial cells.7,25,26 Although at one time these were thought to represent
paramyxoviruses, more recent studies suggest that they may be derived from
infolded endoplasmic reticulum. They have also been identified in pretibial
myxedema, lupus erythematosus, dermatomyositis, malignant atrophic papu-
losis, and various lymphomas.27

Differential diagnosis
The principal clinical and pathological differential diagnoses include lupus
erythematosus and polymorphous light eruption. Distinguishing between
lupus erythematosus and reticular erythematous mucinosis may be very diffi-
cult, particularly as one condition may evolve into the other.28 Histologically,
reticular erythematous mucinosis lacks the epidermal changes of lupus ery-
thematosus and the immunofluorescent findings are usually, but not always,
negative.7–9 As noted above, there are a few reports in which granular
Fig. 8.24
Reticular erythematous mucinosis: there is a perifollicular and perivascular infiltrate
immunoglobulin deposition at the dermoepidermal junction has been iden-
in the upper and mid dermis. tified.2,10,24 The presence of several immunoreactants favors a diagnosis of
lupus erythematosus. Clinical and serological studies are also necessary to
establish a diagnosis of lupus erythematosus.
In polymorphous light eruption, mucin deposition is much less striking and
is limited to the papillary dermis.29 Perifollicular inflammation is not a feature
of polymorphous light eruption. In addition, epidermal changes of spongiosis –
sometimes with vesiculation in papular and eczematous lesions and mild basal cell
hydropic change in the plaque variant – serve as further distinguishing features.30
Polymorphous light eruption resolves once exposure to sunlight has ceased, in
contrast to reticular erythematous mucinosis where the lesions persist.
Histologically, reticular erythematous mucinosis also shows some overlap
with lymphocytic infiltrate of Jessner.2 Mucin deposition, however, is not gen-
erally a feature of the latter condition and the inflammatory cell infiltrate is
always more prominent.

Polymorphous light eruption (including

juvenile spring eruption and lambing ears)
Clinical features
Fig. 8.25 Polymorphous (polymorphic) light eruption, which is the most common
Reticular erythematous mucinosis: the infiltrate consists of mature lymphocytes ­photodermatosis, usually presents in young people as recurrent erythematous
with a lesser number of histiocytes. papules, vesicles and/or plaques following exposure to ultraviolet (UV) light
(Figs 8.27, 8.28).1–6 The face, chest, upper back, and extremities are the most
common sites of involvement.5 Most patients have multiple lesions.5 In one
study of 138 patients, the mean age at onset was 26 years.5 There is a predilec-
tion for young women, with 89% of patients being female.7,8 The vast majority
of lesions are associated with pruritus. Most patients require less than 30 min-
utes of sun exposure to elicit clinical features.5 Onset following light ­exposure
typically takes 18–24 hours. Either the UVA or UVB part of the light spectrum
may cause lesions.2,9 Lesions are caused by UVA light in 56% of cases, UVB
in 17%, and both UVA and UVB ranges in 26% of cases.2 However, some
authors have not been able to elicit lesions with UVB light.4 Exposure result-
ing in sunburn is not necessary for the development of the condition.4 Some
patients report symptoms resulting from light exposure through glass.4
Polymorphous light eruption most often occurs in patients with fair skin;
however, dark-skinned individuals can also be affected. The disease is more
common in people residing in northern latitudes. One study showed that the
prevalence rates for London (UK) and Perth (Australia) were 14.8% and
5.2%, respectively.10 In a recent retrospective analysis, however, the ­incidence
of photosensitivity reactions and polymorphous light eruption in ­particular
was found to be roughly comparable for dark-skinned and Caucasian
­individuals.11 The pinpoint papular variant of polymorphous light eruption
Fig. 8.26 has only recently been recognized and appears to be particularly common
Reticular erythematous mucinosis: increased dermal mucin (hyaluronic acid) separates on dark skin.11,12 It is characterized by numerous grouped, small, 1–2-mm
the collagen fibers (Alcian blue stain). ­papules, which may be accompanied by small vesicles in the acute phase.13
268 Superficial and deep perivascular inflammatory dermatoses
Fig. 8.27
Polymorphous light eruption: patients present with erythematous papules and
vesicles on sun-exposed skin. From the collection of the late N.P. Smith, MD,
The Institute of Dermatology, London, UK.
Fig. 8.28
Polymorphous light eruption: the eruption is typically symmetrical and is usually
pruritic. By courtesy of the Institute of Dermatology, London, UK.
It appears that the incidence of polymorphous light eruption is much more
common than is demonstrated by contact with healthcare workers. In one
survey, 21% of workers in a Swedish pharmaceutical company had symp-
toms consistent with polymorphous light eruption; however, only 3% had
sought medical attention for their symptoms.7
Biopsy of experimentally induced lesions shows similar histological fea-
tures compared to clinical lesions.4 Given the role of sun exposure in its
pathogenesis, it comes as no surprise that polymorphous light eruption is
most often seen in spring and summer.4 In addition, it is not uncommon for
the first sign of disease to manifest during a vacation to southern latitudes.
The features, which develop after a latent period of hours to days, commonly
subside completely within days and heal without sequelae.1 However, once
the disease is established, persistence for many years is common.3 Overall,
however, there is diminution of light sensitivity over time, but this process
often takes years.3 In a large study, the mean disease duration of the condition
was 10.5 years.5 Patients with a duration of up to 53 years have been stud-
ied.7 The distribution of lesions often changes with time.5
One study showed that thyroid disease was present in 14% of patients.14
This same study found lupus erythematosus in only 2 of 94 patients. The
authors concluded that the risk of lupus erythematosus was not increased in
patients with polymorphous light eruption. Authors of another study, how-
ever, have suggested that a subgroup of patients with polymorphous light
eruption may be at an elevated risk for lupus erythematosus.15
Juvenile spring eruption appears to be either a variant of polymorphous
light eruption or a closely related disorder.16–21 In one study, the prevalence was
6.7% with a male predominance.16 The lesions are characterized by erythema-
tous papules and vesicles located on sun-exposed portions of the helix of the
ear following light exposure. They tend to be pruritic. In one study, 4 of 18
patients also had lesions of typical polymorphous light eruption.17 As its name
implies, the lesions tend to occur in the spring. A positive family history is
present in some patients.19 A disorder, clinically and histologically reminiscent
of juvenile spring eruption, has also been reported to develop in farmers at the
time of lambing and calving. It is provisionally termed ‘lambing ears’.22
Pathogenesis and histological features
The pathogenesis of polymorphous light eruption is poorly understood.
Study of adhesion molecule expression has led some authors to propose that
polymorphous light eruption is immunologically mediated.23 Specifically,
vascular endothelial expression of endothelial leukocyte adhesion molecule-1
(ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), and keratinocyte
and endothelial expression of intercellular adhesion molecule-1 (ICAM-1) in
biopsies of induced lesions has been documented.23 The authors noted that
their results were similar to those seen in delayed-type hypersensitivity reac-
tions. In addition, reduced skin infiltration by neutrophils following UVB
exposure was noted.24 However, the triggering antigen(s) are unknown.23 It
appears that polymorphous light eruption may be a heritable disorder. In one
study, 46% of patients reported a positive family history.7
Histologically, a perivascular lymphohistiocytic infiltrate is present in the
superficial and sometimes deep dermis (Figs 8.29, 8.30).25–27 A characteristic,
but not uniformly present feature, is papillary dermal edema, which is often
marked. The presence of massive papillary dermal edema may be associated
with subepidermal or intradermal vesicle formation.
Papular and papulovesicular lesions may show epidermal acanthosis,
spongiosis, occasional dyskeratotic cells, and lymphocyte exocytosis.25,27
Spongiosis may sometimes become so severe as to lead to intraepidermal ves-
icle formation.25 Other authors, however, have not found spongiosis to be a
significant feature.26 Basal cell vacuolization, usually mild, is found in some
cases.25,27,28 Periadnexal involvement by a chronic inflammatory cell ­infiltrate
Fig. 8.29
Polymorphous light
eruption: there is papillary
dermal edema and a
dense superficial and deep
perivascular inflammatory
cell infiltrate.

Fig. 8.30
Polymorphous light eruption: incipient subepidermal vesiculation is evident. Note
the red cell extravasation and lymphocytic infiltrate.
may be present in papular and papulovesicular lesions.25 Some authors have
reported increased eosinophils and neutrophils; however, others have not
confirmed this observation.25,26 Papillary dermal erythrocyte extravasation
is commonly present.25 Finally, features secondary to scratching, such as
­hyperkeratosis and acanthosis, may be seen.27
Immunofluorescence studies have shown that immunoreactants (C3, IgG,
and IgM) may be present along the basement membrane zone.3 However,
when staining is evident, it is usually weak.3
Juvenile spring eruption of the ears is characterized by a perivascular lym-
phohistiocytic infiltrate often associated with subepidermal vesicle formation.20
In early lesions, helper-inducer T lymphocytes predominate and increased
numbers of dermal Langerhans cells are present.26 With chronicity, cytotoxic
suppressor T cells become more conspicuous.
Differential diagnosis
It should be noted that there is considerable variability in both the clini-
cal and histological descriptions of polymorphous light eruption. This has
led some authors to suggest that polymorphous light eruption likely repre-
sents a group of related disorders rather than a single entity.25,26 Phototesting,
therefore, is probably the best ‘gold standard’ for establishing the diagnosis.
Compared with reticular erythematous mucinosis, mucin deposition is absent
or much less prominent in polymorphous light eruption. Clinically, polymor-
phous light eruption resolves once exposure to sunlight has ceased in contrast
to the persistent lesions of reticular erythematous mucinosis.
Histologically, polymorphous light eruption also shows some overlap with
other causes of gyrate erythema such as lymphocytic infiltration of Jessner.
The presence of marked papillary dermal edema, when present, favors poly-
morphous light eruption. A clinical history of documentation of resolution
of lesions with cessation to light exposure may sometimes be the only way to
distinguish these entities. In cases where the diagnosis is in doubt, phototest-
ing may often be necessary.
The histological features of lupus erythematosus are sometimes difficult
to distinguish from polymorphous light eruption, particularly when the lat-
ter is associated with positive immunofluorescence. However, most cases of
polymorphous light eruption are negative with immunofluorescence testing.
When immunoreactants are present, usually only weak staining is observed.
Careful clinical and serological evaluation should resolve any confusion
between these conditions.
Actinic reticuloid is another eruption associated with exposure to UV light.
Compared with polymorphous light eruption, actinic reticuloid is more typi-
cally associated with a dense cellular interstitial infiltrate involving the pap-
illary and reticular dermis, and ­sometimes extending into the subcutaneous
fat. It is composed of lymphocytes, histiocytes, variable numbers of eosino-
phils, and plasma cells. The presence of multinucleate stellate myofibroblasts
Tumid lupus erythematosus 269
and giant cells is a conspicuous feature that favors actinic reticuloid. Finally,
the finding of large atypical, hyperchromatic cerebriform lymphoid cells and
blast forms is characteristic of actinic reticuloid.
Tumid lupus erythematosus
Clinical features
Lupus erythematosus is discussed in detail in Chapter 17 and the reader is
referred there for a comprehensive discussion of the disease. In this section
only the tumid variant of lupus erythematosus is discussed.
Tumid lupus erythematosus (lupus erythematosus tumidus) is a rare mani-
festation of lupus that some authors believe to be sufficiently characteristic
to justify classification as a distinctive subtype of chronic cutaneous lupus
­erythematosus.1 However, the lack of an agreed-upon diagnostic gold stan-
dard makes this designation somewhat controversial. Further study and
refinement of criteria for inclusion into this subtype of lupus and to allow for
reliable distinction from other inflammatory dermatoses is necessary.
Raised erythematous plaques, which have been described as ‘succulent’,
characterize the clinical lesions.1 Follicular plugging is not a feature.2 Annular
and gyrate forms are seen in some patients.1 The sun-exposed areas such
as the face, chest, arms, and shoulders are most commonly affected.1–4 In
the largest series published to date, patients with this clinical appearance
accounted for 16% of the total number of patients seen in a large cutane-
ous lupus clinic.1 Approximately equal numbers of male and female patients
are affected, in contrast to the preponderance of females affected by other
subtypes of cutaneous lupus.2,4 In this variant, young adults are most often
encountered but presentation in childhood is rare.4,5 In most patients, lesions
can be reproduced by exposure to UVA or UVB light.1,3,6 Development of
tumid lupus erythematosus has also been reported following highly active
antiretroviral therapy in the setting of HIV as a manifestation of immune
restoration as well as in the setting of estrogen and infliximab treatment.7–9
Unusual and rare presentations include unilateral distribution in addition to
symmetrical involvement of both elbows.10,11
Histological features
Biopsy shows a superficial and perivascular ‘cuffed’ lymphocytic infiltrate
(Fig. 8.31).12 Periadnexal involvement is also seen in many cases. Abundant
dermal mucin is commonly present (Fig. 8.32).2,12,13 In contrast to other
­variants of lupus erythematosus, epidermal changes (e.g., follicular plugging,
­vacuolar interface changes, and thickened basement membrane) are generally
not apparent.1,2,12
Fig. 8.31
Tumid lupus erythematosus: there is a perivascular lymphocytic infiltrate. The
collagen fibers are separated by excess dermal mucin. By courtesy of J. Cohen,
MD, Dermatopathology Laboratory, Tucson, Arizona, USA.
270 Superficial and deep perivascular inflammatory dermatoses

As can be seen from the above discussion, tumid lupus erythematosus is

a controversial entity. To some extent, the problem is a matter of seman-
tics and definitions. Indeed, some authors have taken the position that
reticular erythematous mucinosis and Jessner's lymphocytic infiltrate of
the skin would be more appropriately regarded as tumid lupus.18 Clearly,
further studies are necessary to more clearly define the clinicopathologi-
cal features of tumid lupus erythematosus and its distinction from similar
entities.

Perniosis, atypical chilblains and cold

equestrian panniculitis
Clinical features
Perniosis (chilblains) is characterized by sensitivity to cold, damp weather
and is therefore seen during the cold months of the year. The disease seems to
be more common in environments where inadequate heating is problematical
for a few months of the year and is less common in localities characterized by
Fig. 8.32 harsh frigid winters where adequate home heating is the norm.1 Exposure to
Tumid lupus erythematosus: the mucin is Alcian blue positive. By courtesy of
cold water sometimes appears to play a role.2
J. Cohen, MD, Dermatopathology Laboratory, Tucson, Arizona, USA.
Patients present with painful, erythematous nodules on the ­distal extremi-
ties, especially the fingers and the toes (Fig. 8.33).1,3 Other exposed sites,
Direct immunofluorescence staining fails to demonstrate reactivity.1 such as the nose and ears, may also be affected (Fig. 8.34). Lesions may be
The infiltrate cell infiltrate consists of a mixture of CD4+ and CD8+ reac- ­complicated by blister formation or ulceration. In most patients, the ­condition
tive T lymphocytes.2,14 remits during summer but often recurs during winter months. Patients with
anorexia nervosa may be at increased risk of developing perniosis.4,5
Differential diagnosis Horse-riding enthusiasts who wear tight clothing during cold weather may
The concept of tumid lupus erythematosus has been expanded in a recent develop similar lesions on the thighs (Fig. 8.35). This disease is associated
large series of patients.1 Whether there is justification for classification of with panniculitis and has been termed ‘equestrian cold panniculitis’.6
the disorder in these patients as a variant of lupus erythematosus or not is Patients with lesions that persist into warmer seasons appear to be at a
debatable. None met the criteria for lupus erythematosus and most did not higher risk of developing lupus erythematosus.7 One group has designated
have significantly elevated antinuclear antibodies (ANA). However, occa- patients with some criteria, but not meeting diagnostic thresholds for con-
sional patients have been shown to develop skin lesions consistent with dis- nective tissue diseases such as lupus erythematosus, as having ‘atypical
coid lupus erythematosus, including prominent e­ pidermal changes.13,15 ­chilblains’.7 This subset of patients appears to be at higher risk of developing
In addition to patients similar to those described by Kuhn et al.,1 patients unequivocal features of connective tissue disease. It is reasonable to evaluate
that do fit the criteria for discoid lupus erythematosus (DLE), subacute cuta- all patients with perniosis for evidence of lupus erythematosus. Occasionally,
neous lupus erythematosus (SCLE) or systemic lupus erythematosus (SLE) patients with perniosis who present without clinical manifestations of
rarely develop lesions that show a dense superficial and deep perivascular and ­connective ­tissue disease eventually develop SLE.8
periappendigeal infiltrate in the absence of significant epidermal changes.16
Distinction of these subgroups of tumid lupus from lymphocytic infiltrate of
Jessner and polymorphous light eruption based on histological examination
alone may be difficult if not impossible.17 Some authors have suggested that
some cases reported as lymphocytic infiltrate of Jessner or reticular erythema-
tous mucinosis, in fact, represent tumid lupus.18
The histological features of tumid lupus erythematosus may be difficult to
distinguish from polymorphous light eruption. The latter condition, which is
the most common photodermatosis, usually presents in young ­people, par-
ticularly females, as recurrent, erythematous papules, vesicles and/or plaques
following exposure to UV light. Lesions, which develop after a latent period
of hours to days, commonly subside completely within days and heal with-
out sequelae.19 A dense perivascular lymphohistiocytic infiltrate, often
associated with papillary dermal edema, is present in the superficial and
sometimes deep dermis.20 The presence of significant papillary dermal edema
favors polymorphous light eruption. Furthermore, the latter often has focal
­epidermal changes, particularly spongiosis and lacks dermal mucin.
Lymphocytic infiltrate of the skin (Jessner) may be difficult to distinguish from
tumid lupus erythematosus.3 In such cases, immunocytochemistry may some-
times be helpful. The infiltrate in lymphocytic infiltrate is HLA-DR negative in
contrast to lupus erythematosus in which the lymphocytes and often the kera-
tinocytes are HLA-DR positive.21 Leu 8 (immunoregulatory T-cell) expression Fig. 8.33
Perniosis: erythematous
is also more frequently seen in lymphocytic infiltrate.21 Epidermal Langerhans
nodules are present over
cells are often increased in number in lymphocytic infiltrate whereas they are the fingers. From the
frequently reduced in discoid lupus.22 The presence of significant amounts of collection of the late N.P.
dermal mucin favors a diagnosis of tumid lupus erythematosus. Smith, MD, The Institute
Erythema annulare centrifugum differs from tumid lupus by the lack of of Dermatology, London,
significant dermal mucin. UK.
 Perniosis, atypical chilblains and cold equestrian panniculitis 271

Fig. 8.36
Perniosis: there is hyperkeratosis, acanthosis, and a heavy lymphocytic infiltrate.
Note the marked subepidermal edema.
Fig. 8.34
Perniosis: in this patient,
the nose is affected.
From the collection of the
late N.P. Smith, MD, The
Institute of Dermatology,
London, UK.

Fig. 8.37
Perniosis: there is marked subepidermal edema and red cell extravasation.

Fig. 8.35
Equestrian cold
panniculitis: tender
erythematous lesions on
buttock and thigh.
By courtesy of the
Institute of Dermatology,
London, UK.

Pathogenesis and histological features

The pathogenesis of perniosis is not well understood. Clearly, cold is
a requirement for development of symptoms. Tight clothing may play a
role in the development of perniosis at nonexposed sites. In some patients,
particularly children, the presence of cryoproteins may play a role in the
disease.9
Biopsy reveals a cuffed perivascular lymphocytic infiltrate with ­variable
vascular fibrinoid change (Figs 8.36–8.38). The inflammatory ­infiltrate Fig. 8.38
may be superficial but often extends into the deep dermis and ­subcutaneous Perniosis: the infiltrate consists largely of lymphocytes.
272 Superficial and deep perivascular inflammatory dermatoses
Fig. 8.39
Perniosis: this example shows a heavy mural infiltrate consistent with lymphocytic
vasculitis.
a­ dipose tissue. In some cases it is difficult to demonstrate strict criteria for
lymphocytic vasculitis (Fig. 8.39). In other examples, however, fibrinoid
­vascular damage with thrombi is extensive. Papillary dermal edema, which
may be marked, is often present.10 Interface changes, either vacuolar interface
or lichenoid dermatitis, may sometimes be seen.11 A chronic inflammatory
infiltrate around sweat glands has occasionally been noted.7
Biopsy of cold panniculitis shows a perivascular chronic inflammatory
infiltrate that tends to be prominent at the dermal–subcutaneous tissue
junction.6
The inflammatory infiltrate is mostly composed of CD3+ T cells with a minor
subpopulation of CD20+ B cells and scattered CD68+ macrophages.11,12
Differential diagnosis
The biopsy findings are non-specific and other diseases causing cuffed
perivascular lymphocytic reactions and lymphocytic vasculitis enter into the
differential diagnosis. The diagnosis is rendered only after careful clinical cor-
relation. Patients often have some features of, but fail to meet criteria for,
connective tissue disease.7 Also, lesions very similar, or identical, to perniosis
may be seen in patients with cutaneous or systemic lupus erythematosus.8,11,13
Frank lymphocytic vasculitis and interface changes appear to be more com-
mon in patients with chilblain lupus erythematosus than in idiopathic chil-
blains; however, the presence or absence of these findings may not be reliable
discriminators.7,11 A positive lupus band test or antinuclear antibodies favors
a diagnosis of chilblain lupus erythematosus.7
Chilblain lupus erythematosus
Clinical features
Lupus erythematosus is discussed in detail in Chapter 17 and the reader is
referred there for a comprehensive discussion of the disease. In this section,
only chilblain lupus erythematosus (lupus pernio) will be discussed.
Chilblain lupus erythematosus may be a manifestation of either discoid
or systemic lupus erythematosus and shares many clinical and ­histological
­similarities with idiopathic chilblains (Fig. 8.40). It develops almost
­exclusively in females during the winter months.1 Lesions are characterized
by itchy, ­painful, erythematous or blue-purple papules, plaques, and nodules
on the fingers, heels, and soles of the feet; the hands, calves, knees, knuckles,
elbows, nose, and ears are less often affected.2 Hyperkeratotic fissured lesions
and ulcers are also sometimes present.3 Patients may develop chilblains many
years after the typical discoid rash, or lesions may develop simultaneously.
Occasionally, chilblains are the sole manifestation.3 While the majority of
cases are sporadic, familial disease with an autosomal dominant inheritance
has also been reported.4–7
Fig. 8.40
Chilblain lupus erythematosus: resolving perniosis involving the tips of the thumb, ring,
and little fingers. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Approximately 15% of patients develop SLE, particularly those who
develop discoid and perniotic lesions simultaneously and those with DLE-
erythema multiforme-like syndrome in addition to perniosis.1,2,8 Patients with
severe chilblains that persist into warmer seasons appear to be at higher risk
of lupus erythematosus compared to those with the idiopathic form.9 Patients
with some criteria, but not meeting diagnostic thresholds for connective ­tissue
disease, have been designated as having ‘atypical chilblains’.9 These individ-
uals appear to be at higher risk of eventually developing frank connective
­tissue disease.9 Based on the above observations, it is clear that patients with
perniosis should be evaluated for evidence of lupus erythematosus.
Pathogenesis and histological features
While the pathogenesis of sporadic disease remains elusive, mutations in the
DNA exonuclease TREX1, located on chromosome 3, have recently been
reported in the autosomal dominant familial form of chilblain lupus.4–7 The
function of TREX1 is the digestion of single-stranded DNA. Recent work has
shown that lack of TREX1 function may lead to accumulation of reverse tran-
scribed DNA with subsequent stimulation of interferon production, which
ultimately may be a trigger for autoimmunity.10,11 Mutations in TREX1 have
also been reported in other autoimmune disorders such as Aicardi-Goutieres
syndrome, an encephalopathy characterized by basal ganglia calcification and
white matter alterations.6,12 The development of chilblains is not infrequently
seen in patients with this syndrome with clinical and histological findings
similar to chilblain lupus erythematosus.13,14
Biopsy reveals a cuffed perivascular lymphocytic infiltrate with edema, red cell
extravasation, and variable vascular fibrinoid change (Fig. 8.41). Some biopsies
show frank lymphocytic vasculitis. The inflammatory infiltrate often extends into
the deep dermis and subcutaneous adipose tissue. Interface epidermal changes,
ranging from focal vacuolar changes to a lichenoid tissue reaction, are often
­present.2,15 Chronic inflammation around sweat glands is sometimes seen.9
The infiltrate is mostly composed of T cells, occasional macrophages, and
scattered B cells.
Differential diagnosis
Other diseases associated with a ‘cuffed’ perivascular lymphocytic infiltrate
and lymphocytic vasculitis must be considered in the differential diagnosis.
The diagnosis is rendered only after careful clinical and serological corre-
lation. Distinction from idiopathic chilblain perniosis is not possible based
on histological features alone. The presence of lymphocytic vasculitis and
interface changes appears to be more common in chilblain lupus compared
with idiopathic chilblains, but these features are not reliable discriminators.9
A positive lupus band test and the presence of antinuclear antibodies favor a
diagnosis of chilblain lupus erythematosus.
 Pigmented purpuric dermatoses 273

Fig. 8.42
Fig. 8.41 Majocchi's disease: characteristic brown plaques on the backs of the knees in a
Chilblain lupus male. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
erythematosus: there is
subepidermal edema with
red cell extravasation and
a superficial perivascular
lymphocytic infiltrate.

Pigmented purpuric dermatoses including

Majocchi's disease, Schamberg's disease,
pigmented purpuric lichenoid dermatitis
of Gougerot and Blum and itching purpura
Clinical features
The term pigmented purpuric dermatoses (purpura simplex, chronic capil-
laritis) encompasses a number of clinical syndromes characterized by orange/
brown pigmentation (due to hemosiderin deposition likened to ­cayenne
­pepper), interspersed with fine pinpoint purpura (due to extravasated red
blood cells).1–4 All are of unknown etiology. These disorders may show Fig. 8.43
overlapping clinical and histological features. Indeed, some authors no lon- Schamberg's disease: a localized area of capillaritis showing characteristic cayenne
ger consider their classification to have nosological value. In addition to pepper speckling over the lateral malleolus of a male. By courtesy of R.A. Marsden,
the ­disorders listed below, unusual clinical presentations include unilateral MD, St George's Hospital, London, UK.
­disease, ­zosteriform distribution, and concomitant morphea in addition to
familial disease.5–9
• In Majocchi's disease, the lesions tend to be discrete and annular, vary
from one to several centimeters in diameter, and are associated with
telangiectases (Fig. 8.42).
• Schamberg's disease is characterized by purpura and petechiae with
conspicuous pigmentation; there is a marked preponderance of males and
presentation in childhood is unusual (Figs 8.43, 8.44).10 Lesions, usually
irregular in shape and occurring predominantly on the lower limbs, may
remain for 10 years or longer. In some cases, the findings may mimic
those of chronic venous insufficiency. The lesions are asymptomatic in
most cases. However, some patients complain of pruritus.
• In pigmented purpuric lichenoid dermatitis of Gougerot and Blum,
patients, predominantly males, develop lichenoid papules in addition to
purpuric lesions, most often on the legs.
• Itching purpura (pruriginous angiodermatitis) also shows a male
predominance and is associated with an acute onset of widely distributed
orange macules (Figs 8.45, 8.46). It commonly begins on the dorsal
surface of the feet or ankles, but soon spreads to affect the thighs,
buttocks, trunk, and arms. This variant is associated with a shorter Fig. 8.44
duration than the others, with most patients being free from lesions by Schamberg's disease: in this patient, the bilateral distribution over the malleoli mimics
1 month. The itching, which is of unknown etiology, is usually severe. the effects of venous stasis. By courtesy of R.A. Marsden, MD, St George's Hospital,
Similar appearances may be caused by drug sensitivity. London, UK.
274 Superficial and deep perivascular inflammatory dermatoses

Fig. 8.47
Fig. 8.45 Pigmented purpura: there is an upper dermal heavy perivascular lymphocytic infiltrate.
Itching purpura: these
small macules are widely
distributed over both legs.
By courtesy of J. Newton,
MD, St Thomas' Hospital,
London, UK.

Fig. 8.48
Pigmented purpura:
the infiltrate consists
of lymphocytes and
histiocytes. Note the red
cell extravasation.
Fig. 8.46
Itching purpura: close-up
view of a typical orange
macule. By courtesy of J. the later stages they may not be present when hemosiderin-laden macrophages
Newton, MD, St Thomas' become conspicuous (Fig. 8.49). An iron stain is useful to demonstrate
Hospital, London, UK. ­hemosiderin. Recently, cases of pigmented purpuric dermatosis associated
with ­granulomatous inflammation have been described and designated granu-
lomatous pigmented purpuric dermatoses.13,14 Some cases of granulomatous
Since lichen aureus has more distinctive features, it is discussed separately ­pigmented dermatosis appear to be associated with hyperlipedemia.15
(see below).
Differential diagnosis
Histological features It should be emphasized that extravasated red blood cells and hemosid-
All variants show similar histopathological features. A perivascular lympho- erin associated with a lymphocytic capillaritis are non-specific findings.
cytic infiltrate is associated with reactive endothelial changes and extravasated The ­differential diagnosis is broad and includes other forms of ­perivascular
red blood cells (Figs 8.47, 8.48).11 The lymphocytes are predominantly of the ­lymphocytic infiltrates and lymphocytic capillaritis. Careful clinical cor-
T-helper subset.12 The density of the infiltrate is highly variable. The Gougerot- relation is necessary to establish a correct diagnosis. Progression of lesions
Blum variant is often associated with a dense lichenoid lymphocytic infiltrate. mimicking ­pigmented purpuric dermatoses to mycosis fungoides has been
Extravasated red blood cells are usually appreciated in early lesions, while in documented.16,17 However, this appears to be an uncommon event and
 Lichen aureus 275

Fig. 8.49 Fig. 8.50

Pigmented purpura: there Lichen aureus: golden-
is abundant hemosiderin red-brown plaques on the
deposition as revealed ankle. By courtesy of M.
with the Perl Prussian blue Price, MD, St Thomas'
stain for iron. Hospital, London, UK.

it is more likely that these cases represent examples of purpuric cutane- fashion immediately below the epidermis (Figs 8.51, 8.52). In contrast
ous T-cell ­lymphoma from the beginning. The absence of epidermotropism to lichen planus, however, there is no evidence of basal cell hydropic
and ­cytological atypia favors pigmented purpuric dermatitis over a T-cell degeneration and cytoid bodies are not usually found. A Grenz zone is
­lymphoproliferative disorder. However, in rare cases, distinction may be sometimes present, although the infiltrate may abut the overlying epi-
­difficult or ­impossible and ­ancillary investigations such as immunohistologi- dermis. Lymphocytic exocytosis is sometimes present. Scattered within
cal and T-cell gene rearrangement studies may be indicated. Adding to this the infiltrate are increased numbers of blood vessels. Hemosiderin-laden
occasionally difficult distinction, cases of pigmented purpuric dermatoses macrophages are present in the deeper aspect of the infiltrate or in the
with clonal T-cell gene rearrangements have been reported.13,18 Therefore, it adjacent noninfiltrated dermis. Purpura is a variable feature and there is
appears that the results of gene rearrangement studies may not always ­reliably no evidence of frank vasculitis.
aid in this differential diagnosis. All information – clinical, ­histological, immu-
nohistological, and genetic – should be evaluated in context.
Differential diagnosis
There may be some histological overlap with the Gougerot-Blum variant of
Lichen aureus pigmented purpuric lichenoid dermatitis but lichen aureus tends to be more
localized.
Clinical features
Lichen aureus (lichen purpuricus) is a rare variant of the pigmented purpu-
ric dermatoses. It may be differentiated from the other forms by virtue of
its distinctive clinical and histological features.1–4 It is, therefore, discussed
separately.
Lichen aureus shows a male predilection (2:1) and tends to affect the
younger age group, with a peak incidence in the fourth decade. Children
may occasionally be affected.3 Lesions are usually asymptomatic, although
pruritus is an occasional feature. The disease is characterized by discrete
or confluent lichenoid macules and papules, which may be golden yellow,
bronze, purple, or dark brown, and may resemble a bruise (Fig. 8.50).
Sometimes a purpuric element is evident. The lesions of lichen aureus are
characteristically very persistent, although occasionally spontaneous reso-
lution is a feature. They occur most often on the lower legs, but may affect
quite a wide variety of sites, including the arms, hands, trunk, thighs, and
vulva.5,6 Lesions are usually unilateral and limited to only one or two sites;
they consist of either solitary ovoid maculopapules 3–5 cm in diameter or
irregular plaques up to 20 cm across. Rarely, a zosteriform pattern has been
described.7

Histological features
The epidermis is structurally normal. A dense lymphohistiocytic infil- Fig. 8.51
trate is present in the upper dermis, usually distributed in a bandlike Lichen aureus: there is a dense bandlike infiltrate in the upper dermis.
276 Superficial and deep perivascular inflammatory dermatoses

Fig. 8.52 Fig. 8.53

Lichen aureus: the infiltrate consists of lymphocytes and histiocytes. Note the marked Pruritic urticarial papules and plaques of pregnancy: there is focal spongiosis. Note
red cell extravasation. the perivascular upper dermal infiltrate.

Pruritic urticarial papules and plaques

of pregnancy
Clinical features
Pruritic and urticarial papules and plaques of pregnancy (PUPPP, also known
as polymorphic eruption of pregnancy, toxemic rash of pregnancy, toxic ery-
thema of pregnancy, late onset prurigo of pregnancy) is a common dermatosis
of uncertain etiology with an estimated incidence of 0.5%.1,2 The disorder is
most frequently seen in the primigravida.3,4 Characteristically, it presents late in
pregnancy, towards the end of the third trimester with an average time of onset
in the 36th week.3,4 Rarely, presentation during the postpartum period has been
documented.3–5 In a recent study, the male to female infant ratio in affected
patients was 2:1.6 In one large series, 76% of patients were primigravidas.3,4
As its name indicates, urticarial papules and plaques are associated with
vexatious pruritus. Patients frequently complain that pruritus interferes with
sleep.3 At onset, papules are often localized to the abdomen along lines of
stria distensae. This pattern is seen in approximately 50% of patients.1,3 Small
vesicles are occasionally present.3 With time, the papules spread to involve the
proximal limbs and torso and coalesce to form plaques.4 The distal extremi-
ties are rarely affected.4,7 Sparing of the face is a helpful diagnostic clinical
clue. Typically, the lesions resolve shortly after delivery. Importantly (see dif- Fig. 8.54
ferential diagnosis section below), PUPPP does not usually recur with subse- Pruritic urticarial papules
quent pregnancies. and plaques of pregnancy:
One group found PUPPP was associated with increased maternal weight high-power view showing
gain and increased newborn weight compared with a control population.8,9 spongiosis.
Some studies suggest a relationship between PUPPP and twin gestation with
two such reports documenting 10% and 16% of cases, respectively, associated
with twin gestations.3,8–10 These data have led some authors to postulate that biopsies had eosinophils in the infiltrate. However, other authors report con-
abdominal distension may play a role in the pathogenesis of PUPPP.8 Other trary experience, with most biopsies showing eosinophils. It is our experi-
reported association include hypertensive disorders and induction of labour.11 ence that most biopsies show at least rare eosinophils if multiple sections are
Rarely, congenital abnormalities have been noted in association with PUPPP examined.
but this may be due to small statistical sampling. In one report, one child had The lymphohistiocytic infiltrate is also variable in density, ranging from
hypoplastic dental enamel, while another developed congenital laryngomal- modest numbers of cells to a dense infiltrate with a tightly ‘cuffed’ perivas-
acia requiring surgical intervention.3 In this same series, another child was cular distribution.3 Mild papillary dermal edema is a common finding but
reported to have a ventriculoseptal defect. Most authors, however, believe that marked edema is rarely seen.3 The additional feature of spongiotic vesicula-
there is no direct association between PUPPP and congenital abnormalities. tion characterizes later lesions. Less common manifestations include eosino-
philic spongiosis, and rarely eosinophil-rich subepidermal blistering.
Histological features
Early lesions (urticarial papules) of polymorphic eruption of pregnancy show Differential diagnosis
epidermal and upper dermal edema accompanied by a perivascular lympho- As can be deduced from the above histological description, the biopsy findings
histiocytic infiltrate with variable numbers of eosinophils (Figs 8.53–8.55). are non-specific. The main differential diagnosis includes urticaria, hypersen-
Often, the number of eosinophils is modest and in one series only 17% of sitivity reactions, and pemphigoid gestationis. Usually, clinical examination
 Pregnancy prurigo 277

pregnancy suggested that there is significant clinical and histological overlap

between eczema of pregnancy, pruritic folliculitis of pregnancy and prurigo
of ­pregnancy and that they should be regarded as a single disease complex
termed ‘atopic eruption of pregnancy’.6
The histological features are not specific, comprising mild spongiosis,
lymphocytic exocytosis, and a superficial perivascular lymphohistiocytic
infiltrate with occasional eosinophils (Figs 8.56 and 8.57). Frequently, his-
tological features of excoriation are present. Immunofluorescence studies are
negative.

Differential diagnosis
The histological features are non-specific and clinical correlation is necessary
to render a firm diagnosis. The diagnosis is perhaps best approached as one of
exclusion, and underlying etiologies should be sought. The major differential
diagnosis includes hypersensitivity reactions (drug eruption, insect bites, etc.)
with superimposed prurigo nodularis.

Fig. 8.55
Pruritic urticarial papules and plaques of pregnancy: the infiltrate consists of
lymphocytes, histiocytes, and eosinophils.

and history will allow distinction from hypersensitivity reactions, which

may show identical histological features. Urticaria can be distinguished by
the presence of neutrophils. In our experience, distinction between the pre-
bullous phase of pemphigoid gestationis and PUPPP is the most common rea-
son for which the clinician performs a biopsy. Distinction is important since
pemphigoid gestationis, but not PUPPP, may be associated with significant
fetal morbidity. The presence of a subepidermal vesicle or marked papillary
dermal edema favors pemphigoid gestationis; however, some early lesions
will lack these features. Furthermore, PUPPP is frequently associated with
mild papillary dermal edema. Immunofluorescence studies are often neces-
sary for definitive diagnosis. Pemphigoid gestationis is associated with base-
ment membrane staining for C3 and sometimes IgG. Most cases of PUPPP
show negative immunofluorescence results.12 However, it should be noted
that there have been a few purported cases of PUPPP in which weak C3 Fig. 8.56
Pregnancy prurigo: there is a superficial perivascular inflammatory cell infiltrate.
staining in a linear pattern along the basement membrane was reported.3 In
some laboratories, granular deposits along the basement membrane have also
been described in cases of PUPPP.3,13 However, PUPPP is not associated with
positive strong linear immunofluorescence staining along the basement mem-
brane – a result that would strongly favor pemphigoid gestationis.13 As men-
tioned above, in contrast to pemphigoid gestationis, PUPPP does not tend to
recur during subsequent pregnancies.

Pregnancy prurigo
Clinical features
Pregnancy prurigo (prurigo gravidarum, prurigo gestationis) affects 1 in
300 pregnancies, presenting as pruritic, erythematous, 0.5–1.0-cm papules
and nodules with a predilection for the extensor surfaces of the extremities
and the abdomen.1–8 Superimposed features of excoriation with scale-crust
may be seen. Lesions usually present during the third trimester but may
present at all stages of pregnancy.6 The condition usually disappears fol-
lowing delivery, but in some cases it persists into the puerperium. Blistering
is not a feature. Fetal and maternal health does not appear to be adversely
affected.5

Pathogenesis and histological features

The pathogenesis of pregnancy prurigo is unknown. It has been suggested
that the condition represents pruritus gravidarum in a background of Fig. 8.57
atopic dermatitis.1,5 Patients often have a history of atopy.5 Serum IgE may Pregnancy prurigo:
be elevated in patients regardless of whether or not there is a positive his- the infiltrate consists
tory of atopy.5 Of interest, eczematous dermatitis appears to be common in of lymphocytes with
­pregnancy.5 Furthermore, a recent comprehensive analysis of dermatoses of occasional eosinophils.
278 Superficial and deep perivascular inflammatory dermatoses

Urticarial vasculitis
Clinical features
Urticarial vasculitis is an uncommon condition characterized clinically by
chronic urticaria and histologically by leukocytoclastic venulitis.1–3 In some
patients, urticarial vasculitis is associated with antibody–antigen complexes –
a type III hypersensitivity reaction.4,5 In many patients, however, no underly-
ing cause is discovered.
Patients may have, in addition to urticarial skin lesions, angioedema, arth-
ralgia, gastrointestinal symptoms, and evidence of renal involvement. The
spectrum of illness ranges from mild symptoms to a serious systemic illness,
for which treatment with corticosteroids is sometimes necessary.6
The disease shows a female predominance (2:1) and is most often seen in
the third, fourth or fifth decade. It is rare in children.7 The cutaneous lesions
are urticarial in appearance, but usually last 24–72 hours (Figs 8.58–8.60).8
Pruritus, a burning sensation, or pain, are common complaints. The fre-
quency of attacks varies from daily to monthly. The skin lesions are edem-
atous, raised, and erythematous, and are associated with nonblanchable
purpura.
Systemic manifestations/associations include joint pain, stiffness and swell- Fig. 8.59
ing, particularly of the hands, elbows, feet, ankles, and knees. Frank arthri- Urticarial vasculitis: in
this patient, there is an
tis is extremely rare but may be associated with the development of valvular
extensive urticarial plaque.
heart disease.9,10 Proteinuria and hematuria may be seen in some patients.
By courtesy of J. Newton,
Many patients are hypocomplementemic.4,11 Rarely, renal biopsy reveals the MD, St Thomas' Hospital,
features of focal or diffuse proliferative glomerulonephritis. Crescentic glom- London, UK.
erulonephritis, and mesangial and membranous nephropathy have also been
documented.6,12–14 Abdominal pain associated with nausea, vomiting, and
diarrhea is a feature in some patients.
The erythrocyte sedimentation rate (ESR) is raised in many cases and in
about 50% of patients there is hypocomplementemia. The presence of the lat-
ter correlates with systemic involvement.6,15 There may also be depression of
the early classical pathway components C1q, C4, and C2. Patients with hypo-
complementemic urticarial vasculitis have a high prevalence of autoantibodies
to endothelial cells and antibodies against C1q are invariably present.16–18 The
term ‘Schnitzler's syndrome’ has been applied to patients with urticarial vas-
culitis and monoclonal IgM gammopathy.19–24 Hepatosplenomegaly, elevated
ESR, elevated white blood cell count, fever, and joint pain are ­characteristic

Fig. 8.60
Urticarial vasculitis:
note the bizarre annular
purpuric urticarial plaque.
By courtesy of J. Newton,
MD, St Thomas' Hospital,
London, UK.

features and renal insufficiency has also been documented.20–22,25 An underly-

Fig. 8.58
Urticarial vasculitis: note
the urticaria with a livid
hue. By courtesy of J.
Newton, MD, St Thomas'
Hospital, London, UK.
ing lymphoproliferative disorder is present in a minor subset of patients.19
Importantly, urticarial vasculitis (especially the hypocomplementemic vari-
ant) is often associated with, or heralds the onset of, a variety of systemic dis-
eases, including SLE, arthritis, interstitial lung disease, pericarditis, systemic
sclerosis, mixed connective tissue disease, relapsing polychondritis, inflam-
matory myositis, hepatitis, inflammatory bowel disease, serum sickness, pol-
yarteritis nodosa and Wegener's granulomatosis, viral infections, Sjögren's
syndrome, cryoglobulinemia, polycythemia rubra vera, adverse reaction to
drugs, and as a response to sunlight.6,15,26–44 In one study, more than 50% of
 Urticarial vasculitis 279

patients had uveitis, scleritis, conjunctivitis or episcleritis.6 It appears that

patients with hypocomplementemia have more severe disease.26 Some authors
have postulated that hypocomplementemic urticarial vasculitis represents a
form of systemic lupus erythematosus.45 Others, however, have shown no
significant difference in the association with lupus in patients with normo-
complementemic compared with hypocomplementemic urticarial vasculitis.6
A diagnosis of urticarial vasculitis in any patient should initiate an evaluation
for underlying disease. Fortunately, urticarial vasculitis usually has a benign
outcome.6
Urticarial vasculitis has been documented in association with malig-
nancy.6,46–51 Given the rarity of this association, it may well be coincidental.

Histological features
In urticarial vasculitis, vascular damage is superimposed on a background
of dermal edema and inflammation typical of urticaria. The vasculitis affects
the superficial vascular plexus. Extravasation of red blood cells is evidence
of vascular damage. The vasculitis shows features of leukocytoclastic vas-
culitis except that the histological features tend to be subtle and are easily­
Fig. 8.63
Urticarial vasculitis: there is a heavy lymphocytic and eosinophil infiltrate. In this
example, there are conspicuous flame figures.

overlooked (Figs 8.61–8.63). Mild or focal fibrinoid changes associated with

few neutrophils and sparse karyorrhexis are typical. In our experience, the
vasculitis is usually low grade in nature. Others have shown that endothe-
lial necrosis is unusual.52 Nevertheless, more impressive necrotizing vasculitis
may sometimes be encountered (Fig. 8.64). Urticarial vasculitis appears to
­represent a spectrum of disease ranging from urticaria with very mild ­vascular
injury to frank necrotizing vasculitis.53–55

Differential diagnosis
Clinical correlation is necessary to distinguish urticarial vasculitis from
other forms of leukocytoclastic vasculitis. Although urticarial vasculitis
is often associated with subtle, low-grade vascular injury, this pattern
should not be relied upon in the distinction from other forms of vasculi-
tis. In short, the pathologist's role in diagnosis is to confirm the presence
of vasculitis.

Fig. 8.61
Urticarial vasculitis: in this example of an early lesion, there is a conspicuous
perivascular eosinophil infiltrate. There is no evidence of vessel wall damage.

Fig. 8.64
Urticarial vasculitis: this
Fig. 8.62 biopsy of a purpuric lesion
Urticarial vasculitis: in this field, there is marked edema accompanied by a mixed shows features of florid
lymphocytic and eosinophil infiltrate. vasculitis.
280 Superficial and deep perivascular inflammatory dermatoses
Tumor necrosis factor receptor-associated
periodic syndrome (familiar Hibernian fever)
Clinical features
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare
autosomal dominant condition with a predilection for individuals of Irish and
Scottish descent.1–5 Other terms used to describe this disorder include familial
Hibernian fever, benign autosomal dominant familial periodic fever, and auto-
somal dominant periodic fever with amyloidosis. Patients usually present in
infancy or early childhood with prolonged episodes of fever accompanied by (in
descending order of frequency) abdominal pain, cutaneous manifestations, myal-
gia, headache, arthralgia, and pleuritic chest pain.3 Rare associations include
central nervous system involvement due to a ­demyelinating disorder, IgA neph-
ropathy, and small vessel vasculitis with concomitant relapsing panniculitis.6–8
Cutaneous manifestations include migratory asymptomatic, nonscaly
­erythematous macules and plaques, annular and serpiginous lesions measur-
ing up to 28 cm in diameter.2,3 The trunk and extremities are predominantly
affected with lesions presenting proximally and migrating distally.3 Patients
may also develop conjunctivitis and periorbital edema.2 Amyloidosis is an
occasional complication.9
Pathogenesis and histological features
TRAPS is due to a mutation of the TNFRSF1A gene which encodes the tumor
necrosis factor receptor.3 The gene has been localized to chromosome 12p13.4
More than 60 mutations have been identified in the TNFRSF1A gene so far
but the precise disease mechanism remains elusive.10
Histologically, the skin lesions are characterized by dermal edema and a
superficial and deep perivascular and interstitial infiltrate of lymphocytes and
a lesser number of macrophages.1–3 There is no evidence of vasculitis. Small
numbers of neutrophils or plasma cells may occasionally be present.3
The infiltrate consists of CD3+ T lymphocytes and CD68+ macrophages.
CD4+ T-helper and CD8+ T-suppressor forms are both represented. CD20+
B lymphocytes are not present.
Eosinophilic, polymorphic and pruritic
eruption associated with radiotherapy
Clinical features
Rueda and coworkers have recently documented a polymorphic cutaneous erup-
tion which develops in females undergoing radiotherapy for cancer (eosinophilic,
polymorphic, and pruritic eruption associated with radiotherapy, EPPER).1–6
Although a wide spectrum of tumors may be present, cervical squamous carci-
noma is by far the most common. The cutaneous lesions are intensely pruritic and
include excoriations, erythematous papules, vesicles, blisters, and panniculitis-
like lesions. The extremities, particularly the legs, are predominantly affected.
Pathogenesis and histological features
The pathogenesis of this condition is unknown.
Histologically, the eruption is characterized by a superficial and deep
lymphohistiocytic infiltrate accompanied by conspicuous eosinophils. The
epidermis is hyperkeratotic and there is mild acanthosis frequently accom-
panied by spongiosis. Other manifestations include eosinophilic spon-
giosis, bullous pemphigoid-like subepidermal blistering, and eosinophilic
panniculitis.
Direct immunofluorescence may disclose perivascular deposits of C3 and
IgM. Indirect immunofluorescence studies are negative.
The lymphocytes are of the CD3+ T-cell phenotype with a predominance
of CD4+ T-helper cells over CD8+ T-suppressor cells. B cells are absent.
Viral exanthemata
A variety of viral infections may present with cutaneous eruptions (Table 8.1).
Although some viruses are associated with an eruption with distinc-
tive ­clinical features, others are affiliated with a non-specific maculo-
papular ­dermatosis. Exceptionally, exanthemata may represent a primary
­cutaneous infection. More commonly, the clinical features are a manifes-
tation of an immune response, such as an immune complex disease or a
­cell-mediated hypersensitivity reaction, to an infection at an extracuta-
neous site.
Biopsy of a viral exanthem often shows a superficial perivascular lym-
phocytic infiltrate. Some cases may show epidermal pathology such as inter-
face changes with dyskeratotic cells. The histological features are entirely
­non-­specific and distinction from hypersensitivity reactions (e.g., a drug erup-
tion) is impossible without clinical (often including serological ­investigation)
­correlation. Viruses that infect cutaneous sites may be ­visualized by light
microscopy including immunohistochemistry, or demonstrated by viral ­culture,
immunological testing, PCR or DNA hybridization. Skin ­manifestations of
viral infections are described in detail in Chapter 18.
Table 8.1
Viruses associated with cutaneous eruptions
Cytomegalovirus
Enterovirus (coxsakievirus, echovirus)
Epstein-Barr virus
Hepatitis B virus
Human immunodeficiency virus
Paramyxovirus
Parvovirus
Roseola (human herpesvirus-6)
Rubella
Rubeola (measles)
Toga virus
 Granulomatous, necrobiotic and Chapter

See
www.expertconsult.com
for references and
additional material
perforating dermatoses
9
Sarcoidosis  281 Necrobiotic xanthogranuloma  306 Granulomata in congenital
immunodeficiency syndromes  314
Granuloma annulare  288 Palisaded neutrophilic and granulomatous
dermatitis  308 Aluminum granuloma  315
Necrobiosis lipoidica  295
‘Metastatic’ Crohn's disease  309 Perforating disorders  316
Rheumatoid nodule  300
Granulomatous cheilitis  310 Reactive perforating collagenosis  316
Pathogenesis and histological features  301
Perforating folliculitis  318
Differential diagnosis  301 Acne agminata  310
Elastosis perforans serpiginosa  319
Elastolytic granulomata  302 Perioral dermatitis  310 Hyperkeratosis follicularis et parafollicularis in
Annular elastolytic giant cell granuloma  302 cutem penetrans  321
Demodicosis  311 Perforating pseudoxanthoma elasticum  322
Actinic granuloma (O'Brien)  302
Atypical facial necrobiosis lipoidica  304 Infective granulomata  311 Necrotizing infundibular crystalline
Granuloma multiforme  304
Foreign body granulomata  311 folliculitis  323
Rheumatic fever nodule  306
Granulomatous contact dermatitis  313 Chondrodermatitis nodularis chronica
helicis  324

Sarcoidosis
Clinical features
Sarcoidosis (Gr. sarkos, flesh; eidos, form), so-named because its histological
features were originally thought to resemble a sarcoma (Boeck), is a common
systemic disease of unknown etiology. It is characterized and defined by the
presence of noncaseating granulomata, usually (but not invariably) affecting
multiple organ systems.1–10 Manifestations are variable. Patients may present
with:
• an acute and usually self-limiting variant,
• a chronic form exclusively affecting the skin (up to between 20%
and 40% of patients with cutaneous sarcoidosis do not have systemic
involvement),
• a serious systemic chronic variant with widespread lesions, which affects
multiple systems, is associated with high morbidity, and may occasionally
be fatal.
Sarcoidosis is more commonly encountered in industrialized countries and
shows particularly high incidences in northern Europe (including the UK),
Fig. 9.1
the USA, and New Zealand, where as many as 20/100 000 of the population
Sarcoidosis: this patient presented with multiple plaques with raised margins
may be affected. It presents particularly in people in their third and fourth on the neck. From the collection of the late N.P. Smith, MD, the Institute of
decades and shows a female predominance.11 In the USA, sarcoidosis is com- Dermatology, London, UK.
mon among blacks and there is a similar tendency in the UK (Figs 9.1, 9.2).
An epidemiological study of sarcoidosis in the Detroit, Michigan, area found
that African-Americans living there had a 3.8 times greater risk of developing children and occurring mainly during teenage years presents with a multisys-
the disease compared with Caucasians.12 The disease is rare in Asians.13 First- temic disease similar to that seen in adults. Younger children under the age of
and second-degree relatives of patients with sarcoidosis seem to have a sig- 4 present with a cutaneous rash, arthritis, and uveitis.18 Infantile sarcoidosis
nificant risk of developing the disease compared to the normal population.14 should not be confused with Blau's syndrome. This disease is inherited in an
The disease is rare in children, presents mainly in teenagers and although the autosomal dominant fashion and is characterized by sarcoidal granulomata
manifestations are usually similar to those seen in adults, infants may present in the skin, uveal tract and joints but with no pulmonary involvement.19,20
with symptoms simulating juvenile rheumatoid arthritis (Fig. 9.3).15–17 Two Despite the similarities between both diseases, no genetic linkage has been
forms of sarcoidosis have been identified in children. A variant affecting older identified.
282 Granulomatous, necrobiotic and perforating dermatoses

form of sarcoidosis is associated with a good prognosis, with most patients

­experiencing resolution within 6 months of onset of symptoms.25–27 In one
study, however, 16% of patients who presented with erythema nodosum
developed chronic disease.26
A not uncommon mode of presentation is the development of a wide-
spread, usually asymptomatic, maculopapular eruption. Individual lesions
are erythematous or violaceous, 3–6 mm in diameter, and most commonly
seen on the face (particularly in a periorbital distribution), the trunk, the
extensor aspects of the extremities, and the neck (Figs 9.4, 9.5). In this
­variant the patient may also develop acute lymphadenopathy and uveitis, and
a chest X-ray examination can reveal features of early respiratory involve-
ment. Spontaneous resolution sometimes occurs. Occasionally, micropapular
lesions are seen, particularly on the face and limbs (Fig. 9.6). Rarely patients
develop sheets of pinhead-sized lichenoid papules on the trunk and limbs.
The onset is abrupt and lesions may appear in crops. Some patients develop
nodules and plaques, which may occur anywhere on the body, but most
often affect the face, extremities, buttocks, and shoulders (Figs 9.7–9.11).
Annular or serpiginous lesions are also encountered and sometimes there is a
prominent telangiectatic component (angiolupoid sarcoid) (Figs 9.12, 9.13).10
Fig. 9.2 Rarely, epidermal changes result in a psoriasiform or even ­ichthyosiform
Sarcoidosis: papules are present on both upper and lower lips. From the collection
of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Fig. 9.4
Fig. 9.3 Sarcoidosis: widespread erythematous plaques on the upper arm, some with
Sarcoidosis: the condition
an annular appearance. By courtesy of R.A. Marsden, MD, St George’s Hospital,
is rare in children.
London, UK.
There are widespread
micropapules on this
child’s face. By courtesy
of C.T.C. Kennedy, MD,
Bristol Royal Infirmary,
Bristol, UK.

Rarely, sarcoidosis presents in monozygotic twins.21 Coexistence with

common variable immune deficiency is also a rare occurrence.22
Cutaneous lesions occur in 20–35% of patients with systemic sarcoido-
sis and may be classified into non-specific (erythema nodosum) and spe-
cific (granulomatous) subtypes.10 Cutaneous sarcoidal granulomata appear
to be associated with a poorer prognosis and an increased incidence of pul-
monary fibrosis and uveitis. Chronic facial lesions have been shown to be
more commonly associated with involvement of the lungs, sinuses, and
eyes.23 Erythema nodosum occurs quite commonly in sarcoidosis, reported
incidences varying from 11% to 31%.24 There is a significant female pre-
dominance (3:1). Interestingly, erythema nodosum appears to be relatively
uncommon in both African-Americans and Caucasians in the USA. It pres-
ents as erythematous, tender, subcutaneous nodules, usually on the anterior
tibial regions. Erythema nodosum may be associated with pyrexia, polyarth- Fig. 9.5
ralgia (wrists, knees, and ankles), a very high erythrocyte sedimentation rate Sarcoidosis: characteristic mauve plaque on the malar area with an infiltrative
(ESR) and bilateral hilar lymphadenopathy (Lofgren's syndrome). This acute appearance. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.
 Sarcoidosis 283

Fig. 9.6
Sarcoidosis: micropapular variant. Note the tiny lichenoid papules. By courtesy of Fig. 9.8
the Institute of Dermatology, London, UK. Sarcoidosis: erythematous
plaque adjacent to the
eye. From the collection
of the late N.P. Smith,
MD, the Institute of
Dermatology, London, UK.

Fig. 9.7
Sarcoidosis: there is extensive facial involvement, a commonly affected site. From
the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

appearance.28 An exceptional case mimicking lipodermatosclerosis has been

described.29 Chronic skin lesions are associated with pulmonary fibrosis, ocu-
lar, and bone involvement.
Most characteristic of sarcoidosis, however, is lupus pernio. This chronic
violaceous plaque most often affects the nose, cheek, and ears, but lesions
also sometimes affect the fingers and knees (Fig. 9.14). It is a particularly dis-
figuring variant and resolution is especially complicated by marked scarring.
Lupus pernio is often associated with lesions in the upper respiratory tract
and can be followed by nasal obstruction and septal perforation. Patients also
have severe pulmonary fibrosis, bone cysts, and ocular lesions. This variant
has an insidious onset and is associated with a prolonged course and poor
prognosis.15
Patients with sarcoidosis not uncommonly develop lesions in scar tis-
sue30,31 and also in relation to trauma at the sites of desensitizing injections,
­tattoos, venipuncture, surgery, laser, cosmetic fillers, and BCG (Fig. 9.15).32–37
A single case attributed to copper-containing earrings has been described.38
Sarcoidal granulomata in association with foreign bodies do not necessarily
imply a diagnosis of sarcoidosis. However, a small number of patients with
sarcoidal granulomata in association with silica and tattoo pigment may have
systemic sarcoidosis or the latter may develop subsequently.39 Awareness of
this problem is important as such cutaneous granulomata may be the first
Fig. 9.9
Sarcoidosis: the
extremities are commonly
affected. From the
collection of the late N.P.
Smith, MD, the Institute of
Dermatology, London, UK.
manifestation of the disease. Sarcoidosis has also been documented present-
ing in a tattoo in association with interferon-alpha (IFN-α) treatment for
chronic hepatitis C.40 Interestingly, sarcoidosis has also been reported rarely
in patients receiving interferon and ribavirin for chronic hepatitis C,41,42 and
in rare patients on interferon-alpha therapy for melanoma.43,44 Sarcoidosis in
patients with chronic hepatitis C may present concomitantly with the disease
and unrelated to medication, or more often triggered by treatment, mainly
ribavirin and interferon-alpha.45
Hypopigmented lesions may be seen in black patients.46 Unusual cuta-
neous manifestations include subcutaneous nodules, ichthyosiform lesions,
284 Granulomatous, necrobiotic and perforating dermatoses
Fig. 9.10
Sarcoidosis: these grouped nodules are present on sun-damaged skin of the upper
chest. By courtesy of the Institute of Dermatology, London, UK.
Fig. 9.11
Sarcoidosis: small nodules on the anterior aspect of the neck. By courtesy of R.A.
Marsden, MD, St George’s Hospital, London, UK.
­erythroderma, scarring and nonscarring alopecia, lymphedema, nail dystro-
phy in the absence of underlying bone changes, verrucous lesions, generalized
atrophy, leonine facies, palmar erythema, and leg ulcers with or without gran-
ulomatous vasculitis.47–61 Lesions of scarring alopecia may clinically mimic
discoid lupus erythematosus.62 Subcutaneous nodules are rare and present as
persistent, freely mobile, often painful lesions measuring 5–15 mm in diam-
eter. It has been suggested that subcutaneous lesions are more often associ-
ated with systemic disease.63 In a further study the subcutaneous involvement
occurred at the beginning of the disease and the associated systemic disease
was not severe.64 Oral and genital involvement is rare but disease restricted to
the vulva has been documented.65–67 Sarcoidosis has also been described pre-
senting as a testicular mass.68
Ninety percent of patients with sarcoidosis have pulmonary involvement.27
Bilateral hilar lymphadenopathy is the commonest intrathoracic manifesta-
tion of sarcoidosis and together with pulmonary involvement forms the most
frequent lesion. Intrathoracic manifestations in sarcoidosis are classified into
five subgroups: 6,10
• Stage 0: normal chest X-ray,
• Stage I: bilateral hilar and/or paratracheal lymphadenopathy with no
pulmonary involvement,
• Stage II: lymphadenopathy with pulmonary infiltrates,
Fig. 9.12
Sarcoidosis: annular
lesions on the ankle. By
courtesy of the Institute of
Dermatology, London, UK.
Fig. 9.13
Sarcoidosis: close-up view of an annular lesion. Note the beaded appearance.
By courtesy of the Institute of Dermatology, London, UK.
• Stage III: pulmonary infiltrates, but no lymphadenopathy,
• Stage IV: irreversible fibrosis and bullae, cysts, emphysema.
Stage I disease is frequently associated with spontaneous resolution; pro-
gression to stage II disease is uncommon. Severe pulmonary involvement as
seen in stage III patients correlates with deep chronic plaque lesions and lupus
pernio. Patients have interstitial fibrosis and eventual cor pulmonale, which
may prove fatal.
Systemic vasculitis involving small- to large-caliber vessels has been found
in some adults and children with sarcoidosis.69 This manifestation tends to be
more common in African-American and Asian patients.69
Ocular lesions develop in about 20% of patients with sarcoidosis. Acute
anterior uveitis is the most common manifestation; it is frequently bilateral
and shows a predilection for females. It correlates with a benign outcome and
erythema nodosum. Chronic uveitis also affects the anterior chamber and if
untreated may progress to glaucoma and blindness. Other lesions include
retinal vein perivasculitis, disc edema, and neovascularization. Conjunctival
 Sarcoidosis 285

Peripheral lymphadenopathy develops in about 30% of patients. However,

histological examination of peripheral lymph nodes will reveal ­granulomata
in about 75% of patients with sarcoidosis. Although splenomegaly is only
present in 10–25% of patients, granulomata are present in about 50%
of cases. Splenic disease is usually asymptomatic, but patients may have
­abdominal pain, hypersplenism and, very rarely, splenic rupture. Splenic
­disease ­correlates positively with a high frequency of intrathoracic sarcoido-
sis. Liver function test abnormalities are quite common and about 20% of
patients have hepatomegaly; 60% of patients have hepatic granulomata on
­histological examination.
Cardiac lesions are uncommon, but are of particular importance due to
the associated mortality.6 In a recent autopsy series, 50% of all deaths were
due to cardiac disease.72 This same study found that the clinician often does
not appreciate the presence of cardiac involvement – the antemortem diag-
nosis of cardiac lesions was made in only 29% of patients.72 Granulomata
may occur at any site, but appear to show a predilection for the ­conduction
­system. Clinical manifestations include ventricular tachycardia, complete
heart block, congestive cardiac failure, pericardial effusion, and myocardial
infarction. Sarcoidal granulomata may affect small and large blood vessels, in
particular the pulmonary vasculature.
Fig. 9.14 Muscle involvement is usually asymptomatic. Histological examination of
Sarcoidosis: lupus pernio.
random muscle biopsies reveals granulomata in as many as 50% of patients.
The nose shows typical
Rare features include asymptomatic palpable nodules and a polymyositis-like
scaly violaceous swelling.
By courtesy of the syndrome.
Institute of Dermatology, Although a rare complication, patients with sarcoidosis appear to be more
London, UK. prone to develop cryptococcosis than other infections.73
Radiologically demonstrable bone lesions occur in about 15% of
patients. Early lesions consist of osteoporosis, cortical thinning, and ­mottled
­rarefaction. Established lesions are cystic and are sometimes associated
with pathological fractures. The hands and feet are predominantly affected
(Fig. 9.16). Destruction of the nasal bones can result from direct infiltration
in patients with lupus pernio.
Hypercalcemia and, particularly, hypercalcuria are important complica-
tions of sarcoidosis. This is possibly due to increased intestinal absorption of
calcium and abnormal production of 1,25-dihydroxyvitamin D.74 It is more
often transitory, but in a small proportion of patients it is persistent and
sometimes complicated by the development of renal failure due to nephrocal-
cinosis. Granulomata are found on histological examination of the kidney in
up to 40% of patients.
Laboratory investigations reveal a wide variety of abnormalities of the
immune system (see below). Patients may demonstrate elevated levels of
serum angiotensin-converting enzyme (ACE). Unfortunately, this finding is
not specific for sarcoidosis, increased values also being found in patients with
diabetes mellitus, alcoholic liver disease, and leprosy. It is sometimes of value

Fig. 9.15
Sarcoidosis: tattoo
reaction. There are
multiple dome-shaped
nodules. By courtesy
of the Institute of
Dermatology, London, UK.

granulomata may be present in up to 30% of patients; therefore biopsy can

be a useful and relatively safe method of establishing the diagnosis. The lacri-
mal gland is also sometimes affected.
Neurological involvement occurs in 5–15% of patients with systemic sar-
coidosis. Clinical manifestations include facial nerve palsy, Guillain-Barré
syndrome, optic nerve disease, meningitis, seizure, and encephalopathy.6,70,71
In one study, neurosarcoidosis was the presenting symptom in 31% of
patients.70 The combination of uveitis, facial nerve palsy, fever, and swelling
of the parotid gland is known as uveoparotid fever (Heerfordt's syndrome).
This condition is often associated with central nervous system involvement. Fig. 9.16
Hypothalamic and pituitary lesions are rare and may manifest as diabetes Sarcoidosis: there is marked swelling of the distal interphalangeal joints. By courtesy
insipidus or panhypopituitarism. of R.A. Marsden, MD, St George’s Hospital, London, UK.
286 Granulomatous, necrobiotic and perforating dermatoses
in monitoring the level of disease activity in patients known to have sarcoido-
sis. Patients may also display increased levels of serum and urinary lysozyme,
serum beta-2-microglobulin, and collagenase.
The Kveim test was used in the past to aid in diagnosis. A homogenate of
known sarcoid tissue is injected intradermally at a marked (India ink) site, and
4–6 weeks later the injection site is biopsied. A positive result depends upon
the detection of an epithelioid cell granuloma. False-positive reactions may
occur with other diseases including Crohn's disease, infection ­(mycobacterial,
fungal), berylliosis, silicosis, asbestosis, and lymphoma. The stimulatory
­‘sarcoidal’ antigen of the Kveim reagent has not been identified.75 The Kveim
test is almost never used nowadays because of difficulties in obtaining the
homogenate of sarcoid tissue.
Although sarcoidosis is associated with a high morbidity, the mortality ­rate
is low, being of the order of 3–6%. Causes of death include cardiac involve-
ment and respiratory or renal failure. The prognosis is better in females and
appears to be improved in those with a positive purified protein derivative
(PPD) skin test and normal serum immunoglobulin levels. The severity of dis-
ease is greater in blacks and Asians compared with Caucasians.76 Of interest,
despite the very marked upset in immunological phenomena, patients do not
seem to have an associated greatly increased risk of opportunistic infections
except as a consequence of therapy (e.g., corticosteroids).
The association between sarcoidosis and a number of systemic diseases
is probably coincidental. Sarcoidosis has been documented in association
with vitiligo, pernicious anemia, autoimmune thyroiditis, Graves' disease,
chronic hepatitis, Addison's disease, Sjögren's syndrome, diabetes mellitus
and ulcerative colitis, lymphoma, human immunodeficiency virus (HIV)
infection, and primary biliary chirrosis.77–88 Interestingly, patients with
acquired immunodeficiency syndrome (AIDS) usually develop manifesta-
tions of sarcoidosis after antiretroviral therapy is started. This phenome-
non is the result of the immune restoration syndrome.85,89 Associations with
cutaneous autoimmune disease include dermatitis herpetiformis and linear
IgA disease.90,91 A single case of trachyonychia associated with sarcoidosis
has been reported.92
Pathogenesis and histological features
The pathogenesis of sarcoidosis is poorly understood. The demonstration of
familial clustering suggests hereditary susceptibility to sarcoidosis in at least
a subset of patients.14,93
Despite intensive studies, the etiology and pathogenesis of sarcoidosis
remains elusive.94,95 It is likely, however, that sarcoidosis represents a reaction
pattern that may develop in a predisposed patient on exposure to one or more
infective agents or other antigens.
The role of mycobacteria in the pathogenesis of sarcoidosis is a controver-
sial topic. Attempts at detection of mycobacterial DNA by polymerase chain
reaction (PCR) have produced conflicting results. While some authors have
failed to detect mycobacterial DNA, others have identified DNA of various
strains of tuberculous and nontuberculous mycobacteria.96–100 In one study,
although amplified mycobacterial DNA was detected by PCR in 38% of sar-
coidosis patients, mycobacterial DNA was also detected in tissue in 44% of
control patients.101 Furthermore, most studies published in the literature fail
to report more than 6% positivity for Mycobacterium tuberculosis DNA in
patients with sarcoidosis.102 In another interesting study, cell wall deficient
acid-fast bacteria (L forms) were cultured from the blood of 19 of 20 patients
with sarcoidosis but not from controls.103 In summary, these mixed results
between laboratories have not clarified the role of mycobacteria in the patho-
genesis of sarcoidosis. It seems, however, that mycobacteria may be of etio-
logical importance in at least a subset of cases.
Propionibacterium acnes DNA has also been identified in tissues of
patients with sarcoidosis, including involved lymph nodes.104,105 The signifi-
cance of this finding remains uncertain. Human herpesvirus 8 DNA has not
been demonstrated in tissues of patients with sarcoidosis.105
The occasional association with known autoimmune diseases, such as pro-
gressive systemic sclerosis and systemic lupus erythematosus (SLE), has inevi-
tably led to the proposal of an autoimmune pathogenesis. Although many
familial cases have been reported in the literature, no consistent pattern of
inheritance has emerged. The results of human leukocyte antigen (HLA)
typing have shown associations with particular features of the disease; for
example, HLA-A1 and HLA-B8 are associated with arthritis, HLA-A1 is
also associated with uveitis, and HLA-B13 may be associated with a chronic
refractory variant.10 Patients with HLA-DR17 have a better prognosis.106 One
study has shown that patients with sarcoidosis have an increased frequency of
a glutamine residue at position 69 of the B1 chain of the HLA-DPB molecule
compared with a control population.107 This is particularly interesting since
a similar polymorphism has been documented in patients with chronic beryl-
lium disease, a disorder also characterized by granulomata and which shares
some pathological features in common with sarcoidosis.
Immunological investigations in patients with sarcoidosis have produced
an immense wealth of data, which reveal that there is clearly an associated
state of abnormal immunological hyperactivity. There are alterations of both
cell-mediated and humoral immunity. Despite great efforts to clarify the
immunobiology of sarcoidosis, particularly with regard to the precise anti-
gens that may facilitate the disease, we still do not have a clear understand-
ing of the disease process. Sarcoidosis, at least in part, appears to be due
to a hyperactive T-helper cell proliferation with lymphokine production.108
Increased T-helper (Th1, Th2) cells are present in the alveolar lung paren-
chyma. Several studies have demonstrated selective activation of certain oli-
goclonal T-cell subsets.109–112 In one study, there was a correlation between
the particular oligoclonal T-cell subsets and disease activity.109 Th1 lympho-
cytes (T cells expressing interleukin (IL)-2 and IFN-γ) preferentially accumu-
late in pulmonary parenchyma and the alveolar space compared with Th2
lymphocytes (T cells expressing IL-4 and IL-5).113 Compared with T-cells in
peripheral blood, T cells obtained by bronchoalveolar lavage show greater
expression of IFN-γ and tumor necrosis factor alpha (TNF-α).106 Of interest,
patients with HLA-DR17 show a muted cytokine response, a finding that is
perhaps related to the better prognosis observed in this subset of patients.107
T lymphocytes, in turn, stimulate B cells. Abnormalities of humoral
immunity include a non-specific polyclonal hypergammaglobulinemia and
circulating immune complexes in acute forms of the disease, particularly in
association with erythema nodosum.
The paramount puzzle in unraveling the pathogenesis of sarcoidosis is
identifying the initial event(s) that lead to the disease. Despite our increas-
ing knowledge of the immunobiology of sarcoidosis, we seem no closer to
answering this key question.
Histologically, sarcoidosis is characterized by a dense, noncaseating
granulomatous infiltrate in the dermis (Figs. 9.17, 9.18), which sometimes
extends into the subcutaneous fat. The granulomata are discrete and strik-
ingly uniform in size and shape. They are composed of epithelioid histiocytes
with abundant eosinophilic cytoplasm and oval or twisted vesicular nuclei
often containing a small central nucleolus (Fig. 9.19). Variable numbers of
Langhans giant cells are present and sometimes a scattering of lymphocytes
is seen at the peripheral margin of the granuloma (Fig. 9.20). Discrete small
Fig. 9.17
Sarcoidosis: the dermis is replaced by uniform circumscribed nests of non-
caseating granulomata.
 Sarcoidosis 287

central foci of fibrinoid necrosis are sometimes present but caseation ­necrosis
is rare (Fig. 9.21).114,115 Transepidermal elimination is sometimes seen.116
The epidermis is usually normal although occasional cases display acantho-
sis and sometimes the granulomata are focally lichenoid. A predominantly
lichenoid pattern may exceptionally be seen.117 Exceptional cases of sarcoido-
sis may display histologic findings that focally overlap with granuloma annu-
lare, palisading neutrophilic and granulomatous dermatitis, and interstitial
­granulomatous dermatitis.118 Further histologic findings described include
elastophagocytosis, perineural granulomas resembling leprosy, mucin deposi-
tion, and an infiltrate rich in plasma cells.115
In some cutaneous lesions, inclusion bodies are present, although much
less frequently than in lymph nodes. The Schaumann body, a basophilic,
­laminated, rounded, conchoidal structure composed of calcium carbonate, cal-
cium oxalate, phosphate, iron, and dolomite, is not specific for sarcoidosis and
is seen in a number of other granulomatous conditions including ­tuberculosis
and berylliosis (Fig. 9.22).119–121 The asteroid body is a small intracytoplasmic
eosinophilic star-shaped structure; it is not specific for ­sarcoidosis, being seen
also, for example, in tuberculosis, tuberculoid leprosy, ­berylliosis, and atypi-
cal facial necrobiosis. It is also commonly found in necrobiotic xanthogran-
Fig. 9.18 uloma.122 Initial studies suggested that the asteroid body was ­composed of
Sarcoidosis: note the paucity of lymphocytes and absence of necrosis.
collagen but more recent reports, using ­immunohistochemistry, suggest that

Fig. 9.19
Sarcoidosis: the epithelioid cells are composed of pink cytoplasm with a central oval Fig. 9.21
or sometimes twisted vesicular nucleus containing a small basophilic nucleolus. Sarcoidosis: occasionally small foci of ‘fibrinoid’ necrosis may be seen in the center
The granuloma also contains lymphocytes and occasional fibroblasts. of the granuloma, but cellular detail is not lost.

Fig. 9.20 Fig. 9.22

Sarcoidosis: in this example the granulomatous reaction is associated with abundant Sarcoidosis: in this lymph node biopsy specimen, fragmented, laminated
foreign material. Schaumann bodies are seen. They are very rarely a feature of cutaneous sarcoidosis.
288 Granulomatous, necrobiotic and perforating dermatoses

it is a product of the microtubular system.123,124 The presence of foreign mate-
rial in sarcoidal granulomata does not exclude the diagnosis of sarcoidosis. In
fact, polarizable material has been found in up to 5% of cases.125–127
It has been shown that the gli-1 oncogene is consistently and abnormally
expressed in the cells forming the granulomata not only in sarcoidosis but
also in granuloma annulare and necrobiosis lipoidica. This observation raises
the possibility of trials using inhibitors of gli-1 signaling to treat this group of
granulomatous disorders.128
The visceral lesions are characterized by an identical histology of nonca-
seating granulomata, which may be accompanied by significant scarring, for
example in the lung, where advanced cases are characterized by interstitial
fibrosis and sometimes honeycomb lung formation. In the liver, granulomata
are most commonly found in the portal tracts or in relation to central veins.
Splenic lesions are randomly distributed and are not usually associated with
significant fibrosis.
Differential diagnosis
Sarcoidosis must be approached as a diagnosis of exclusion and has to be
distinguished from the numerous conditions that may be associated with a
noncaseating granulomatous histology, including some forms of tuberculo-
sis, tuberculoid leprosy, berylliosis, fungal infections, Crohn's disease, and
foreign body granulomatous reactions.129 Therefore, the use of special stains,
including the Ziehl-Neelsen preparation for mycobacteria and the periodic
­acid-Schiff (PAS) and methenamine silver reactions for fungi, is mandatory
before diagnosing sarcoidosis. Depending on the clinical context, culture
may also be required to exclude an infective etiology. Tuberculoid leprosy
is characterized by nerve involvement, a feature that is usually absent in
sarcoidosis.
Some of the granulomata seen in a variety of primary immunodeficiency
syndromes closely mimic those found in sarcoidosis and histological distinc-
tion may be impossible. A study comparing granulomata in sarcoidosis to
those seen in primary immunodefiencies found a much lower rate of CD4+/
CD8+ cells in the former as opposed to the latter.130
Labial and gingival involvement may be histologically mistaken for
Crohn's disease and granulomatous cheilitis (Miescher). It is worth noting
that in rare cases oral involvement in Crohn's disease may precede systemic
manifestations by several years. Metastatic Crohn's disease may be difficult
to distinguish from sarcoidosis. The former often show nonsuppurative gran-
ulomata in a diffuse pattern and surrounded by a thin cuff of lymphocytes.
Further frequent findings include the presence of numerous eosinophils and
ulceration, findings not often seen in sarcoidosis.131
Granulomatous lesions that have been described in exogenous ochronosis
appear to be related to sarcoidosis.132 However, similar lesions have also been
described as showing changes mimicking actinic granuloma.133
Other documented associations of granuloma annulare include morphea,
chronic hepatitis C infection, autoimmune thyroiditis, secondary hyperpara-
thyroidism, sarcoidosis, Plummer's disease, myelodysplastic syndrome, met-
astatic carcinoma, and a bee sting.25–33 Granuloma annulare has also been
described after vaccination for tetanus and diphtheria, hepatitis B and tuber-
culosis (BCG), and after mesotherapy.34–38 It may also develop in the scars
of herpes zoster.39–42 It is important to highlight that most patients with the
condition heal after variable periods of time, and long follow-up has not
revealed consistent associations with any systemic diseases.43 A further study
has found no consistent relationship between malignant neoplasms and gran-
uloma annulare.44 However, it has been suggested that elderly patients with
lesions that do not have typical features of granuloma annulare but display
microscopic findings resembling granuloma annulare should be investigated
for an underlying malignancy, especially lymphoma.44
Granuloma annulare has developed during treatment with allopurinol,
amlodipine, daclizumab, and antitumor necrosis factor.45–48 Interferon-alpha
has been associated with generalized interstitial granuloma annulare.49 It is
most likely, however, that granuloma annulare-like eruptions secondary to drug
administration often represent interstitial granulomatous drug eruptions.
Localized granuloma annulare
The localized variant is the commonest type. It usually presents in the first
three decades and is associated with a female preponderance (2.25:1). Lesions
consist of one or several papules, which may be skin-colored, red or viola-
ceous, and are typically distributed to form an annular or arcuate lesion 1–5
cm in diameter (Figs 9.23–9.27). About 50% of patients have solitary lesions.
The acral sites are most commonly affected, in particular the knuckles and
dorsum of the fingers. In a small proportion of patients, lesions are present
on both the upper and lower limbs, and occasionally the trunk is affected.
Lesions on the palms are exceptional.50 Facial involvement appears to be
uncommon.51,52 In a reported case, lesions were restricted to the area involved
by a Becker's nevus.53 Although lesions may be persistent, approximately 50%
of patients can anticipate resolution by about 2 years from onset. However,
recurrences are, unfortunately, quite common. Patients in which the disease
arises earlier in life appear to have earlier resolution of lesions.54 Interestingly,
on occasion lesions regress spontaneously after biopsy.55 In one case, spon-
taneous resolution resulted in mid-dermal elastolysis.56 Rarely, granuloma
annulare has been reported in families and in monozygotic twins.57 A case has
been documented in which the lesions recurred seasonally with sun-exposed
areas.58 There has only been a single case report of cutaneous granuloma
annulare with similar lesions in an intra-abdominal location.59 In one case,
granuloma annulare was the first sign of adult T-cell leukemia/­lymphoma and

Granuloma annulare
Clinical features
Granuloma annulare is a common, usually asymptomatic, dermatosis of
unknown etiology.1,2 It may be divided into six clinical subsets:
• localized,
• generalized,
• perforating,
• subcutaneous,
• papular,
• linear.
Unusual clinical variants include pustular follicular lesions and presenta-
tion with patches.3,4 A single case presenting as contact dermatitis has been
reported.5 Granuloma annulare (often with widespread disseminated lesions)
has been described in patients with HIV infection and sometimes may be the
presenting sign.6–18 Granuloma annulare, mainly the generalized variant (see Fig. 9.23
below), has also been reported in association with both Hodgkin's and non- Localized granuloma annulare: a typical annular lesion over the knuckle. Stretching
Hodgkin's lymphoma.19–22 Exceptionally, anterior uveitis and concomitant of the skin reveals a translucent beaded margin. By courtesy of R.A. Marsden, MD,
skin lesions have been described.23,24 St George’s Hospital, London, UK.

Fig. 9.24
Localized granuloma annulare: in this patient multiple lesions are present on the feet.
From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig. 9.25
Localized granuloma annulare: this arm lesion shows a characteristic beaded margin.
From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig. 9.26
Localized granuloma annulare: close-up view of annular lesions. By courtesy of the
Institute of Dermatology, London, UK.
Granuloma annulare 289
Fig. 9.27
Localized granuloma annulare: in this patient there is a large plaque on the ankle
with a hint of central clearing. By courtesy of the Institute of Dermatology,
London, UK.
in a further patient it was associated with angioimmunoblastic T-cell lym-
phoma.60,61 Very rarely, acral, localized granuloma annulare may present as
an acute and painful eruption.62
Generalized granuloma annulare
Generalized lesions occur in approximately 15% of patients with granuloma
annulare.2,63 As with the localized form, there is an increased incidence in
females; however, the median age differs the majority of cases occurring in
patients in the fourth to seventh decades, with the rest appearing during the
first decade. Patients with generalized granuloma annulare have an increased
incidence of HLA-Bw35.64 Generalized granuloma annulare is defined as
lesions occurring on at least the trunk and either upper or lower extremities,
or both.2 Most lesions are papules, which may be distributed in an annular
pattern, but maculopapules and nodules also occur. They vary in hue from
flesh-colored or red, to tan, brown or yellow. Numbers vary from several
dozen to hundreds (Figs 9.28 to 9.30). A single patient has been documented
with generalized disease accompanied by marked swelling of the hands and
another patient developed the disease following erythema multiforme.65,66
Lesions may be asymptomatic or pruritic.2 As with the localized form, the
Fig. 9.28
Generalized granuloma annulare: innumerable papules are present on this patient’s
arms. By courtesy of J. Williams, MD, Brigham and Women’s Hospital, Boston, USA.
290 Granulomatous, necrobiotic and perforating dermatoses
Fig. 9.29
Generalized granuloma annulare: there are widespread papules and plaques.
By courtesy of the Institute of Dermatology, London, UK.
Fig. 9.30
Generalized granuloma
annulare: in this patient
numerous annular lesions
are present. From the
collection of the late
N.P. Smith, MD, the
Institute of Dermatology,
London, UK.
disease is persistent, but some patients experience resolution within 4 years.
Anetoderma has been exceptionally reported as a complication of general-
ized granuloma annulare.67 A remarkable association with giant cell arteri-
tis, gastrointestinal stromal tumor, and other internal malignancies including
ovarian and gastric cancer has been reported.68–70 Tuberculous lymphaden-
its was an association in one case.71 In two instances, the condition was the
initial manifestation of chronic myelomonocytic leukemia.72 An association
with lymphoma, including Hodgkin's disease, has also been described.73
A patient with hepatitis B developed generalized granuloma annulare, and viral
DNA was detected in the skin lesions by PCR.74 A further case presented in a
photosensitive distribution and healed with scarring and milia formation.75
Perforating granuloma annulare
Perforating granuloma annulare is distinguished by the presence of tran-
sepidermal elimination of necrobiotic collagen.10,18,76–79 Clinically, the lesion
­presents as a group of papules with an umbilicated crust usually located on
Fig. 9.31
Perforating granuloma annulare: the extremities are most often affected. Necrotic
debris and crust can be seen. From the collection of the late N.P. Smith, MD, the
Institute of Dermatology, London, UK.
the extremities, often the dorsum of the hands (Fig. 9.31). Presentation of
lesions on the ears has exceptionally been described, as has a generalized vari-
ant.80–82 It may affect both children and adults, and both localized and gener-
alized forms exist. Spontaneous resolution sometimes occurs within months
or years of onset. An exceptional case of perforating granuloma annulare
which developed following tattooing has been reported.83
Subcutaneous (deep) granuloma annulare
The subcutaneous variant is synonymous with the pseudorheumatoid nod-
ule of childhood and deep granuloma annulare.84–87 Lesions may present
de novo or arise in association with typical cutaneous papules. It occurs
in childhood, often affecting the underlying periosteum and involving pre-
dominantly the lower legs (particularly the tibia), feet, buttocks, hands,
and head.88 Lesions may also present on the penis or eyelid.89,90 An excep-
tional case of numerous lesions limited to the scalp of a child which
regressed spontaneously has been reported.91 A further patient presented
with a periorbital subperiostal lesion and in another patient the lesion was
congenital.92,93 In one study of 47 patients, the mean age was 4.3 years.88
In some instances, there is a past ­history of trauma. By definition, such
children do not have rheumatoid arthritis or rheumatic fever. The lesion
usually regresses after several years. However, recurrences appear in 19%
of patients.88
Papular granuloma annulare
Papular granuloma annulare presents as flesh-colored or hypopigmented,
1–3-mm diameter papules on the dorsal aspect of the hands, usually in male
children. Occasional lesions may be umbilicated or generalized (Figs 9.32,
9.33).94
Linear granuloma annulare
The linear variant is very rare and may have a bilateral distribution.95,96
Rarely, it may follow Blaschko's lines.97 This variant overlaps and may in
some cases be the same as the condition described as interstitial granuloma-
tous dermatitis.
Pathogenesis and histological features
The cause of granuloma annulare is unknown. The original concept that it
represented a tuberculid has long since been discounted. Although it has been
reported at the site of previous herpes zoster infection and verruca vulgaris,
it is unlikely that an infectious pathogenesis exists. Borrelia has been dem-
onstrated by focus-floating microscopy in a number of biopsies of patients

Fig. 9.32
Papular granuloma annulare: widespread papules are present on this patient’s back
and shoulders. By courtesy of the Institute of Dermatology, London, UK.
Fig. 9.33
Papular granuloma annulare: numerous small, scaly papules are present.
By courtesy of the Institute of Dermatology, London, UK.
with granuloma annulare raising the possibility of a pathogenetic role for
the organism in some cases of the disease.98 However, a study based on PCR
found no association between granuloma annulare and Borrelia infection.99
There is a wide variety of currently possible pathogenetic mechanisms, most
of which have some merit, but none of which satisfactorily clarifies the pre-
cise mechanism by which the lesions of granuloma annulare develop.100
Particularly popular are an immune complex vasculitic process and a cell-
mediated delayed hypersensitivity reaction. Evidence in favor of the former
has been the detection, by direct immunofluorescence, of immunoreactants
(IgM and complement) in blood vessel walls in some patients.100 Elevated lev-
els of circulating immune complexes have also been recorded.101 The histology
may reveal features suggestive of a vasculitic process, including endothelial
swelling, vessel wall thickening (due to the deposition of PAS-positive mate-
rial), vascular occlusion, and necrosis (Fig. 9.34).102 All of the latter changes
may, of course, develop as a consequence of the inflammatory process rather
than cause it. A recent study of serial sections of 38 biopsies in 35 patients
found no evidence of a vasculitic process in any of the cases.103
In favor of a cell-mediated delayed hypersensitivity reaction are:
• the finding of activated T-lymphocytes in lesions of granuloma annulare
on electron microscopic examination,
Granuloma annulare 291
Fig. 9.34
Granuloma annulare: view through the edge of a necrobiotic focus. In the center a
small blood vessel shows fibrinoid necrosis with occlusion. This is an uncommon
finding.
• the predominance of T-helper inducer cells in the infiltrate,
• the histopathological resemblance of the infiltrate to that of conditions of
known delayed hypersensitivity pathogenesis, including sarcoidosis and
tuberculosis.104
It has been suggested that Th1 lymphocytes expressing interferon-gamma
induce a delayed hypersensitivity reaction leading to macrophages becoming
aggressive effector cells that express tumor necrosis factor-alpha and matrix
metalloproteinases.105 If tumor necrosis factor alpha plays a role in the induc-
tion of the disease, then agents that block this cytokine may be useful in
treating the condition. Although some patients respond to these agents other
do not and the reason for this is not clear. Monozygotic twins with general-
ized granuloma annulare and the 8.1 ancestral haplotype, a genotype that
leads to increased production of tumor necrosis alpha, have responded well
to adalimumab.106
Patients with granuloma annulare may have raised serum migration
inhibition factor activity.87 Defective neutrophil migration has also been
reported.107,108 Other proposed pathogenetic mechanisms include collagen
damage by macrophage lysosomal hydrolytic enzymes as the initial event,
or a primary disorder of collagen leading to an allergic or nonallergic tissue
reaction. The increased incidences of diabetes mellitus and HLA-B8 may
also be of pathogenetic significance (compare with necrobiosis lipoidica).109
In a study of a group of pediatric patients with multiple lesions of granu-
loma annulare it was found that they had significantly lower serum insulin
values than the control group and showed mild impairment of glucose tol-
erance.110 However, these children, often had a family history of diabetes
mellitus.
Although there are reports of generalized granuloma being associated with
sunlight, this appears to be of doubtful significance.2
It has been shown that the glioma-associated oncogene homologue ­gli-1,
a member of the vertebrate zinc finger transcription factor genes of the gli
superfamily is highly expressed in a number of granulomatous disorders
including granuloma annulare.111 The relevance of this in the pathogene-
sis of granuloma annulare is not clear but it raises the possibility of using
inhibitors of gli-1 signaling in the treatment of granulomatous noninfectious
diseases.
The most characteristic histological lesion seen in granuloma annulare is
the palisading granuloma (Figs 9.35–9.38). This consists of a central core of
degenerate (necrobiotic) collagen, surrounded by an often radially arranged
infiltrate of lymphocytes, histiocytes, and fibroblasts. Elastic tissue may be
absent within these foci and there can be phagocytosis of elastic fibers by
giant cells at the periphery of the granuloma (Fig. 9.39).112 However, altered
elastic fibers are not a constant finding. Solar elastosis is not a feature of
granuloma annulare. In some lesions the altered collagen has a somewhat
292 Granulomatous, necrobiotic and perforating dermatoses
Fig. 9.35
Localized granuloma annulare: the characteristic appearance of a well-circumscribed
palisading granuloma consisting of a necrobiotic center surrounded by a cellular
infiltrate.
Fig. 9.36
Localized granuloma annulare: the collagen is fragmented and in part granular. Note
the peripheral palisade of histiocytes, occasional lymphocytes, and fibroblasts.
basophilic appearance due to the presence of acid mucopolysaccharides, but
more commonly there is eosinophilia, due in part to fibrin deposition (Fig.
9.40). Heparin sulfate is an important component of the mucin in granuloma
annulare but not of other cutaneous diseases associated with mucin deposi-
tion (Fig. 9.41).113
Occasionally, sparse karyorrhectic debris is present in the center of the
lesion and sometimes the necrobiotic foci contain lipid droplets. More
often, however, the collagenous degeneration is not organized into a nod-
ular pattern, but affects isolated fibers in a random pattern, an appear-
ance often best appreciated on low-power examination (Fig. 9.42).114 In
this so-called diffuse or interstitial form of granuloma annulare, affected
fibers, which are swollen and intensely eosinophilic, alternate with appar-
ently normal fibers to give a rather disorganized appearance (Figs. 9.43,
9.44). Necrobiosis is minimal or absent. Characteristically, the collagen
fibers are separated by mucin, which stains positively with Alcian blue at
pH 2.5. Histiocytes are often seen infiltrating around and between affected
fibers, and this feature may be a helpful clue to the diagnosis in early
Fig. 9.37
Localized granuloma
annulare: this lesion is
from the palm of the
hand, an uncommonly
affected site. There is a
sharply delineated focus
of necrobiosis in the deep
reticular dermis.
Fig. 9.38
Localized granuloma annulare: the necrobiosis is advanced, presenting as eosinophilic
granular debris. The histiocytic palisade is well established.
cases when the collagen changes are inconspicuous and should, therefore,
encourage examination of additional sections to detect more typical features
(Fig. 9.45).
An almost inevitable feature of granuloma annulare is the presence of a
perivascular chronic inflammatory cell infiltrate, both within the lesion and
in the adjacent tissue. Well-formed sarcoidal granulomata with associated
giant cells are seen in some cases. Significant numbers of eosinophils may be
encountered.115 In one study, eosinophils were present in 66% of biopsies, of
which 14% showed more than 10 eosinophils per high-power field.115 Plasma
cells are rare and this is useful in the differential diagnosis with necrobiosis
lipoidica (see below). Neutrophils are a rare finding and when present, par-
ticularly in association with changes of vasculitis, it is likely that there is an
association with systemic disease.116
 Granuloma annulare 293

Fig. 9.39 Fig. 9.42

Localized granuloma annulare: there is loss of elastic tissue within the granuloma. Diffuse granuloma annulare: the collagen bundles are arranged haphazardly. Note
Elastic-van Gieson. the circumferential lymphocytic infiltrate.

Fig. 9.40 Fig. 9.43

Localized granuloma annulare: the red-staining material in the center of the Diffuse granuloma annulare: individual fibers are swollen and intensely eosinophilic.
granuloma is fibrin. Martius scarlet blue. The apparent separation of the fibers is due to increased mucin.

Fig. 9.41 Fig. 9.44

Localized granuloma annulare: in this example there is abundant mucin in the Diffuse granuloma annulare: higher-power view showing the dense interstitial
center of the necrobiotic focus. Alcian blue stain. histiocytic infiltrate.
294 Granulomatous, necrobiotic and perforating dermatoses

Fig. 9.45 Fig. 9.47

Diffuse granuloma annulare: high-power view. Perforating granuloma annulare: close-up view showing the dermal perforation and
transepidermal elimination of collagenous debris.

Fig. 9.46
Perforating granuloma annulare: scanning view showing widespread typical Fig. 9.48
granuloma annulare (in the upper-right quadrant degenerate collagen is undergoing Subcutaneous granuloma annulare: within the subcutaneous fat and involving the
transepidermal elimination). fascia is a massive necrobiotic nodule.

Although the relationship with Borrelia infection is debatable, it has been

suggested that formation of pseudorosettes in granuloma annulare may sug-
gest infection with the organism.117
In perforating granuloma annulare the necrobiotic debris is present in
close proximity to the epidermis and may be seen to be engulfed by the latter
to form a perforating channel by which the necrotic material is extruded to
the surface (Figs. 9.46, 9.47). If serial sections are performed, the perforation
is often shown to occur through a hair follicle.
The subcutaneous lesions are much larger than the superficial ones
(Figs. 9.48, 9.49) and are frequently composed of multiple nodules. There is
­usually massive necrobiosis and abundant mucin; on occasions, lipid droplets
are evident. Mucin, however, may be minimal or not apparent and if fibrin
deposition is present, distinction from rheumatoid nodule is impossible.
A dense rim of lymphocytes, histiocytes, and fibroblasts surrounds the necro-
biotic center. Multinucleate giant cells are common and eosinophils are often
present. The latter appear to be more common in this variant than in ordinary
granuloma annulare. Fibrosis of the surrounding tissue may be marked. In
up to 25% of cases of subcutaneous granuloma annulare, changes of classic
granuloma annulare may be seen in the dermis.118 Fig. 9.49
Papular and linear variants show histological features similar to those Subcutaneous granuloma annulare: note the intensely eosinophilic necrobiosis and
described for typical granuloma annulare. surrounding fibrosis.
 Necrobiosis lipoidica 295

Differential diagnosis
Granuloma annulare must be distinguished from necrobiosis lipoidica,
­rheumatoid nodule, actinic granuloma, and granuloma multiforme. Points of
­distinction are summarized in Table 9.1.
Granuloma annulare-like lesions with the added features of vasculitis and
a significant component of acute inflammatory cells may be encountered in
the setting of systemic disease.116,119 This pattern of disease is discussed in
detail in the section on palisaded neutrophilic and granulomatous dermatitis
and related disorders.
Granuloma annulare-like drug eruptions have been reported. The ­presence
of associated interface changes favors a drug eruption.10,120
Very rarely, scleromyxedema may focally mimic interstitial granuloma
annulare histologically.121 However, the changes simulating granuloma annu-
lare are focal, and elsewhere in the biopsy there are more typical features of
scleromyxedema including fibrosis and increase in fibroblasts.
Occasionally, infection by Mycobacterium marinum may mimic intersti-
tial granuloma annulare. The microscopic features may be so similar that the
diagnosis can only be made by special stains and culture.122
Although epithelioid sarcoma, with its associated geographic necrosis,
may bear a superficial resemblance at low-power examination to granuloma
annulare, the degree of nuclear atypia and pleomorphism in the former con-
dition should afford their distinction in the majority of cases. In addition,
epithelioid sarcoma often shows perineural tumor infiltration. It should be
noted, however, that mitotic activity may be encountered in granuloma annu-
lare.123 In difficult cases, keratin, epithelial membrane and, in up to 60% of
cases, CD34 antigen immunoreactivity in epithelioid sarcoma should assist in
this differential diagnosis.
Rare cases of mycosis fungoides may be associated with a tissue reac-
tion resembling granuloma annulare.124,125 The presence of interstitial
­lymphocytes with nuclear atypia and epidermotropism, a feature not seen
in granuloma annulare, should resolve this differential diagnosis. However,
in difficult cases, immunophenotyping and gene rearrangement studies may
be required.
Necrobiosis lipoidica
Clinical features
Necrobiosis lipoidica is a disease of unknown etiology which shows a strong
association with diabetes mellitus.1–6 Although the affiliation is likely to
have pathogenic implications, the precise mechanism by which the lesions
of necrobiosis lipoidica develop is, nevertheless, unknown and the nature
of the relationship between the two diseases is unclear. Therefore, although
the diagnosis of diabetes is most often established before the onset of the
skin lesions, on occasion, typical plaques may precede the apparent onset
of ­diabetes ­mellitus by several years. The course of the cutaneous disease
does not appear to be related to the hyperglycemia, and treatment of diabetes
does not affect the outcome of the cutaneous lesions. In one study, proteinu-
ria, retinopathy, and smoking were more common in patients with necro-
biosis ­lipoidica compared with patients with diabetes but no skin disease.7
Interestingly, however, only a minority of patients with necrobiosis lipoidica
has diabetes mellitus. It has been shown that 11% of patients with necrobio-
sis lipoidica have diabetes mellitus and a further 11% develop the disease or
altered glucose tolerance on follow-up.8
Necrobiosis lipoidica may develop in both juvenile (type I) and ­maturity-onset
(type II) diabetes. Interestingly, the condition improves in ­diabetic patients
after pancreatic transplant.9 Necrobiosis lipoidica has been ­documented in
patients with endocrine disorders other than diabetes such as hypo- and
hyperthyroidism, and also in association with inflammatory bowel disease
and vasculitis.10 One nondiabetic patient with necrobiosis lipoidica and
ataxia telangiectasia has been reported.11 Exceptionally, necrobiosis lipoidica
and granuloma annulare have presented simultaneously.12,13 The ­disease has
also been documented in association with sarcoidosis.14,15
Necrobiosis lipoidica shows a marked female preponderance (3.3:1) and,
although a wide age range may be affected, patients present most often in the
fourth decade (those associated with diabetes mellitus) or fifth decade (those
not associated with diabetes mellitus). The condition is rare in childhood

Table 9.1
Differential diagnosis of palisading granulomata and variants

Granuloma Subcutaneous Necrobiosis Rheumatoid Actinic Granuloma

annulare (GA) GA Perforating GA lipoidica (NL) Atypical NL nodule granuloma multiforme
Epidermis Normal Normal Transepidermal Normal or Normal Normal Normal or Normal
elimination atrophic or atrophic
acanthotic
Location of Superficial Deep dermis Superficial Deep dermis Upper and Deep dermis Upper and Upper and mid
lesion dermis and subcutis dermis and subcutis mid dermis and subcutis mid dermis dermis
Necrobiosis Circumscribed Massive sharp Circumscribed Diffuse and Rarely Massive Absent Focal
or ill defined border marked present sharp margin
Mucin Common Abundant Common Variable Absent Common Absent Present
Lipid Occasional Variable Variable Common Absent Variable Absent Absent
Fibrosis Absent Marked Absent Common; may Absent Common Usually Slight
be marked absent
Loss of elastica Yes Yes Yes Yes Yes Yes Very marked Yes
Vascular Common Variable Minimal Common Absent Variable Absent Absent
thickening
Capillary Absent Common Absent Variable Absent Common Absent Absent
hyperplasia
Giant cells Relatively few Common Relatively few Common Common Relatively Abundant; Common
few contain elastica
Asteroid bodies Absent Absent Absent Absent Present Absent Not Absent
uncommon
Palisading of Common Common Common Variable Absent Common Infrequent Inconspicuous
histiocytes degree in

Reprinted from Muhlbauer JE. Granuloma annulare. J Am Acad Dermatol 3:217–230; Copyright Elsevier 1980, with permission from the American Academy of Dermatology, Inc.
296 Granulomatous, necrobiotic and perforating dermatoses

and is often associated with diabetes mellitus. It also appears to be related to

underlying renal and retinal disease.16–20 Familial cases may also occur, with
or without, diabetes.21–23 A case of monozygotic twins with diabetes mellitus
type 2 and necrobiosis lipoidica has been reported.24
The characteristic lesion, sometimes referred to as a sclerodermatous
plaque, is round or oval, circumscribed, and often has a slightly elevated
rim. It is typically a few millimeters to several centimeters in diameter.
Newly acquired lesions are often red-brown in color, but with progression
the center of the lesion becomes yellowish and the peripheral border may
acquire a violaceous hue. Larger plaques are usually irregular and more
variably shaped. Scaling and telangiectasia may become evident. Ulceration
appears to be relatively frequent and has been reported in up to 13% of
patients.25–27 Perforating necrobiosis lipoidica is very rare and may be seen
very exceptionally in children.28,29 In perforating cases, the clinical appear-
ance may consist of a focal scaly depression or comedone-like lesions.
Atypical forms may also be found: patients sometimes manifest papules
and nodular lesions, and occasionally plaques resembling granuloma annu-
lare are seen. (It should be noted, however, that rarely these two conditions
appear to coexist.)12,30 Clinical presentations with papulonecrotic and nod-
uloulcerative lesions mimicking gummata or erythema induratum have been Fig. 9.51
documented, albeit exceptionally.25 The lesions may be solitary or multiple, Necrobiosis lipoidica:
often symmetrical, and show a predilection for the lower extremities, in typical lesion with an
erythematous border.
particular the pretibial area (Figs 9.50–9.53). They can also occur on the
From the collection of the
arms, hands, fingers, abdomen, nipples, and back; rarely the face or scalp
late N.P. Smith, MD, the
is affected, in which case diabetes is seldom present.31 Generalized lesions Institute of Dermatology,
may exceptionally occur.32 London, UK.
It is doubtful whether the so-called atypical necrobiosis lipoidica of the
face and scalp represents a variant of necrobiosis lipoidica. The name was
chosen because of the coexistence of typical lesions of necrobiosis lipoid-
ica on the shins of one of the patients in the original series. However, most
patients do not present with classic lesions of necrobiosis lipoidica elsewhere
and the microscopic findings do not resemble the latter entity.33
Involvement of the penis with lesions resembling chronic balanitis has been
described.34–36 Rarely, lesions are associated with Koebner's phenomenon.37–39
Necrobiotic and silicotic granulomata developing within phlebectomy scars
have also been reported.40
The disease tends to chronicity. It is of interest that necrobiosis lipoid-
ica has been reported to be associated with cutaneous hypo- or complete
anesthesia in both diabetic and nondiabetic patients.41,42 One study found

Fig. 9.52
Necrobiosis lipoidica: lesion on shin showing atrophy and telangiectasia.
From the collection of the late N.P. Smith, MD, the Institute of Dermatology,
London, UK.

loss of nerves within lesions and, based on this finding, the authors pos-
tulated that destruction of nerves might explain the sensory loss that is
observed in some patients.42,43 Hypohidrosis and partial alopecia have also
been reported.44
Rarely, squamous carcinoma may arise in longstanding lesions.45–49
One such case developed in association with perforating necrobiosis
lipoidica.50
Fig. 9.50
Necrobiosis lipoidica: Pathogenesis and histological features
characteristic, bilateral,
symmetrical lesions.
The precise pathogenesis of necrobiosis lipoidica is unknown. Of primary
From the collection of the importance is the temporal relationship between collagen degeneration and
late N.P. Smith, MD, the the inflammatory infiltrate.51 The close association of necrobiosis lipoidica
Institute of Dermatology, and diabetes mellitus suggests a causal relationship, but the exact mechanism
London, UK. is uncertain. In the past, some 60% of patients with necrobiosis ­lipoidica were
 Necrobiosis lipoidica 297

Gli-1, the glioma-associated oncogene homologue, has been found to be

Fig. 9.53
Necrobiosis lipoidica:
chronic lesion with
ulceration and crusting.
From the collection of the
late N.P. Smith, MD, the
Institute of Dermatology,
London, UK.
expressed in a number of granulomatous skin disorders including necrobiosis
lipoidica.64 The explanation for this is not clear but it suggests that inhibitors
of gli-1 may be used in the treatment of the disease.
Recently, spirochetal microorganisms, likely to be Borrelia, have been
identified in lesions of necrobiosis lipoidica in patients from central Europe.65
The significance of this finding is unclear.
The histopathological features are variable, depending to some extent on
the presence or absence of coexistent diabetes mellitus.66,67 The palisading
granuloma with necrobiosis is more typical of the diabetes-related variant,
whereas a granulomatous sarcoidal type of reaction is more often a feature
of nondiabetes-related necrobiosis. Nevertheless, there is very considerable
overlap and in the majority of cases one cannot predict, on histological
grounds alone, which cases are, and which are not, diabetes-related.
The epidermal changes are usually inconspicuous or absent. There may,
however, be acanthosis or atrophy, and hyperkeratosis is not uncommon.
The hallmark of necrobiosis lipoidica is the palisading necrobiotic granu-
loma. Large, often confluent areas of necrobiosis are present, usually centered
in the lower dermis, although the superficial dermis and subcutaneous fat may
also be affected (Figs 9.54–9.56). When the subcutaneous fat is involved,
the changes are seen mainly in the septa. The foci of necrobiosis consist of

reported as having coexistent diabetes mellitus.2,4,52,53 However, its reported

prevalence in diabetes is only of the order of 3/1000.51 Furthermore, a recent
study has found that only a minority of patients with necrobiosis lipoidica
have diabetes.8
It has been suggested that the lesions develop as a consequence of diabetic
microangiopathy: the vessel walls in lesions of necrobiosis lipoidica are typi-
cally thickened by a diastase-resistant PAS-positive material. This does not
explain the development of necrobiosis lipoidica in nondiabetic patients or
the absence of the disease in patients with established microvascular lesions.
An association with venous insufficiency and hypercholesterolemia has been
suggested in a very small group of patients.54 The significance of this finding is
therefore unclear. Study of microcirculation by Doppler flowmetry and ­oxygen
partial pressure in necrobiosis lipoidica lesions in nondiabetics has demon-
strated an altered microcirculation.55 Low oxygen and high carbon dioxide
pressures, presumably reflecting ischemia, characterize necrobiotic plaques.56
Such vascular changes, although possibly causal, could equally well develop as
a consequence of the necrobiotic changes. Aberrant platelet aggregation may
also play a role in pathogenesis. Platelet survival times are markedly reduced
in patients with necrobiosis lipoidica.57 Whether this is of pathogenic impor-
tance is uncertain.
Autoantibodies against cytoskeleton proteins have been observed in sera
from patients with necrobiosis lipoidica. These autoantibodies (IgG anti-
troponin, antidesmin, antikeratin, anti-insulin, antitrinitrophenol, and IgA
and IgM antikeratin) were found to be elevated in patients with necrobiosis
lipoidica compared with diabetic patients without evidence of necrobiosis
lipoidica.58 What role, if any, these autoantibodies play in the pathogen-
esis of necrobiosis lipoidica is unclear. Synthesis of collagen by fibroblasts
cultured from lesions is decreased compared with fibroblasts from normal
skin.59
Also of uncertain significance is the reported detection, by immunofluo-
rescence, of immunoreactants (IgM and C3) in blood vessel walls in some
cases of necrobiosis lipoidica.60,61 Epidermal dendritic S-100-positive cells are
increased in number.62 Whether this reflects an immunological aspect to the
development of necrobiosis lipoidica has yet to be determined.
Glut-1 (the human erythrocyte glucose transporter) is expressed by the
fibroblasts in areas of sclerotic collagen from biopsies of patients with necro-
biosis lipoidica.63 This raises the possibility of an altered transport of glucose Fig. 9.54
in the affected areas contributing to the histopathological features seen in this Necrobiosis lipoidica: the epidermis is unaffected; there is extensive necrobiosis in
disease. the reticular dermis. A heavy chronic inflammatory cell infiltrate is present.
298 Granulomatous, necrobiotic and perforating dermatoses

e­ osinophilic, swollen or degenerate collagen, often appearing hyalinized with

a surrounding infiltrate of variable numbers of lymphocytes and histiocytes
(Fig. 9.57). Aggregates of lymphoid cells, with or without germinal center
formation, are frequently found.68 Plasma cells are almost invariably ­present.
In a single case, the plasma cell infiltrate was mononclonal, and ­further
­investigations revealed an underlying monoclonal gammopathy.69 The necro-
biotic foci sometimes contain mucin. Palisading is variable, being more con-
spicuous in those instances associated with a heavy inflammatory cell infiltrate.
The areas of necrobiosis are associated with loss of elastic tissue (Fig. 9.58).
Usually, epithelioid histiocytes and giant cells are evident and sometimes there
are well-formed granulomata resembling the sarcoidal type of necrobiotic his-
tological reaction (see below) (Fig. 9.59). Very rarely, asteroid bodies are iden-
tified.70 Lipid droplets, best seen with oil red O or Sudan IV staining on frozen
tissue, are almost invariably present in the necrobiotic foci. Usually, a mild to
moderate perivascular lymphocytic infiltrate is seen in the adjacent dermis.
Cholesterol clefts are rare and only exceptionally may be prominent.71,72
A careful search often reveals vascular changes in necrobiosis lipoidica. These
consist of blood vessel wall thickening, with intimal proliferation and narrow-
ing of the lumen. Occasionally thrombi are noted. Sometimes increased num-
Fig. 9.55 bers of vessels are a feature. The vascular changes are more obvious in patients
Necrobiosis lipoidica: the lesion extends down to the subcutaneous fat.

Fig. 9.56 Fig. 9.58

Necrobiosis lipoidica: high-power view of Figure 9.54. Necrobiosis lipoidica: note the complete absence of elastic tissue. Elastic-van
Gieson.

Fig. 9.57 Fig. 9.59

Necrobiosis lipoidica: the degenerate collagen is surrounded by a palisade of Necrobiosis lipoidica: there is a granulomatous infiltrate with conspicuous
histiocytes, lymphocytes, and fibroblasts. multinucleate giant cells.
 Necrobiosis lipoidica 299

with associated diabetes mellitus or other systemic disease. These changes are
particularly severe in those cases where necrobiosis is very marked. One study
also showed that neutrophilic and granulomatous vasculopathies correlated
with systemic disease.73 In addition, telangiectatic superficial venules are a com-
mon feature. Cases with necrobiosis-like features and significant vasculitis and
neutrophilic infiltrates in the setting of systemic disease are discussed in detail
in the section on palisaded neutrophilic and granulomatous dermatitis associ-
ated with systemic disease. In lesions with anesthesia, S-100 shows destruction
of nerve fibers in the areas of necrobiosis.42,43
In the diffuse variant there is very widespread necrobiosis with a mini-
mal inflammatory cell response; such cases are usually associated with dia-
betes (Fig. 9.60). Sometimes linear infiltrates of histiocytes between collagen
fibers are a feature, as in granuloma annulare. Lipomembranous fat necrosis
is noted in occasional cases.74
In the sarcoidal type of necrobiosis lipoidica, which is more often noted
with the nondiabetes mellitus-associated variant, the appearances are those
of naked ­epithelioid cell granulomata, particularly in the lower dermis
(Fig. 9.61). Langhans and foreign body giant cells are usually ­conspicuous
and a ­lymphocytic and plasma cell infiltrate may be evident (Fig. 9.62).
Necrobiosis is usually ­minimal; multiple levels may have to be examined Fig. 9.61
Necrobiosis lipoidica (granulomatous variant): well-defined noncaseating granulomata
before its ­presence is ­confirmed (Fig. 9.63). The sarcoidal type of necrobiosis
replace the reticular dermis. Necrobiosis is present to the left of center.
lipoidica in patients without ­diabetes mellitus has in the past been described as
Miescher's granuloma.
Perforating necrobiosis lipoidica is associated with transepidermal
­elimination of necrobiotic collagen and also degenerated elastotic material
(Figs 9.64–9.66).71,75,76

Differential diagnosis
Necrobiosis lipoidica must be distinguished from granuloma annulare, rheu-
matoid nodule, actinic granuloma, and granuloma multiforme. Points of
­distinction are summarized in Table 9.1. The presence of massive necrobio-
sis associated with numerous cholesterol clefts, bizarre multinucleated giant
cells, and Touton-type giant cells distinguishes necrobiotic xanthogranu-
loma from necrobiosis lipoidica. As noted above, prominent cholesterol cleft
­formation, which is a feature that usually suggests necrobiotic xanthogranu-
loma, may rarely be seen in necrobiosis lipoidica.66,67 Small punch ­biopsies
may not be adequate for definitive evaluation and sampling bias may be
­misleading. Clinical correlation should be taken into consideration before
making a final diagnosis.

Fig. 9.62
Necrobiosis lipoidica (granulomatous variant): the naked granulomata are very
reminiscent of sarcoidosis. Note the multinucleate giant cells.

Fig. 9.60
Necrobiosis lipoidica
(diffuse variant): a
broad band of confluent Fig. 9.63
necrobiosis has destroyed Necrobiosis lipoidica (granulomatous variant): higher-power view of the necrobiotic
the entire reticular dermis. focus seen in Figure 9.61.
300 Granulomatous, necrobiotic and perforating dermatoses
Fig. 9.64
Perforating necrobiosis lipoidica: there is widespread hyperkeratosis and crusting.
A perforating channel is seen on the right side of the picture.
Fig. 9.65
Perforating necrobiosis:
close-up view of the
perforating channel.
Rheumatoid nodule
Clinical features
Rheumatoid nodules are subcutaneous lesions that develop at sites of trauma
or at pressure points in approximately 30% of adults with rheumatoid arthri-
tis.1–3 They are most commonly found on the extensor aspect of the forearms
and elbows (particularly the olecranon process), the feet, knees, knuckles,
buttocks, scalp, and back (Figs 9.67, 9.68).4 They have also been described
involving a wide variety of other sites, including the abdominal wall, heart
(pericardium, myocardium, and valves), larynx, lungs, pleura, splenic cap-
sule, peritoneum, mesenterium, eye, bridge of nose, pinna, ischial tuberosity,
thyrohyoid membrane, and Achilles tendon.5,6 Lesions are often fixed to the
underlying periosteum or deep fascia. They present as firm, asymptomatic,
dome-shaped masses in the subcutaneous fat or deeper tissues and measure
Fig. 9.66
Perforating necrobiosis:
the dermis immediately
beneath the site of
perforation shows severe
necrobiotic change.
Fig. 9.67
Rheumatoid nodules: lesions on the knuckles are commonly seen in rheumatoid
arthritis. By courtesy of Dr J.C. Pascual, MD, Alicante, Spain.
from several millimeters to 5 cm in diameter. Numbers may vary from one to
over a hundred. Ulceration sometimes occurs. Intrapulmonary rheumatoid
nodules have been exceptionally associated with leflunomide in a patient with
rheumatoid arthritis.7 A case of large cavitary pulmonary lesions in a patient
with HIV has been reported.8
Rheumatoid nodules are more commonly found in patients with severe
rheumatoid arthritis and are associated with a high titer of rheumatoid fac-
tor, joint erosions, and an increased incidence of rheumatoid vasculitis.9
They are not, however, specific for rheumatoid arthritis, being found in
approximately 5–7% of patients with SLE (although in this condition they
tend to be localized about the hands) and occasionally in seronegative anky-
losing spondylitis.10,11 Clinically similar lesions have also been reported in
patients with scleroderma. Presentation of multiple rheumatoid nodules on
the fingers in association with little or no arthritis has been described as
rheumatoid nodulosis.12–14 This, however, can be associated with destruc-
tive arthritis.15 A similar name (cutaneous nodulosis) has been given to the
 Rheumatoid nodule 301

Fig. 9.68 Fig. 9.69

Rheumatoid nodule: close-up view. By courtesy of Dr J.C. Pascual, MD, Alicante, Rheumatoid nodule: there is massive necrobiosis with adjacent scarring and a
Spain. dense lymphocytic infiltrate. Rheumatoid nodules characteristically occur in the soft
tissues.

development of multiple small nodules at different sites during methotrexate

therapy for rheumatoid arthritis.16 Etanercept has been linked to the excep-
tional development of extensive pulmonary nodulosis while infliximab and
the aromatase inhibitor letrozole are associated with accelerated cutaneous
nodulosis.17–19

Pathogenesis and histological features

Although these lesions develop at sites of pressure and trauma (implying
pathogenetic significance), there is some evidence in support of an immune
complex-mediated pathogenesis, as both IgG and IgM have been detected
by immunofluorescence in the walls of blood vessels adjacent to rheumatoid
nodules.20 Similarly, both rheumatoid factor and complement have been dem-
onstrated within the substance of rheumatoid nodules. Localization of IgM
rheumatoid factor and terminal complement complexes C5b-9 has been dem-
onstrated on the luminal surface of endothelial cells in rheumatoid nodules.21
C4d has been shown in association with palisading macrophages and in areas
of fibrinoid necrosis, further supporting the role of complement activation in
the pathogenesis of the lesions.22 Proinflammatory cytokines and cell adhe-
sion molecules (TNF-α, IL-1β, IL-Ra RNA, E-selectin) have been shown in
rheumatoid nodules and are likely to play a role in mediating injury.23 The Fig. 9.70
Rheumatoid nodule: in this example, tendon can be seen on the right side of the
expression of cytokines in the rheumatoid nodule is very similar to that in
field.
the synovial lining in rheumatoid joints and suggests that the pathogenesis of
both is very similar and driven by Th1 lymphocytes.24 The cytokines involved
include IFN-γ, IL-1beta, TNF-α, IL-12, IL-18, IL-15, and IL-10.23 Although
massive central necrosis is predominant, apoptosis has been demonstrated
Differential diagnosis
throughout the nodule.25 In some cases of deep granuloma annulare the histological changes are similar
Rheumatoid nodules are typically located in the subcutaneous fat or to rheumatoid nodule. Deep granuloma annulare (‘pseudorheumatoid nod-
soft tissues although they may extend into the deeper reticular dermis. This ule’) tends to have more mucin deposition and less fibrin than typical rheu-
is in contrast to the more superficial location of both granuloma annu- matoid nodules.28 Therefore, the latter are referred to as ‘red’ granulomas
lare and necrobiosis lipoidica. They are multinodular and associated with and the former as ‘blue’ granulomas.29 However, some rheumatoid nodules
very extensive necrobiosis (Figs 9.69, 9.70). Fibrin deposition is often seen do contain mucin. Clinicopathological and serological correlation is advised
in the center of the nodule.26 Immunoglobulin, lipid, glycosaminoglycans, before establishing a definitive diagnosis.
and nucleoproteins may also be present. Old lesions are sometimes associ- Compared to rheumatoid fever nodule, rheumatoid arthritis nodules tend
ated with cyst formation due to liquefactive degeneration of the contents of to be better circumscribed and surrounded by a well-defined palisade of his-
the nodules. A well-developed palisade of histiocytes and occasional giant tiocytes. In addition, the fine fibrinoid strands that form the center of a rheu-
cells characteristically surrounds necrobiotic foci and fibrinoid material matic fever nodule contrast with the more dense sheet-like areas of necrobio-
(Fig. 9.71). Asteroid inclusions are not a feature. The outer layer is com- sis and fibrin deposition in the rheumatoid arthritis nodule.
posed of vascular granulation tissue, and in older lesions marked fibrosis Patients combining the features of severe rheumatoid arthritis with pali-
is a frequent accompaniment. An inflammatory cell infiltrate of lympho- sading granulomata accompanied by a neutrophilic infiltrate and leukocyto-
cytes, plasma cells, and eosinophils is often present. Leukocytoclastic vas- clastic vasculitis have been described.9 These lesions are discussed under the
culitis has occasionally been reported to affect the blood vessels in and rubric of palisaded neutrophilic and granulomatous dermatitis with vasculi-
around early nodules. A rare case with perforation of the epidermis has tis. In short, lesions showing these features may be associated with a number
been documented.27 of systemic diseases, including rheumatoid arthritis.
302 Granulomatous, necrobiotic and perforating dermatoses
Fig. 9.71
Rheumatoid nodule: the necrobiotic connective tissue is surrounded by a well-
developed histiocytic palisade.
Fig. 9.72
Rheumatoid nodule: the palisading histiocytes may sometimes show mitotic
figures which may lead the unwary to consider epithelioid sarcoma.
Although epithelioid sarcoma, with its associated geographic necrosis,
may bear a superficial resemblance at low power to rheumatoid nodule, the
degree of nuclear atypia and pleomorphism in the former should allow easy
­distinction between these conditions (Fig. 9.72). However, in difficult cases,
keratin and epithelial membrane antigen immunoreactivity in epithelioid
­sarcoma should assist in the differential diagnosis.
Elastolytic granulomata
This is a controversial group of diseases, the prototype of which is the actinic
granuloma. Other entities that probably belong to this group include atypical
facial necrobiosis lipoidica and granuloma multiforme (see below). It has been
suggested that all these conditions represent examples of granuloma annulare
occurring in different clinical settings.1–4 However, the clinicopathological
features are distinctive and the pathological process clearly relates to the pri-
mary destruction of elastic fibers by a granulomatous infiltrate. In granuloma
annulare, as in diseases such as sarcoidosis, destruction of ­elastic fibers does
not always occur and when it does, it tends to occur focally, ­developing as a
secondary phenomenon.5
Annular elastolytic giant cell granuloma
Clinical features
The term ‘annular elastolytic giant cell granuloma’ has been used to describe
not only cases of actinic granuloma but also lesions in which destruction of
elastic fibers occurs in the absence of solar elastosis.6 In fact, some cases pres-
ent at sites with little sun exposure and the disease may also occur in chil-
dren.7 Thus, although the terms actinic granuloma and elastolytic giant cell
granuloma have been used interchangeably in the literature, the latter term
should be reserved for elastolytic granulomata occurring in skin without solar
elastosis.8
Lesions usually present on the trunk and neck and rarely on proximal limbs.
They vary in size but tend to be large. Despite the name annular, some cases
present with papules or reticular erythema.9 In those that are annular there is
an advancing raised border which may be papular. Rarely, lesions are general-
ized.10 Spontaneous resolution is rare.9 A reported case describes a lesion that
developed at the site of an old burn scar and spread after trauma.11
Elastolytic granulomata have rarely been described in association with
adult T-cell leukemia lymphoma, primary cutaneous CD4-positive small/
medium-sized pleomorphic T-cell lymphoma, acute myelogenous leukemia,
and monoclonal gammopathy.12–14 Elastolytic granulomata have also been
documented in internal organs.15 The latter, however, probably represents
sarcoidosis with prominent elastolysis.
Pathogenesis and histological features
Elastic fibers become altered through an unknown mechanism and appear
to induce factor XIIIa-positive cells and CD68-positive macrophages to form
granulomata.16
Histological features may be identical to those of actinic granuloma (see
below) except for the absence of solar elastosis. Ideally, in annular lesions the
biopsy should be a wedge including the center, the advancing edge, and nor-
mal skin for comparison purposes. This is not always possible, particularly
in lesions that do not have an annular configuration. The center of the lesion
is completely devoid of elastic fibers and there is usually no inflammation.
The loss of elastic fibers appears to be irreversible.17 In the advancing margin
there is a granulomatous reaction with fragmentation and phagocytosis of
elastic fibers. In one case, histology showed features of mid-dermal elastolysis
­leading the authors to suggest that annular elastolytic giant cell granuloma
may possibly represent a prodromal or inflammatory stage of the disease.18
Differential diagnosis
Many granulomatous reactions, including infections, often display elas-
tophagocytosis. However, in these conditions the change is mild and focal.
In granuloma annulare, there is usually very little or no elastophagocytosis,
while in annular elastolytic giant cell granuloma there is no necrobiosis or
palisading granuloma.19
Actinic granuloma (O’Brien)
Clinical features
Actinic granuloma develops on the sun-damaged skin of the neck, face, upper
chest or arms of middle-aged patients.1–5 It may also affect the conjunc-
tiva, and a single case affecting the upper lip has been reported.6–9 A further
case presented as alopecia.10 The incidence is equal in men and women, and
­individuals with blond hair and freckled skin are predisposed, particularly
those living in sunny climates. An association with the longstanding use of
sunbeds and with doxycycline phototoxicity has also been described.11,12
Lesions present as one or more skin-colored or pink papules, which
enlarge to form annular or arcuate plaques up to 1 cm in diameter. The edge
of the lesion is somewhat raised, forming a border 0.2–0.5 cm in width.
These annular plaques enlarge slowly and the center may gradually clear to
appear ­relatively normal or slightly atrophic with variable depigmentation.
Lesions are asymptomatic and there is no evidence of anesthesia. They do not
develop on nonsun-damaged skin. Spontaneous resolution may take place
after months or years.
 Elastolytic granulomata 303

Bilateral periocular actinic granulomata have been documented in a patient

with renal failure.13 Other rare associations include relapsing polychondritis,
cutaneous amyloidosis, and giant molluscum contagiosum.14–16

Pathogenesis and histological features

The pathogenesis of actinic granuloma is poorly understood. It has been sug-
gested that the antigenic stimulus for the formation of granulomata in both
actinic granuloma and temporal arteritis is actinically degenerated elastic
tissue.17,18 Interestingly, phototesting in a single case failed to reproduce the
lesions of actinic granuloma.19
The features are best appreciated by examination of a radial biopsy
through the edge of a lesion and including uninvolved skin.20,21 The epidermis
may be normal or atrophic. The peripheral unaffected skin shows gross solar
(actinic) elastosis (Figs 9.73–9.75). Within the rim of the lesion there is a for-
eign body giant cell reaction in association with, and engulfing, fragmented
elastotic material (elastoclasis) (Figs. 9.76, 9.77).20,21 The granulomatous
reaction is centered in the zone of solar elastosis and, accordingly, tends to be
confined to the superficial dermis.22 The giant cells may contain asteroid bod-
ies. There is an accompanying chronic inflammatory cell infiltrate composed
Fig. 9.75
of histiocytes, lymphocytes, and plasma cells. Necrobiosis is not a feature Actinic granuloma: the granulomatous infiltrate is associated with degenerate
elastic fibers.

Fig. 9.73 Fig. 9.76

Actinic granuloma: a granulomatous reaction is present the superficial dermis Actinic granuloma: elastotic material is seen in the cytoplasm of the giant cell in the
surrounding an ill-defined necrobiotic process. Solar elastosis is evident. centre of the field.

Fig. 9.74
Actinic granuloma: in addition to solar elastosis, this example also shows interface Fig. 9.77
change with conspicuous cytoid bodies. Actinic granuloma: high-power view of basophilic degenerate elastic fibers.
304 Granulomatous, necrobiotic and perforating dermatoses

of this condition. Palisading of histiocytes is either absent or minimal and,

if present, is related to the elastotic debris. Dermal mucin does not appear
to be increased.22 Fibroblasts are scant and fibrosis is minimal. In the actinic
granuloma, blood vessels appear normal. Within the central zone the collagen
appears relatively normal, although it is more obviously horizontally aligned
and may appear more closely packed than normal. Slight scarring is present
in the central area where elastic tissue is absent.22

Differential diagnosis
The facial location, presence of elastophagocytosis, and absence of necro-
biosis aid in distinguishing actinic granuloma from other granulomatous
lesions. The absence of dermal mucin, necrobiosis, and palisading granu-
loma and the presence of marked elastoclasis and mild scarring help to distin-
guish actinic granuloma from granuloma annulare, the disorder that it most
resembles.14,23

Atypical facial necrobiosis lipoidica

Clinical features Fig. 9.79
This variant of necrobiosis lipoidica deserves separate mention because of its Atypical facial necrobiosis lipoidica: a dense granulomatous infiltrate occupies the
dermis.
unusual clinical features and distinctive histology.1–5 Atypical facial necro-
biosis lipoidica, which predominantly affects females (9:1), usually develops
in the absence of diabetes mellitus, and manifests most often in the fourth
decade. Patients present with one or more annular, nonscaling plaques on the
upper face and scalp, which typically have slightly raised, relatively uniform
borders and measure 1–5 cm in diameter (Fig. 9.78). Although early lesions
are erythematous with a brown border, older lesions are characterized by cen-
tral depigmentation. Atrophy, however, is minimal or absent. Patients may,
in addition, show involvement of other sites, including the arms, hands, and
trunk. Very rarely, patients have concomitant typical necrobiosis lipoidica on
the shins. It is for this reason that the name was originally coined. We now
believe, however, that the condition probably has no relationship whatsoever
to necrobiosis lipoidica. It is much more likely that it represents a variant of
an annular elastolytic granuloma.

Histological features
The condition is characterized by a dense granulomatous infiltrate, with con-
spicuous giant cells, involving the dermis (Figs 9.79, 9.80). The infiltrate has
a rather irregular distribution, being dispersed between individual collagen
bundles. Occasional circumscribed granulomata may sometimes be a feature.
Asteroid bodies are often found in the cytoplasm of giant cells. Typically,
there is loss of elastic tissue in the areas of granulomatous inflammation.
Fig. 9.80
Atypical facial necrobiosis lipoidica: close-up view of the granulomata. Note the
conspicuous giant cells.

Rarely, ill-defined foci of necrobiosis are noted (Fig. 9.81), but well-defined
palisading granulomata are not present. In cases with coexistent necrobiosis
lipoidica, biopsies from the affected areas on the shins show the typical histo-
logical features of this condition.

Differential diagnosis
In contrast to actinic granuloma with which this condition is often confused,
the surrounding skin does not show evidence of significant solar elastosis and
elastoclasis.

Fig. 9.78
Atypical facial necrobiosis lipoidica: atrophic plaque on forehead with a well-defined
edge. From the collection of the late N.P. Smith, MD, the Institute of Dermatology,
London, UK.
Granuloma multiforme
Clinical features
This dermatosis of unknown etiology is of particular importance because clin-
ically it can be confused with leprosy; however, it is not associated with cuta-
neous anesthesia.1,2 Granuloma multiforme, which shows a marked female
predominance, is seen most often in Central Africa, especially eastern Nigeria.
It has also been documented in the Congo, Uganda, India, and Tunisia.3–6
The disease is very common in some villages. It particularly affects patients
 Elastolytic granulomata 305

Fig. 9.81 Fig. 9.83

Atypical facial necrobiosis lipoidica: an ill-defined focus of necrobiosis is present. Granuloma multiforme: there are multiple large irregular plaques. By courtesy of the
Institute of Dermatology, London, UK.

over 40 years of age. Lesions, which tend to chronicity, are found on the
upper and exposed parts of the body. They commence as small, flesh-colored,
indurated, pruritic papulonodules, 1–8 mm in diameter and raised 1–3 mm
above the skin surface, which extend peripherally and coalesce to form annu-
lar lesions and plaques (Figs 9.82, 9.83). Very large lesions become irregular
and develop scalloped or gyrate borders. Central healing may be associated
with residual hypopigmentation.

Histological features
The epidermis is normal. Situated within the dermis is an ill-defined, irregu-
lar, necrobiotic lesion (Fig. 9.84).7 In general, this affects individual collagen
fibers, producing a rather haphazard picture of abnormal fibers interspersed
with unaffected ones and associated with a histiocytic infiltrate (Fig. 9.85).
Only rarely is a well-defined palisading granuloma seen. In addition to his-
tiocytes, giant cells are commonly found and the tissues show a perivascular
lymphocytic infiltrate with variable numbers of plasma cells and eosinophils.

Fig. 9.84
Granuloma multiforme: there is extensive necrobiosis.

Fig. 9.82
Granuloma multiforme:
typical annular lesions
with raised borders in a
child. By courtesy of R.A.
Marsden, St George’s Fig. 9.85
Hospital, London, UK. Granuloma multiforme: necrobiosis is seen in the center.
306 Granulomatous, necrobiotic and perforating dermatoses
Fig. 9.86
Granuloma multiforme: note the complete loss of elastic tissue. Elastic-van Gieson.
The giant cells do not contain asteroid bodies. Perineural involvement is not
a feature.1 The adjacent vasculature is normal. Loss of elastic tissue is typical
in relation to the inflammatory infiltrate and healed areas are characterized
by absence of elastic tissue and mild superficial scarring (Fig 9.86).1
Differential diagnosis
The exact nosological position of granuloma multiforme is unknown. It is
probably a clinicopathological variant of elastolytic granuloma. An associa-
tion with sun exposure has been suggested.8 The granulomata do not show
a perineural distribution, thus helping to distinguish granuloma multiforme
from leprosy. Nevertheless, since infection must be excluded before giving a
definitive diagnosis, stains for organisms (especially mycobacteria and fungi)
must be performed to exclude this possibility. Culture should also be per-
formed when clinically appropriate.
Rheumatic fever nodule
Clinical features
Fortunately, effective antimicrobial therapy has relegated rheumatic fever to
a rare pediatric infection. As a consequence, complications of rheumatic fever
are only rarely encountered in dermatology practice. In older studies, approx-
imately one-third of patients with rheumatic fever develop papules that had a
tendency to occur over bony prominence of the knee, elbows, fingers, ankles,
spine, scalp, and rarely at other sites.1–3 Most patients had multiple nodules.
In one report, the number of nodules ranged from 1 to 108.1 Lesions per-
sisted from days to several months. Interestingly, in a more recent study of
44 patients with rheumatic fever, only one had a single subcutaneous nodule.4
Histological features
Biopsy shows central gossamer fibrin associated with variable numbers of
neutrophils, lymphocytes, plasma cells, and karyorrhexis. The lesions are
often not well circumscribed and histiocytes surround the lesion, forming a
poorly defined palisade.
Differential diagnosis
The histological features of the rheumatic fever nodule are not pathog-
nomonic. Clinical correlation is required to establish a definite diagnosis.
The rheumatic fever nodule can be classified under the rubric of ‘palisaded
neutrophilic and granulomatous dermatitis associated with systemic dis-
ease’. Rheumatic fever nodule is discussed separately, however, because of
its historic interest and its longstanding recognition as a distinct clinical
entity. The differential diagnosis is therefore that of palisaded ­neutrophilic
and ­granulomatous dermatitis. Other systemic diseases, including con-
nective ­tissue disease, infection, ­vasculitis, neoplasia, and inflammatory
bowel ­disease, may be associated with lesions with similar histology. The
reader is referred to this section for a more detailed discussion of this
group of disorders. In short, a diagnosis of rheumatic fever nodule should
only be made in the setting of confirmed rheumatic fever. In the absence
of such history, a careful search for other underlying systemic diseases is
necessary.
Rheumatoid arthritis nodules tend to be better circumscribed and sur-
rounded by well-defined palisade of histiocytes. In addition, the fine fibrinoid
strands that form the center of a rheumatic fever nodule contrast with the
more dense sheetlike areas of necrobiosis in the rheumatoid arthritis nodule.
Necrobiotic xanthogranuloma
Clinical features
Necrobiotic xanthogranuloma (necrobiotic xanthogranuloma with parapro-
teinemia) is an extremely rare condition of unknown etiology.1–3 It occurs
equally in men and in women, in the late middle aged and elderly (average
age at presentation is 56 years). The disease is characterized by the develop-
ment of nodules and plaques, which show a predilection for the face, neck,
trunk and, less commonly, proximal limbs. The facial lesions are charac-
teristically periorbital (most often infraorbital) in distribution and consist
of papules that progress to nodules, and plaques that may form irregular
ulcers (Fig. 9.87). Although periorbital involvement is fairly constant, in
some patients this feature is absent.4,5 Scarring and telangiectasia are com-
mon. Lesions are sharply demarcated and have a distinctive xanthomatous
appearance. Ocular complications are common and include episcleritis,
­keratitis, proptosis, uveitis, and iritis.6 Some patients report pain but this is
not a usual feature.2
The lesions on the trunk and limbs are irregular, well-demarcated, bright
yellow, dermal and subcutaneous plaques measuring up to 25 cm across
(Fig. 9.88). They may be complicated by ulceration, hemorrhage, scarring,
central atrophy, and telangiectases, and typically have a peripheral inflam-
matory border. Violaceous and flesh-colored nodules are sometimes pres-
ent, particularly over the trunk. Unusual presentations include a solitary
nodular lesion mimicking a tumor and, exceptionally, the absence of skin
involvement.7,8 A lesion presenting at the site of a blepharoplasty scar and a
further lesion presenting in the scar of a burn have been reported.9,10
Involvement of myocardium, lung, larynx, kidneys, salivary gland,
and skeletal muscle has been documented.11–16 Patients may have arthritis,
chronic obstructive pulmonary disease, neuropathy or hypertension.2 Other
Fig. 9.87
Necrobiotic xanthogranuloma: indurated yellow plaques are present around both
eyes and on the eyelids. By courtesy of the Institute of Dermatology, London, UK.
 Necrobiotic xanthogranuloma 307

Fig. 9.88 Fig. 9.89

Necrobiotic xanthogranuloma: there are multiple yellow plaques around the shoulders Necrobiotic xanthogranuloma: there is a dense infiltrate extending throughout the
and overlying the clavicles. By courtesy of the Institute of Dermatology, London, UK. dermis into the subcutaneous fat.

reported cases include one associated with Graves' disease, another with
­linear ­morphea, one with scleroderma and one with lichen sclerosus.2,17–19 In
another patient there was an association with syncitial giant cell hepatitis.20
Nodular transformation of the liver is a feature noted in rare patients.14,21
Laboratory investigations reveal anemia, leucopenia, and a raised ESR.
Most patients with necrobiotic xanthogranuloma have an associated mono-
clonal paraproteinemia, usually IgG kappa type. Few present with a lambda
paraprotein and an exceptional case has been documented with two mono-
clonal paraproteins. Some patients have multiple myeloma or B-cell lym-
phoma.22–26 A case with associated Hodgkin's lymphoma has also been
reported.27 Diabetes mellitus is sometimes present and occasionally hyper-
lipidemia. Other associations that may be encountered include low serum
complement levels and cryoglobulinemia.

Pathogenesis and histological features

The pathogenesis of necrobiotic xanthogranuloma is unknown. The plasma
cells in the infiltrate are consistently polyclonal, supporting a reactive pro-
cess.3 Direct immunofluorescence has shown IgM, C3, and fibrinogen deposi-
Fig. 9.90
tion in blood vessel walls.6 It has more recently been suggested that activation
Necrobiotic xanthogranuloma: there is extensive necrobiosis and a dense histiocytic
of monocytes is responsible for the intracellular accumulation of lipoprotein- infiltrate with conspicuous giant cells.
derived lipids and the hypocholesterolemia.28 Focus-floating microscopy of
six cases demonstrated the presence of Borrelia.29 The significance of this
finding is unclear.
Necrobiotic xanthogranuloma has a very distinctive histological appear-
ance.6,26 Large areas of marked necrobiosis alternate with foci of xanthogran-
ulomatous infiltration throughout the reticular dermis with extension into
the subcutaneous fat (Fig. 9.89).4 Exceptionally, necrobiosis is absent.30
Involvement of the subcutaneous fat is predominantly in a septal distribution
and can mimic panniculitis.31 The necrobiotic collagen appears as amorphous
eosinophilic debris (Fig. 9.90). The granulomatous infiltrate is composed of
epithelioid and foamy histiocytes in addition to conspicuous giant cells, many
of which are of the Touton type (Figs 9.91, 9.92). Foreign body giant cells
are also present. Lymphocytes and plasma cells are often prominent and for-
mation of germinal centers is sometimes seen. A characteristic feature is the
presence of large and bizarre angulated giant cells with considerable numbers
of nuclei irregularly grouped together within copious eosinophilic cytoplasm
in the tissue immediately adjacent to foci of necrobiosis (Fig. 9.93). Asteroid
bodies, which are often found in the cytoplasm of giant cells, have been sug-
gested as a useful diagnostic finding.32 Frozen sections and oil red O staining
for fat may reveal focal lipid droplets. Cholesterol clefts and lipid vacuoles
are sometimes seen within the foci of necrobiosis and xanthogranulomatous Fig. 9.91
inflammation (Fig. 9.94). In rare cases, however, lipid deposition and giant Necrobiotic xanthogranuloma: in this field, there are conspicuous xanthomatized
cells are inconspicuous.33 The granulomatous and necrobiotic process may histiocytes.
308 Granulomatous, necrobiotic and perforating dermatoses

affect muscular arteries. Staining for elastic fibers reveals their absence in the
necrobiotic areas; Alcian blue staining may reveal small amounts of inter-
stitial mucin. As with most necrobiotic disorders, transepidermal elimina-
tion of necrobiotic collagen is sometimes a feature.34 A case with prominent
elastophagocytosis has been described.35The lungs and heart may show giant
cells, granulomata, necrobiosis or a combination of these features in patients
with systemic disease.12

Differential diagnosis
The clinical and histological features are distinctive: the presence of ­massive
necrobiosis associated with numerous cholesterol clefts, bizarre multinucle-
ated giant cells, and Touton-type giant cells distinguishes necrobiotic xan-
thogranuloma from necrobiosis lipoidica and other necrobiotic dermatoses.
It should, however, be noted that prominent cholesterol cleft formation may
rarely be seen in necrobiosis lipoidica.36 Small punch biopsies may not be ade-
quate for definitive evaluation and sampling bias may be misleading. Clinical
correlation should be taken into consideration before making a definitive
diagnosis.
Fig. 9.92
Necrobiotic xanthogranuloma: Touton giant cells are sometimes prominent.
Palisaded neutrophilic and granulomatous
dermatitis
Clinical features
Palisaded neutrophilic and granulomatous dermatitis (interstitial granu-
lomatous dermatitis) is a term that has been applied to a reaction pattern
of necrobiotic and granulomatous inflammation encountered in the setting
of systemic disease.1 Other terms that have been applied to similar, overlap-
ping and, in some cases, probably identical lesions, include interstitial granu-
lomatous dermatitis with arthritis, rheumatoid papules, superficial ulcerating
rheumatoid necrobiosis, cutaneous extravascular necrotizing granuloma, and
Churg-Strauss granuloma.1–6 Myriad underlying systemic diseases have been
purported to be associated with these lesions including rheumatoid arthri-
tis, lupus erythematosus, systemic sclerosis, Sjögren's syndrome, thyroiditis,
Raynaud's syndrome, hepatitis, inflammatory bowel disease, lymphoprolif-
erative disorders, myelodysplastic syndrome, vasculitis (Wegener's granulo-
matosis, Churg-Strauss syndrome, Takayasu's arteritis, periarteritis nodosa),
hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, mixed
cryoglobulinemia, drug reactions (especially sulfonamides), carcinoma, diabe-
tes, and infections (streptococcal, HIV, Epstein-Barr virus, parvovirus).1–4,7–12
Fig. 9.93 In most cases an underlying systemic disease is found, and it is rare that an
Necrobiotic xanthogranuloma: angulated giant cells with darkly staining nuclei are underlying disease is not detected.13
commonly present. The lesions are mainly located on the extremities and less commonly the
trunk in an adult.1 Children are seldom affected.14,15 The disease is character-
ized by papules and nodules, which are often arranged in a linear pattern.
These linear lesions may be confluent and have been described as linear bands
or cords with a ‘ropelike’ consistency (the so-called rope sign). Plaques have
also been described.6

Pathogenesis and histological features

Fig. 9.94
Necrobiotic xanthogranuloma: cholesterol clefts are a characteristic feature.
The pathogenesis of palisaded neutrophilic and granulomatous dermatitis
most likely depends on the associated/underlying disease. In a number of
cases autoantibodies, particularly anti-DNA in type, are found.16 It has been
suggested that the disease is mediated by immune complexes.17 Direct immu-
nofluorescence studies have demonstrated fibrin and IgM in the vasculature
of some patients.1
A variety of histological patterns have been described. These patterns may
be seen in the same or different biopsies from the same patient, emphasizing
the fact that they are not separate diseases.18 Some biopsies resemble the inter-
stitial variant of granuloma annulare without a well-defined palisade, loosely
organized histiocytes, and variable numbers of neutrophils with nuclear dust.
Fibrin is also seen. In fact, some would label these lesions as falling within the
spectrum of granuloma annulare.4 However, mucin deposition is not as marked
as seen in granuloma annulare and the changes are more ill defined. In other
­samples, ­palisaded histiocytes surround individual collagen bundles and in

Fig. 9.95
Palisaded neutrophilic and granulomatous dermatitis: an interstitial inflammatory
cell infiltrate is present in the center of the field, mimicking diffuse granuloma
annulare.
Fig. 9.96
Palisaded neutrophilic and granulomatous dermatitis: close-up view showing
necrobiosis, histiocytes, and neutrophils associated with karyorrhexis.
the ­background there is a neutrophilic infiltrate with karyorrhexis (Figs 9.95,
9.96). In late stages, fibrosis may be seen. The various changes described are
more likely to represent the evolution of the lesions. Variable numbers of eosino-
phils may be noted and, when present, appear to occur mostly in patients with
a peripheral eosinophilia. Frank leukocytoclastic vasculitis is present in some
cases.18 A few cases may resemble necrobiosis lipoidica.4
Differential diagnosis
From the above discussion it can be seen that a number of different terms
have been proposed to describe lesions resembling granuloma annulare or
rarely necrobiosis lipoidica but with the added features of acute and eosino-
philic inflammation, karyorrhexis and neutrophils with leukocytoclasia and
rarely with leukocytoclastic vasculitis. Some authors include these changes
within the spectrum of granuloma annulare and necrobiosis lipoidica.4 The
precise terminology preferred by the dermatopathologist is probably not
important. More significant than any nosological nuances is issuing a report
that alerts the clinician to the possibility that the patient may have underly-
ing systemic disease and that, when such lesions are encountered, appropriate
clinical evaluation is necessary.10
‘Metastatic’ Crohn’s disease 309
‘Metastatic’ Crohn’s disease
Clinical features
Patients with Crohn's disease may present with cutaneous and oral lesions,
the most frequent of which are aphthous stomatitis, pyoderma gangrenosum,
and erythema nodosum.1 Metastatic cutaneous lesions in Crohn's disease are
rare and defined as the presence of sterile granulomatous lesions that occur
at sites not contiguous with the gastrointestinal tract. They predominantly
involve the skin of the lower limbs, genitalia, perineum, perianal region, and
lips. One review of the literature showed that approximately 50% of patients
with cutaneous Crohn's disease have involvement of the lower extremi-
ties.2 Most affected patients are adults but lesions may rarely be seen in chil-
dren.3 The lesions present as single or multiple papules, plaques, nodules,
and ulcers.2–12 Vulval tumor-like masses, vulval or penile swelling, and herpes
virus-like lesions have occasionally been described.10,13,14 Penile lesions may
sometimes occur.15 Colostomy site involvement has also been documented.
One patient has been reported as presenting with an erysipelas-like erup-
tion involving the lip and nasolabial region and a further patient presented
with involvement of the nipple.5,16 In some patients, mucocutaneous lesions
precede evidence of bowel involvement.7,17,18 Of uncertain significance is the
finding that cutaneous Crohn's disease seems to be highly associated with
involvement of the large bowel.13 The duration of lesions is variable, typically
lasting from months to years.
Pathogenesis and histological features
The pathogenesis of mucocutaneous Crohn's disease is not understood.
Histologically, lesions are usually manifest as ill-defined, noncaseating,
and nonsuppurative granulomata present in the superficial (often papil-
lary) dermis; however, granulomata may also involve the deep dermis and
even ­subcutaneous adipose tissue.19,20 The granulomata are surrounded by
a small cuff of lymphocytes.20 In addition, there is a superficial and deep,
perivascular, mixed inflammatory cell infiltrate. The granulomata resemble
those seen in the bowel. Necrobiotic collagen has been described in a num-
ber of cases.19 Lymphocytes and plasma cells are also commonly present and
eosinophils can be prominent.20 Ulceration of the epidermis may be seen.20
Recently, the histological features of metastatic Crohn's disease have been
expanded to include the findings of significant necrobiosis with leukocyto-
clasis, and vasculitis (see palisaded neutrophilic and granulomatous derma-
titis, above).19,21
Differential diagnosis
Since the histological features of cutaneous Crohn's disease are non-specific,
a definitive diagnosis requires clinical confirmation of the presence of asso-
ciated bowel disease. Therefore, endoscopy, evaluation of gastrointestinal
biopsies, and review of clinical findings all play a role in confirmation of this
diagnosis. Sarcoidosis may be indistinguishable from metastatic Crohn's dis-
ease; however, the granulomata of the former tend to be more discrete and
compact. Eosinophils may be prominent in metastastic Crohn's disease and
are rare in sarcoidosis.20 Mycobacterial infection is also an important differ-
ential diagnosis; therefore liberal use of special stains for microorganisms is
essential. Culture should be performed as deemed clinically appropriate.
As noted above, cutaneous granulomata may precede evidence of bowel
involvement.7,16,17 Therefore, patients with granulomatous skin disease of
uncertain etiology should be followed up carefully for evidence of bowel
disease.
Granulomatous cheilitis may also show identical histological features.
Studies have documented patients presenting with granulomatous cheili-
tis who subsequently developed clinical manifestations or pathological evi-
dence (without gastrointestinal symptoms) of Crohn's disease.20,22–27 One
group study described a patient in whom granulomatous cheilitis antedated
development of Crohn's disease by 7 years.28 It appears, therefore, that some
patients with granulomatous cheilitis are at risk for development of Crohn's
disease and require gastrointestinal evaluation and careful clinical follow-up.
Similarly, vulval Crohn's disease precedes development of bowel involvement
in 25% of cases.13
310 Granulomatous, necrobiotic and perforating dermatoses

Granulomatous cheilitis
Granulomatous cheilitis (cheilitis granulomatosa, Meischer's cheilitis, orofa-
cial granulomatosis) is discussed elsewhere.

Acne agminata
Clinical features
Acne agminata (lupus miliaris disseminatus faciei, acnitis, papular tuberculid) is
a rare condition originally thought to be a form of tuberculid but an association
with tuberculosis has since been excluded.1–4 Some authors consider this disease
to be synonymous with granulomatous rosacea. However, the distinctive clini-
cal presentation, and the absence of typical rosacea in patients affected by the
disease, argue against this. Recently, a new name has been suggested for the dis-
ease: facial idiopathic granulomata with regressive evolution (FIGURE).5
Clinical presentation is characterized by fairly monomorphous yellowish-
brown papules typically involving the central face with predilection for peri-
ocular areas (Fig. 9.97). The disease is limited to the eyelids in rare cases.6 Fig. 9.98
Involvement of axillae or upper limbs is an exceptional finding.7–9 There is Acne agminata: there are multiple caseating granulomata.
no sex predilection and the age range is wide although most cases occur in
young to middle-aged adults.10 An exceptional case during pregnancy has
been documented.11 Response to conventional treatment for rosacea is often
ineffective but lesions tend to regress spontaneously over a period of months
or even years, leaving mild scarring.12

Pathogenesis and histological features

As suggested by some synonyms, infection by mycobacteria has been favored
by certain authors as a potential etiological factor. This theory is no longer ten-
able due to the absence of past or present systemic tuberculosis and the ­constant
failure of isolation of bacilli. In a study from Israel, mycobacterial DNA was
not detected by PCR.1 It has been suggested that the development of lesions is
due to an unusual granulomatous reaction to ruptured hair follicles.13
The histological features vary with the stage of evolution and may be
entirely non-specific.14 A biopsy from a well-established lesion shows a ­central
area of well-defined caseous necrosis surrounded by multinucleate giant cells
and epithelioid cells (sometimes indistinguishable from tuberculous infection)
(Figs 9.98 and 9.99). Serial sections often reveal a relationship of the necrosis

Fig. 9.99
Acne agminata: close-up view. The condition is not a tuberculid. Special stains and
culture for tubercle bacilli are invariably negative.

to a destroyed hair follicle. Special stains may demonstrate a ring of elastic

fibers in the center of the necrotic focus, possibly representing the isthmus of
the hair follicle. The granulomata are not usually related to Demodex follicu-
lorum as is often the case in granulomatous rosacea. Focal vasculitis is only
exceptionally seen.

Differential diagnosis
The diagnosis is fairly easy in the presence of granulomata surrounding an
area of caseation necrosis since the latter is not usually a feature of either
granulomatous rosacea or perioral dermatitis. In biopsies showing only focal
granulomatous inflammation, establishing the diagnosis may require very
careful clinicopathological correlation.

Fig. 9.97
Acne agminata: note the
characteristic distribution
of papules on the cheek
and around the eyes.
From the collection of the
late N.P. Smith, MD, the
Institute of Dermatology,
London, UK.
Perioral dermatitis
Clinical features
Perioral dermatitis (perioral granulomatous dermatitis, periorificial derma-
titis) is a common dermatosis that may represent a variant of rosacea.1–6
It is discussed in this section since it can, on occasion, be associated with
­granulomatous histology. Patients are usually young women but the ­condition

Fig. 9.100
Perioral dermatitis: erythema and papules in a characteristic distribution. From the
collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
can occur in children.1,7 Presentation in identical twins is exceptional but has
been documented.8 A granulomatous variant of perioral dermatitis has been
described in children.9–11 It tends to be more common in Afro-Caribbean
children and has been labeled facial Afro-Caribbean childhood eruption
(FACE).9 Typically, perioral dermatitis consists of erythematous papules and
pustules with a characteristic distribution on the chin and nasolabial folds
(Fig. 9.100). Involvement of the inner cheeks, the skin around the nose,
forehead or periocular area is unusual. Based on the fact that some cases
show perinasal and periocular involvement, the name periorificial dermatitis
has been suggested.12 Extrafacial and generalized involvement has also been
documented.13 The clinical appearances may mimic acne but comedones are
absent.14
Pathogenesis and histological features
The pathogenesis of perioral dermatitis is not clearly understood but
the condition seems to be etiologically linked in some cases to the use of
potent topical steroids, the application of cosmetics, certain toothpastes,
epoxy diacrylates in dental composite resins, contraceptive pills, and some
moisturizing creams.15–23 In rare patients, the disease appears during preg-
nancy and may flare up before the menstrual period.23 Even inhaled cor-
ticosteroids have triggered perioral dermatitis.24 Physical sunscreens with
high sun protection factor have also been blamed for causing the disease
in children.25 Multiple dental fillings with a mercury-containing amal-
gam induced perioral dermatitis in a girl and in a further case the disease
appears to have been triggered by orthognathic surgery.26,27 An association
has also been reported in renal transplant patients on systemic steroids and
azathioprine.28
Biopsy shows mild acanthosis, focal spongiosis, and hyperkeratosis with
parakeratosis and a mild perivascular and periadnexal lymphohistiocytic
infiltrate. The appearances are almost indistinguishable from those found in
rosacea.29 Ruptured hair follicles with microabscess formation are occasion-
ally seen. Sometimes granulomata with sarcoidal features are present.30 Giant
cells have also been documented, in which case distinction from sarcoidosis
may be difficult.1,31 In most cases, clinical correlation resolves any diagnostic
difficulties.
Demodicosis
There are two species of Demodex that live in a symbiotic relationship
in human hair follicles. The mites are D. folliculorum and D. brevis.
The former is mainly found in the infundibulum of the hairs and the lat-
ter in the sebaceous glands. They are ubiquitous in the skin but there is
Foreign body granulomata 311
a ­predilection for the face. Their pathogenetic role in skin diseases has
always been ­controversial and they are often regarded as innocent bystand-
ers. However, it does seem that in a small number of cases, particularly in
immunocompromised patients, they have an important role in causation of
disease.1–4 The mites do not appear to be a primary factor in the develop-
ment of rosacea although they may play a part in the granulomatous form
of the disease. Traditionally, three facial forms of involvement have been
described: pityriasis folliculorum, rosacea-like demodicosis, and demodi-
cosis gravis. Skin eruptions attributed to the mites, however, have variable
manifestations and include a rosacea-like eruption, a perioral dermatitis-
like eruption, chronic blepharitis, follicular plugging and erythema and a
disseminated form in immunocompromised patients.1–12 Localized pustules
and even abscesses have also been reported.13 An unusual case of a patient
with demodicosis presenting as a facial plaque after ophthalmic herpes
zoster has been described. In a further case, the ­disease mimicked favus
in a child.14 Adults are mainly affected but cases in children have been
reported.9–11,15
Pathogenesis and histological features
The pathogenetic link between the mites and cutaneous disease is a matter of
controversy. In cases where there seems to be a clear link, the density of mites
is very high.4
Histologically, the findings combine suppurative and granulomatous
changes. Dilated hair follicles with multiple mites are seen and there is forma-
tion of neutrophilic pustules. This is associated with a variable, perifollicular
mononuclear cell infiltrate composed of lymphocytes and plasma cells. When
the hair follicle ruptures, focal granulomata are seen and often contain frag-
ments of the mites.
Infective granulomata
Infections, particularly fungal and mycobacterial, are often associated with
granulomatous inflammation. Conversely, the vast majority of routine
biopsies showing granulomatous inflammation are not due to an infection.
However, when faced with a specimen showing granulomatous inflamma-
tion, the pathologist must maintain a low threshold for performing stains
for organisms and for issuing recommendations for microbiology culture.
If such an approach is not taken, the vast majority of infectious causes of
granulomatous inflammation will be misdiagnosed. In addition, although
pathologists tend to associate certain patterns of granulomatous inflam-
mation with infection by specific organisms (e.g., caseating granulomatous
inflammation and Mycobacterium tuberculosis), it should be remembered
that the same organism can cause several different patterns of granuloma-
tous inflammation (e.g., Mycobacterium leprae). Similarly, mixed suppu-
rative and granulomatous inflammation may result from both atypical
mycobacteria and deep ­fungal infections. A practical corollary to this is
that the pathologist should order several special stains to evaluate for a
variety of organisms rather than relying on a single stain for the most likely
culprit.
Specific infectious causes of granulomatous inflammation are discussed in
detail in Chapter 18.
Foreign body granulomata
A wide variety of substances when present within the dermis may result in
a foreign body giant cell reaction and can mimic primary granulomatous
disorders. These are summarized in Table 9.2 and examples are shown in
Figures 9.101–9.108. Therefore, when examining specimens with granu-
lomatous inflammation of uncertain etiology, all sections should be exam-
ined with polarized light to exclude foreign material. Most foreign body
granulomatous reactions occur as a result of external foreign matter, particu-
larly suture material. It can also occur as a result of injury from sea urchin
spines, particularly on acral sites.1–4 The granulomata formed are often for-
eign body and sarcoidal, but other types of granulomata including necrobi-
otic, suppurative, and tuberculoid have been described.4 Interestingly, a study
312 Granulomatous, necrobiotic and perforating dermatoses

Table 9.2
Important causes of foreign body granulomata

Endogenous Exogenous
Keratin Silica Graphite Cactus spine
Hair shaft Beryllium Paraffin Vegetable oil
Ruptured cyst Zirconium Shrapnel Mineral oil
contents
Released lipids Talc Sutures Food particles
Urate crystals Silicone Arthropods Wood splinters
Tattoo pigment Sea urchin spine

Fig. 9.103
Foreign body granuloma:
this free hair shaft has
been partially engulfed by
foreign body giant cells.

Fig. 9.101
Foreign body granuloma: there is a florid granulomatous reaction to shrapnel.

Fig. 9.104
Foreign body granuloma: high-power view

found Mycobacterium marinum DNA using PCR in a number of sea urchin

granulomata raising the possibility that the organism may be involved in the
­pathogenesis of the ­disease.5 Foreign body granulomatous reactions second-
ary to internal foreign bodies are mainly secondary to hair shafts within the
dermis after folliculitis or to fragments of keratin as a result of ruptured epi-
dermoid or trichilemmal cysts. Another source of foreign body granuloma-
tous r­ eaction to internal material is gout.
The pathologist should be particularly aware that beryllium and zir-
conium may be associated with granulomata that mimic sarcoidosis, the
so-called ­sarcoidal ‘naked’ granuloma. It is especially important to think
Fig. 9.102 of these agents as rare possible causes of granulomata since neither is vis-
Tattoo site: foreign body ible with routine or polarization microscopy. Beryllium was once used in the
and sarcoidal responses ­manufacture of fluorescent light bulbs. Following exposure to beryllium,
may occasionally be seen patients may develop either systemic berylliosis or have cutaneous involve-
in tattoo reaction. ment only. Pulmonary lesions follow inhalation.5 Skin involvement, in the
 Granulomatous contact dermatitis 313

Fig. 9.105
Suture granuloma: suture fragments are present; note the multinucleate giant cells.

Fig. 9.107
Bioplastique and silicone
granuloma: note sclerosis
and cystic spaces.

Fig. 9.106
Suture granuloma: when viewed with polarized light, suture fragments show
birefringence.

form of papules, follows direct inoculation.6 Diagnosis of chronic beryllium
disease is based on demonstration of a cell-mediated response to beryllium by
patch testing.6 Diagnosis may also be established by laser microprobe mass
spectrometry.6,7
Zirconium was once added to antiperspirants.8 Patients developed pap-
ules at sites where the substance was used and interstitial lung disease also
occurred.9 More recently, elephantiasis following nodal involvement has
been described in patients with beryllium and zirconium exposure from min-
eral-rich soil (podoconiosis).10 Diagnosis may be made using spectrographic
analysis.6,7,11
Foreign body granulomata following esthetic microimplants are relatively
uncommon nowadays, as the material used is greatly improved. Silicone gran-
ulomata are sometimes found and occasionally one encounters foreign body
granulomata to cosmetic microimplants such as Dermalive (hyaluronic acid
and acrylic hydrogel), artecoll (PMMA-microspheres), bioplastique (polym-
ethylsiloxane), and bioalcamid.12,13 Foreign body granulomata to iron oxide
after permanent p ­ igmentation of the eyebrows have also been reported.14
A metastatic silicone granuloma mimicking acne agminata and ­associated
with the sicca complex has been reported in a silicone breast implant
patient.15
Fig. 9.108
Bioplastique and silicone granuloma: note silicone spaces resembling lipoblasts in
the left of the field. On the right there are irregular cystic space containing foreign
material.
Granulomatous contact dermatitis
Clinical features
There are rare reports of a granulomatous reaction to metals, mainly pal-
ladium and less commonly gold and a titanium alloy, particularly at the
site of ear piercing but also in relation to piercing at other body sites.1–8
Granulomata induced by titanium have also been reported after implanta-
tion of a titanium-containing pacemaker.9 Areas of swelling, induration, or
red papules and/or nodules develop at the site of piercing and this may occur
shortly after or weeks and even months after the patient starts wearing ear-
rings. Most cases have been reported in adults but similar lesions may be
seen in children.10
A granulomatous contact dermatitis to propolis has also been
described.11
314 Granulomatous, necrobiotic and perforating dermatoses

Pathogenesis and histological features

The pathogenesis is likely to be a delayed hypersensitivity reaction to the
metal. This is proven by the fact that patients usually have a positive patch
test to palladium or less frequently gold. A positive reaction to zinc has also
been found.
Throughout the dermis and sometimes extending into the subcutis, there
is a prominent, diffuse granulomatous inflammatory cell infiltrate. This
­comprises epithelioid histiocytes and scattered giant cells surrounded by
lymphocytes and sometimes plasma cells are present. Necrosis is not usually
seen. In a case report of a reaction to titanium alloy (containing titanium,
aluminium, and vanadium) brown-black particles were demonstrated his-
tologically within the cytoplasm of macrophages.8 In another example trig-
gered by gold earrings, intracytoplasmic crystalline inclusions were found
within macrophages.6

Differential Diagnosis
The differential diagnosis from sarcoidosis and other granulomatous pro-
cesses may be difficult. The clinical history of piercing and the sites affected
are useful in achieving a correct diagnosis. Fig. 9.110
Tuberculoid granulomata in agammaglobulinemia: high-power view

Granulomata in congenital
immunodeficiency syndromes
A number of inherited immune deficiency diseases may on occasion present
with noninfectious granulomata involving different organs ­including the
skin.1–4 These diseases include combined immune deficiency, chronic granu-
lomatous disease, ataxia telangiectasia, common variable ­immunodeficiency,
and X-linked infantile hypogammaglobulinemia (Figs 9.109–9.112).
In combined immune deficiency, cutaneous tuberculoid and necrobiotic
granulomata may occur and in a single instance perineural invasion was
identified, closely mimicking tuberculoid leprosy.5,6 Cutaneous granulomata
in chronic granulomatous disease may show caseation necrosis without a
detectable trigger and can also be associated with foreign bodies.7,8 In ataxia
telangiectasia, patients present with either necrobiotic or tuberculoid gran-
ulomata.9–11 In common variable immunodeficiency, tuberculoid, sarcoidal,
and caseating granulomata have been documented.12–14 In X-linked infan-
tile hypogammaglobulinemia, caseating granulomata have been reported.15
An unusual perforating neutrophilic and granulomatous dermatitis has been
reported in a patient with agammaglobulinemia.16 It is important to highlight
the fact that affected patients have an immune deficiency; therefore, every
Fig. 9.111
effort should be made to rule out an infectious process with special stains Necrotizing granuloma in agammaglobulinemia: there is very extensive dermal
and cultures. necrosis with a surrounding granulomatous infiltrate.

Fig. 9.109
Tuberculoid granulomata in agammaglobulinemia: there is a diffuse granulomatous Fig. 9.112
infiltrate throughout the dermis. Necrotizing granuloma in agammaglobulinemia: high power view.
 Aluminum granuloma 315

Aluminum granuloma
Clinical features
Aluminum granuloma refers to the persistent, sometimes painful, subcutaneous
nodules that develop at the sites of vaccination or hyposensitization with agents
containing aluminum hydroxide as an absorbing agent (Fig. 9.113).1–5 If a vac-
cine is erroneously applied intradermally, lesions may occur within the dermis.6
The term granuloma is a misnomer as lesions do not usually consist of granu-
lomatous inflammation. The lesions develop after a few weeks or years after the
injections and are thought to be secondary to a hypersensitivity reaction to alu-
minum hydroxide. Often, patients have positive patch tests to aluminum hydrox-
ide. The most common vaccine associated with this reaction is tetanus toxoid
but any vaccine containing aluminum hydroxide as an absorbent may induce the
reaction, including hepatitis A and C and human papillomavirus vaccines.7
Intramuscular vaccines induce a condition described as macrophagic myo-
fasciitis. This condition has been described both in children and adults.8,9

Pathogenesis and histological features Fig. 9.114

The occurrence of the nodules appears to be the result of a delayed hypersen- Aluminum granuloma: there is a dense inflammatory cell infiltrate within the
subcutaneous fat.
sitivity reaction to aluminum.
Four histological patterns, which can overlap, may be found:10
• A predominantly lobular panniculitis with fairly non-specific findings
including focal inflammation consisting of lymphocytes, histiocytes,
and plasma cells with fat necrosis. Loose subcutaneous collections of
histiocytes with a slightly granular, bluish cytoplasm are always found
but their number varies and the change may be subtle.
• A prominent subcutaneous, predominantly mononuclear, inflammatory
cell infiltrate with eosinophils and focal formation of germinal centers
often mimicking a marginal zone lymphoma (Figs 9.114–9.116). Plasma
cells are often prominent. Careful examination reveals scattered grouped
histiocytes with bluish granular cytoplasm.
• A deep granuloma annulare-like infiltrate with numerous histiocytes
surrounding an area of necrobiosis (Figs 9.117, 9.118). All the
histiocytes show a characteristic bluish granular cytoplasm.
• A pattern with hyaline necrosis of the subcutaneous lobule mimicking
lupus profundus. This is associated with lymphocytes, and plasma cells
and germinal centers may also be seen. Careful examination reveals the
presence of typical histiocytes with bluish granular cytoplasm.
A case with numerous mast cells and associated with urticaria has been
described.11
The material within the histiocytes represents aluminum. Confirmation of Fig. 9.115
the presence of aluminum can be done histochemically with the use of azurin Aluminum granuloma: the infiltrate consists of lymphocytes, histiocytes and plasma
stain or by energy dispersive X-ray microanalysis. cells.

Fig. 9.113 Fig. 9.116

Aluminum granuloma: multiple depressed nodules with scarring are evident. From Aluminum granuloma: the histiocytes have markedly granular cytoplasm due to the
the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK. presence of aluminum.
316 Granulomatous, necrobiotic and perforating dermatoses

disease in the same biopsy.33 Drugs including sirolimus and indinavir have
also been associated with the disease.34,35 The inherited cases are not associ-
ated with any systemic disorder. Reactive perforating collagenosis has also
been reported in a patient with HIV/AIDS in association with end-stage renal
failure.36 Perforating collagenosis is seen in approximately 10% of patients
with renal failure.1,2,37 Patients may develop lesions either before or after dial-
ysis treatment.2 In most cases, underlying diabetes ­mellitus is also present.1,2,37
Affected individuals suffer generalized pruritus and crusting papules. A single
case with a zosteriform distribution has also been documented.38
Following mild trauma, such as a scratch or insect bite, patients develop
flesh-colored papules 1–2 mm in diameter. These enlarge, become umbili-
cated and, over the course of about 4 weeks, grow to reach a diameter of
some 5–10 mm (Figs 9.119–9.121). Rarely, giant lesions are observed.39 The
umbilicated area contains keratinous debris, which is dark brown, hard, and
leathery. It is also very densely adherent, and bleeding results if detachment is
attempted. This is followed by regression. The papules flatten, and by 6–8 weeks

Fig. 9.117
Aluminum granuloma: in this example there is a palisading granuloma surrounding
a necrobiotic nodule.

Fig. 9.119
Reactive perforating collagenosis: there are multiple pink papules, some showing
central umbilication with crusting. By courtesy of D. McGibbon, MD, St Thomas’
Hospital, London, UK.

Fig. 9.118
Aluminum granuloma: the histiocytes have finely granular cytoplasm.

Perforating disorders
Reactive perforating collagenosis
Clinical features
This is a very rare disorder of uncertain etiology in which patients are predis-
posed to develop an unusual skin reaction to mild trauma, causing damaged
collagen to be extruded through the epidermis.1–4 Although sporadic cases do
occur, in many instances reactive perforating collagenosis appears to be an
inherited condition, autosomal recessive and dominant variants having been
described.5–8 Reactive perforating collagenosis has been documented in asso-
ciation with the Treacher Collins syndrome.9 The disease shows an equal sex
incidence, most cases presenting in childhood, although lesions tend to per-
sist into adult life. In familial cases the expression of the disease is variable
and can sometimes be mild and subtle.10 Lesions may be precipitated by sun Fig. 9.120
Reactive perforating
­exposure.10 An acquired variant occurring in adulthood and associated with
collagenosis: an example
IgA nephropathy, diabetes mellitus, chronic renal failure, ­hydronephrosis, on the cheek of a young
lung fibrosis, herpes zoster infection, cytomegalovirus, scabies, lymphoma, boy. By courtesy of E.
leukemia, and carcinoma (including papillary thyroid carcinoma and hepato- Young, MD, Wycombe
cellular carcinoma) has been described.11–32 In a single patient with Mikulicz's General Hospital, High
disease, the condition showed histologic features of IgG4-related sclerosing Wycombe, UK.
 Perforating disorders 317

Fig. 9.121 Fig. 9.123

Reactive perforating collagenosis: close-up view. By courtesy of E. Young, MD, Reactive perforating collagenosis: irregular, swollen collagen fibers have penetrated
Wycombe General Hospital, High Wycombe, UK. the epidermis.

from onset all that remain are residual scars or hypopigmented areas. It is of
interest that lesions develop only after mild superficial trauma, deep penetrat-
ing wounds healing normally. A positive Koebner phenomenon is character-
istic and lesions may be induced by gentle needle scratching. Lesions tend
to be rather polymorphic: as old lesions heal, new ones develop. They are
distributed primarily on the upper and lower extremities and face, although
the trunk may be affected.40,41 Rarely, the palms and soles may be involved.
Mucosal involvement has also been described in one patient.42 The severity of
this condition seems to increase in cold weather, whereas there is a reduction
in the number of lesions in summer. Exceptionally, secondary bacterial infec-
tion within the lesions may occur.43

Pathogenesis and histological features

The pathogenesis of reactive perforating collagenosis has not been eluci-
dated.44 Transepidermal elimination of type IV collagen has been demon-
strated but the mechanism that triggers the process is not clear.45
A broadened dermal ridge containing degenerate, basophilic collagen char-
acterizes early, nonumbilicated lesions. The overlying epithelium is atrophic
and centrally is composed of a thin layer of parakeratotic material. At the lat-
eral margins there is typically acanthosis. In the fully established umbilicated
lesion the central plug is composed of parakeratotic debris, degenerate collagen,
and inflammatory cells (Figs 9.122, 9.123).46 The epidermis deep to the plug
Fig. 9.124
Reactive perforating
collagenosis: close-up
view of collagen fibers
within the epidermis.

is markedly thinned and is traversed focally by vertically orientated collagen

fibers (Figs 9.124, 9.125). Elastic fibers are not present within the extruded
connective tissue debris. On either side of the cup-shaped deformity, the epider-
mis is acanthotic and hyperkeratotic. A lymphohistiocytic infiltrate is present
in the superficial dermis. The histological appearances in reactive perforating
collagenosis and acquired perforating collagenosis are identical. Distinction
between these disorders requires clinical correlation (Figs 9.126, 9.127).

Fig. 9.122
Reactive perforating collagenosis: this is a transverse section through the center of
a lesion. Note the crust overlying multiple points of incipient perforation.
Differential diagnosis
Changes identical to those seen in reactive perforating collagenosis may be
seen following trauma in ‘normal’ patients without stigmata of the disease.
Not uncommonly, biopsies of patients with prurigo nodularis/lichen ­simplex
chronicus (but who do not meet clinical criteria for reactive perforating
­collagenosis) show transepidermal elimination of collagen in a pattern simi-
lar to that seen in perforating collagenosis. Table 9.3 highlights points of
­distinction among the perforating disorders.
318 Granulomatous, necrobiotic and perforating dermatoses

Fig. 9.125 Fig. 9.127

Reactive perforating collagenosis: transepidermal elimination is seen to better Reactive perforating collagenosis: higher-power view.
advantage with this Masson’s trichrome stain.

Perforating folliculitis
Clinical features
Perforating folliculitis is a not uncommon, usually asymptomatic, derma-
tosis of unknown etiology that superficially resembles Kyrle's disease.1–3
It shows a female predominance (2:1) and, although a wide range of age
groups may be affected, the majority of patients present in the third decade.
The disease is characterized by the development of discrete, erythematous
follicular papules, 2–8 mm in diameter, each containing a small central white
keratotic core. Lesions most often affect the extremities, with a predilection
for the hairy portions of the arms, forearms, and thighs. The buttocks may
also be involved (Figs 9.128, 9.129). Koebnerization is not usually a feature.
Duration of the rash is variable, ranging from several months to years and
remissions and exacerbation may punctuate the course. Some patients present
with features of more than one perforating disease (i.e., perforating folliculitis
and elastosis perforans serpiginosa).4
Perforating folliculitis is associated with renal failure in some patients.5–7
It has also been reported in the setting of HIV infection and recently was
Fig. 9.126 described in two dialysis patients with markedly elevated serum ­silicon
Reactive perforating collagenosis: this example developed in a patient with chronic ­levels.8,9 Primary sclerosing cholangitis may rarely be ­associated with
renal failure. ­perforating ­folliculitis.10,11 A number of medications have been ­associated with
­perforating folliculitis including sorafenib, infliximab, and etanercept.12,13
Table 9.3
Differential diagnosis of perforating disorders

Reactive perforating
Kyrle’s disease collagenosis Elastosis perforans serpiginosa Perforating folliculitis
Age of patient Average 30 years (20–60) Childhood Second decade Third decade
Sex distribution ♂=♀ ♂=♀ 4 ♂=♀ 2 ♀=♂
Site Extensor lower extremities; upper Upper and lower Side and back of neck; upper Hair-bearing portions of
extremities; head, neck and trunk extremities; face extremities; face; lower extremities arms, forearms, thighs
Koebner phenomenon Occasionally positive Positive Occasionally positive Negative
Associated diseases Diabetes mellitus; renal failure; None; (acquired variant Down’s syndrome; Ehlers-Danlos None
hepatic insufficiency; congestive renal failure) syndrome; osteogenesis imperfecta;
cardiac failure pseudoxanthoma elasticum
Mode of inheritance ? autosomal recessive
? autosomal dominant
Histology Transepidermal elimination of Transepidermal Transepidermal elimination of Intrafollicular
degenerate parakeratin and elimination of collagen abnormal elastic tissue curled- up hair;
inflammatory debris transepidermal limination
of degenerate connective
tissue
 Perforating disorders 319

The subsequent exposure of the follicular contents to the underlying ­dermis

results in necrosis of connective tissue and subsequent transepidermal
elimination.
The histopathological features of perforating folliculitis are those of a
widely dilated hair follicle containing ortho- and parakeratotic keratin, baso-
philic necrotic debris, connective tissue elements, and degenerate inflam-
matory cells (Fig. 9.130).2 A curled-up hair is sometimes found within the
keratinous plug or extruded into the perifollicular dermis. Typically, the
infundibular follicular epithelium is disrupted at single or multiple foci.
The underlying degenerate dermis, including collagen and elastic fibers, may
be seen to impinge upon the perforated follicle. The adjacent epidermis often
shows pseudoepitheliomatous hyperplasia. A foreign body giant cell reaction
is sometimes found within the superficial dermis.

Differential diagnosis
Perforating folliculitis is differentiated from Kyrle's disease by uniform fol-
licular involvement associated with infundibular epithelial perforation (com-
pared with perforation at the base of the lesion in Kyrle's disease) and the
presence of tortuous hairs. Although elastic fibers may be found within
the dilated follicle, they are neither abnormal in appearance nor increased
Fig. 9.128
in quantity as seen in elastosis perforans serpiginosa. Table 9.3 highlights
Perforating folliculitis:
discrete scaly lesions on points of distinction among the perforating disorders. Keratosis pilaris is
the buttocks and thighs. associated with keratotic plugs that tend to be folliculocentric, but perfora-
By courtesy of K. Green, tion and inflammation are not features.
MD, Lister Hospital,
Stevenage, UK.
Elastosis perforans serpiginosa
Clinical features
Elastosis perforans serpiginosa (L. serpere, to creep) is a rare dermatosis asso-
ciated with transepidermal elimination of abnormal elastic tissue.1–3 It shows
a male predominance (4:1) and presents most often in the second decade.
A case with simultaneous onset in two sisters has been reported.4 Another
unusual case has been documented in an individual with a 47 XYY karyotype
and unilateral atrophoderma of Pasini and Pierini.5
The primary lesion is a 2–5-mm flesh-colored or red keratotic papule
containing an adherent plug, removal of which is associated with ­bleeding.
Classically, the papules are arranged in an arcuate or serpiginous pattern,
although sometimes they are randomly distributed (Fig. 9.131). Most often
the lesions are confined to one site, with the back and sides of the neck being
most frequently affected. Symmetrical involvement is very rare.6 Other sites
include the upper extremities, face, lower extremities, and abdomen, in
decreasing order of frequency. The penis is very rarely involved.7 In those cases
where multiple sites are involved, symmetrical distribution is characteristic.

Fig. 9.129
Perforating folliculitis:
close-up view. By courtesy
of K. Green, MD, Lister
Hospital, Stevenage, UK.

Pathogenesis and histological features

Although the exact etiology is unknown, the frequent finding of a distorted,
curled hair within the dilated follicle, often associated with disruption of
the epithelium, and the occasional presence of hair fragments within the
adjacent dermis suggest that mechanical disruption of follicular epithelium
by hair may be the cause of this condition. The lesions of perforating fol-
liculitis occur most commonly on the extensor aspects of the extremities,
suggesting that trauma may be implicated. It has been proposed that, as Fig. 9.130
with Kyrle's disease, chronic friction leads to abnormal keratinization of Perforating folliculitis: this field shows a dilated hair follicle containing keratinous
the follicular epithelium, which eventually results in follicular ­perforation. and basophilic debris. A hair shaft is visible.
320 Granulomatous, necrobiotic and perforating dermatoses

abnormality of copper metabolism associated with reduced numbers of

elastic fibers in arterial walls. It may be, therefore, that ­penicillamine
locally depletes the dermis of copper, resulting in ­abnormally formed elastic
tissue and the subsequent development of elastosis p ­ erforans serpiginosa.
In the established lesion there is a marked increase in elastic tissue in
both the reticular and papillary dermis (Fig. 9.132). The vertically ori-
entated fibers of the latter are thicker than normal and can be seen to
penetrate the epidermis. A section through the center of the lesion shows
characteristic transepithelial perforating canals, which may be transepi-
dermal, parafollicular or transfollicular in location and straight, wavy
or screwlike in configuration (Figs 9.133, 9.134). The canal contents
­consist of a basophilic mass comprising degenerate epithelial cells, inflam-
matory debris, and numerous elastic fibers (Fig. 9.135). The superficial
plug is composed predominantly of keratinous material and basophilic
debris. Sometimes elastic fibers are ­identified in the stratum corneum. The
­epithelium on either side of the perforating canal is acanthotic and may

Fig. 9.131
Elastosis perforans
serpiginosa: typical scaly
serpiginous eruption on
the elbow. By courtesy
of M.M. Black, MD,
St Thomas’ Hospital,
London, UK.

Rarely, lesions are widely disseminated. The eruption is usually asymptomatic,

although mild pruritus is sometimes a feature. Koebnerization is occasionally
noted.
Although elastosis perforans serpiginosa may occur as an isolated phenom-
enon, in quite a high proportion of cases it develops in association with other
conditions including Down's syndrome, Ehlers-Danlos syndrome, osteogen-
esis imperfecta, Marfan's syndrome, pseudoxanthoma elasticum, cutis laxa,
acrogeria, the Rothmund-Thomson syndrome and Moya Moya disease.8–17
Rarely, elastosis perforans serpiginosa may develop as a complication of pen-
Fig. 9.132
icillamine therapy for Wilson's disease and cystinuria.9,18–23 In patients treated Elastosis perforans serpiginosa: the epidermis is markedly thickened. Multiple
with penicillamine it may be associated with pseudoxanthoma elasticum and perforating channels containing basophilic debris are present.
cutis laxa.24,25 It has also been described in a patient with juvenile rheumatoid
arthritis.9

Pathogenesis and histological features

The pathogenesis of elastosis perforans serpiginosa is not entirely under-
stood. The documentation of familial cases suggests that a genetic component
plays a role in a subset of patients.26 The common association of elastosis
perforans serpiginosa with a variety of connective tissue disorders raises the
possibility of an elastic tissue defect as being of pathogenetic ­significance.
Histochemical and enzyme studies have confirmed that it is the elastic tissue
that is undergoing transepidermal elimination: electron ­microscopic studies
have shown that the elastic fibers are increased in size and have a convoluted
and branched pattern.27 It appears that these abnormal fibers have an irritant
effect, resulting in epidermal proliferation and their eventual engulfment by
the epidermis. Following epidermal growth with consequent upward migra-
tion, the abnormal elastic tissue is expelled via perforating canals. Recently,
it has been demonstrated that the 67 kD elastin receptor is present in the
keratinocytes associated with the ­elimination of elastic material in elastosis
perforans serpiginosa.28,29 This expression varies with the stage of the disease
and suggests that the elastin-keratinocyte interaction plays an important role
in the transepidermal elimination of elastin.28,29
It is of particular interest that this condition has been described follow- Fig. 9.133
Elastosis perforans
ing the use of the copper chelating agent penicillamine.9,18,19 Tissue copper
serpiginosa: this picture is
deficiency is known to be associated with damage to the elastica of arter- taken through the center
ies in experimental animals. The Blotchy mouse, which develops fusiform of a characteristic tortuous
aortic aneurysms, has a copper metabolism defect that includes reduced perforating canal. Note the
activity of the copper-dependent enzyme lysyl oxidase which is essential degenerate elastic tissue
for cross-linking the elastin molecules. In Menkes' syndrome, there is an at the base of the lesion.
 Perforating disorders 321

Hyperkeratosis follicularis et parafollicularis

in cutem penetrans
Clinical features
Hyperkeratosis follicularis et parafollicularis in cutem penetrans (Kyrle's dis-
ease) is a very rare dermatosis of unknown etiology.1–4 It has an equal inci-
dence in men and women and an age of onset ranging from 20 to 60 years,
with an average of 30 years. The disorder is characterized by a widespread,
asymptomatic, and typically bilateral eruption of 1–8-mm papules, each con-
taining a central cone-shaped keratotic plug. Although lesions are located
most often on the extensor aspect of the lower extremities, they may also
affect the upper extremities, head, neck, and trunk (Figs 9.136, 9.137). They
may or may not be related to hair follicles. The mucous membranes, palms,
and soles are characteristically spared. Ocular changes have been ­documented
in a single kindred with the disease.5 In a further patient, there was involve-
ment of the conjunctiva and oral mucosa.6 Lesions may coalesce into plaques
and, occasionally, a Koebner-like appearance is present. There is no evidence
to suggest that Kyrle's disease has a genetic etiology. However, the disease
exceptionally can be seen in siblings and families.5,7,8 It is sometimes asso-
ciated with diabetes mellitus, renal failure, hepatic insufficiency, and con-
gestive cardiac failure.9,10 It is unclear whether Kyrle's disease is a distinct
Fig. 9.134 entity. Some cases clearly overlap with a perforating folliculitis and reports
Elastosis perforans of examples in patients with diabetes and renal failure may actually represent
serpiginosa: high-power examples of the latter condition. An overlap with Flegel's disease has also
view. been described.11

Pathogenesis and histological features

The precise pathogenesis of Kyrle's disease is unknown; however, it has been
suggested that the lesions develop as a consequence of rapid and abnormal
keratinization, which proceeds at a faster rate than epidermal proliferation,
with consequent premature and abnormal differentiation of all the epidermal
layers. In most instances, this is complicated by dissolution of the epidermal
basement membrane region, with extrusion of keratinous debris into the der-
mis and subsequent development of a foreign body granulomatous reaction.
Following this, the epithelium adjacent to the site of the breach ­proliferates
downwards and, by fusion medially, eventually walls off the inflamma-
tory debris. Subsequent epidermal proliferation deep to the debris results in

Fig. 9.135
Elastosis perforans serpiginosa: the elastic fibers stain strongly with elastic-van Gieson in
the superficial dermis, but less strongly as the fibers undergo transepidermal elimination.

manifest pseudoepitheliomatous hyperplasia. Commonly, a foreign body

giant cell reaction is present in the superficial dermis and occasionally elas-
tophagocytosis is evident.
In the penicillamine-induced variant the elastic fibers characteristically have
an irregular, serrated, saw-toothed border.7 Ultrastructur­ally, this gives the lateral
borders of the affected elastic fibers a ‘lumpy bumpy’ appearance.5

Differential diagnosis
Although elastic fibers may be found within the dilated follicle in perforat-
ing folliculitis, they are neither abnormal in appearance nor increased in Fig. 9.136
Kyrle’s disease: multiple
quantity as seen in elastosis perforans serpiginosa. Keratosis pilaris is associ-
umbilicated lesions are
ated with keratotic plugs that tend to be folliculocentric but perforation and present on the thigh. The
inflammation are not features. Kyrle's disease is differentiated from elastosis largest contains a keratin
­perforans serpiginosa by perforation of a keratin plug at the base of the lesion plug. By courtesy of M.M.
­associated with curled hairs in the former. Table 9.3 summarizes the points of Black, MD, St Thomas’
distinction among the perforating disorders. Hospital, London, UK.
322 Granulomatous, necrobiotic and perforating dermatoses

Fig. 9.137 Fig. 9.139

Kyrle’s disease: multiple keratotic lesions are present on the dorsum of the foot. Kyrle’s disease: this lesion shows a flask-shaped epidermal invagination containing
By courtesy of the Institute of Dermatology, London, UK. parakeratotic debris. In the lower-left corner of the lesion is a laminated focus of
basophilic degenerate material.

­eventual transepidermal elimination. Transepidermal elimination or perfora-

tion, it seems, is of secondary rather than primary importance in this disorder.
From this description, it follows that in early lesions there may be no evidence
of an epidermal breach.
In a single case, reported regression of the lesions was seen after treatment
with clindamycin, raising the possibility of a bacterial agent in the etiology
of the disease. However, there is very little additional evidence to suggest that
the process may be triggered by bacteria.12
The histological features of an established lesion consist of a keratotic
plug filling an epidermal invagination.13–15 The keratinous plug shows parak-
eratosis and contains basophilic cellular debris (Figs 9.138, 9.139). Elastic
tissue is absent. The epithelium deep to the plug shows parakeratosis, which
extends to the point of epidermal disruption (Figs 9.140–9.143). Where the
keratinous debris is in contact with the dermis there is often a granuloma-
tous infiltrate. In more advance cases, downward epidermal proliferation and
encirclement results in incorporation of the basophilic keratotic debris into
the lower reaches of the epidermis and hence subsequent elimination. A lym-
phohistiocytic infiltrate is often seen around the epidermal downgrowth and
the superficial blood vessels. An exceptional case with acantholytic dyskera- Fig. 9.140
Kyrle’s disease: a
tosis mimicking Darier's disease has been described.16
somewhat earlier lesion
in which perforation
has not yet occurred.
Note the thinning of the
epidermis basally. Where
parakeratosis is evident
there is absence of the
granular cell layer.

Differential diagnosis
Kyrle's disease must be distinguished from reactive perforating collagenosis
and elastosis perforans serpiginosa. In the former, collagen bundles may be
seen entering the lesion from the dermis; in the latter, the basophilic material
is elastic tissue. Kyrle's disease must also be distinguished from perforating
folliculitis (see above). Table 9.3 highlights points of distinction in the differ-
ential diagnosis of perforating disorders.

Perforating pseudoxanthoma elasticum

Pseudoxanthoma elasticum (Grönblad-Strandberg syndrome) is an inherited
Fig. 9.138 generalized degenerative disease of elastic tissue of which there are autosomal
Kyrle’s disease: scanning view through the center of an established lesion showing dominant and autosomal recessive variants. The disease is briefly discussed in
the keratin plug. this section since a perforating variant is recognized.
 Necrotizing infundibular crystalline folliculitis 323

Perforating pseudoxanthoma elasticum is seen predominantly in multipa-

rous, obese, middle-aged and frequently hypertensive black women who present
with isolated abdominal, periumbilical involvement.1–6 Whether this represents
a forme fruste or a distinct entity is not yet known (so-called acquired pseudox-
anthoma elasticum). In some cases, however, transepidermal elimination is seen
in patients with systemic manifestations (Fig. 9.144).7 The perforating variant
may be associated with renal failure.6
The perforating subtype is characterized by transepidermal elimination of
the degenerate elastic tissue.7,8

Necrotizing infundibular crystalline

Fig. 9.141
Kyrle’s disease: this high-power view shows parakeratosis of the residual epithelium.
folliculitis
Clinical features
Only three cases of this distinctive entity have been reported. The first
two cases were described as a perforating disorder under the rubric tran-
sepidermal elimination of urate-like crystals but it has more recently been
­suggested that it represents a form of folliculitis.1,2 Two patients were male
with in­volvement of the back and the third patient was a female with a rash
on the face and a previous history of acne vulgaris. They all presented with
multiple umbilicated papules with waxy keratinous material in the center.
The lesions were asymptomatic and transient, and resolved spontaneously
without any treatment.

Pathogenesis and histological features

Although the material within the umbilicated craters resembles urate crystals
(monosodium urate monohydrate), none of the patients had evidence of gout
or hyperuricemia.
Histology is characteristic and consists of a crater full of eosinophilic
­filamentous material surrounded by an amorphous matrix and bulging
into the dermis (Figs 9.145, 9.146). Focally, the filaments are distributed
in a ­parallel fashion mimicking urate crystals. The crystals are negatively
­birefringent. Although in the first two cases a relationship with the hair
­follicles was not described, in the most recent case partially destroyed hair fol-
licles were demonstrated. The residual infundibular portion of the hair folli­
cles showed ­vacuolar and filamentous degeneration. By electron ­microscopy,
the ­filamentous ­material appears to represent tonofilaments.

Fig. 9.142
Kyrle’s disease: in this example there is incipient perforation.

Fig. 9.144
Fig. 9.143 Perforating pseudoxanthoma elasticum: multiple small crusted lesions are seen in a
Kyrle’s disease: high-power view showing liquefactive degeneration of the background of typical yellow papules. By courtesy of the Institute of Dermatology,
basal layer. London, UK.
324 Granulomatous, necrobiotic and perforating dermatoses
Fig. 9.145
Necrotizing infundibular crystalline folliculitis: note a crater like area containing
filamentous material.
Fig. 9.146
Necrotizing infundibular crystalline folliculitis: filamentous material mimicking urate
crystals.
Chondrodermatitis nodularis chronica
helicis
Clinical features
Chondrodermatitis nodularis chronica helicis presents as a small, usually soli-
tary, painful dome-shaped nodule on the helix of the ear, most commonly in
males over 40 years of age (mean age 60 years) and develops as a consequence
of chronic trauma (Fig. 9.147).1–3 Bilateral involvement is very rare.4 The
process is less common in women, when it is usually located on the antihe-
lix. Cases in children are exceptional.5 The pain is typically severe enough to
wake the patient at night if the affected ear touches the pillow. In the majority
of patients, symptoms are present for 2–3 years.3
On close examination, a firm crust with a small erosion or tiny channel
underneath usually covers the nodule. Lesions measure 3–15 mm in diameter.6
After surgical treatment there is a recurrence rate of 20%. Chondrodermatitis is
frequently mistaken for squamous cell or basal cell carcinoma, but the clinical
history and auricular location should allow the diagnosis to be made without
difficulty. Nevertheless, histological confirmation is advisable. An association
with systemic sclerosis and childhood dermatomyositis has been reported.7,8
Fig. 9.147
Chondrodermatitis
nodularis: this presents
as a crusted lesion on the
helix and may be clinically
misdiagnosed as an
epithelial neoplasm.
By courtesy of R.A.
Marsden, MD, St George’s
Hospital, London, UK.
A further study described an association with systemic vascular diseases and
connective tissue diseases including lupus erythematosus and rheumatoid
arthritis in a group of younger patients, with a predilection for females.9
Pathogenesis and histological features
The etiology is multifactorial, but trauma is likely to be of primary importance.
The exposed position of the ear, together with a known history of solar or physi-
cal trauma, appears important as many patients have outdoor jobs and evidence
of solar damage elsewhere. Of historic interest, in the past there appeared to be
a high frequency of cases in telephonists and nuns (wearing a wimple), again
supporting the role of physical trauma to the ear. Other ­factors including cold,
anatomical aberrations of the ear (such as a poor ­vascular supply), and senile
degeneration of the cartilage may play a role in development.3 Recently, it has
been suggested that the process is due to arteriolar narrowing in the perichondrial
region of the pinna.10 It is most unlikely, however, that the cartilaginous changes
described below are anything other than secondary. An exceptional case described
the simultaneous occurrence of the disease in middle-aged monozygotic twins.11
The pathogenetic mechanism of chondrodermatitis nodularis has been
interpreted as representing the process of transepidermal elimination.3 This
phenomenon occurs when a disturbance in the dermis initiates an epidermal
response. Foreign material in the dermis may elicit one of three responses:
• If the material is inert, there is no response.
• If the material is an irritant, either a superficial abscess or necrosis will
develop.
• The material (in this case degenerate collagen) may be eliminated by a
gradual process of transepidermal elimination.
Ulceration, although usual, may not be seen in early lesions.3,6 The epithe-
lium on either side of the ulcer is hyperplastic and shows features of lichen
simplex chronicus (Figs 9.148, 9.149). Pseudoepitheliomatous hyperplasia
is occasionally evident.6,12 Lesions have sometimes been shown to be related
to the follicular infundibulum.6 The crateriform ulcer contains keratinous
and epidermal debris superimposed on a focus of fibrinoid necrosis of the
underlying dermal collagen (Fig. 9.150). The base and radial edges of the
lesion contain granulation tissue and a variable chronic inflammatory cell
infiltrate, comprising lymphocytes, histiocytes, and occasional plasma cells
(Fig. 9.151). Vascular thromboses and hair shaft fragments are sometimes
evident.6 Nerve hyperplasia may be found and it has been suggested that this
may explain the pain experienced by pressure.13
 Chondrodermatitis nodularis chronica helicis 325

Fig. 9.150
Fig. 9.148 Chondrodermatitis nodularis: note the fibrin and intensely eosinophilic degenerate
Chondrodermatitis nodularis: this is a section through the center of the lesion cartilage.
showing ulceration. The adjacent epithelium is hyperkeratotic, parakeratotic, and
acanthotic. There is chronically inflamed granulation tissue at the base of the lesion.
Cartilage is evident in the center field.

Fig. 9.151
Fig. 9.149 Chondrodermatitis nodularis: high-power view of granulation tissue and
Chondrodermatitis nodularis: there is abundant granulation tissue at the base and inflammation.
adjacent to the ulcer.

It is thought that the pathogenetic process at advanced stages of this dis-
ease represents the transepidermal or, occasionally, transfollicular ­elimination
of damaged collagen.3,14 There are often degenerative changes present in
the underlying cartilage, including hyalinization, tinctorial changes, and
­perichondritis. Occasionally, degenerate and fragmented cartilage may also
be seen undergoing transepidermal elimination. The adjacent dermis often
shows marked solar elastosis.3
Differential diagnosis
Punch biopsies, which show the characteristic layering of fibrin, granula-
tion tissue, and degenerating cartilage, are diagnostic and distinctive. Often,
superficial shave biopsies sample only fibrin and granulation tissue without
cartilage. Nevertheless, if the clinical setting is appropriate, the diagnosis can
still be suggested.
 Inflammatory diseases of the
10
Chapter

subcutaneous fat
See
www.expertconsult.com
for references and
additional material
Bostjan Luzar and Eduardo Calonje

Erythema nodosum  327 Crystal-storing histiocytosis  346 Familial partial lipodystrophy (Dunnigan
Erythema nodosum-like lesions in Behçet’s Gouty panniculitis  346 variant)  354
disease  332 Familial partial lipodystrophy (Köbberling
Nodular vasculitis  346 variant)  354
Weber-Christian disease  332 Familial partial lipodystrophy associated with
Subcutaneous sarcoidosis  349
α1-Antitrypsin deficiency-associated mandibuloacral dysplasia  355
Neutrophilic lobular panniculitis associated
panniculitis  333 Acquired lipodystrophy  355
with rheumatoid arthritis  349
Factitial and traumatic panniculitis  334 Acquired generalized lipodystrophy  355
Eosinophilic panniculitis  350 Acquired partial lipodystrophy  355
Cold panniculitis  337
Infective panniculitis  350 Localized lipoatrophy  356
Cytophagic histiocytic panniculitis  337 Lipoatrophic panniculitis  356
Acute infectious id panniculitis –panniculitic
Subcutaneous Whipple’s disease  339 bacterid  352 Lipophagic panniculitis of
childhood  357
Pancreatic panniculitis  339 Sclerosing panniculitis  352 Connective tissue panniculitis  357
Subcutaneous fat necrosis of the Membranous fat necrosis  353 Lupus erythematosus profundus  358
newborn  340 Scleroderma panniculitis  361
LIPODYSTROPHY  354 Dermatomyositis panniculitis  361
Sclerema neonatorum  343 Postirradiation pseudosclerodermatous
Familial lipodystrophy  354
panniculitis  361
Cutaneous oxalosis  343 Congenital generalized lipodystrophy
(Berardinelli-Seip syndrome)  354
Calciphylaxis  344

Inflammatory diseases of the subcutaneous fat are a source of considerable

confusion and often cause diagnostic difficulty to clinicians and pathologists
alike. This stems in part from the use of classifications and clinical descrip-
tions based upon time-honored but outdated literature.1–4 Inadequate biopsy
specimens are also a source of considerable difficulty, particularly the punch
biopsy specimen, which often yields no subcutaneous fat at all. Similarly,
histological subdivision into diseases that affect the lobule and those that
affect the septa is to some extent artifactual and sometimes unrewarding since
most disorders affect both.2,3,5 There is also a somewhat monotonous clinical
­presentation, with most patients complaining of deep-seated, variably tender
or painful nodules, often affecting the lower extremities.
The subcutaneous fat has a limited repertoire of responses to noxious
stimuli. Fat necrosis is a common manifestation of many forms of pannicu-
litis and as a consequence there is often considerable histological overlap.
Although there are many variants of fat necrosis – including enzymatic, crys-
talline, ­suppurative, hyalinizing and microcystic – lipophagic fat necrosis is
the ­subtype most commonly encountered and is often a secondary feature
in many forms of panniculitis (Fig. 10.1). This is characterized by a lobular
infiltrate of histiocytes, xanthomatized cells, and foreign body giant cells,
­frequently accompanied by granulomata (Fig. 10.2).
It is important to remember that the subcutaneous fat may be involved
in a secondary manner, for example, in the vasculitides, the deep cutaneous Fig. 10.1
fungal infections, by metastatic tumor, and following surgery or ­radiotherapy Lipophagic fat necrosis: numerous xanthomatized histiocytes have engulfed free
(Figs 10.3, 10.4). In this chapter the panniculitides are classified, where lipid following fat necrosis.
­possible, on an etiological basis (Table 10.1).
 Erythema nodosum 327

Table 10.1
Classification of panniculitis

• Erythema nodosum
– subacute nodular migratory panniculitis/erythema nodosum migrans
• Erythema induratum
– nodular vasculitis
• Panniculitis associated with connective tissue disease
– lupus panniculitis
– morphea profunda/scleroderma/eosinophilic fasciitis
– dermatomyositis
– connective tissue panniculitis
• Lipoatrophy
– localized (involutional; inflammatory, e.g. lipophagic panniculitis/
granulomatous lipoatrophy)
– lipodystrophy
• Factitial or traumatic panniculitis
– injection-induced (steroids, insulin, narcotics, other drugs)
– sclerosing lipogranuloma
– blunt trauma
• Cold panniculitis
– popsicle panniculitis
– equestrian panniculitis
Fig. 10.2 • Panniculitis of newborn or infants
Lipophagic fat necrosis: in this field xanthomatized multinucleated foreign body – sclerema neonatorum
giant cells are present. Such an infiltrate is a common manifestation of many forms – subcutaneous fat necrosis of the newborn
of panniculitis and merely reflects the presence of fat necrosis. • Drug-induced
– direct (local) effect, e.g. due to injection
– systemic effect or reaction
– poststeroid panniculitis
– lobular panniculitis secondary to ciprofloxacin
– Panniculitis associated with α1-antitrypsin deficiency
• Calcifying panniculitis
– renal failure
– parathyroid disease
• Pancreatic panniculitis
• Gouty panniculitis
• Panniculitis with cytophagic histiocytes
– cytophagic histiocytic panniculitis
– malignant histiocytosis
– sinus histiocytosis with lymphadenopathy
–  T-cell lymphoma
• Eosinophilic panniculitis
– parasitic infection
– Well’s syndrome
– incidental finding of eosinophils in other forms of panniculitis
• Lipomembranous panniculitis
• Non-infectious subcutaneous granulomatous disease
– granuloma annulare, necrobiotic xanthogranuloma, rheumatoid
Fig. 10.3 nodule, sarcoidosis
‘Malignant’ panniculitis: this patient had a known history of bronchial small cell
• Infectious panniculitis
carcinoma and presented with a subcutaneous nodule on the chest wall.
• Subcutaneous Whipple’s disease
• Hemorrhagic panniculitis secondary to atheromatous emboli
• Vasculitis involving the panniculus
• Periarteritis nodosa
Reproduced with permission from Peters, M.S. and Daniel Su, W.P. (1992). Panniculitis.
Dermatologic Clinics, 10, 37–57.

There is considerable histological overlap in the various types of ­panniculitis

and one must take into account all the clinical information before attempting to
reach a definitive diagnosis. In patients in whom the ­diagnosis of ­panniculitis is
suspected, a deep surgical incisional biopsy is essential (Fig. 10.5). The punch
biopsy has no role whatsoever in the diagnosis of panniculitis.

Fig. 10.4
‘Malignant’ panniculitis: high-power view showing basophilic tumor cells with
hyperchromatic nuclei. Note the crush artifact.
Erythema nodosum
Clinical features
Erythema nodosum represents the commonest form of nodular panniculitis
and is the prototype of septal panniculitis.1,2 It is, of course, a clinical ­syndrome
rather than a specific disease in its own right, representing a ­complex of
symptoms and signs with multiple and very variable etiologies.3,4 It ­typically
328 Inflammatory diseases of the subcutaneous fat

Fig. 10.5
Panniculitis: a deep surgical biopsy is essential in all cases where panniculitis is
suspected. Fig. 10.7
Erythema nodosum:
the lesions are raised
and erythematous. By
courtesy of the Institute of
Dermatology, London, UK.

Fig. 10.6
Erythema nodosum:
typical erythematous
nodule on the shins of a
young woman. From the
collection of the late N.P.
Smith, MD, the Institute of
Dermatology, London, UK.
affects young adults and shows a marked predilection for women (as high as
9:1 in some series). Children are only rarely affected.5 Patients ­present with
a sudden onset of bright red, warm, tender nodules; these typically affect
the anterior and lateral aspects of the lower legs, but the arms, face, calves,
and trunk are occasionally involved (Figs 10.6, 10.7).6,7 Involvement of the
soles of the feet is rare although it appears to be more often encountered
in children.8,9 The lesions are usually multiple, bilateral, symmetrically dis-
tributed, elevated above the skin surface, and measure 1–15 cm in diameter.7
Ulceration and scarring are not features. Subsequently, the erythema fades to
a bluish or livid hue and then to a yellow discoloration, reminiscent of a bruise
(Fig. 10.8). The duration of the illness is 3–6 weeks. Patients ­sometimes also
have pyrexia, malaise, and vague aches and pains in the joints. Laboratory
findings may include a raised erythrocyte sedimentation rate (ESR), leukocy-
tosis, and mild anemia.3
Two clinical variants have been described.
• Erythema nodosum migrans (subacute nodular migratory panniculitis,
migratory panniculitis) is similar to classic erythema nodosum, but the
lesions appear to migrate due to central clearing of established lesions
Fig. 10.8
Erythema nodosum: in
this patient the lesions
are healing and show a
characteristic bruiselike
appearance. By courtesy
of the Institute of
Dermatology, London, UK.
and the development of new nodules at the periphery.10–13 The lesions,
which may persist for months or years, are usually associated with only
mild symptoms.10 Recurrences are sometimes encountered. Scarring
is not a feature. This variant is typically asymmetrical, unilateral,
and distributed solely on the leg. It also shows a marked female
predominance (approximately 9:1), but tends to affect an older age group
than classic erythema nodosum (mean age 50 years).11
• Chronic erythema nodosum, a somewhat controversial entity, is
characterized by the presence of nodules over a course of months or even
years.14 Otherwise, the clinical features appear indistinguishable from the
more typical condition.
 Erythema nodosum 329

Pathogenesis and histological features

The etiology and pathogenesis of erythema nodosum are unknown. Despite
the very occasional finding of immunoreactants (IgM or IgG, and C3) in the
blood vessel walls, an immune complex-mediated vasculitis is not consid-
ered likely.6 It is probable that erythema nodosum represents a non-specific
hypersensitivity reaction that involves delayed hypersensitivity mechanisms
in addition to a type 3 component.
There are many known associations. Although some are certainly of sig-
nificance in the etiology of this dermatosis, many are probably coincidental
(Table 10.2).15–28 In the earlier part of the twentieth century, tuberculo-
sis was noted in up to 90% of adult patients with erythema nodosum, but
this is now found in less than 1% of cases. Today, the more frequent asso-
ciations include streptococcal infections, sarcoidosis, ulcerative colitis and
Crohn's disease, Sweet's syndrome, Behçet's disease, menstruation, preg-
nancy, estrogens and the oral contraceptive, cat scratch disease and various
drug treatments (e.g., bromides, antibiotics, and sulfonamides). Other infec-
tious conditions that have been described in association with erythema nodo-
sum include cytomegalovirus, Epstein-Barr virus, parvovirus b19, Yersinia,
Mycoplasma, Chlamydia, Brucella, Bartonella, Rickettsia, Helicobacter Fig. 10.9
pylori, hepatitis B, ­atypical mycobacterial infections (e.g., swimming pool Erythema nodosum: this example shows the classical appearance of septal inflammation
granuloma), Salmonella, Shigella, meningococcal septicemia, Q fever, lep- with spread into the immediately adjacent lobule, giving rise to a lacelike appearance.
tospirosis, ­syphilis, human immunodeficiency virus (HIV), kerion, histo-
plasmosis, blastomycosis, amebiasis, ascaris, Chlamidophila pneumonia,
and giardiasis.15,25–27,29–49 Additional drugs that have been implicated in the
development of erythema nodosum include isotretinoin, interleukin (IL)-2,
minocycline, thalidomide, echinacea, gold salts, hepatitis B vaccine, all-trans-
retinoic acid, capecitabine, azathioprine, aromatase inhibitors, cabergoline,
and lidocaine.16,50–62 Erythema nodosum has also been reported following
a variety of malignancies including Hodgkin's lymphoma, myelodysplastic
syndrome, hairy cell leukemia, acute myeloid leukemia, acute myelomono-
cytic leukemia, diffuse large B-cell lymphoma, hypernephroma, non small cell
lung carcinoma, pheochromocytoma, carcinoid tumor, hepatocellular carci-
noma, carcinomas of the colon, pancreas and uterine cervix, and after radio-
therapy.63–79 In 20–30% of patients no obvious cause is identified (idiopathic
erythema nodosum).2 Erythema nodosum in renal transplant recipients can
be related to infections, malignancies, drugs, inflammatory bowel disease or
autoimmune diseases.80
Erythema nodosum migrans seems to be particularly related to ­pregnancy,
the oral contraceptive, streptococcal infection, and thyroid disease.10–12 Many
cases, however, have no obvious associated predisposing factors or conditions.
Histologically, erythema nodosum represents the prototype of septal pan-
niculitis. It is characterized by a combination of features, including vascular Fig. 10.10
change, septal inflammation, hemorrhage, and a variable degree of acute Erythema nodosum: in the acute phase, venulitis is very occasionally present
or chronic panniculitis (Fig. 10.9). Although it is often said that erythema although many sections or levels must be examined before its presence is detected.
nodosum characteristically affects the septal component of the panniculus,
it should be noted that there is not infrequently involvement of the lobule,
in part or in whole, particularly if older lesions are biopsied. In the past,
cases of the latter might have been diagnosed as Weber-Christian disease.
Frank vasculitis is only very exceptionally encountered. When present, it
involves the small veins, and very occasionally medium-sized vessels within the
connective tissue septa.81 It may be acute and necrotizing, associated with thrombo-
sis and hemorrhage, or may manifest as chronic venular ­inflammation associated
with endothelial cell swelling (Figs 10.10, 10.11). The overlying dermis typically
shows a perivascular and periadnexal chronic inflammatory cell infiltrate.

Table 10.2
Erythema nodosum: etiology

Streptococcus Sarcoidosis
Tuberculosis Sweet’s syndrome
Chlamydophila psittaci Cat scratch disease
Crohn’s disease Yersinia infection
Drugs Ulcerative colitis Fig. 10.11
Behçet’s disease Malignancy Erythema nodosum: in this field there is a thrombosed venule associated with
marked hemorrhage.
330 Inflammatory diseases of the subcutaneous fat

In the early stages, the septal inflammation may be acute, ­characterized

by an infiltrate of neutrophil polymorphs, but this is soon replaced by
­lymphocytes and histiocytes (Figs 10.12–10.14).82,83 Eosinophils are some-
times found and rarely they can be conspicuous. Septal collections of histio-
cytes surrounding a cleftlike space (so-called Miescher's radial granuloma)
are said to be a characteristic feature, although they have been reported in
Sweet's syndrome, nodular vasculitis, and necrobiosis lipoidica (Figs 10.15–
10.17).2,84,85 Further progression leads to the development of a frankly gran-
ulomatous infiltrate in which giant cells may be conspicuous. Coagulation
and caseation-like necrosis are never seen in erythema nodosum (compare
with nodular vasculitis below). Sometimes the connective tissue in the fibrous
septa shows fibrinoid necrosis, and ­hemorrhage is almost invariably present
(Figs 10.18–10.20).
Characteristically, the septal infiltrate (lymphocytes, histiocytes,
and ­granulomata) spills over to affect the periphery of the fat lobule
to give a delicate lacy appearance, but fat necrosis is not usually pres-
ent. On occasion, however, otherwise typical erythema nodosum may be
­associated with fat necrosis and a neutrophil inflammatory cell infiltrate
(Fig. 10.21).81,86
If an older lesion is biopsied, septal fibrosis can sometimes be quite marked. Fig. 10.14
Erythema nodosum: close-up view of cellular infiltrate.
Residual granulomatous inflammation is usually present.

Fig. 10.12 Fig. 10.15

Erythema nodosum: there is septal thickening with a lymphohistiocytic infiltrate. Erythema nodosum: collections of histiocytes known as Miescher’s granulomata
are a common finding. Fibrinoid necrosis affecting a small venule is also present.

Fig. 10.13 Fig. 10.16

Erythema nodosum: this view shows the interface between the septum and the Erythema nodosum: in this example multiple small granulomata are evident in the
lobule. thickened septa.
 Erythema nodosum 331

Fig. 10.17 Fig. 10.20

Erythema nodosum: high-power view of granulomata. Erythema nodosum: in this example there is massive hemorrhage. Subsequent
breakdown with hemosiderin formation accounts for the clinical appearance of bruising.

Fig. 10.18 Fig. 10.21

Erythema nodosum: fibrinoid necrosis of the connective tissue septa is an occasional Erythema nodosum: focal fat necrosis associated with lipid-laden histiocytes.
feature.

A B

Fig. 10.19
Erythema nodosum: there is marked red cell extravasation.
332 Inflammatory diseases of the subcutaneous fat

Erythema nodosum migrans is characterized by densely scarred and

thickened interlobular septa accompanied by a conspicuous granulomatous
­infiltrate (Figs 10.22, 10.23). Numerous giant cells may be seen and often
they form a palisade along the septal borders. Granulation tissue-like ­vascular
proliferation is often a conspicuous feature. Vasculitis is absent and hemor-
rhage is not usually seen.
In chronic erythema nodosum the histological changes are similar to, but
usually milder, than those of the acute variant.11

Differential diagnosis
At scanning magnification, vasculitic processes affecting the septa of the subcu-
taneous fat may be mistaken for erythema nodosum. Occasionally, the features
of leukocytoclastic vasculitis are seen within the septa in the absence of the more
usual superficial dermal involvement.87 Such instances present as erythematous
nodules, usually affecting the lower legs. Similarly, superficial thrombophlebi-
tis presents within the subcutaneous fat septa. In this condition, however, the
vein is the focus of the inflammatory process with associated thrombosis and
there is little or no involvement of the lobule. Cutaneous polyarteritis nodosa
affects muscular arteries within the lower dermis and subcutaneous fat septa
and, therefore, should not be confused with erythema nodosum.87 Nephrogenic Fig. 10.23
Erythema nodosum migrans: close-up view showing granulomata and newly
systemic fibrosis can rarely be associated with mild septal mononuclear cell
formed blood vessels.
infiltrates and granulomata, thereby simulating erythema nodosum.88

Erythema nodosum-like lesions in

Behçet’s disease
Recurrent erythematous, tender, nodular lesions on the lower extremities
(clinically reminiscent of erythema nodosum) are a common manifestation
of Behçet's disease.1–6 Erythema nodosum-like lesions develop in more than
40% of the patients during the course of the disease.7 Erythema nodosum-like
lesions and superficial thrombophlebitis could represent predictive markers
for visceral involvement.8
The fronts of the shins are most often affected but lesions may also
occur on the arms, face, neck, and buttocks.2 Although histologically they
have been described as showing erythema nodosum-like features, more
commonly they are characterized by a lobular or mixed septal and lobular
panniculitis associated with a neutrophil-rich infiltrate, neutrophilic vas-
culitis (affecting arterioles and venules), and associated fat necrosis.2,9 Less
often, a lymphocytic vasculitis and, exceptionally, polyarteritis nodosa-
like features are encountered. Miescher's granulomata may sometimes
be present.2,10

Weber-Christian disease
As originally defined by Christian in 1928 (relapsing febrile nodular nonsup-
purative panniculitis), this disorder was characterized by recurrent attacks of
fever associated with the development of subcutaneous tender nodules (par-
ticularly over the extremities), which were histologically characterized by the
presence of nonsuppurative panniculitis which healed to leave a depressed
scar.1–4 Lesions were said to affect mainly young white females, and although
the lower extremities were predominantly affected, the upper extremities,
buttocks, abdominal wall, breasts, and face could also be involved. Arthritis,
arthralgias, and myalgias were often present.3 A systemic variant – which
was potentially fatal and affected the intestines, mesentery, lungs, heart, and
­kidneys – was also recognized.3,5
Since 1928 there have been many case reports in the literature dealing with
this so-called ‘specific disease’. In general, however, many of the (particularly
earlier) studies used imprecise clinical and histological diagnostic criteria.
Some were certainly examples of erythema nodosum. In the light of cur-
rent knowledge of the panniculitides, many cases would now be reclassified.
A Weber-Christian-like disease may be seen in erythema nodosum, fac-
titial panniculitis, lupus panniculitis, pancreatic fat necrosis-associated
­panniculitis, α1-antitrypsin deficiency-associated panniculitis, connective
Fig. 10.22 ­tissue ­diseases, subcutaneous panniculitic T-cell lymphoma, and gamma-
Erythema nodosum migrans: there is marked septal thickening with conspicuous delta T-cell ­lymphoma.6–15 The term has also been applied to cases of infective
granulomata. Granulation tissue extends into the adjacent lobule. ­panniculitis, and panniculitis following jejuno-ileal bypass surgery.16–19

It seems unlikely, therefore, that Weber-Christian disease represents a ­distinct
entity in its own right. It is proposed, therefore, to take this opportunity to bury
it once and for all. As suggested by Patterson, ‘a clinical diagnosis of Weber-
Christian disease should signal the beginning of a search for the true cause
of the disorder’.9 Likewise, the term Rothmann-Makai syndrome should be
­abandoned.20 More often than not it probably represents erythema nodosum.
a1-Antitrypsin deficiency-associated
panniculitis
Clinical features
Deficiency of α1-antitrypsin is associated with a severe and particularly
intractable form of panniculitis.1–14 Patients have recurrent episodes of pain-
ful or tender nodules which are particularly resistant to therapy. The disease
shows a slight male predominance (3:2), and although a wide age range can
be affected (7–73 years), most patients are in their fourth or fifth decade.5,7
Children, however, may occasionally be affected.5 The nodules, which are
often precipitated by trauma, develop most often on the trunk and proximal
extremities, but the buttocks, chest, back, and abdomen are sometimes also
affected (Fig. 10.24). Occasionally, the disease spreads to the genitalia and
involvement of the abdominal fat has been described.
The nodules may be erythematous and are frequently associated with
ulceration and the spontaneous discharge of clear or serosanguinous fluid.5
Deeply penetrating sinuses associated with liquefaction of the subcutaneous
tissues are an important complication.
Fever is a common accompaniment and patients often have pulmonary prob-
lems including panacinar emphysema, chronic obstructive pulmonary disease,
effusions, and embolic phenomena.5,15 Peripheral edema and ­anasarca are occa-
sional manifestations. This is a particularly severe form of panniculitis, which
has recently been successfully treated by the use of infusions of commercial
α1-antitrypsin concentrate or liver transplantation.5,9,16,17 It is thought that many of
the previously reported cases of Weber-Christian disease belong to this group.18
Panniculitis in association with α1-antitrypsin deficiency has been induced
by cryosurgery,19 pregnancy, cesarean section delivery, and clarithromy-
cin leak at the site of intravenous application.17,19–21 In one patient with
the enzyme defect, Sweet's syndrome was followed by the development of
acquired cutis laxa (Marshall's syndrome).22 An acquired α1-antitrypsin defi-
ciency ­panniculitis following liver transplantation has been reported recently,
which was successfully treated with re-transplantation of the liver.23
Pathogenesis and histological features
α1-Antitrypsin (a glycoprotein of hepatic derivation) is a serine protease inhib-
itor (PI) that greatly modifies the effects of proteolytic enzymes, account-
ing for at least 90% of serum proteolytic enzyme inhibition. In addition to
Fig. 10.24
α1-Antitrypsin deficiency-associated panniculitis: note the extensive involvement of
the buttocks in this young female. By courtesy of M.R. Pittelkow, MD, Mayo Clinic,
Rochester, New York, USA.
Weber-Christian disease 333
antitrypsin inhibition, it is also responsible for inhibition of chymotrypsin,
collagenase, elastase, factor VIII, and kallikrein.7 Its deficiency has been asso-
ciated with panacinar emphysema, noninfective (neonatal and adult) hepati-
tis, and cirrhosis. More recently, associations have also been described with
cutaneous vasculitis, atopic dermatitis, psoriasis, nodular prurigo, and cold
urticaria.24 It has been proposed that absence of the protease inhibitor is asso-
ciated with unrestrained complement activation with increased inflammatory
cell activity, endothelial injury, and resultant autolytic tissue damage.25
Immunoglobulin (IgM) and complement (C3) have been identified in
blood vessel walls in patients with this variant of panniculitis.6 The signifi-
cance of this is uncertain.
The gene for α1-antitrypsin on chromosome 14 has in excess of 75 alleles
and is inherited as an autosomal dominant.7 Deficiency occurs in between
1:3000 to 1:5000 of white North Americans.26 The MM genotype is most
common and individuals with normal activity are coded PiMM. The ZZ
genotype is associated with deficient α1-antitrypsin activity and the pan-
niculitis is usually found in PiZZ individuals.27 Instances of panniculi-
tis in PiMZ, PiSZ, PiMS, PiSS, and Null patients, however, have also been
recorded.28–31 Panniculitis may also develop as a consequence of dysfunc-
tional α1-antitrypsin.31,32 Recognition of this particular form is of importance
as serum α1-antitrypsin levels are normal and therefore the diagnosis can eas-
ily be missed.
The earliest changes consist of necrosis of the connective tissue in the retic-
ular dermis and septa of the subcutaneous fat accompanied by a neutrophil
polymorph inflammatory cell infiltrate (Fig. 10.25).33 The histological fea-
tures of an established lesion are those of a predominantly acute panniculitis
(Fig. 10.26). The changes, which affect the septa and the paraseptal aspect
of the lobule, are characteristically focal in nature. In acutely inflamed areas,
large numbers of neutrophil polymorphs infiltrate the lobule. Fat necrosis is
common and a characteristic feature is said to be the presence of normal fat
adjacent to necrotic and inflamed fat (Figs 10.27, 10.28).6,34 Special stains
often show fragmentation and loss of elastic tissue.6 Z-type α1-antitrypsin
polymers have been demonstrated in the lesional as well as unaffected fatty
tissue by immunohistochemistry in a single patient.35 Foci of hemorrhage
associated with vascular thrombosis may be present, but there is no evidence
of active vasculitis (Fig. 10.29).6 Elsewhere, a histiocytic infiltrate is conspic-
uous, involving both the deep vasculature and adjacent panniculus. Lipid-
laden foamy macrophages are sometimes evident and multinucleate giant
cells are occasionally found. Healing is by fibrous scarring.
Differential diagnosis
The clinical features may suggest traumatic or factitial panniculitis. The
heavy neutrophil infiltrate can cause diagnostic confusion with an infectious
etiology.10 In cases of doubt, special stains for microorganisms should be
performed.
Fig. 10.25
α1-Antitrypsin deficiency-associated panniculitis: early lesion showing necrosis and
acute inflammation of the deep reticular dermis. Blood vessels are also affected.
By courtesy of M.R. Pittelkow, MD, Mayo Clinic, Rochester, USA.
334 Inflammatory diseases of the subcutaneous fat
Fig. 10.26
α1-Antitrypsin deficiency-associated panniculitis: there is intense acute inflammation
extending from the septum into the edge of the lobule. Note the necrosis of the
adjacent dermal connective tissue. By courtesy of M.R. Pittelkow, MD, Mayo Clinic,
Rochester, USA.
Fig. 10.27
α1-Antitrypsin deficiency-associated panniculitis: in this field hemorrhage is evident
in addition to the inflammatory changes. By courtesy of M.R. Pittelkow, MD, Mayo
Clinic, Rochester, USA.
Fig. 10.28
α1-Antitrypsin deficiency-associated panniculitis: high-power view showing an intense
neutrophil infiltrate. By courtesy of M.R. Pittelkow, MD, Mayo Clinic, Rochester, USA.
Fig. 10.29
α1-Antitrypsin deficiency-associated panniculitis: note the organizing thrombus.
By courtesy of M.R. Pittelkow, MD, Mayo Clinic, Rochester, USA.
Factitial and traumatic panniculitis
Clinical features
Factitial panniculitis is by definition self-induced and vigorously denied, and
may be caused by mechanical, physical, or chemical means. The diagnosis is
always worth considering in those patients with bizarre clinical lesions and
inflammatory changes in the subcutaneous fat that defy ready classification.
It should be particularly sought in those patients with panniculitis who have
a known history of psychiatric illness or drug or alcohol abuse. Lesions are
most commonly found on the more accessible sites including the buttocks
and thighs.
Mechanical causes include local pressure and repeated blunt trauma; the
latter may be readily recognized by the presence of obvious bruising. Cold is
another possible cause of factitial panniculitis.
By far the most common etiology is the subcutaneous injection of chemical
substances including drugs, oily materials, and organic matter.1–4 Panniculitis
has been described as a complication of morphine and tetanus antitoxoid
injections. Similarly, repeated injections of pentazocine cause a characteris-
tic woody fibrosis of the skin and subcutaneous fat accompanied by deeply
penetrating ulcers and hyperpigmented halos.5–7 Pentazocine abuse has been
described, particularly in members of the medical profession.5 There appears
to be a relationship with a personal or family history of diabetes mellitus. It
has been suggested that peripheral ischemia may be the pathogenetic link.7
A similar problem has recently been described following injections of the
­opioid ketobemidone.8
An important cause of factitial panniculitis is the repeated injection of
oily materials including paraffin and liquid silicon (paraffinoma, scleros-
ing lipogranuloma, lipogranulomatous panniculitis) (Fig. 10.30).1,2,4,9–13
Sclerosing lipogranuloma was a condition usually seen in the male genitalia
that developed as a consequence of the injection of paraffin oil and related
compounds into the penis in the mistaken belief that this would enhance erec-
tions. Povidone (polyvinylpyrrolidone), a synthetic dispersing or suspending
agent which has been used in both pharmaceutical products and hair sprays,
may result in a particular characteristic histological variant of panniculitis.14,15
Associated features have included pulmonary lesions, lymphadenopathy, and
hepatosplenomegaly. Organic substances that have been implicated in the eti-
ology of factitial panniculitis include food matter, milk, and even feces.
Nodular cystic fat necrosis is a distinct posttraumatic lesion that is seen
­predominantly in adolescent boys and middle-aged women. Lesions, which are
usually found on the legs, are often associated with a history of trauma.16
Traumatic fat necrosis is a not uncommon condition and occurs predom-
inantly in middle-aged or elderly females with large pendulous breasts. Its
importance is that it may be clinically mistaken for a malignancy. In addition, it
can be seen to involve the arms, trunk, buttocks, and thighs of the very obese.
 Factitial and traumatic panniculitis 335

careful examination may reveal foamy histiocytes or giant cells lining the
edges of these cystic cavities (Fig. 10.32).9 There is often associated dense
fibrous scarring. Early lesions sometimes show a marked granulomatous
component.9 Similar features have been described following a grease gun
injury.29
In panniculitis due to pentazocine abuse the histological features include
dense dermal fibrosis accompanied by variable scarring of the subcutaneous
fat.5 A ‘Swiss cheese’ appearance may be evident. Small-vessel thrombosis is
frequently present.5
Povidone panniculitis is characterized by histiocytic accumulation of
gray-blue, Congo red-positive foamy material accompanied by necrosis and
hemorrhage.14
Lesions caused by blunt trauma show the features of an organizing hematoma.
Granulomata and foci of hemosiderin pigment may additionally be present.30
Nodular cystic fat necrosis is thought to have an ischemic pathogenesis.
Histologically, it is characterized by an encapsulated nodule of necrotic (anu-
cleate) fat cells (Fig. 10.33).31,32 Variable inflammation is present.
Fat necrosis with histiocytes (lipophages) and giant cells is a com-
mon histological finding in specimens taken from sites of previous sur-
Fig. 10.30 gery of the subcutaneous fat (or deeper). Zelickson and Winkelmann have
Paraffinoma: note the infiltrated plaque with foci of retraction. By courtesy of the
Institute of Dermatology, London, UK.

A number of therapeutic injections have been associated with the devel-

opment of panniculitis including interferon-beta (IFN-β),17–21 glatiramer
acetate,22–24 nadroparin-calcium25 and granulocyte colony stimulating fac-
tor.26 Aluminum granuloma may present as a panniculitis. Panniculitis
has also been documented following vitamin K1 injections27. Two patients
with factitial panniculitis caused by electroacupuncture have been recently
described.28

Pathogenesis and histological features

The histological features of factitial panniculitis are not usually specific and
depend to some extent upon the cause. In some instances, therefore, the
changes are those of acute lobular inflammation associated with fat necrosis
and a neutrophil polymorph infiltrate. In older lesions, mononuclear cells,
lipid-laden histiocytes, and foreign body giant cells become predominant and
sometimes the response becomes frankly granulomatous. On other occasions
the septa may be primarily affected, thereby mimicking erythema nodosum.
Calcification is occasionally evident.2 It is sometimes rewarding to view the
sections with polarized light, as birefractile material may be identified, raising
the possibility of the factitious nature of the condition. Fig. 10.32
Paraffinoma is characterized by the presence of round or oval spaces Paraffinoma: on high-power examination, the cystic spaces can often be seen to be
lined by lipophages.
within the dermis and subcutaneous fat (‘Swiss cheese’ pattern) (Fig. 10.31);

Fig. 10.31 Fig. 10.33

Paraffinoma: empty spaces of variable size (due to the removal of lipid during Nodulo-cystic fat necrosis: typical low-power appearance; note the encapsulated
processing) characterize this lesion. The appearance is often likened to Swiss cheese. fatty cyst, scarring, and chronic inflammation.
336 Inflammatory diseases of the subcutaneous fat

described this as lipophagic panniculitis.31 Hemosiderin deposits are also

­commonly found and in many instances fragments of suture material may
be identified.
The histological features of traumatic fat necrosis are not specific and are
characterized by fat necrosis accompanied by a variable inflammatory cell
infiltrate (Figs 10.34, 10.35). In early lesions this is predominantly composed
of neutrophils, later replaced by lymphocytes and monocytes. Aggregates of
lipophages are seen frequently and often the reaction becomes frankly granu-
lomatous. Fat cysts are a common feature. With resolution, fibrosis takes
place (Fig. 10.36). As evidence of the traumatic nature of the lesion, foci of
hemosiderin deposition are not uncommon (Fig 10.37). Occasionally, the
presence of fat necrosis is complicated by focal calcification (Fig. 10.38).
Panniculitis after subcutaneous injection of interferon-beta can mimic
histologically erythema nodosum, lupus panniculitis, and pancreatic
panniculitis.18–20
Glatiramer acetate-induced panniculitis is characterized histologically by
a predominantly lobular inflammatory infiltrate composed of lymphocytes,
plasma cells, and scattered neutrophils and eosinophils in the background of
lipophagic granulomata.23 Reactive germinal centers may also be seen.
Interferon-beta-induced panniculitis and glatiramer acetate-induced Fig. 10.36
Traumatic fat necrosis: scarring is a feature in more chronic lesions.
­panniculitis are frequently associated with subsequent lipoatrophy.18,22

Fig. 10.37
Fig. 10.34 Traumatic fat necrosis: there is marked hemosiderin deposition.
Traumatic fat necrosis: there is intense lobular inflammation with septal fibrosis and
hemorrhage.

Fig. 10.35 Fig. 10.38

Traumatic fat necrosis: collections of lipophages are characteristic. Traumatic fat necrosis: in this example there is marked granular calcification.
 Cytophagic histiocytic panniculitis 337

Cold panniculitis
Clinical features
This rare condition was originally described in infants and young children
who developed tender, warm, erythematous plaques on exposed sites, namely
the cheeks and submental region, after experiencing low temperatures,1–6 and
usually appeared within the first 72 hours after exposure.7 These plaques
resolved spontaneously after 2–3 weeks, with no residual sequelae. The appli-
cation of an ice cube to a child's skin may result in the development of simi-
lar lesions. Identical changes have also been described in infants following
the sucking of ice lollies (popsicles; ‘popsicle panniculitis’).8–11 Increased satu-
rated fat content having a higher melting point may precipitate the develop-
ment of panniculitis in children.
A similar phenomenon has been described in young women following
horse riding in cold weather (equestrian cold panniculitis); these patients
develop indurated red-violaceous plaques on the superolateral aspect of the
thighs following prolonged riding in freezing conditions (Fig. 10.39).12–14
There is a tendency to ulcerate; healing is associated with postinflammatory
Fig. 10.40
hyperpigmentation and the development of depressed scars. It is thought that
Cold panniculitis: an intense inflammatory cell infiltrate is present at the junction
these lesions occur as a result of extremely cold temperatures combined with between the dermis and subcutaneous fat. By courtesy of P.H. Cooper, MD,
the effect of noninsulated, but tight-fitting, clothes which impair the circula- University of Virginia Medical Center, USA.
tion around the thighs. Recently, two patients with cold agglutinins and this
condition have been described.13
Chilblains (perniosis) also represent localized, abnormal inflammatory
responses to the cold.15 They have an acral distribution (e.g,. dorsal surfaces
of the fingers and toes) and present as pruritic erythematous lesions, which
may blister or ulcerate.

Histological features
The features of cold panniculitis are most noticeable at the interface between
the dermis and subcutaneous fat (Fig. 10.40).3,8 The infiltrate, which con-
tains lymphocytes, histiocytes, and neutrophils, extends from a perivascular
location into the adjacent fat where it is associated with adipocyte necrosis
and the development of small cysts (Fig. 10.41). Excess hyaluronic acid may
sometimes be present. Granulomata are not usually conspicuous.16 The blood
vessels show thickening of their walls and endothelial swelling, but frank vas-
culitis is not a feature.

Fig. 10.41
Cold panniculitis: the infiltrate consists of lymphocytes and histiocytes.

The histological features of perniosis include intense papillary dermal

edema and a superficial perivascular mononuclear infiltrate. The blood ­vessel
wall characteristically shows very marked edema and often there is fibrin
deposition.15

Cytophagic histiocytic panniculitis

Fig. 10.39
Cold panniculitis: there are
ulcerated lesions on this
patient’s thigh. From the
collection of the late
N.P. Smith, MD, the
Institute of Dermatology,
London, UK.
Clinical features
Cytophagic histiocytic panniculitis (panniculitis associated with hemophago-
cytic syndrome) was originally described as a serious disorder of immune
dysregulation.1–3 It may develop in association with a number of underlying
conditions including viral infections such as cytomegalovirus and Epstein-
Barr virus.4–8 HIV infection has also rarely been incriminated.7 Bacteria,
fungi, and parasites are sometimes of etiological significance.9–11 The condi-
tion has been described as a complication of phenytoin therapy, following
bone marrow transplantation, in systemic lupus erythematosus (SLE), and as
an adverse reaction to interferon-alpha (IFN-α) therapy.12–15 Some examples
in the earlier literature were described as Weber-Christian disease.16
Of particular importance, the hemophagocytic syndrome may also be
associated with a number of malignancies, most commonly T-cell lymphoma
338 Inflammatory diseases of the subcutaneous fat
(nodal or cutaneous).8,16–18 It is likely that many of the cases of the entity
described in the past represent examples of lymphomas including subcutane-
ous panniculitis-like T-cell lymphoma, nasal-type extranodal natural killer/T-
cell lymphoma and, particularly, gamma delta T-cell lymphoma. Rarely, an
underlying systemic B-cell lymphoma has been incriminated.19 Most patients
are immunosuppressed; however, very exceptionally, the cause is unknown
(idiopathic histiocytic cytophagic panniculitis).17,20 It is, therefore, of particu-
lar importance that all patients diagnosed with this condition are investigated
to exclude an underlying lymphoma, particularly of T-cell lineage.
Clinically, the cutaneous manifestations of cytophagic histiocytic pan-
niculitis include erythematous to violaceous or hemorrhagic nodules, which
particularly affect the lower limbs and trunk (Figs 10.42, 10.43). In many
patients however, the distribution is much more widespread. Ulceration is
sometimes seen. Severe localized or generalized edema may also be a feature.18
Constitutional symptoms including pyrexia, malaise, weight loss, fatigue, and
Fig. 10.42
Cytophagic histiocytic panniculitis: an extensive, erythematous, indurated plaque
is present on the upper arm. By courtesy of M. Cook, MD, St George’s Hospital,
London, UK.
Fig. 10.43
Cytophagic histiocytic
panniculitis: in this
example the lesions
are hemorrhagic and
ulcerated. By courtesy of
M. Cook, MD, St George’s
Hospital, London, UK.
myalgia may be present. Patients commonly develop hepatosplenomegaly,
lymphadenopathy, hypertriglyceridemia, anemia, leukopenia, thrombocy-
topenia, and disseminated intravascular coagulopathy.2–4 Steatohepatitis may
complicate exacerbation of cytophagic hemorrhagic panniculitis.21
The course of the disease is variable and to some extent depends upon the
underlying cause.22–31 Some patients have a prolonged indolent disease over
many years before progressing to clinical evidence of systemic hemophago-
cytosis. Rarely, patients may present with cutaneous lesions and a relatively
benign illness; 20,25,30,32 others have a rapidly progressive condition with
hemophagocytosis and its sequelae from the outset. The mortality rate for
these last patients is high. In addition to the direct effects of bone marrow fail-
ure and disseminated intravascular coagulation, systemic infections including
opportunist bacteria and fungi are important causes of death.8
Pathogenesis and histological features
Hemophagocytosis appears to develop as a consequence of excess T-cell
cytokine production, either virally induced or as a consequence of neoplas-
tic transformation. Tumor necrosis factor-alpha (TNF-α) and IL-2 may be of
particular importance.8 Perforin gene mutation has been detected in a child
with cytophagic lymphocytic panniculitis associated with fatal hemophago-
cytic lymphohistiocytosis.33
Histologically, the lesions are characterized by an infiltrate of histiocytes
with abundant eosinophilic cytoplasm and uniform, variably hyperchromatic
or vesicular nuclei containing small nucleoli. Variable numbers of lympho-
cytes and neutrophils are also present. Although the distribution is predomi-
nantly lobular, septal involvement is usually apparent and the lower dermis
is also often involved (Fig. 10.44). Red cell extravasation is typically pres-
ent and frequently the lesions are frankly hemorrhagic. Erythrophagocytosis
is invariably a feature and phagocytosis of lymphocytes or nuclear debris is
also often evident (Fig. 10.45). The enlarged and distended histiocytes are
sometimes described as ‘bean-bag’ cells (Fig. 10.46).2,3 Giant cells and gran-
ulomata are not usually a feature unless there is concomitant fat necrosis.
Lymphoid nuclear atypia is evident in those cases in which a T-cell lymphoma
is present (see below).
Differential diagnosis
Cytophagic histiocytic panniculitis must be distinguished from other condi-
tions in which erythrophagocytosis or hemophagocytosis may be a feature
including subcutaneous T-cell panniculitic lymphoma, angiocentric lym-
phoma, and cutaneous Rosai Dorfman disease.
In subcutaneous panniculitic T-cell lymphoma, the lymphocytes show cyto-
logical atypia with karyorrhexis and mitotic activity (Fig. 10.47). Angiocentric
T-cell lymphoma is characterized by an angioinvasive and ­frequently
Fig. 10.44
Cytophagic histiocytic panniculitis: there is a cellular infiltrate associated with fat
necrosis.

Fig. 10.45
Cytophagic histiocytic panniculitis: note the histiocytes with abundant eosinophilic
cytoplasm, some of which show erythrophagocytosis.
Fig. 10.46
Cytophagic histiocytic panniculitis: in the center of the field are several multinucleated
giant cells containing phagocytosed nuclear debris (‘bean-bag’ cells).
Fig. 10.47
Subcutaneous panniculitic T-cell lymphoma: numerous histiocytes showing
hemophagocytosis are present. In addition, however, there are conspicuous
hyperchromatic and irregular atypical lymphocytes.
Pancreatic panniculitis 339
a­ ngiodestructive atypical lymphoid infiltrate usually accompanied by wide-
spread coagulative necrosis. In cutaneous Rosai-Dorfman disease, the infiltrate
is usually centered on the dermis. Lymphophagocytosis is often marked but
erythrophagocytosis is not usually present. The histiocytes are characteristically
S-100 protein positive.
Subcutaneous Whipple’s disease
Clinical features
Whipple's disease is a rare condition which most often affects males and is due
to infection with the bacillus Tropheryma whippeli.1,2 It is characterized by
small intestinal involvement leading to malabsorption accompanied by fever
and arthritis, although virtually any organ system may be affected. Cutaneous
lesions include hyperpigmentation, erythroderma, purpura, vasculitis,
­erythematous and urticarial lesions, eczematous dermatitis and lichenoid gran-
ulomatous lesions.3,4 Exceptionally, subcutaneous nodules have been described
3,5–7 with occasional symmetrical distribution on inner thighs and forearms.8
Histological features
Involvement of the subcutaneous fat presents as a predominantly septal ‘pan-
niculitis’ characterized by a mixed inflammatory cell infiltrate consisting
of lymphocytes, neutrophils, and foamy periodic acid-Schiff (PAS)-positive
histiocytes.4,8
Electron microscopy reveals degenerate bacilli within membrane-bound
vesicles in the cytoplasm of the histiocytes.3
More recently, diagnostic polymerase chain reaction (PCR) and immuno-
histochemical techniques have become available.9
Pancreatic panniculitis
Clinical features
In pancreatic panniculitis the association of subcutaneous fat necrosis (meta-
static fat necrosis) with pancreatic disease is very rare, but is of particular
importance because sometimes the underlying pancreatic lesion is clinically
silent. The pancreatic diseases include acute pancreatitis, chronic pancreatitis,
pancreatic pseudocyst, pancreatic divisum, and pancreatic neoplasms (mostly
acinar cell carcinoma, but also ductal carcinoma, neuroendocrine carcinoma,
and intraductal papillary mucinous neoplasm).1–24 Pancreatic panniculitis has
also been described as a possible adverse drug reaction following renal trans-
plantation for SLE and following simultaneous pancreas-kidney transplanta-
tion for type I diabetes.25,26 There are two additional reports of the disease
developing in a background of lupus erythematosus.27,28 Pancreatic pannicu-
litis has also been reported following L-asparaginase treatment for acute lym-
phoblastic leukemia and in a patient with nephrotic syndrome due to rapidly
progressing glomerulonephritis.29,30
Patients present with multiple, exquisitely tender nodules, which are ery-
thematous or violaceous in appearance (Figs 10.48, Figs 10.49). The lower
extremities, buttocks, and trunk are most often affected, although occasion-
ally the upper arms, thorax, and scalp are involved. Occasionally, the nodules
ulcerate and release a creamy or oily discharge (Fig. 10.50). Joint manifesta-
tions (pain and swelling) are an important feature of this syndrome, occur-
ring in approximately 54% (pancreatitis-associated) to 88% (pancreatic
carcinoma-associated) of patients.5,31–35 The ankles are most often affected,
but the knees, elbows, wrists, metacarpophalangeal, and metatarsophalan-
geal joints are occasionally involved. A single case with chondronecrosis
and osteonecrosis has been reported.36 Additional features include pleural
effusions (in 25%), ascites (in 30%) and, very occasionally, pericardial effu-
sion.4 Intramedullary fat may also be affected and intestinal involvement has
rarely been documented.1,35 Peripheral blood eosinophilia is quite a com-
mon laboratory finding (19% in pancreatitis-associated; 65% in pancreatic
carcinoma-associated). Males are affected more often than females (pan-
creatitis 2:1; carcinoma 7:1) and patients are most often in the fourth, fifth
or sixth decade. This disease is associated with a high mortality, 42% in
­pancreatitis-associated variants and up to 100% in those cases presenting
with an u­ nderlying carcinoma.4
340 Inflammatory diseases of the subcutaneous fat
Fig. 10.48
Pancreatic panniculitis:
early lesions are often
erythematous. By courtesy
of J.C. Pascual, MD,
Alicante, Spain.
Fig. 10.49
Pancreatic panniculitis: a more advanced lesion. From the collection of the late
N.P. Smith, MD, the Institute of Dermatology, London, UK.
Pathogenesis and histological features
The development of subcutaneous fat necrosis in association with pancreatic
disease is due to the release into the peripheral circulation of trypsin, lipase,
phospholipase, and amylase.7,37 It has been postulated that trypsin damages
the vasculature, particularly in dependent sites, thereby permitting lipase to
enter the surrounding tissues. In vivo evidence suggests that this may be too
simplistic a viewpoint.9 Serum lipase levels do not always correlate with sub-
cutaneous fat necrosis and examples of patients with fat necrosis and normal
serum lipase levels have been documented.10 The reports of Wilson et al. and
Simkin et al., however, provide striking in vivo evidence to support a patho-
genetic role for released pancreatic enzymes.31,32
Histologically, the features are pathognomonic and are identical to
those seen in the peripancreatic adipose tissue following an episode
of acute ­hemorrhage pancreatitis (Fig. 10.51). Although very early
changes can show features of septal panniculitis without fat necrosis or
Fig. 10.50
Pancreatic panniculitis: the nodules may ulcerate and release blood-stained fluid.
By courtesy of J.C. Pascual, MD, Alicante, Spain.
Fig. 10.51
Pancreatic panniculitis: the changes predominantly affect the lobules.
­vasculitis, most ­frequently, however, the changes are lobular in distribu-
tion and are characterized by the presence of ghost cells (Fig. 10.52).38
The ­latter are anucleate, ­composed of amorphous granular debris, and
often show a rim of eosinophilia (Fig. 10.53). Stippled basophilia due
to ­calcification is commonly found (Fig. 10.54). A neutrophil poly-
morph response is usually ­evident around the foci of fat necrosis, and
hemorrhage is an almost invariable feature (Fig. 10.55). The uninvolved
­surrounding fat is heavily infiltrated by acute and chronic inflammatory
cells ­including large numbers of macrophages, many of which have foamy
cytoplasm due to ingested lipid, and occasional multinucleate giant cells
(Fig. 10.56). There is no evidence of a vasculitis. Birefringent crystals
have been described in the mesenteric fat and within affected joints but
not in the subcutaneous fat.39,40
Subcutaneous fat necrosis of the newborn
Clinical features
This uncommon disease presents in full-term or post-term neonates in the
first few weeks of life.1–4 Affected babies develop painless subcutaneous nod-
ules measuring from a few millimeters to several centimeters in diameter.
The overlying skin may appear normal or be erythematous or violaceous.
 Subcutaneous fat necrosis of the newborn 341

Fig. 10.52 Fig. 10.55

Pancreatic panniculitis: there is extensive enzymatic fat necrosis. Note the Pancreatic panniculitis: there is a heavy neutrophil infiltrate.
characteristic ghost cells.

Fig. 10.53 Fig. 10.56

Pancreatic panniculitis: close-up view of ghost cells. Pancreatic panniculitis: as with other forms of fat necrosis, lipophages are often
evident.

Lesions are symmetrical and distributed over bony prominences, the arms,
shoulders, buttocks, thighs, and cheeks (Fig. 10.57). The nodules frequently
soften and become fluctuant, occasionally liquefying. The disease is usually
self-limiting and benign, spontaneous resolution occurring within a period of
weeks to months in the majority of cases. Occasionally, however, it is asso-
ciated with hypercalcemia, dyslipidemia, thrombocytopenia, and lactic aci-
dosis.4–11 Hypercalcemia may be asymptomatic and associated with failure
to thrive, fever, vomiting, irritability, and seizures.1,12 Calcium deposits have
been described in the kidneys, liver, inferior vena cava, and heart.4,13 Delayed
onset of hypercalcemia up to 6 months after occurrence of the subcutaneous
fat necrosis of the newborn is also possible.14 Exceptionally, this disease can
prove fatal.

Pathogenesis and histological features

Fig. 10.54
Pancreatic panniculitis: the stippled basophilia represents calcification.
The pathogenesis of the hypercalcemia is unknown. A number of theo-
ries have been proposed including calcium release from resolving plaques,
elevated parathormone and prostaglandin E2 levels, increased vitamin D
sensitivity and, most recently, lesional histiocytic production of excessive
1,25-dihydroxyvitamin D3 with resultant increased intestinal absorption of
calcium.15–23
342 Inflammatory diseases of the subcutaneous fat

Fig. 10.58
Fig. 10.57 Subcutaneous fat necrosis of the newborn: multiple foci of fat necrosis with chronic
Subcutaneous fat necrosis inflammation are present.
of the newborn: crusted,
ulcerated nodules on both
cheeks. By courtesy of the
Institute of Dermatology,
London, UK.

The cause of subcutaneous fat necrosis of the newborn is unknown, but

most cases are related to some form of fetal distress, including obstetric or other
birth trauma, cord accidents, meconium aspiration, infections, hypothermia,
placenta previa, cesarean section and neonatal asphyxia.2,4 Pre-eclampsia and
maternal diabetes have also been associated with this condition.4,7 A primary
abnormality of subcutaneous fat may be of some importance.24 Neonatal fat
is characterized by elevated levels of saturated fatty acids which have a high
melting point and are therefore susceptible to precipitation as a consequence
of neonatal hypothermia. Deficiency of brown fat has also been proposed
as a potential etiological factor.25 Although not histologically confirmed, a
case of simultaneous development of sclerema neonatorum and subcutane-
ous fat necrosis of the newborn was described in an infant following cesar-
ean section for fetal distress, hypothermia, neonatal respiratory distress, and
hypoglycemia.26
Subcutaneous fat necrosis has also been described after hypothermic car-
diac surgery, as a complication of congestive heart failure in an infant with A
ventricular septal defect and patent ductus arteriosus, associated with mater-
nal diabetes, increased blood pressure, smoking, thrombosis-related risk
­factor, a possible complication of cocaine abuse, following the in partum use
of calcium-channel blockers and as a consequence of prolonged exposure in
very cold weather.4,27–33
The histological changes are characteristic.21,34–36 The subcutaneous fat
is the scene of intense necrosis. Individual adipocytes are swollen and con-
tain abundant radially arranged eosinophilic crystalline spaces resulting
from dissolved lipid (Figs 10.58, 10.59). The crystals are largely composed
of triglycerides.35 There is a heavy inflammatory cell infiltrate comprising
polymorphs, lymphocytes, histiocytes, and numerous foreign body giant
cells (Fig. 10.60). Large numbers of eosinophils have been described in two
cases.21 Multinucleated giant cells containing eosinophilic granules in their
cytoplasm have recently been reported.37,38 The significance of these granules
is unknown, and their origin from degranulating eosinophils has been pos-
tulated.37 Older lesions may show fibrosis and foci of calcification. Systemic
involvement is sometimes present.36
B
Differential diagnosis
It is of interest to note that identical histological features were seen some years Fig. 10.59
ago in the poststeroid panniculitis syndrome.39–44 This condition occurred in (A, B) Subcutaneous fat necrosis of the newborn: individual adipocytes are swollen
children who had been treated for rheumatic fever or ­glomerulonephritis and contain characteristic, radial, eosinophilic crystals.

Fig. 10.60
Subcutaneous fat necrosis of the newborn: surrounding the foci of fat necrosis is a
chronic inflammatory infiltrate containing numerous foreign body giant cells.
with very large doses of steroids; sudden withdrawal of the steroids resulted
in the development of subcutaneous swellings up to 4 cm across on the
cheeks, arms, and trunk. The disease is now of historic interest only due to
the ­standard practice of steroid taper when withdrawing the drug. The skin
overlying the nodules was erythematous, warm, and itchy. In mild cases the
panniculitis resolved spontaneously; in more severe examples it subsided fol-
lowing the reintroduction of steroids. Poststeroid panniculitis has recently
also been reported in an adult patient.45
Sclerema neonatorum
Clinical features
Sclerema neonatorum is a very rare condition associated with high morbidity
and mortality (75–90%).1 It is sometimes confused with, and therefore must
be distinguished from, subcutaneous fat necrosis of the newborn.2–4 Infants
present in the first week of life (average age of onset, 4 days; range, birth to
70 days) with a diffuse, rapidly spreading, waxlike thickening and induration of
the subcutaneous fat, resembling lard. This usually commences about the but-
tocks, thighs, and trunk and often spreads to involve the whole body, excluding
the palms, soles, and genitalia. The fat is typically tethered to the underlying
fascia and the skin cannot be grasped between the fingers. Pitting edema is not
a feature.
Affected infants are usually hypothermic, but body temperature may be
normal or, rarely, raised.5,6 Some of the infants are premature, but they are
a minority. The children commonly have some other associated illness, such
as septicemia, pneumonia, diarrhea, dehydration, intestinal obstruction, con-
genital heart disease or other congenital malformations.7 A patient with both
sclerema neonatorum and concurrent subacute fat necrosis of the newborn
has been described.8
Pathogenesis and histological features
The etiology and pathogenesis of this condition are uncertain. It is thought
that the structural alterations of the subcutaneous fat probably predate the
development of the clinical features. Neonatal subcutaneous fat is character-
ized by a higher content of saturated fatty acids (palmitic and stearic) and a
lower content of unsaturated fatty acids (oleic) than adult subcutaneous fat.2
It also has higher melting and solidification points. It has been suggested that
infants with sclerema neonatorum have an inadequately developed enzyme
system for converting saturated to unsaturated fatty acids.2 It is thought that
this, in association with stress, might result in the precipitation of triglycerides
and consequent solidification of the subcutaneous fat. Recently, it has been
proposed that redistribution of blood flow to the systemic circulation with
resultant relative ischemia of the subcutaneous fat may be of ­pathogenetic
Cutaneous oxalosis 343
importance.9 Sclerema neonatorum is characterized by increased blood lipid
peroxidation and diminished superoxidase dismutase activity, which raises
the possibility that free radicals may play a role in its pathogenesis.10 There is
no evidence of vasculitis.
The histological features are surprisingly bland. The subcutaneous fat
is greatly thickened and the fibrous septa are broader than normal. The
adipocytes, which are increased in size, may contain radially orientated
fine crystals identical to those described in subcutaneous fat necrosis of
the newborn although often they are inconspicuous.1,11 In contrast to the
latter condition, however, there is no necrosis or significant inflammatory
cell infiltrate. Calcification is rarely a feature.1 The dermis may appear
sclerotic with hyalinization and the epidermis atrophic with loss of the rete
ridges.11
Cutaneous oxalosis
Clinical features
Oxalosis, in which there is widespread deposition of calcium oxalate in the
tissues, may represent a primary metabolic disease or a secondary phenom-
enon due to increased intake of oxalate precursors or defective excretion.1–5
Secondary oxalosis can also result from pyridoxine deficiency, glycerol
­infusion, methoxyflurane anesthesia, excessive ascorbic acid, extensive hemo-
dialysis, peritoneal dialysis, and ethylene glycol poisoning.2
Primary oxalosis, which is associated with overproduction of oxalate, is
an autosomal recessive condition and includes three subtypes:
• Type I, which is most often encountered, develops as a result of deficiency
of the hepatic enzyme alanine:glyoxylate aminotransferase with resulting
increased urinary excretion of oxalate, glycolate and glyoxylate.1–3
• Type II (L-glyceric aciduria) results from cytosolic D-glycerate
dehydrogenase and glyoxylate reductase deficiencies with associated
increased urinary excretion of L-glycerate and oxalate accompanied by
normal glycolate and glyoxylate excretion.4
• Type III develops as a result of primary small intestinal disease associated
with excessive oxalate reabsorption.5
Calcium oxalate crystal deposition occurs most commonly in the kidneys
(calcium oxalate stones and chronic renal failure).4 With the onset of the
latter, hyperoxalemia develops with resultant deposition of oxalate crystals
in the blood vessels, retina, myocardium, cardiac conducting system, central
nervous system, peripheral nerves, bones, and joints.6
Cutaneous manifestations may occur in both primary and secondary
forms.6–24 Lesions most often result from vascular involvement, patients
presenting with acrocyanosis, livedo reticularis, Raynaud's phenomenon,
and distal gangrene (Fig. 10.61).7–12 Ulceronecrotic lesions reminiscent
Fig. 10.61
Cutaneous oxalosis: this child shows gangrene with ulceration. By courtesy of
N. Saxe, MD, Groote Schuur Hospital, Cape Town, South Africa.
344 Inflammatory diseases of the subcutaneous fat

Fig. 10.62 Fig. 10.64

Cutaneous oxalosis: note the radially orientated, needle-shaped crystals. Cutaneous oxalosis: in this field there is dramatic vascular involvement with
destruction of the media and massive intimal thickening.

Calciphylaxis
Clinical features
Calciphylaxis was originally defined by an experimental model in rats, in
which sensitization with parathormone or dihydrotachysterol followed by
the injection of a challenging agent such as a metal salt resulted in localized
necrosis and calcification.1 The term was subsequently adopted to describe
a condition in which an abnormality of calcium/phosphate metabolism is
­followed by calcification of the vasculature of the subcutaneous fat with
­subsequent thrombosis accompanied by extensive skin necrosis.2–7
Calciphylaxis presents clinically as an often bilateral and symmetrical,
­pruritic, and frequently painful/tender eruption most often affecting the
lower limbs (Fig. 10.65). Less often, lesions may affect the breasts, but-
tocks, ­abdomen, and penis.8–24 Lesions are often well-delineated, livedoid,
­violaceous plaques and nodules associated with ischemic necrosis of the under-
lying ­tissues, sometimes extending down to the fascia. Ulceration is ­typically
­present and sometimes bullae are a feature. Gangrene and ­autoamputation
may accompany acral involvement.6 Intestinal involvement with massive
Fig. 10.63 hemorrhage has exceptionally been documented.16
Cutaneous oxalosis: note the radial crystals viewed under polarized light.

of ­calciphylaxis have also been documented.13–15 Less often, crystals are

­deposited in the skin of the face and the fingers as miliary deposits, as dermal/
subcutaneous nodules or as painful subungual nodules.16–21 Exceptionally,
generalized cutaneous nodules have been documented.22 Vascular involve-
ment is said to be more common in patients with primary disease whereas
cutaneous extravascular lesions are predominantly seen in patients with sec-
ondary disease.21

Histological features
Calcium oxalate crystals are yellow to brown, radially arranged, needle-
shaped or rectangular in shape (Figs 10.62, 10.63). In the skin they may
be found in the reticular dermis or within the subcutaneous fat. Vascular
involvement may also be seen where the media of arteries is predomi-
nantly affected (Fig. 10.64). Less commonly, crystals may be seen within
the lumina of smaller arteries or arterioles.1,11,12 The crystals show striking
yellow or blue birefringence when examined in polarized light. They are
sometimes accompanied by a foreign body giant cell reaction, particularly Fig. 10.65
when present as dermal or subcutaneous deposits.8,18,22–24 In those cases Calciphylaxis: ulcerated gangrenous lesion with surrounding erythema. By courtesy
associated with gangrene or livedo reticularis, fibrin thrombi may also be of A. Qureshi, MD, Department of Dermatology, Brigham and Women’s Hospital,
detected.8 Boston, USA.
 Calciphylaxis 345

Calciphylaxis is associated with considerable morbidity and a high mortal-

ity of up to 60%.4,14 The majority of patients succumb to secondary infection.
Calciphylaxis due to the end-stage kidney disease can exceptionally develop
in children, with four patients reported to date.25

Pathogenesis and histological features

The precise mechanism by which the subcutaneous vasculature undergoes
calcification is uncertain but is probably multifactorial. In the majority of
patients, however, sensitization occurs as a consequence of abnormal cal-
cium/phosphorus metabolism in a setting of chronic renal failure and second-
ary or tertiary hyperparathyroidism. Frequently, the patients are undergoing
dialysis. Less often, there is a background of primary hyperparathyroidism
or hypervitaminosis D.4,12,14,17 Although in many patients calcium deposition
occurs in association with an increased calcium-phosphorus product, in a
significant proportion of patients calcium and phosphorus levels are nor-
mal.4 It has been suggested that in such patients the calcification develops as
a direct response to excess parathormone or vitamin D. Challenging agents
resulting in the vascular precipitation of calcium salts are unknown but a
number of substances (including albumin, corticosteroids, and immunosup-
Fig. 10.67
pressives) have been incriminated.12 Calciphylaxis has also been described in Calciphylaxis: calcification of the small vessels and capillaries within the subcutaneous
association with decreased functional protein C.13 Very rarely, the ­condition fat is evident.
has presented in a patient with no evidence of a renal disorder or increase
in parathormone level.17 Malignant tumors, rheumatoid arthritis, giant cell
arteritis, as well as alcoholic liver disease have been implicated in these
patients.26
Histologically, the characteristic feature is calcification of the small- to
medium-sized arteries and arterioles (Figs 10.66, 10.67). Calcified debris
may sometimes be present within the lumina and occasionally the vessels
are thrombosed (Fig. 10.68). Intimal fibroblastic proliferation with ­luminal
narrowing has also been described (Fig.10.69).9 Hemorrhage within the
­subcutaneous fat may be seen and fat necrosis accompanied by a lobu-
lar lymphohistiocytic infiltrate has been documented in a number of cases
(Fig. 10.70). Interstitial calcification is only rarely a feature.9 Exceptionally,
pseudoxanthoma elasticum-like changes have been documented.27 In a related
phenomenon, epidermal and follicular calcification have been described in
the absence of vascular lesions in a patient with toxic epidermal necrolysis in
a background of hyperparathyroidism.28

Differential diagnosis
Calcification involving small arteries and arterioles not accompanied by
thrombosis has been described in patients with nephrogenic systemic fibro-
sis.29 Furthermore, incidental vascular calcifications can also be found in
patients with peripheral vascular disease, renal insufficiency, and diabetes Fig. 10.68
mellitus.30 Calciphylaxis: note the thrombosed vessel in the center of the field.

Fig. 10.66 Fig. 10.69

Calciphylaxis: there is focal fat necrosis and widespread calcification affecting the Calciphylaxis: in addition to mural calcification, there is marked intimal fibroblastic
small vessels. Note the thickened and fibrosed septa. proliferation.
346 Inflammatory diseases of the subcutaneous fat

Fig. 10.70 Fig. 10.72

Calciphylaxis: fat necrosis with conspicuous lipophages. In addition there is widespread Crystal-storing histiocytosis: within the dermis are large histiocytes with abundant
calcification. eosinophilic cytoplasm.

Crystal-storing histiocytosis
Clinical features
Crystal-storing histiocytosis is an extremely rare condition which has been
described in patients with lymphoplasmacytic neoplasms associated with kappa
light chain monoclonal gammopathy including lymphoplasmacytic lymphoma
(immunocytoma), monoclonal gammopathy of uncertain significance, multiple
myeloma, extramedullary plasmacytoma, maltoma, and large cell B-cell lym-
phoma.1–5 Primary cutaneous involvement is exceptional and the literature on
this aspect is limited to only three case reports.6–8 These patients presented with
erythematous asymptomatic subcutaneous nodules and tumors (Fig. 10.71).

Histological features
The condition is characterized by the presence of histiocytes containing eosino-
philic crystals which have been likened to Gaucher cells (pseudo-Gaucher
cells) admixed with lymphoma cells (Fig. 10.72).3 The crystals are variably

Fig. 10.73
Crystal-storing histiocytosis: the cytoplasm contains large eosinophilic crystals.

­ olygonal to rhomboid or needle-shaped and stain positively with PAS and

p
phosphotungstic acid hematoxylin (Fig. 10.73).6,7 Erythrophagocytosis may
also be evident.3
The histiocytes express CD68, and sometimes immunoglobulin heavy and
light chains may be stained weakly.3
Ultrastructurally, the crystals are sometimes membrane bound (of lysosomal
derivation) and display platelike, rectangular, trapezoid, and rhomboid
shapes with a distinct hexagonal lattice structure.3,6,7 The tumor cells may
also ­contain intracytoplasmic crystals.3

Gouty panniculitis
There are very occasional reports of gout presenting as a crystalline lobular
panniculitis.1–5

Nodular vasculitis
Fig. 10.71
Crystal-storing
histiocytosis: this
Clinical features
patient presented with Nodular vasculitis (erythema induratum) is a rare condition which usually
marked swelling of the presents in young or middle-aged women, often in those with an eryth-
face and the eyelids. rocyanotic circulation.1 Males are only rarely affected.2 Patients present

Fig. 10.74
Nodular vasculitis: early
lesion presenting as an
erythematous nodule
on the calf of a middle-
aged female. By courtesy
of M.M. Black, MD,
St Thomas’ Hospital,
London, UK.
Fig. 10.75
Nodular vasculitis: typical bilateral involvement of the calves. By courtesy of the
Institute of Dermatology, London, UK.
with painful, tender, violaceous, indurated nodules particularly affecting
the calves although the shins, feet, ankles, thighs, and upper limbs may
sometimes be involved (Figs 10.74, 10.75). Lesions are often bilateral and
the overweight with fat calves are most often affected. Seasonal variation
has been noted with an increased incidence being recorded in the cold win-
ter months. Skin lesions often recur over many years. Ulceration is com-
mon and scarring with hyperpigmentation frequently accompanies healing
(Figs 10.76–10.78).
In those cases that represent a manifestation of underlying tuberculo-
sis, the term erythema induratum (Bazin's disease) is frequently applied. In
this condition, there is invariable hypersensitivity to intradermal injection
of purified protein derivative (PPD) at a dilution of 1:10 000 and a com-
plete clearing of all skin lesions following treatment with antituberculous
chemotherapy.3–6
Nodular vasculitis 347
Fig. 10.76
Nodular vasculitis: the nodules frequently ulcerate. By courtesy of R.A. Marsden,
MD, St George’s Hospital, London, UK.
Fig. 10.77
Nodular vasculitis: in this severely affected patient ulcerated lesions are present on
the shins in addition to the calves. By courtesy of R.A. Marsden, MD, St George’s
Hospital, London, UK.
Pathogenesis and histological features
The relationship between erythema induratum and nodular vasculitis has for
many decades been the subject of controversy. Similarly, the association of
the former condition with an underlying tuberculous infection has been the
subject of prolonged debate.
As outlined above, the more recent literature gives considerable support to
the notion that occult tuberculosis is present in many patients with erythema
induratum and that the two terms are, therefore, synonymous in a substan-
tial proportion of cases. Thus, erythema induratum may be associated with
evidence of active tuberculosis.7–11 Although cultures of lesions are invari-
ably negative, the more recent demonstration of Mycobacterium tuberculosis
DNA by PCR in lesional tissue adds strong additional support to the proposal
of an underlying tuberculous etiology.12–21
Nodular vasculitis can, therefore, be regarded as a hypersensitivity reaction
in which mycobacterial antigens are one important cause. Immune complex
and delayed hypersensitivity mechanisms have both been proposed.13 Other
predisposing factors for this condition have not yet generally been identi-
fied although nodular vasculitis has been described in association with acute
348 Inflammatory diseases of the subcutaneous fat

Fig. 10.78 Fig. 10.80

Nodular vasculitis: Nodular vasculitis: well-formed epithelioid granulomata and multinucleate giant cells
multiple scarred lesions. are present.
Note the marked
hyperpigmentation.
By courtesy of the
Institute of Dermatology,
London, UK.

myeloid leukemia, chronic hepatitis C infection, and as an adverse drug reac-

tion associated with propylthiouracil.20,22–25 Nodular vasculitis has recently
been reported in a patient with ulcerative colitis.26 Bacille Calmette-Guerin
(BCG) vaccination, distal painful peripheral neuropathy, and granulomatous
aortic valve stenosis may on occasion be associated with erythema induratum
of Bazin.27–29
The histological features combine septal and lobular changes (Fig.
10.79). The presence of vasculitis has traditionally been regarded as a
sine qua non for the diagnosis of nodular vasculitis (erythema indura-
tum). Nevertheless, a recent study analyzing 101 biopsy specimens from
86 patients with clinical features of erythema induratum failed to detect
the presence of vasculitis in 9.9% of specimens, even after examination of
multiple serial sections.30
In a biopsy from an established lesion, the septa are widened and chron-
ically inflamed (Fig. 10.80). Acute vasculitis (affecting septal and ­lobular
veins and venules) with a heavy inflammatory cell infiltrate consisting of Fig. 10.81
Nodular vasculitis: vascular involvement as seen in this field is a characteristic
feature.

­ eutrophils, lymphocytes, and histiocytes is typically present, sometimes

n
accompanied by vessel wall necrosis and thrombosis (Fig. 10.81). The most
frequently affected are small lobular veins, followed by both septal veins and
lobular venules.30 In addition, septal arteries may also be involved by the vas-
culitic process.30
Occasionally, septal granulomatous inflammation can also be evident.
Lobular inflammation may occasionally be limited to a focal ele-
ment adjacent to an acutely inflamed vessel.31 More frequently, how-
ever, it presents as nodular lesions scattered throughout the whole lobule
or affecting multiple lobules. Fat necrosis is invariably present and is
often florid. The features are varied and range from typical lipophagic
fat necrosis to coagulative or more rarely caseation-like necrosis ( Figs
10.82, 10.83 ).32 Neutrophils, lymphocytes, and histiocytes with xan-
thomatized forms are typically seen. Granulomata are often present and
giant cells of both foreign body and Langerhans type are frequently a
feature ( Fig. 10.84 ).
Fig. 10.79 In biopsies from chronic or resolving lesions, fibrosis of both the septa
Nodular vasculitis: note the distinct nodules of granulomatous inflammation at the and lobules is often present. Giant cells and granulomata may still be
periphery of the lobule. present.
 Neutrophilic lobular panniculitis associated with rheumatoid arthritis 349

Differential diagnosis
Due to the frankly granulomatous nature of the histology, it is mandatory to
exclude infective causes of panniculitis, particularly mycobacterial and fungal
infections, including cryptococcosis, mycetoma, chromomycosis, sporotricho-
sis, and aspergillosis. Subcutaneous sarcoidosis should also be considered,
although in this condition granulomata are also seen in the dermis. Asteroid
inclusions and Schaumann bodies, which are both features of sarcoidosis (see
below), are not characteristic of erythema induratum.

Subcutaneous sarcoidosis
Clinical features
Involvement of subcutaneous fat in patients with sarcoidosis is rarely encoun-
tered by histopathologists even though it may occur in as many as 1.4% to
6% of all patients with this disease.1–3 Most often it presents as asymptomatic
or tender, flesh-colored to erythematous, subcutaneous nodules with frequent
clustering, principally affecting the extremities although a more general-
Fig. 10.82 ized distribution has also been documented.2–10 Exceptionally, ­subcutaneous
Nodular vasculitis: note the presence of numerous lipophages. involvement may be the initial or even the only feature of sarcoidosis.6,11
Isolated subcutaneous sarcoidosis has also been reported following inter-
feron treatment for melanoma.12,13 More commonly, however, subcutane-
ous lesions are associated with visceral disease, particularly bilateral hilar
lymphadenopathy.
Subcutaneous sarcoidosis shows a predilection for females and the major-
ity of patients are in the fifth and sixth decades.6

Histological features
The changes, which predominantly involve the lobule, consist of well-formed,
noncaseating granulomata, sometimes associated with fibrosis, which may
extend into the septa. Typically, the granulomata are of the ‘naked’ type, i.e.,
devoid of a peripheral rim of lymphocytes, and giant cells of both foreign
body and Langerhans types are usually present. Exceptionally, caseation and
calcification have been described.14,15

Differential diagnosis
Subcutaneous sarcoidosis is a diagnosis of exclusion; other causes of gran-
ulomatous inflammation – including mycobacterial and fungal infections,
foreign body reactions, and so-called ‘metastatic Crohn's disease’ – must be
Fig. 10.83 considered in the differential diagnosis.16,17
Nodular vasculitis: the eosinophilic necrotic debris reminiscent of caseation is a
typical feature.
Neutrophilic lobular panniculitis associated
with rheumatoid arthritis
Clinical features
Also known as pustular panniculitis, this rarely described entity has been
documented in middle-aged females who presented with painful nodules
predominantly affecting the lower legs.1–5 Similar changes have also been
reported on the back, upper arms, forearms, and nasal bridge in an infant
with juvenile rheumatoid arthritis.6 Blister formation, pustulation, ulceration,
and discharge of oily, necrotic debris may occur.3–5

Pathogenesis and histological features

Fig. 10.84
Nodular vasculitis: granulomata may be seen within the lobule and also in the septa.
The pathogenesis may be related to circulating immune complexes since high
levels have been identified in patients with this condition.3,4
The lobules and septa are infiltrated by neutrophils with central lobu-
lar necrosis accompanied by a histiocytic and giant cell response.2–5 Small
numbers of eosinophils are sometimes present.4 Nuclear dust can be con-
spicuous and cyst formation with membranous change has been described.4,5
Leukocytoclastic vasculitis affecting the dermal arterioles and venules may
be seen.4 Endothelial swelling, hemorrhage, and fibrin deposition may also
be present.7
350 Inflammatory diseases of the subcutaneous fat

Neutrophilic lobular panniculitis has also been reported in a patient with

nonrheumatoid arthritis.8

Differential diagnosis
Factitial disease and infections must always be excluded in neutrophil-rich
panniculitides. Similarly, pancreatic disease-associated panniculitis and α1-
antitrypsin deficiency-associated panniculitis are typically linked with a lobu-
lar neutrophil-rich infiltrate. The lobular panniculitis associated with bowel
bypass is also typically neutrophil rich.9,10

Eosinophilic panniculitis
Clinical features
Eosinophilic panniculitis is not a disease in its own right, but represents a
reaction pattern that may be found under a variety of circumstances.1 It is
seen more often in females than males (3:1). Although a wide age range is
affected, there are two peaks: one in the third decade and the other in the
sixth decade and above. Patients present predominantly with nodules and Fig. 10.86
plaques, although papules and pustules are sometimes seen.2–5 Lesions, which Eosinophilic panniculitis: note the massive eosinophilic infiltrate.
may be single or multiple, affect the legs, arms, trunk, and face in decreasing
order of frequency.
Eosinophilic panniculitis may be found in association with erythema
nodosum, immune complex-mediated vasculitis, atopic dermatitis, refractory
anemia, chronic recurrent parotitis, artifact, leukocytoclastic vasculitis, drug
reactions, eosinophilic cellulitis, insect bites, toxocariasis, gnathostomiasis,
Fasciola infection, human immunodeficiency virus (HIV), specific immuno-
therapy with aqueous lyophilized bee venom, injection site reactions, trauma,
and in patients with lymphoma.5–19 On rare occasions, no obvious underlying
condition can be detected.19 Other than in those patients with an associated
neoplasm, eosinophilic panniculitis appears to be a self-limiting and benign
condition.7

Histological features
The histological features affect the lobules and the septa and are character-
ized by an intense infiltrate of eosinophils, which may be accompanied by
variable numbers of other inflammatory cells including neutrophils, lym-
phocytes, and monocytes (Figs 10.85, 10.86). Vasculitis is usually not seen.

Fig. 10.87
Eosinophilic panniculitis: note the flame figure in the center of the field.

Fat necrosis is sometimes present. On occasions, typical ‘flame figures’, as

seen in eosinophilic cellulitis, may be noted (Fig. 10.87). The changes some-
times extend into the reticular dermis and occasionally the underlying fascia
is involved.

Fig. 10.85
Eosinophilic panniculitis:
there is a heavy,
predominantly lobular
inflammatory cell infiltrate.
Infective panniculitis
Clinical features
The clinical features in patients with infective panniculitis are not spe-
cific and include nodules, ulcerated lesions, abscesses, and erythema
nodosum-like lesions.1 Patients are usually, but not invariably, immuno-
suppressed. The legs and feet are the sites most often affected. Specific
infections, which have presented with panniculitis, include Histoplasma
capsulatum, Pseudomonas aeruginosa, Candida albicans, Aspergillus spp.,
Zygomycetes, Cryptococcus neoformans, Fusarium spp., Mycobacterium
avium intracellulare, Mycobacterium ulcerans, Mycobacterium mari-
num, Mycobacterium tuberculosis, Mycobacterium chelonei, Brucella
ssp, Neisseria meningitidis, Streptococcus pyogenes, Staphylococcus
aureus, Actinobacillus, Actinomyces spp., Coxiella burnetii and cytome­
galovirus.2–28
 Infective panniculitis 351

Histological features
Epidermal changes may include parakeratosis, acanthosis and spongio-
sis.1 The dermis is edematous and often shows a perivascular and intersti-
tial inflammatory cell infiltrate containing many neutrophils. Hemorrhage is
sometimes present.
Most commonly, the subcutaneous fat shows features of a mixed septal/
lobular panniculitis (Figs 10.88–10.92).1 Erythema nodosum-like features
may be evident.1 Changes suggestive of an infective etiology include a promi-
nent neutrophilic infiltrate, hemorrhage, basophilic necrosis and necrosis of
sweat glands, vascular proliferation, and discrete abscess formation.1,29
Granulomata are sometimes conspicuous in atypical mycobacterial infec-
tions. On other occasions acute inflammatory changes with abscess forma-
tion are seen (e.g., Mycobacterium chelonei infection). In the latter condition,
organisms may be identified in microcysts lined by neutrophil polymorphs.1
Mycobacterial infection may also occasionally manifest as phlebitis.30 Deep
fungal infections commonly involve the subcutaneous fat, presenting as granu-
lomatous or mixed suppurative and granulomatous inflammatory processes.
From the above description, it is obvious that special stains for bacteria
and fungi should be performed in all cases of panniculitis where the etiology Fig. 10.90
is uncertain. Culture may also be necessary in some instances. Infective panniculitis: in this example, there is a granulomatous infiltrate.

Fig. 10.88 Fig. 10.91

Infective panniculitis: there is intense acute inflammation with abscess formation. Infective panniculitis: a twisted hypha typical of zygomycosis is present.

Fig. 10.89 Fig. 10.92

Infective panniculitis: this example is due to cryptococcal infection. Note the typical Infective panniculitis: numerous cocci are present in this section from a patient with
yeast forms (arrowed). necrotizing fasciitis.
352 Inflammatory diseases of the subcutaneous fat

Acute infectious id panniculitis –

panniculitic bacterid
This is a recently described variant of lobular neutrophilic panniculitis, which
likely represents an id reaction to infections other than Mycobacterium
tuberculosis.1

Clinical features
Following primary infection elsewhere (sinusitis, breast and dental abscess,
impetigo, cellulitis, viral pharyngitis, Pseudomonas pneumonia, and ulcer-
ative colitis) all 10 patients (4 males, 6 females) presented with sudden
­development of tender nodules on the lower extremities, with additional
­involvement of the upper extremities in three patients. The lesions resolved
completely after adequate therapy of the primary focus. Hyperviscosity con-
ditions were ­present in three patients.
A

Histological features
Fat lobules and septa were infiltrated by a prominent inflammatory cell
infiltrate composed predominantly of neutrophils forming small microab-
scesses, accompanied by fat necrosis. Lymphocytes and histiocytes were also
present in the infiltrate, with occasional granuloma formation. Spilling of
the inflammation into the dermis was seen. Vascular changes consisted of
necrotizing vasculitis involving arterioles and venules in the fat lobules and
lower dermis, but also of thrombotic microangiopathy of the capillaries in
the ­subcutaneous fat.
Special stains for microorganisms were negative in all cases. Infection with Fig. 10.93
Sclerosing panniculitis
Mycobacterium tuberculosis was excluded in all patients.
(A & B): (A) the skin
shows features of stasis.
Dense fibrosis has
Differential diagnosis resulted in this inverted
Infection should be excluded with appropriate stains. Neutrophilic ­lobular bottle appearance.
panniculitis associated with rheumatoid arthritis can have a similar morpho­ Note the characteristic
logy, and clinicopathological correlation is vital. symmetry; (B) close-up
view of an early lesion
showing an indurated,
markedly erythematous
plaque. (A) By courtesy
Sclerosing panniculitis of the Institute of
Dermatology, London, UK;
Clinical features (B) By courtesy of J.C.
Sclerosing panniculitis (stasis-associated sclerosing panniculitis, hypo- B Pascual, MD, Alicante,
Spain.
dermatitis sclerodermaformis, lipodermatosclerosis, lipomembranous
change in chronic panniculitis) is a relatively common condition which
most often develops in middle-aged or elderly, overweight females with
a history of peripheral venous disease including varicose veins, throm-
bophlebitis, and deep venous thrombosis.1–7 Less often, the condition
follows arterial ischemia. Patients present with indurated, wood-like, The histological features are variable depending upon whether the biopsy
sclerodermiform plaques affecting the lower legs in a stocking distri- represents an early stage in the development of this disorder or an established
bution and characteristically resembling an inverted bottle appearance lesion.5,11
(Fig. 10.93).1,3 Often the changes are bilateral and symmetrical.2 The Within the subcutaneous fat, early lesions are characterized by cen-
overlying skin may show additional changes of venous stasis including trilobular ischemia with infarction of fat cells and vascular congestion/­
atrophy, ulceration, hyperpigmentation and telangiectasia. Patients with hemorrhage.5 Vascular thrombosis may also be seen but there is no evidence
sclerosing panniculitis and systemic sclerosis frequently have associated of vasculitis. A lymphocytic infiltrate is present in the septa and this may spill
­pulmonary hypertension.8 over to affect the edge of the lobule. Hemosiderin deposition is ­commonly
present.
In established lesions, ischemic changes may still be evident but more
Pathogenesis and histological features often there is microcystic change with hyalinization within the fat lob-
The pathogenesis of sclerosing panniculitis is venous stasis within the centri- ule (Figs 10.94–10.96). Membranous fat necrosis is often present and
lobular capillaries leading to ischemia and eventual infarction of the subcu- lipophagic changes may be evident. Septal scarring is present, which in
taneous fat. Increased interstitial fibrinogen as a result of excessive capillary advanced lesions can be marked with resultant atrophy of the subcutane-
permeability due to venous hypertension is thought to be of importance.4 ous fat.
Fibrin deposition around the dermal capillaries results in hypoxia. In addi- The dermis typically shows the features of stasis including chronic inflam-
tion, there is some evidence to suggest that increased matrix metalloprotei- mation, fibrosis, vessel-wall thickening, lobular capillary proliferation, and
nases and urokinase-type plasminogen activator may be of importance in the hemosiderin deposition. Acanthosis, spongiosis, and lichenification may be
pathogenesis.9,10 evident.
 Membranous fat necrosis 353

Differential diagnosis
The absence of sclerodermiform dermal changes and the presence of features
of venous stasis distinguish end-stage sclerosing panniculitis from morphea
profunda, scleroderma and acrodermatitis chronica atrophicans (a late mani-
festation of Lyme disease).

Membranous fat necrosis

Fig. 10.94
Sclerosing panniculitis:
there is typical microcystic
change.
Clinical features
Membranous fat necrosis is a non-specific change found predominantly in the
subcutaneous fat. It was first described, however, in patients with progressive
sudanophilic leukoencephalopathy (Nasu-Halola's disease).1–3 This is a rare
condition in which cystic lesions develop in subcutaneous fat and bone mar-
row associated with pathological fractures and cerebral lesions resulting in
seizures and presenile dementia.
Subsequently membranous change has been recognized as a common
manifestation of venous stasis-associated disease.4–7 It has, however, also
been observed in association with numerous other conditions includ-
ing arterial insufficiency, diabetes mellitus, erythema nodosum, nodular
­vasculitis, infective panniculitis, pancreatic disease-associated panniculitis,
subcutaneous sarcoidosis, morphea, morphea profunda, cytophagic histio-
cytic panniculitis, dermatomyositis, systemic sclerosis, lupus panniculitis,
necrobiosis lipoidica, and nodular cystic fat necrosis.6–16 It has also been
described in the breast, in appendices epiploicae, within an ovarian cys-
tic teratoma and following subcutaneous elemental mercury injections.17–21
Membranocystic change accompanied by myospherulosis has also been
documented.22

Pathogenesis and histological features

Although in the majority of cases an ischemic pathogenesis is likely, its pres-
ence following trauma and in a background of infection suggests that other
mechanisms are sometimes responsible. The membrane change likely repre-
sents altered adipocyte cell membranes although recently a contribution by
histiocytes has been postulated.5–7
Histologically, it presents as amorphous, autofluorescent, eosinophilic,
PAS-positive membranes outlining cysts within the lobules of the subcutane-
ous fat (Fig. 10.97). Pseudopapillary and arabesque patterns are commonly
present (Figs 10.98, 10.99). The membrane also stains for lipid using Sudan
black and is luxol fast blue positive.5 This is thought to represent ceroid, at
least in part.23
Ultrastructurally, the membrane is composed of perpendicularly orien-
tated microvilli alternating with dilated tubular crypts reminiscent of smooth
endoplasmic reticulum with adjacent electron-dense material.5
Fig. 10.95
Sclerosing panniculitis: close-up view of microcysts.

Fig. 10.96 Fig. 10.97

Sclerosing panniculitis: membranous fat necrosis is evident. Membranous fat necrosis: note the delicate membranes lying within small cystic spaces.
354 Inflammatory diseases of the subcutaneous fat
Fig. 10.98
Membranous fat necrosis: close-up view.
Lipodystrophy
Classification and clinical features
The lipodystrophies are a complex group of disorders characterized by a
familial or acquired, complete or partial loss of subcutaneous fat.1–5 They
have been classified as follows:1
• Familial lipodystrophy including:
– generalized lipodystrophy (Berardinelli-Seip syndrome)
– partial lipodystrophy (Dunnigan and Köbberling variants)
• Acquired lipodystrophy including:
– generalized lipodystrophy (Lawrence syndrome)
– partial lipodystrophy (Barraquer-Simons syndrome)
– HIV-associated lipodystrophy
• Localized lipoatrophy (localized lipodystrophy) including:
– drug-induced lipoatrophy
– pressure-induced lipoatrophy
– panniculitis-associated lipoatrophy
– centrifugal variant lipoatrophy
– idiopathic lipoatrophy.
Familial lipodystrophy
Congenital generalized lipodystrophy
(Berardinelli-Seip syndrome)
This exceedingly rare variant of lipodystrophy is inherited in an autosomal
recessive mode and is usually recognizable at birth.1–4 Its prevalence has been
estimated as 1:12 000 000.1 The sex incidence is equal.
It is characterized by a complete absence of metabolically active subcutane-
ous fat in association with insulin resistance, hyperinsulinemia, hypertriglyc-
eridemia with normal or slightly raised cholesterol, and nonketotic diabetes
mellitus.4 Mechanical fat such as is found in the orbits, on the palms and
soles, and around the external genitalia is unaffected.1 Patients also have a
voracious appetite associated with a hypermetabolic state and marked hyper-
hidrosis. Additional features include an anabolic syndrome with increased
height velocity, advanced bone age, muscular hypertrophy, masculine body
build, acromegaloid stigmata, hepatomegaly, enlarged external genitalia in
childhood, abundant curly hair on the scalp, hypertrichosis, umbilical ­hernia,
acanthosis nigricans, mild mental retardation with hydrocephalus, and
­hypothalamic–pituitary dysfunction.4,5
Diabetes is thought to develop as a consequence of extensive pancreatic
amyloid deposition with loss of β-cells.6 Postmortem studies have demon-
strated fatty liver with cirrhosis.7
Fig. 10.99
Membranous fat necrosis: the features are highlighted with a Masson’s trichrome
stain.
The genes for congenital generalized lipodystrophy have been mapped
to human chromosome 9q34 and 11q13, and are designated AGPAT2 and
BSCL2 (seipin gene), respectively.8–10 Not all patients have mutations in these
genes, suggesting the presence of additional yet unidentified genetic loci.11
Diagnostic criteria as outlined in Table 10.3 have recently been
recommended.1
Familial partial lipodystrophy (Dunnigan
variant)
This is another exceedingly rare condition with an estimated prevalence
of less than 1 in 15 000 000 of the population.1 The original cases were all
females and therefore a sex-linked dominant mechanism, lethal in hemizy-
gous males, was postulated.12,13 The more recent publication of families with
affected male members suggests, however, that an autosomal dominant mech-
anism is at play.14
Patients are normal at birth but at puberty they lose subcutaneous fat from
the extremities and to a lesser extent from the trunk.15 The face is spared and,
indeed, in some patients, excessive fat deposition on the face and neck has
been documented. Diabetes mellitus, hypertriglyceridemia, and low serum
high density lipoprotein (HDL) cholesterol levels become manifest in early
adulthood.1,16,17 Patients may develop chylomicronemia and pancreatitis.1
Acanthosis nigricans, hirsutism, menstrual abnormalities, and polycystic ova-
ries are also sometimes evident.1
The gene responsible for familial partial lipodystrophy has been mapped
to chromosome region 1q21-22.18–20 It has been identified as the lamin A/C
gene, which codes for a nuclear envelope protein lamin.21–23
Diagnostic criteria as outlined in Table 10.3 have recently been
recommended.1
Familial partial lipodystrophy (Köbberling
variant)
This is an exceedingly rare variant in which only a small number of affected
pedigrees have been documented.1,24–26 Sporadic variants have also been
described.1,26,27 In these patients, loss of fat is limited to the extremities. There
may be increased truncal fat.1,26 Hypertriglyceridemia, arterial hypertension,
insulin resistance or diabetes mellitus are usually present, and the patients
have increased risk for premature cardiovascular disease and pancreati-
tis.1,26 Acanthosis nigricans has been described in a single patient.26 To date,
­documented affected patients have been female.
 Acquired lipodystrophy 355

Table 10.3
Lipodystrophies: diagnostic criteria

Disorder Essential criteria Confirmatory criteria

Congenital generalized Generalized lack of body fat Acanthosis nigricans
lipodystrophy Extreme muscularity from birth Acromegaloid features
Umbilical hernia
Clitoromegaly and mild hirsutism
Severe fasting or postprandial hyperinsulinemia
Onset of diabetes or impaired glucose tolerance test in teenage years
Hypertriglyceridemia with low HDL cholesterol concentration
Characteristic body fat distribution on MRI
Familial partial Normal physical appearance at birth Normal or excessive facial adipose tissue
lipodystrophy Loss of subcutaneous fat of the extremities Acanthosis nigricans
(Dunnigan variant) commencing at puberty Mild to moderate fasting or postprandial hyperinsulinemia
Muscular-appearing extremities Onset of diabetes or impaired glucose tolerance after age 20 years
commencing at puberty Hypertriglyceridemia with low serum HDL cholesterol concentrations
Characteristic body fat distribution on MRI
Acquired generalized Generalized loss of subcutaneous fat Loss of fat from palms and soles
lipodystrophy developing in childhood or later Severe fasting or postprandial hyperinsulinemia
Extreme muscularity appearing in childhood Impaired glucose tolerance or diabetes
or later Hypertriglyceridemia with low serum HDL cholesterol concentrations
Nodular panniculitis preceding onset of lipodystrophy
Coexistence of autoimmune diseases
Acquired partial Gradual loss of subcutaneous fat of the Normal or excess fat on hips and lower extremities
lipodystrophy face, neck, trunk, and upper extremities Proteinuria
developing in childhood or adolescence Biopsy proven mesangiocapillary glomerulonephritis
Low serum C3 levels
Presence of C3 nephritic factor
Absence of insulin resistance
Presence of other autoimmune diseases
Characteristic body fat on MRI
HDL, high density lipoprotein; MRI, magnetic resonance imaging. Derived from Garg, A. (2000) American Journal of Medicine, 108, 143–152.

Familial partial lipodystrophy associated
with mandibuloacral dysplasia
This autosomal recessive variant of lipodystrophy is characterized by the
presence of a variety of bony defects including mandibular and clavicular
hypoplasia, acroosteolysis, delayed closure of cranial sutures, and joint
contractures associated with cutaneous hyperpigmentation.28,29 Genetically,
it is a heterogeneous disorder. Mutations in genes encoding nuclear lamina
proteins and zinc metalloproteinase have been detected.30–33 Lipodystrophy
varies from loss limited to the extremities (type A) through to general-
ized loss (type B). Patients also have insulin-resistant hyperinsulinemia and
hypertriglyceridemia and diminished serum HDL cholesterol levels.29
Acquired lipodystrophy
Acquired generalized lipodystrophy
Acquired generalized lipodystrophy (Lawrence syndrome, lipoatrophic dia-
betes, lipoatrophic panniculitis, lipodystrophic diabetes) can be subclassified
into three variants:
• Type 1: the panniculitis variant,
Acquired partial lipodystrophy
• Type 2: the autoimmune disease variant,
• Type 3: the idiopathic variant,
and affect 25%, 25%, and 50% of the patients, respectively.34
Acquired generalized lipodystrophy is similar to the congenital form
although there is a predilection for females (3:1).1,34–37 Patients present in
childhood or adolescence with fat loss, which progresses over a period of
months or years.1 The entire body is affected, particularly face, arms, and
legs. The muscles of the extremities appear unduly prominent. Children with
this disorder may have a voracious appetite.
Features of an inflammatory nodular panniculitis appear to have pre-
ceded the onset of lipodystrophy in a number of cases (lipoatrophic
­panniculitis).34,38,39 These patients appear to have less severe fat loss and lower
prevalence of hypertriglyceridemia and diabetes in comparison with patients
having the autoimmune or idiopathic variant of the disease.34
Autoimmune diseases associated with acquired generalized lipodystrophy
include juvenile dermatomyositis in particular, followed by Hashimoto's thy-
roiditis, juvenile rheumatoid arthritis, adult-onset dermatomyositis, ­systemic
lupus erythematosus, systemic sclerosis, Sjögren's syndrome, and vitiligo.1,40–42
Liver involvement may be marked with steatosis, autoimmune hepatitis,
and cirrhosis supervening in a substantial number of cases.4,43 Additional
features include severe insulin resistance, diabetes, hyperinsulinemia, and
hypertriglyceridemia accompanied by low serum HDL cholesterol con-
centrations.1,34 Acquired generalized lipodystrophy can also be associ-
ated with cerebellar degeneration, unicameral bone cysts, and proteinuric
nephropathy.44–46
A preceding viral illness has frequently antedated the development of acquired
generalized lipodystrophy although whether this is causal or not is unclear.1,4
A case of panniculitis of the acquired generalized lipodystrophy variant was
reported recently, presumably triggered by pulmonary tuberculosis.47
Diagnostic criteria as outlined in Table 10.3 has been recommended.1
Acquired partial lipodystrophy (Barraquer-Simon syndrome, progressive lip-
odystrophy, cephalothoracic progressive lipodystrophy) is one of the more
common variants of lipodystrophy. Females are affected three times more
often than males.1 Patients present in late childhood or adolescence with grad-
ual loss of the subcutaneous fat of the face followed by the neck, ­shoulders,
arms, thorax, and upper abdomen (Fig. 10.100).1,48–50 The distal subcutane-
ous fat is typically spared and sometimes, in contrast, there is even excessive
fat deposition around the pelvis and on the legs.
Mesangiocapillary (membranoproliferative) glomerulonephritis (MCGN II)
and hypocomplementemia often accompany this variant.51–53 C3 levels are usu-
ally low in contrast to C1q, C4, C5, C6, factor B, and properdin, which are
356 Inflammatory diseases of the subcutaneous fat
A B
normal.54,55 The glomerulonephritis and low C3 have been shown to be due
to an IgG autoantibody, the C3 nephritic factor (C3NeF).56 It has been shown
that the latter has the capacity to induce adipocyte lysis.57 Three patients have
recently been described that presented with low C4 complement levels, wide-
spread acquired lipodystrophy, and chronic autoimmune hepatitis.58
An association with a number of other autoimmune diseases including
Sjögren's syndrome, dermatomyositis, hypothyroidism, and SLE has also been
documented.59–62 Patients may in addition develop hyperlipidemia, ­nonketotic
diabetes mellitus, acanthosis nigricans, and hirsutism.1 Hepatomegaly due to
fat accumulation is occasionally present. Extrinsic allergic alveolitis has been
reported in a single patient.63
Expression gene analysis in a single patient with acquired partial
­lipodystrophy demonstrated down-regulation of the PPARγ gene, which is nor-
mally associated with adipocyte differentiation, as well as reduced ­expression
of mitochondrial genes.64 In addition, heterozygous mutations of the LMNB2
gene have been detected in three out of four analyzed patients.65
Diagnostic criteria as outlined in Table 10.3 have recently been
recommended.1
Localized lipoatrophy
Clinical features
Localized disease (lipoatrophy) is a much more common phenomenon. The
subject has, however, been made extremely complicated by virtue of the large
number of synonyms that have been used to describe the same disease process
over the years (e.g., lipodystrophy, annular lipoatrophy, annular lipodystrophy,
semicircular lipoatrophy, postinjection lipoatrophy, involutional lipoatrophy,
lipodystrophia centrifugalis abdominalis infantilis, centrifugal lipodystrophy).
Essentially, localized lipodystrophy may result from a range of injurious stim-
uli and present at a wide variety of sites but essentially all of the subtypes listed
above are variations of the same disease process which may therefore follow
localized panniculitis, connective tissue diseases, injections, trauma, etcetera.
Lesions affecting the proximal extremities or buttocks should raise the possi-
bility of infection or trauma. Localized lipoatrophy has been described follow-
ing subcutaneous injections of insulin, triamcinolone acetate and iron dextran,
and following vaccinations.66–69 It has also been described as a ­complication of
idiopathic connective tissue diseases including systemic lupus erythematosus
Fig. 10.100
(A, B) Partial lipodystrophy:
note the striking loss of
symmetry due to diminished
fatty tissue of the left side
of the face. By courtesy of
the Institute of Dermatology,
London, UK.
(profundus), dermatomyositis, polymyositis, linear morphea, facial hemiatro-
phy, lichen sclerosus et atrophicus and progressive systemic sclerosis.70–72
Other types of localized lipodystrophy include annular lipodystrophy and
a variant that affects only half the circumference of an extremity (lipoatro-
phia semicircularis). These distinctive annular lesions are likely to result from
a localized pressure effect such as that which may occur with tight cloth-
ing or persistent localized trauma.73–76 Idiopathic variants are also recognized
including lipoatrophy associated with Becker's nevus and lipodystrophia
­centrifugalis abdominalis infantilis.77–80
Pathogenesis and histological features
The exact pathogenesis of lipodystrophy is unknown. A variety of theories has
been proposed, including hypothalamic–pituitary dysfunction (overproduc-
tion of fat-mobilizing peptides and amines), disordered fat metabolism, infec-
tion, and heredity. A currently favored area of research is directed towards
the role of abnormal insulin receptors on fat cells. It has been postulated that
abnormal insulin receptors are associated with diminished uptake of lipid by
fat cells with resultant lipodystrophy, hyperlipidemia, and hyperinsulinemia.
In general, the histopathology of lipodystrophy is noninflammatory in
nature.81–83 There is a progressive diminution of adipocyte lipid accompanied
by a decrease in cell size so that the cells become separated from one another
(Fig. 10.101). The stroma becomes hyalinized or myxomatous and contains
clusters of tortuous capillaries. As the end result resembles embryonic fat, this
process of atrophy is sometimes called ‘reversal of embryogenesis’.
Patients with multiple areas of localized lipoatrophy may show mild
inflammatory changes comprising perivascular and periseptal lymphocytic
infiltration accompanied by minor septal fibrosis.
Lipoatrophic panniculitis
Clinical features
Lipoatrophic panniculitis (atrophic connective tissue panniculitis) represents a
very rarely documented inflammatory form of localized lipoatrophy.1–7 In the
original report, three children developed centrifugally enlarging erythematous
nodules and plaques with atrophic centers on the lower extremities. Healing
of the lesions resulted in the clinical appearances of localized lipoatrophy.
The areas of lipoatrophy coalesced to give an appearance resembling partial
 Localized lipoatrophy 357

A B

Fig. 10.101
Lipodystrophy: (A) there is only a very small residual amount of subcutaneous fat in the center of the field; (B) these tiny adipocytes are reminiscent of embryonic fat. By courtesy
of W.P. D. Su, MD, Mayo Clinic, Rochester, USA.

or total lipodystrophy.1 All three patients had elevated ESRs. Two patients
had associated diabetes mellitus (one with coexistent Hashimoto's thyroidi-
tis) and one developed juvenile rheumatoid arthritis. Peters and Winkelmann
described a similar condition under the rubric ‘atrophic connective tissue dis-
ease panniculitis’.2 Nowadays, this entity would probably be best included in
the spectrum of acquired total or partial lipodystrophy.
have a raised ESR, thrombocytosis, and microcytic anemia. Antinuclear fac-
tor may be present.1 A similar disorder has rarely been described in adults
(adult lipophagic atrophic panniculitis).2 Winkelmann postulates that many
cases of Weber-Christian disease documented in the earlier literature belong
to this disorder (literature summarized in ­reference 1).

Histological features Histological features

In atrophic connective tissue panniculitis the histological features are those
of a lobular panniculitis.1,7 The deep dermis may manifest a ­perivascular
­lymphocytic and histiocytic infiltrate. Lymphocytes and mononuclear
­phagocytes extensively infiltrate the fatty lobules. Eosinophils and multi-
nucleate giant cells are uncommon. In more advanced lesions, there is fatty
­atrophy accompanied by an infiltrate composed mainly of foamy mac-
rophages.3 Vasculitis is not a feature of this disorder.1
Lipophagic panniculitis of childhood
Clinical features
Lipophagic panniculitis of childhood (lipophagic-granulomatous lipoatro-
phy) is exceedingly rare and presents in children as erythematous asymp-
tomatic or tender plaques and nodules affecting the arms or legs, which are
later associated with lipoatrophy.1 Fever is common and the children ­usually
Histologically, lipophagic panniculitis is characterized by panlobular inflam-
mation with histological features of lipoatrophy.1 The inflammatory cell
infiltrate consists of histiocytes and Touton-like lipophages. Occasional
­lymphocytes, neutrophils, and plasma cells may be evident. Eosinophils are
sometimes numerous. There is no evidence of vasculitis.1
Connective tissue panniculitis
Clinical features
This extremely rare chronic condition, originally described in two female
patients by Winkelmann and Padilha-Goncalves, comprises recurrent ­tender
subcutaneous nodules mainly on the shoulders and upper arms, but the cheek,
breast, trunk, neck or leg may also be affected.1 Healing is sometimes asso-
ciated with lipoatrophy and hyperpigmentation, which can be particularly
­disfiguring (Fig. 10.102).2

A B

Fig. 10.102
(A, B) Connective tissue panniculitis: this patient shows diffuse hyperpigmentation associated with generalized scarring and deformity. By courtesy of M.M. Black, MD, London, UK.
358 Inflammatory diseases of the subcutaneous fat

Laboratory findings include leukopenia, anemia, a raised ESR, positive anti-

nuclear antibody, and an unclassifiable antibody to extractable nuclear antigen.3

Histological features
A lymphohistiocytic panniculitis associated with both acute and caseation
necrosis characterizes the lesions. Lipophagic histiocytes and giant cells may
be present, but granulomata are not a feature and there is no evidence of sep-
tal involvement or vasculitis.1,2
At present, this variant of chronic panniculitis has defied further
classification.

Lupus erythematosus profundus

Clinical features
Lupus erythematosus profundus (lupus panniculitis) is an uncommon variant of
panniculitis, which may develop in association with either discoid lupus erythe-
matosus (DLE) or systemic lupus erythematosus (SLE).1–8 The incidence of lupus
panniculitis in SLE ranges from 2% to 10%;4,9–11 DLE is present in from 33%
to 70% of cases.4,5 Lupus panniculitis may, however, also present in the absence
of any other manifestations of lupus erythematosus.9 In a recent series from the
Mayo Clinic, 50% of patients had no evidence of any autoimmune-associated
disease.4 Lupus panniculitis shows a predilection for females (4:1) and most
patients are middle aged.4 Rarely, however, children (including infants) may be
affected.7,12 Rarely, lupus panniculitis may signify recurrence of SLE.13
Patients develop discrete, firm, asymptomatic or painful nodules, one to
several centimeters across, in the subcutaneous fat; the nodules are often
associated with trauma.9 Linear distribution of lupus panniculitis has rarely
been reported and is likely associated with a more aggressive clinical behav-
iour.14 The overlying skin may appear clinically normal or show discoid lupus
plaques, poikiloderma, erythema, atrophy or ulceration (Fig. 10.103).10,15
Anetodermic lupus panniculitis has been associated with antiphospholipid
antibodies.16 Lupus erythematosus profundus is characteristically chronic,
patients developing recurrent crops of lesions. Spontaneous resolution may
occur and leave depressed atrophic disfiguring scars (lipoatrophy) (Fig.
10.104). Sites of predilection include the face, upper and outer parts of
the arm, the breasts, back, and buttocks. Breast involvement with scarring
and calcification may be clinically mistaken for carcinoma (so-called ‘lupus
­mastitis’).17,18 Salivary gland and primary periorbital lesions have also been
documented.19–23 Rarely, the disease may present with generalized lesions.8
Fig. 10.103
Lupus erythematosus
profundus:
erythematoviolaceous
plaques showing
focal ulceration at the
characteristic site. By
courtesy of the Institute of
Dermatology, London, UK.
Fig. 10.104
Lupus erythematosus
profundus: a depressed
scarred area due to end-
stage lipoatrophy.
By courtesy of the
Institute of Dermatology,
London, UK.
In cases with associated SLE, patients frequently manifest arthralgia and
Raynaud's phenomenon; there appears to be a relatively low incidence of
renal and neurological involvement.10 Positive serology may include antinu-
clear antibody, anti-DNA antibody, anti-extractable nuclear antigen (ENA)
antibodies, and rheumatoid factor.9,15 In those patients in whom there is no
evidence elsewhere of lupus erythematosus, a raised antinuclear factor may be
the only serological abnormality.4 Although in these latter patients the prog-
nosis is generally thought to be good, in some patients there is ­considerable
mortality and the disfigurement a source of considerable distress.24,25 Partial
C4 deficiency has been described in a patient with lupus erythematosus
profundus.26
Histological features
In an established lesion the histological features of lupus erythematosus
profundus are virtually diagnostic. The overlying epithelium and super-
ficial dermis may show features of DLE, poikiloderma or be unaffected
(Figs 10.105–10.108).27,28 Within the deep dermis, and extending into the
widened septa of the subcutaneous fat, is a dense chronic inflammatory
cell infiltrate consisting predominantly of nodules of lymphocytes with
lesser numbers of plasma cells (Figs 10.109–10.111).11,13,28 Lymphocytic
nuclear debris or dust within a lymphoplasmocytic infiltrate is frequently
seen.13 Occasionally, lymphoid follicles with germinal centers are evident
(Fig. 10.112). The infiltrate may surround and permeate the walls of
blood vessels and sweat glands; involvement of the perineural sheath is
occasionally a feature (Fig. 10.113).27,29 Less often, frank lymphocytic
vasculitis with mural fibrinoid necrosis and luminal thrombosis is seen
(Fig. 10.114).
The infiltrate often extends into the periphery of the fat lobules and when
associated with fat necrosis there may also be moderate numbers of neutro-
phil polymorphs. The collagen of the deep dermis and the fibrous septa of the
subcutaneous fat show striking fibrinoid degenerative changes. Fibers may be
markedly swollen and intensely eosinophilic, or fragmented into amorphous
granular debris. Similar changes are seen surrounding individual adipocytes.
In more advanced examples, glassy eosinophilic necrosis gives a diffusely
hyalinized appearance to the subcutaneous fat (Fig. 10.115). The foci of col-
lagenous degeneration are sometimes associated with mucin deposition, and
foci of calcification which may on occasion be very prominent.10,13,15,27,28,30
Extensive endarteritis obliterans has been reported in a ­single case of lupus
panniculitis, which was associated with membranocystic changes and
­dystrophic calcification.31
 Localized lipoatrophy 359

Fig. 10.105 Fig. 10.108

Lupus erythematosus profundus: low-power view showing epidermal atrophy Lupus erythematosus profundus: the epidermis appears normal.
with hyperkeratosis and a dense dermal lymphocytic infiltrate with extension into
subcutaneous fat.

Fig. 10.106 Fig. 10.109

Lupus erythematosus profundus: in this example, there are typical features of Lupus erythematosus profundus: the septa are thickened and there is a dense
discoid lupus erythematosus. infiltrate.

Fig. 10.107
Lupus erythematosus profundus: in contrast, this patient showed disease limited to Fig. 10.110
the subcutaneous fat. Lupus erythematosus profundus: the infiltrate is largely lymphocytic.
360 Inflammatory diseases of the subcutaneous fat

Fig. 10.111 Fig. 10.114

Lupus erythematosus profundus: plasma cells, as shown in this field, are sometimes Lupus erythematosus profundus: lymphocytic vasculitis, as noted in this field, is
conspicuous. not uncommon.

Fig. 10.115
Fig. 10.112 Lupus erythematosus profundus: hyalinization of the fat is a characteristic feature.
Lupus erythematosus profundus: lymphoid follicles, as shown in this field, may be
a prominent feature.
By immunohistochemistry, the predominant cells are α/β T-helper lymphocytes,
intermingled with B lymphocytes.13 Molecular analysis by polymerase chain
reaction generally reveals a polyclonal phenotype.13
Immunofluorescence commonly reveals immunoglobulin and complement
at the dermoepidermal junction and sometimes around the superficial blood
vessels.15,27

Differential diagnosis
Similar histological features may be seen in other connective tissue diseases
including linear morphea, morphea profunda, systemic sclerosis, dermatomyo-
sitis, mixed connective tissue disease, and polymyositis.32–35 Recently, Sjögren's
syndrome has been added to the causes of so-called plasma cell panniculitis.36
Lobular panniculitis with sclerosis reminiscent of lupus panniculitis has also
been described in a patient with Degos' disease (malignant atrophic ­papulosis).37
Distinction between lupus profundus and subcutaneous ­panniculitis-like T-cell
lymphoma can, on occasion, be extremely difficult on clinical as well as on
histological grounds.38–41 The presence of atypical lymphocytes with immuno-
histochemical features of cytotoxic T cells (CD3+,CD8+) accompanied by high
proliferation rate and monoclonal TCR-γ gene rearrangement is ­suggestive
of lymphoma.38 Nevertheless, lupus profundus and panniculitis-like T-cell
Fig. 10.113 ­lymphoma may coexist in the same patient.38 Overlapping ­histological ­features
Lupus erythematosus profundus: blood vessel walls are commonly thickened and with characteristics of both lupus profundus and ­subcutaneous ­panniculitis-like -
hyalinized. cell lymphoma are seen in these patients.38,42,43
 Localized lipoatrophy 361

Scleroderma panniculitis
Clinical features
Sclerosis and chronic panniculitis have been recorded as main features in
both generalized morphea and progressive systemic sclerosis.1–3 In addition,
morphea profunda has been described as a sclerosing variant of ­morphea,
which primarily affects the subcutaneous fat analogous to lupus erythemato-
sus ­profundus.4,5 This condition, which shows a female predominance (3:1),
affects a wide age range (9–62 years) and presents primarily as ­subcutaneous
sclerosis.6 The sclerosis may be generalized and extend to the ­digits, or present
as solitary or multiple, localized, inflamed, hyperpigmented or ­erythematous,
asymmetrical and ill-defined plaques with a predilection for the ­shoulders,
upper arms, and trunk.6–8 A variant localized to the paraspinal region in
children has also been described.9,10 Patients with systemic sclerosis can
also develop sclerosing panniculitis. These patients have systemic ­sclerosis
­associated with pulmonary hypertension.11
Histological features
The significant features include thickening and hyalinization of the con-
nective tissue of the deep dermis, subcutaneous fat, and muscular fascia.3
Lipomembranous fat necrosis can also be a feature.12 A perivascular and focal
interstitial lymphocytic and plasma cell infiltrate is present in the subcutane-
ous fat. Exceptionally, plasma cells may be very numerous – so-called plasma
cell panniculitis.13–15 Lymphoid nodules (usually without germinal center for-
mation) are evident and mast cells may be increased in number.6 Scattered
eosinophils are occasionally seen. Mucin deposition is sometimes a feature
and diminished elastic tissue is a frequent finding, although in some cases it
appears increased in quantity.8 Localized osseous metaplasia with transepi-
dermal elimination has been documented.16 The changes in the fascia are
­similar to those described in the subcutaneous fat.
The overlying epidermis may show interface change with basal cell
­vacuolation and lymphocytic exocytosis.1,7
Immunofluorescent findings are variable. In the majority of cases it is neg-
ative, but C3 was found at the dermoepidermal junction in one case and,
in another, C3 and IgM were identified within the blood vessel walls in the
superficial dermal vasculature.6,7
Differential diagnosis
An association of childhood dermatomyositis with subcutaneous panniculitic
T-cell lymphoma has been described in a single case report.15
Postirradiation pseudosclerodermatous
panniculitis
Clinical features
This is a rare complication of high-dose radiotherapy. Thus far, it has only been
described in female patients who have received this treatment modality for breast
carcinoma following radical mastectomy.1–4 Patients present with deep-seated
and progressive induration of the subcutis in the area of previous ­irradiation
(Fig. 10.116), usually within the first year after radiation therapy.1–3
Histological features
The main histological features are localized to the subcutaneous fat where
there is a lobular panniculitis characterized by fat necrosis with foreign body
(lipophagic) granulomata and a lymphocyte and plasma cell infiltrate.1,2 The
septa are grossly thickened by hyalinized collagen. Dermal changes may be
absent or there can be a perivascular and interstitial lymphocyte and plasma
cell infiltrate with atypical myofibroblasts.1 Dilated lymphatics may occasion-
ally be found in the dermis.3 Epidermal changes of radiotherapy are absent.2

Differential diagnosis Differential diagnosis

In patients with this condition, sections should be very carefully scrutinized
Morphea profunda differs from conventional generalized morphea by the
for evidence of recurrent/metastatic breast carcinoma. Immunohistochemistry
deeper involvement of the sclerotic process and the more intense chronic
may prove invaluable.
inflammatory cell infiltrate.6 Some authors regard eosinophilic fasciitis as
Postirradiation pseudosclerodermatous panniculitis can be histologically
part of the spectrum of morphea profunda.6
confused with both morphea profunda and lupus erythematosus profundus.2
Clinicopathological correlation should readily establish the correct diagnosis.
Dermatomyositis panniculitis
Clinical features
Panniculitis has been described as a non-specific incidental finding in biopsy
specimens of skin or muscle from patients with dermatomyositis.1–3 Rarely,
however, it presents as a symptomatic disorder, patients complaining of indu-
rated, erythematous, tender, painful plaques and nodules, located about
the arms, thighs, abdomen, and buttocks.3–11 In some cases, the panniculi-
tis ­precedes the onset of the myositis.3 With chronicity, patients can develop
lipoatrophy.12 Both children and adults may be affected.

Histological features
Dermatomyositis panniculitis is characterized by a predominantly ­lobular
infiltrate of lymphocytes and plasma cells, sometimes accompanied by lym-
phoid follicles with germinal centers.4,5 Focal fat necrosis may be present
and lymphocytic vasculitis has occasionally been documented.6 The septa
of the subcutaneous fat become progressively thickened and hyalinized.
Membranocystic changes have been described in a number of cases,
­particularly in the Japanese.1,12,13 Calcification is a late change, but can be
very prominent.1,14
Mild inflammatory changes may be seen in the subcutaneous fat in Fig. 10.116
patients with dermatomyositis in the absence of panniculitis including focal Postirradiation pseudosclerodermatous panniculitis: erythematous irregular plaque.
­lymphocytic infiltration, fibrosis, and calcification.5 By courtesy of the Institute of Dermatology, London, UK.
11
Chapter

Diseases of the oral mucosa See

www.expertconsult.com
for references and
Sook-Bin Woo additional material

Introduction  363 Lipoma and atypical lipomatous tumor  387 SALIVARY GLAND DISEASE  412
Denture-associated fibrous Reactive conditions  412
HEREDITARY CONDITIONS  364
hyperplasia  387 Mucocele  412
Macular lesions  364 Sialolithiasis  414
Gingival nodules  389
White sponge nevus  364 Necrotizing sialometaplasia  414
Hereditary benign intraepithelial dyskeratosis  364 Gingival fibroma  389 Nicotinic stomatitis  415
Pachyonychia congenita  365 Cheilitis glandularis  416
Pyogenic granuloma  390 Salivary gland neoplasms  416
Dyskeratosis congenita  366
Darier's disease  366 Peripheral ossifying fibroma  391 Pleomorphic adenoma  417
Warty dyskeratoma  366 Canalicular adenoma  418
Peripheral giant cell granuloma  392 Mucoepidermoid carcinoma  418
Tumor-like lesions  366 Polymorphous low-grade adenocarcinoma  419
Parulis  393
Choristomas  366 Adenoid cystic carcinoma  419
Heterotopic brain tissue  368 Peripheral odontogenic fibroma  393 Papillary ductal lesions  420
Epidermoid and dermoid cysts  368
Dermoid tumor (dermoid), teratoma, and Gingival cyst of the adult  395
PREMALIGNANT CONDITIONS  421
epignathus  368 Generalized gingival
Oral lymphoepithelial cyst  369 Leukoplakia, erythroplakia and epithelial
hyperplasia  396
Lingual thyroid  370 dysplasia  421
Congenital granular cell tumor/epulis  370 Varix  398
Submucous fibrosis  424
Lymphangioma of the alveolar ridge  371
Gingival fibromatosis  371
INFECTIONS  399 MALIGNANT LESIONS  425
Juvenile hyaline fibromatosis  372
Hairy leukoplakia  399 Squamous cell carcinoma  425
REACTIVE CONDITIONS  372 Focal epithelial hyperplasia  400 Sarcomatoid carcinoma  427
Leukoedema  372 Basaloid squamous cell carcinoma  428
Morsicatio mucosae oris  373 LICHENOID AND HYPERSENSITIVITY
Adenoid squamous cell carcinoma  429
REACTIONS  402
Benign alveolar ridge keratosis  374 Adenosquamous carcinoma  429
Oral lichen planus and lichenoid
Benign migratory glossitis  375 stomatitis  402 Verrucous carcinoma  429
Median rhomboid glossitis  376
Plasma cell gingivostomatitis  406 Midline destructive disease  430
Smokeless tobacco keratosis  377
Orofacial granulomatosis  407
Foreign body gingivitis  379 PIGMENTED LESIONS  431
Oral Crohn's disease  408
Pyostomatitis vegetans  379 Amalgam tattoo  431

AUTOIMMUNE CONDITIONS  409 Oral melanocytic lesions  432

ULCERATIVE CONDITIONS  380 Oral melanotic macule  432
Desquamative gingivitis  409 Melanoacanthosis  433
Recurrent aphthous stomatitis  380
Mucous membrane pemphigoid   409 Oral melanocytic nevus  434
Traumatic ulcerative granuloma  381 Oral melanoma  434
Pemphigus  411
Medication-induced oral
PAPILLARY LESIONS  383
Paraneoplastic pemphigus  411 pigmentation  435
Squamous papilloma  383
Linear IgA disease  411
OTHER TUMORS  435
Verruciform xanthoma  384
Dermatitis herpetiformis  411
Granular cell tumor  435
TUMOR-LIKE CONDITIONS  385 Epidermolysis bullosa acquisita  411
Ectomesenchymal chondromyxoid
Fibroma  385 Lupus erythematosus  411 tumor  436
Giant cell fibroma  386 Wegener's granulomatosis  412

Introduction
Oral and maxillofacial pathology is the specialty of dentistry that is involved in
the diagnosis and management of diseases of the oral mucosa and ­supporting
bone and soft tissues, teeth, salivary glands, lip vermilion, and perioral skin.
It would be impossible to discuss diseases affecting all of the above entities
in one chapter. As such, this chapter is confined to common and uncom-
mon mucosal lesions that are often seen and biopsied by the oral and max-
illofacial surgeon, dermatologist or an otorhinolaryngologist. If a condition
­presents on the skin in addition to the mouth (such as pemphigus), only a
brief ­mention of the oral manifestations is made since the topic will have been
covered in detail elsewhere in this book.
From a histological perspective, the oral mucosa is divided into nonkera-
tinized and keratinized sites. The former include the labial mucosa (wet sur-
face of the lip), buccal mucosa, maxillary and mandibular sulci (sometimes
also called the ‘vestibule’), ventral tongue, floor of mouth, soft palate, nonat-
tached gingiva and crevicular epithelium (Fig. 11.1). The crevicular epithe-
lium is the continuation of marginal gingiva where it turns to face the tooth.
Any keratin on these surfaces is considered abnormal and should be reported
as such. The linea alba (‘bite line’) which is located on the buccal mucosa
where the upper and lower teeth meet may be thinly parakeratinized and this
is considered within the realm of normal (Fig. 11.2).
Fig. 11.1
Normal mouth: note the maxillary sulcus, attached and nonattached gingiva and teeth.
Fig. 11.2
Normal mouth: the linea alba on the buccal mucosa usually exhibits leukoedema
and may be thinly parakeratinized.
Introduction 363
Keratinized sites include the hard palate mucosa, the attached gingiva
(extending from the tooth for a band of 3–7 mm) and the tongue dorsum.
The tongue is a specialized structure because of its role in taste sensation and
has filiform, fungiform, and circumvallate papillae, the last two also contain-
ing taste buds (Fig. 11.3).
The oral mucosa consists of epithelium and underlying lamina propria that
can be arbitrarily divided into superficial and deep portions, and underlying
muscle or bone. Since there is no muscularis mucosa, there is no true sub-
mucosa. The epithelium of the oral mucosa is thickest on the tongue dorsum
and thinnest on the floor of mouth and is generally two to four times thicker
than the epidermis (Fig. 11.4). Pathologists not familiar with this feature tend
to diagnose normal mucosa as acanthosis or psoriasiform hyperplasia. The
attached gingiva and mucosa of the hard palate abut the periosteum so that
the deep lamina propria appears densely fibrotic (Fig. 11.5). A diagnosis of
‘fibrosis’ is therefore inappropriate since this feature is normal for the site.
The tooth is composed of an outer highly calcified thin shell of enamel on the
visible crown of the tooth; the non-visible portion within the bone is ­covered by
cementum, which is similar in composition and appearance to bone. The bulk
of the tooth consists of dentin and through the tooth runs the pulp containing
fibrovascular and neural tissues (the source of most toothaches). Odontogenic
epithelium is often seen within the gingival tissues and in odontogenic tumors in
the gingiva. This consists of nests of squamous epithelium that may have clear
cytoplasm and sometimes show palisading of the basal cell nuclei (Fig. 11.6).
Fig. 11.3
Normal tongue: the filiform papillae are spires of parakeratin usually associated with
bacterial colonies.
Fig. 11.4
Normal buccal mucosa: the epithelium is nonkeratinized and is 5–25 cells thick.
364 Diseases of the oral mucosa

Fig. 11.5 Fig. 11.7

Normal palate: the palate and gingiva both are thinly keratinized. The dense fibrous White sponge nevus: typical white, thickened, spongy-appearing mucosa. By courtesy
tissue beneath is normal for these sites. of C. Allen, DDS, Columbus, USA.

Fig. 11.6
Odontogenic epithelium: note the small nests composed of squamous cells,
sometimes with subtle palisading at the periphery.

Hereditary conditions
Macular lesions
White sponge nevus
Clinical features
White sponge nevus (Canon white sponge nevus, leukoedema exfoliativum
mucosae oris, familial white folded dysplasia of mouth) is an autosomal domi-
nant condition with high penetrance and variable expressivity. Onset is in early
childhood with 50% of patients diagnosed before age 20.1–3 The buccal mucosa
is almost invariably affected and other common sites are the labial mucosa,
tongue, alveolar mucosa, and the floor of mouth. Nasal, esophageal, vaginal,
anal, and penile mucosae may be involved, but not that of the conjunctiva,
although there is one report of associated colobomas.4 Lesions appear as dif-
fuse, white-to-gray, painless, spongy, folded plaques with a ­tendency to slough
off (Fig. 11.7).2,5,6 There may be periods of exacerbation and remission.
Pathogenesis and histological features
White sponge nevus has been traced to a mutation in the helical domain of
mucosal-specific keratins K4 (on chromosome 12q) and K13 (on chromosome
17q). The mutations are in the form of amino acid deletions, substitutions, and
insertions resulting in keratin filament instability and abnormal aggregation of
tonofilaments.7–9 Since some cases remit with antibiotic ­therapy, this suggests that
infections and/or inflammation may play a role in the e­ xpression of disease.10,11
There is parakeratosis, acanthosis with the formation of large, blunt rete
ridges, vacuolation of cells; anucleate keratinocytes are present superficially
(Fig. 11.8). Dyskeratotic cells exhibit dense peri- and ­paranuclear eosino-
philic condensations and there is insignificant inflammation (Fig. 11.9).5,12,13
Parakeratin plugs and streaks have been noted beneath the superficial kera-
tinocytes. One case that exhibited foci of epidermolytic hyperkeratosis has
been documented.14
The eosinophilic condensations correspond to tonofilament aggregates in
a peri- and paranuclear location.1,12,13,15 Organelles tend to segregate and are
absent in vacuolated cells. Odland bodies are abundant within keratinocytes
but few are present in the intercellular spaces, suggesting a lack of acid phos-
phatase leading to retention, rather than normal shedding, of superficial cells.1
Hereditary benign intraepithelial dyskeratosis
Clinical features
This autosomal dominant disorder of the eye and oral cavity was first
described in a tri-racial isolate (Caucasian, Native American, and African)

Fig. 11.8
White sponge nevus:
the epithelium exhibits
vacuolation, acanthosis,
and dyskeratosis.
Fig. 11.9
White sponge nevus: there are perinuclear eosinophilic keratin condensations and
cytoplasmic vacuolation.
in North Carolina called the Halowar, Haliwa, or Haliwa-Saponi Indians.1
Because of migration, cases have been reported in descendants living now in
New York, Pennsylvania, Virginia, and Washington DC.
The eye lesions, which usually present by the first year of life, are foamy, gelat-
inous plaques in the bulbar conjunctiva in a perilimbic distribution both nasally
and temporally. Patients experience irritation and photophobia and there may be
exacerbations in spring. Corneal vascularization sometimes leads to visual loss.2
Oral involvement is asymptomatic and is therefore generally not noticed
until the second decade. Lesions involve the buccal and labial mucosa, floor
of mouth, lateral and ventral tongue, and gingiva but not usually the dorsum
of tongue or uvula.3–5 The mucosa is white, opalescent, spongy, macerated,
folded, and shaggy, often resembling white sponge nevus (Fig. 11.10). There
is generally no involvement of genital, nasal or rectal mucosa.
Pathogenesis and histological features
Genetic studies have localized the gene for this condition to chromosome
4q35 with a duplication segregating in affected individuals.6
Macular lesions 365
Fig. 11.10
Hereditary benign intraepithelial dyskeratosis: the mucosa appears white and
thickened. By courtesy of J. McDonald, DDS, Cincinnati, USA.
Fig. 11.11
Hereditary benign intraepithelial dyskeratosis: there is hyperkeratosis, dyskeratosis,
and acanthosis. By courtesy of J. McDonald, DDS, Cincinnati, USA.
There is hyperkeratosis and acanthosis (Fig. 11.11). Dyskeratotic cells (also
called ‘tobacco cells’ because of their orange-brown color on Papanicolaou-stained
smears) are present in the mid to upper one-third of the epithelium, appearing
engulfed by adjacent normal keratinocytes; this ‘cell-within-a-cell’ appearance is a
characteristic feature and is well seen in cytological smears (Fig. 11.12)4,7,8
The dyskeratotic cells are packed with tonofilaments and vesicular bodies
that may represent Odland bodies.7 Some keratinocytes also show disappear-
ance of cellular interdigitations and desmosomes.
Pachyonychia congenita
Clinical features
This rare genodermatosis is characterized by nail dystrophy, disorders of the
palmoplantar skin and hair and leukoplakia; the larynx and eye may also be
affected.1 The oral findings, usually noted within the first two decades of life,
are characterized by focal or generalized white hyperkeratotic plaques on the
dorsum and lateral borders of the tongue and buccal mucosa, and are ­present
in 75–95% of cases.1–4 Natal teeth (teeth present at birth) are a common
­finding in the type 2 form of the disease.1,5,6
366 Diseases of the oral mucosa
Fig. 11.12
Hereditary benign
intraepithelial
dyskeratosis: note the
dyskeratosis with the
typical ‘cell-within-a-cell’
structures. By courtesy
of J. McDonald, DDS,
Cincinnati, USA.
Pathogenesis and histological features
Pachyonychia congenita is generally inherited as an autosomal dominant disor-
der characterized by missense mutations of the gene for keratin 6a and 16 (type
1), and 6b and 17 (type 2) located on chromosome 17q.1,7. There is a defect in
the association of protein subunits in the assembly of keratin filaments.
Histologically, there is hyperparakeratosis or hyperorthokeratosis, acan-
thosis, and intracellular vacuolization.3,6,8 Because pachyonychia ­congenita
and dyskeratosis congenita are generally diagnosed on skin biopsy, there are
few detailed reports on the histology of oral lesions.
Dyskeratosis congenita
Clinical features
Dyskeratosis congenita is another genodermatosis that is associated with nail
dystrophy, poikiloderma, oral leukoplakia, and development of pancytope-
nia, often requiring hematopoietic stem cell transplantation. The mucosa
of the conjunctiva, urethra, and genital tract may also be involved.1,2 Oral
­leukoplakia, particularly of the tongue, presents in the second decade of life
and has a high propensity for developing dysplasia and/or squamous cell
­carcinoma at an early age.3,4
Pathogenesis and histological features
It is generally considered to be a premature aging syndrome caused by telom-
erase dysfunction with mutations in the DKC1, TERC or TERT genes.5
Histologically, dyskeratosis congenita shows hyperpara- or orthokeratosis
with dysplasia or squamous cell carcinoma.
Darier's disease
Clinical features
Oral findings occur in approximately 50% of patients with Darier's disease
(Darier-White disease, keratosis follicularis). Mild involvement comprises
minute white or pink keratotic papules, while in more extensive disease
coalescence results in larger plaques or a cobblestone surface. Lesions are gen-
erally asymptomatic.1–4 The palate is the most common site affected, perhaps
because of its normally keratinized nature, followed by the gingiva, tongue,
buccal mucosa, and floor of mouth. The lips are rarely involved.5 Recurrent
parotid or submandibular swelling may be reported in up to approximately
one-third of cases and is most likely the result of strictures in the main duct
causing obstruction.4,5 In general, the degree of oral involvement parallels the
extent of skin lesions.2,5
Pathogenesis and histological features
This disease is associated with a mutation on the ATP2A2 gene on chromo-
some 12q that is involved in cytoplasmic calcium transport which is required
for proper functioning of desmosomes and keratin formation.6
The typical findings are hyperkeratosis, acanthosis, and suprabasal ­clefting
with acantholysis forming vertical villous-like projections protruding into
lacunae. Corps ronds and grains may not be as prominent as in skin lesions.2,5
Papanicolaou-stained smears show an orange-brown staining of the dyskera-
totic ‘grains’ and refractile concentric perinuclear rings and granular bands in
corps ronds.7 The excretory salivary ducts may become metaplastic or involved
by the same process leading to stricture formation and obstruction.1,8,9
Differential diagnosis
Pemphigus vulgaris and pyostomatitis vegetans both exhibit acantholysis but
not generally dyskeratosis; in addition, pemphigus shows intercellular IgG
deposits on direct immunofluorescence.
Warty dyskeratoma
Clinical features
This usually solitary lesion resembles Darier's disease and may present as a
papule or nodule (oral focal acantholytic dyskeratosis) in the oral cavity. It
generally occurs in the fifth or sixth decade and almost always arises on the
keratinized and attached mucosa of the palate or gingiva with a 2:1 female
predominance.1 Most lesions measure less than 1 cm and rare cases develop
on the buccal mucosa and tongue.2–4 Interestingly, the majority of cases occur
on the left side of the mouth, raising the possibility that trauma plays an
important role since most individuals are right-handed and may brush the left
side of the mouth more vigorously. The papular variety appears as a white
papule or plaque while the nodular variety has an umbilicated or crateriform
appearance. There is an association with tobacco use.3,5
Histological features
Oral warty dyskeratoma is characterized by Darier's disease-like features
including suprabasilar clefting with lacunae formation, villous-like ­projections,
corps ronds and grains.3 The papular lesions show multifocal involvement
and sometimes papillary epithelial hyperplasia.6 There is no association with
underlying sebaceous or salivary glands.
Differential diagnosis
Pemphigus vulgaris can be readily distinguished by the clinical history
and the characteristic presence of intercellular IgG deposition on direct
immunofluorescence.
Tumor-like lesions
Choristomas
Osseous choristoma
Clinical features
The majority of these lesions (93%) occur as sessile or pedunculated masses on
the posterior dorsum of the tongue, near the foramen cecum, although other sites
may be involved.1–4 Most develop in the second and third decades and females
are three to five times more likely to be affected.2,4 There may be dysphagia.
Pathogenesis and histological features
Theories of origin include ossification of branchial arch remnants, metaplas-
tic bone formation secondary to trauma, and osteogenesis of unknown cause
from pluripotent mesenchymal cells in the area.

The lesion consists of a well-circumscribed mass of viable lamellar bone
with haversian systems surrounded by fibrous connective tissue; osteoblastic
rimming, hematopoietic and fatty marrow or even cartilage may be present
(Figs 11.13, 11.14).1,5,6
Cartilaginous choristoma
Clinical features
Cartilaginous choristomas present as discrete nodules, usually along the lat-
eral border of the tongue (85% of cases) and less often on the buccal mucosa
and soft palate.1–3 Most occur in adults.4
Pathogenesis and histological features
They may represent developmental malformations that arise from pluripotent
mesenchymal cells of the tongue, metaplastic change secondary to trauma or
cartilaginous rests.
Cartilaginous choristoma consists of a mass of benign mature hyaline car-
tilage surrounded by dense perichondrium; loose myxoid tissue akin to primi-
tive mesenchyme or even mature fat may also be present.2,4,5 Some cases show
ossification and association with salivary glands.2,3 Rare cases of chondrosar-
coma have been reported.6
Fig. 11.13
Osseous choristoma from the tongue: there is a discrete nodule of bone and fatty
tissue.
Fig. 11.14
Osseous choristoma from the tongue: the woven bone shows osteoblastic rimming
and is laid down by the surrounding mesenchymal cells.
Tumor-like lesions 367
Differential diagnosis
Metaplastic cartilaginous nodules are often seen in cases of denture-associated
fibrous hyperplasia but these occur in the maxillary and ­mandibular ­vestibules
associated with denture flanges. Cartilaginous rests are also ­common in the
area of the nasopalatine canal. Some authors believe that cartilaginous rests
of the soft palate/tonsillar area are a metaplastic phenomenon, occurring in
20% of tonsils examined.7 A pleomorphic adenoma with extensive chondroid
metaplasia should also be considered.
Sebaceous choristoma, hyperplasia and adenoma
Clinical features
Sebaceous glands occur as 1–3-mm yellow macules or papules in the
­buccal and labial mucosa in approximately 80% of the adult population­
(Fig. 11.15).1 However, these may become hyperplastic or adenomatous, form-
ing painless papules, plaques or nodules, and are termed sebaceous hyperplasia
or adenoma, respectively.2,3 They occur in the same sites as Fordyce granules.
Rare cases of sebaceous choristomas have been reported in the tongue of
adults. They present as dome-shaped masses in the midline of the dorsum in
the area of the middle or posterior one-third of the tongue, often associated
with a thyroglossal duct.4,5
Histological features
Fordyce granules consist of mature lobules of sebaceous glands that communi-
cate with the surface epithelium via a duct. There may be pseudocyst ­formation
with retention of secretions and adenomatous hyperplasia; the rare occurrence
of hair follicle and Demodex within a Fordyce granule has been reported.6–8
In sebaceous hyperplasia, at least 15 lobules of mature sebaceous glands
empty into ducts that communicate with the surface (Fig. 11.16).2 In the
sebaceous choristoma, mature sebaceous units may be associated with eccrine
glands, hair follicles, and apocrine glands.5 Sebaceous adenomas also show a
proliferation of basaloid cells at the periphery of the lobules.9,10 Some of these
may represent sebaceous adenoma of the minor salivary gland.11
Gastrointestinal choristoma
Clinical features
Almost all of these are cystic lesions that present as swellings of the tongue,
usually on the ventral surface, or the floor of mouth.1–3 Sometimes they appear
as sinuses.4 They are most often seen in infancy or early childhood and may
be associated with orofacial malformations.3
Many theories of pathogenesis have been postulated including epithelial
entrapment, incomplete coalescence of lacunae, and persistence of intestinal
epithelial buds.4,5
The cystic lesions are lined by epithelium typical for the cardiac, fundic
or pyloric regions of the stomach with parietal and Paneth cells.4 However,
Fig. 11.15
Fordyce granules: typical yellow papules of the buccal mucosa.
368 Diseases of the oral mucosa
Fig. 11.16
Sebaceous hyperplasia:
numerous lobules of
sebaceous glands empty
into a central duct.
some are lined by colonic and/or ciliated epithelium.5 Smooth muscle is
­usually identified. The presence of pancreatic tissue has also been reported.6
If ­ectodermal and mesodermal elements are also present, the lesion should be
considered a teratoma.
Pathogenesis and histological features
Heterotopic brain tissue
Clinical features
This uncommon condition presents in the first year of life, most often affect-
ing the palate, tongue (especially the foramen cecum area) or oropharynx,
as a result of displacement of primitive neural elements in an early stage of
­development or neuroglial differentiation from pluripotent cells.1,2 Some
patients have associated palatal defects.3 Respiratory obstruction is a major
cause of morbidity and feeding difficulties if lesions are large.4
Histological features
Mature elements of the central nervous system including astrocytes, oligoden-
drocytes, ependymal tissue, choroid plexus-like tissue and, rarely, neuronal
tissue may all be identified (Fig. 11.17).1,2,5,6
Epidermoid and dermoid cysts
Clinical features
The floor of the mouth is the most common site of presentation and there may
be a slight female predilection; some cases are congenital.1–3 Classification of
these lesions is based on anatomical location such as lingual, submental or
submandibular and on the histological appearance.1,2,4
They present as dome-shaped, yellow masses with a rubbery or doughy con-
sistency. Intraoral lesions cause feeding, swallowing, and speech difficulties
while extraoral variants below the myohoid muscle lead to a noticeable submen-
tal mass. Dumbbell-shaped cysts have both intra- and extraoral swellings.5
While epidermoid and dermoid cysts are cystic structures that occur in
the midline of the floor of mouth in children and young adults, dermoid
tumors or hairy polyps are usually large congenital lesions occurring in the
­nasopharynx and soft palate.
Fig. 11.17
Heterotopic brain tissue: note the presence of glial and ependymal tissue.
Pathogenesis and histological features
The pathogenesis is uncertain. One theory suggests that they arise from
entrapped epithelial rests in the line of fusion of facial processes. Another
proposes that the lining develops from displaced embryonic rests or traumatic
implantation, possibly occurring even in utero.3
Both epidermoid and dermoid cysts are lined by orthokeratinized squamous
epithelium and the lumen is filled with keratinaceous material. Epidermoid
cysts (also called epithelial inclusion cysts) have no adnexa in the wall, while
dermoid cysts always have skin adnexal structures in the wall. Oral dermoid
cysts are three times more common than epidermoid cysts.2
Some cysts also contain gastrointestinal mucosa.6,7 If tissues from all
three germ layers are represented, the term ‘teratoid cyst’ may be more
appropriate.
Differential diagnosis
Gingival cyst of the adult is generally nonkeratinized and is lined by low
cuboidal to columnar or stratified squamous epithelium, with occasional
epithelial plaques and clear cells.8 Gingival cysts of the newborn, which are
generally not biopsied because they exteriorize on their own, are filled with
keratinaceous material.9 Both can be differentiated from epidermoid cysts by
their location on the gingiva.
Dermoid tumor (dermoid), teratoma, and
epignathus
Clinical features
These rare conditions generally present congenitally or in infancy as masses
protruding from the mouth, causing respiratory distress and feeding difficul-
ties. They have been classified as follows:
• dermoid where only ecto- and mesodermal structures are present, and
therefore the tumor is not strictly a teratoma,
• teratoid tumor and teratoma with tissue from all three germ layers
represented (in general, the tissues in teratoid tumor are not as well
organized as in a teratoma),
• epignathus where there is recognizable organ and limb formation;
however, this term is also often applied to any teratoid tumor or
teratoma that arises from the nasopharyngeal or palatal areas.
Of these, the dermoid is the most common.1
Dermoids tend to occur in females (six to seven times more often than in
males) as pedunculated masses in the nasopharynx, oropharynx, and soft
­palate.2,3 The mass is covered by skin, hence its other name, ‘hairy polyp’.
It may also grossly resemble an accessory auricle.4

Teratomas, teratoid tumors, and epignathi present as masses that may
­ rotrude from the mouth, and airway obstruction is a frequent presenting
p organ systems such as limbs, a head or eyes.7,10
symptom; there is a female predilection and most are present at birth.5 Unlike
dermoids, these tumors are often associated with other malformations and
findings such as elevated alpha fetoprotein and polyhydramnios.6,7
Epignathi in particular may be associated with severe congenital malfor-
mations, and stillbirth is a common occurrence. They most often arise from
the hard palate (hence its name), although the posterior nasopharynx and
upper lip can be involved, and there may be palatal clefts and cranial exten-
sion.7–9 Grossly, the tumor sometimes contains rudimentary limbs, or even a
head resembling an incomplete twin or fetus in fetu.10
Lingual (tongue) teratomas are generally not associated with such devel-
opmental defects.11
Histological features
Dermoids are covered by skin with its constituent adnexa. In addition,
­cartilage, bone, muscle, adipose tissue, and even salivary glands may be
­present (Fig. 11.18).3,7,12 Teratomas contain all of the above. In addition,
neural, brain, lung, gastrointestinal, and respiratory tissues are sometimes
present (Fig. 11.19).6,11
Fig. 11.18
Dermoid tumor: note the presence of cartilage and columnar epithelium.
By courtesy of the Registry of Oral Pathology, AFIP, Washington DC, USA.
Fig. 11.19
Teratoma: in addition to endodermal elements, glial tissue is present.
By courtesy of the Registry of Oral Pathology, AFIP, Washington DC, USA.
Tumor-like lesions 369
Epignathi consist of tissues organized to form grossly recognizable specific
Oral lymphoepithelial cyst
Clinical features
Oral lymphoepithelial cysts generally occur in the fourth decade of life
with an equal sex distribution.1,2 These also occur in the parotid gland in
particular in HIV-positive individuals.3 They present as painless yellowish
nodules, usually less than 1 cm in diameter, most commonly affecting the
floor of mouth followed by the posterior ventral tongue, soft palate, and
tonsillar fauces (Fig. 11.20).3–5 They are commonly filled with cheesy, ker-
atinaceous material. Some authors consider lesions which present at sites
where tonsillar ­tissue is normally found to be inflammatory/obstructive
tonsillar reactions.4
Pathogenesis and histological features
Three theories of pathogenesis have been proposed:
• There is enclavement of epithelium within oral lymphoid tissue during
embryogenesis and subsequent proliferation and cystic degeneration.1
• Such lymphoid aggregates are ectopic oral tonsils, where the crypt
openings have been blocked, resulting in retention of secretions.5,6
• The epithelium represents normal excretory salivary ducts and the
lymphoid tissue is a reaction to inflammation or immunological
stimulation.3
The last theory pertains primarily to floor of mouth lesions, a site where
tonsillar/lymphoid tissue is not normally found.
The cyst is lined by parakeratotic stratified squamous ­epithelium and the
lumen is filled with desquamated keratinaceous material (Fig. 11.21).3,4,7 Rare
cases may be lined by pseudostratified columnar epithelium with or without
mucous cells.5 The epithelium usually demonstrates lymphocytic exocytosis
(Fig. 11.22). The surrounding lymphoid tissue may encircle the cyst epithe-
lium completely or partially, and germinal centers are usually well formed
although not always present. Some cases demonstrate communication with
the overlying surface epithelium, often through a narrow opening.
Salivary glands and ducts may be present in the vicinity, especially floor of
mouth lesions.1,3
Differential diagnosis
Mucoceles of the retention type are lined by stratified squamous, columnar,
oncocytic or respiratory epithelium, sometimes with mucous cell metaplasia.
Fig. 11.20
Oral lymphoepithelial cyst: note the yellow nodule located behind the anterior
faucial pillar.
370 Diseases of the oral mucosa
Fig. 11.21
Oral lymphoepithelial cyst: the cyst is completely encircled by lymphoid tissue.
Fig. 11.22
Oral lymphoepithelial cyst: there is lymphocyte exocytosis through the epithelium
and a small germinal center is present.
They may show foci of chronic inflammation but not usually the thick mantle
of lymphocytes with germinal centers. Dermoid and epidermoid cysts lack the
lymphoid mantle, and dermoid cysts contain adnexa in their wall.
Masses and clumps of bacteria may mat together and plug tonsillar crypts,
presenting as an opaque yellow mass that is not covered by epithelium and
that can readily be scraped off.8
Lingual thyroid
Clinical features
Approximately 10% of cadaveric tongues contain nests of thyroid tissue,
with no sex predilection.1,2 However, when thyroid tissue occurs as a mass in
the tongue, the term ‘lingual thyroid choristoma’ or ‘ectopic lingual thyroid’
is used. Since approximately 86% of such tumors consist of the only thyroid
tissue in the body, the terms ‘lingual thyroid ’or ‘ectopic lingual thyroid’ are
more accurate.3
The lesion presents as a rounded, soft-to-firm mass within the base of the
tongue between the foramen cecum and the epiglottis. It may cause ­dysphagia,
dyspnea, dysphonia or hemorrhage.2–4 Females are three to seven times more
likely to be affected than males and there are two peaks of presentation,
i.e., the first and second decades and the fifth and sixth decades, probably
related to hormonal influences;4,5 it is uncommon in children.6 One-quarter
of patients may be hypothyroid.
Pathogenesis and histological features
Since the thyroid anlage develops in the area of the foramen cecum and
descends from there into the neck, failure to descend or persistence of rem-
nants of the anlage which then proliferate, resulting in a noticeable mass.
In most cases, a biopsy is not indicated if technetium scans are positive
for thyroid tissue. Thyroid follicles may contain mature or embryonic thy-
roid epithelium and exhibit microfollicular, macrofollicular or adenomatous
changes.1,5 There may be an associated thyroglossal duct.2 Follicular and pap-
illary carcinomas can sometimes occur, in the same frequency as one would
expect in the normal thyroid gland.7,8; even medullary carcinoma has been
reported.9
Congenital granular cell tumor/epulis
Clinical features
The congenital granular cell tumor presents as a pink, pedunculated mass,
usually on the anterior alveolar ridge with an intact surface (Fig. 11.23).
There is a 10:1 female predilection and it is three times more common in the
maxilla.1 It may cause problems with nursing. Approximately 9% of patients
have multiple nodules and some may have concurrent tongue lesions.2–4
Pathogenesis and histological features
Theories of histogenesis have included epithelial, pericytic, and neural deriva-
tion. The current hypothesis is that it represents a mesenchymal tumor (some
believe of myofibroblastic origin) with evidence of degenerative change. The
latter is supported by lack of growth after birth of the infant, resolution of
some cases over time, histological evidence of degeneration, and lack of recur-
rence in spite of incomplete removal.1,5,6
Histologically, a Grenz zone may or may not be present and the overlying
epithelium is typically atrophic. The cells are round or polygonal with abun-
dant eosinophilic granular cytoplasm, distinct cell borders, eccentric small
nuclei, and inconspicuous nucleoli; a prominent delicate and arborizing cap-
illary network is usually evident (Fig 11.24).3,6 The granules are period acid-
Schiff (PAS) positive and diastase resistant; odontogenic rests may also be
present.4,7
The granular cells do not express S-100 protein but are always vimentin
positive; macrophage/histiocytic markers (such as MAC387 and lysozyme)
are usually negative although CD68 and Ki-M19 immunohistochemistry is
Fig. 11.23
Congenital granular cell epulis: the maxillary alveolus is a typical location for this
tumor. By courtesy of B. Padwa, MD DDS, Boston, USA.

Fig. 11.24
Congenital granular cell epulis: note the large pale cells with granular cytoplasm;
they are S-100 negative.
positive, indicating the presence of phagolysosomes.6,8 Antichymotripsin is
sometimes present.8 Stains for smooth muscle actin, estrogen and proges-
terone receptors, glial fibrillary acidic protein (GFAP), myelin basic ­protein
(MBP), and neurofilament protein are negative.1,6 One report identified
­neuron-specific enolase (NSE) within the granular cells.9
Ultrastructural studies reveal the presence of membrane-bound granules
with electron-dense contents that most likely represent phagolysosomes.1,3,8,10
The presence of subplasmalemmal dense bodies, pinocytotic vesicles contain-
ing precollagenous material, and intracytoplasmic laminin and fibronectin
suggests myofibroblastic differentiation.3,7,8
Differential diagnosis
The cells of granular cell tumor are histologically indistinguishable from
those of congenital granular cell tumor. However, in congenital granular cell
tumor, there is no pseudoepitheliomatous hyperplasia and there is a prominent
arborizing delicate vascular network; importantly, the cells are S-100 negative.
Angulate bodies, seen ultrastructurally in granular cell tumor, are absent.
Congenital gingival leiomyomatous polyp/hamartoma has a similar clini-
cal presentation (usually in the midline of the maxilla) but histologically con-
tains a nonencapsulated proliferation of fusiform and spindle smooth muscle
cells that, as expected, express HHF-35, smooth muscle actin, and desmin but
not S-100 protein.11–13 This condition may also occur at other sites.14
Lymphangioma of the alveolar ridge
Clinical features
Lymphangioma has been identified in approximately 4% of infants, all of
whom were black. They present as dome-shaped, bluish, fluid-filled nodules
usually affecting the posterior maxillary and mandibular alveolar ridge and
are typically 3–4 mm in diameter. Females are twice as likely to be affected as
males and 74% of subjects have more than one lesion.1,2 Many (if not most)
regress by 6 months of age.1,3,4
Histological features
Lymphangioma is characterized by slitlike spaces lined by flattened endothe-
lial cells and filled with red blood cells or sparse, fibrillar, eosinophilic ­material
consistent with lymph.1,2 Rests of odontogenic epithelium may sometimes be
present.
Differential diagnosis
Lymphangioma circumscriptum has an identical histology but is seen in older
patients.
Tumor-like lesions 371
Gingival fibromatosis
Clinical features
In this condition, there is a benign, diffuse, nonhemorrhagic, and fibrotic gin-
gival enlargement, often occurring bilaterally and involving the maxillary and
mandibular gingiva, sometimes to the extent that it may reach the occlusal/
incisal edges of the teeth.1,2 Several forms are recognized. The inherited form
(usually an autosomal dominant trait, but occasionally autosomal recessive),
which is less common, tends to present congenitally or in the first decade of
life, coinciding with eruption of teeth, and often exhibits generalized gingi-
val involvement (Fig. 11.25). There is a strong association with hypertricho-
sis and mental retardation and/or epilepsy. Gingival fibromatosis may also
be a feature of Zimmerman-Laband, Ramon, Rutherford, and Cross syn-
dromes.2,3 An idiopathic form more often occurs later in life with usually
limited involvement of the upper or lower jaw or just one quadrant. There is
no tendency to regression. The most common presentation is overgrowth of
tissue in the area of the maxillary tuberosity and lingual mandible, frequently
in a symmetric fashion.1
Pathogenesis and histological features
The gene for the nonsyndromic form has been localized to chromosome
2p21–22.4
The gingival overgrowth is caused primarily by an increased produc-
tion and reduced metabolism of connective tissue. Native fibroblasts
show elevated rates of proliferation and increased synthesis of fibronectin
and type I collagen.5 Reduced matrix metalloproteinase levels – possibly
mediated by increased production of transforming growth factor beta-1
(TGF-β1) – may result in excess accumulation of extracellular matrix.6
Histologically, there is a diffuse proliferation of bands and whorls of
collagen within a background of excessive ground substance (Fig. 11.26).
Some lesions contain plump, stellate-shaped fibroblasts (Fig. 11.27).
Dystrophic calcification may be seen in up to 43% of cases.2 The overly-
ing epithelium may be slightly acanthotic and there are few inflammatory
cells.
Differential diagnosis
Generalized gingival hyperplasia caused by local irritation or sys-
temic influences (such as medications or hormones) is distinguished
from gingival ­fibromatosis on clinical grounds and by more prominent
inflammation.
Fig. 11.25
Hereditary gingival fibromatosis: there is extensive involvement of the maxillary soft
tissues. By courtesy of G. Gallagher, DMD, Boston, USA.
372 Diseases of the oral mucosa

Juvenile hyaline fibromatosis

Clinical features
Juvenile hyaline fibromatosis is a rare, autosomal recessive disease charac-
terized by pearly papules and larger fibrotic nodules on the skin (around
the face, ears, scalp, neck, and trunk), gingival overgrowth, flexural con-
tractures of the joints, and osteolytic lesions.1–3 Infantile systemic hyalinosis
(another autosomal recessive condition) presents, in addition, with visceral
­involvement and is fatal within the first 2 years of life.4

Pathogenesis and histological features

Mutations of capillary morphogenesis protein 2 (CMG2) causes defects in
basement membrane matrix assembly and mutations in chromosome 4q21.5,6
The hyaline material consists of glycoproteins, glycosaminoglycans, ­collagens,
and possibly components of plasma. There is reduced type III collagen pro-
duction and metabolism, and possibly secondarily elevated type I collagen
metabolism and reduced collagen II and IV.3,7,8
The gingival and skin lesions of juvenile hyaline fibromatosis show depos-
its of PAS-positive, diastase-resistant and Congo red-negative homogenous,
eosinophilic, hyalinized material in the connective tissue (Fig. 11.28).1,3
Fig. 11.26 Fibroblasts are sometimes nested, appearing similar to chondrocytes, and,
Hereditary gingival
on occasion, present as ‘streaks of cells’. The fibroblasts are plump or
fibromatosis: there is
­spindled-shaped with large vesicular nuclei.1
massive accumulation of
fibrous tissue and ground Ultrastructurally, there is discontinuity of the basal lamina with absent
substance. anchoring fibrils; the fibroblasts have distended endoplasmic reticulum
and Golgi filled with fibrillogranular material similar to that present in the
­extracellular space.1–3

Fig. 11.28
Fig. 11.27 Juvenile hyaline fibromatosis: note the abundant eosinophilic, hyalinized fibrocollagenous
Hereditary gingival fibromatosis: plump, stellate-shaped fibroblasts are seen in a material and scattered fibroblasts. By courtesy of J. Sciubba, DDS, Baltimore, USA.
densely collagenized stroma.

Reactive conditions
The prevalence ranges from 20% to 36% among those who do not use
Leukoedema tobacco or chew coca leaves, to 51–68% in those who use tobacco, coca,
or cannabis.3–6 Its incidence increases with age.7 A prevalence of 51% was
Clinical features reported in African-Americans but without mention of tobacco habits.8
This is a benign, painless condition usually affecting the buccal mucosa bilat- Another study found a prevalence of 93% in a Caucasian population lead-
erally. The mucosa has a diffuse gray-white opalescent hue with white wrin- ing the author to question whether this condition is merely a variation of
kles and faint reticulations that usually disappear on stretching except in ­normal.2 Of all tobacco habits, pipe smoking, cigarette smoking, and snuff
severe cases (Fig. 11.29).1,2 are associated with decreasing rates of occurrence.

Fig. 11.29
Leukoedema: note the pale, milky film on the buccal mucosa.
Pathogenesis and histological features
It is generally believed that a low-grade topical injury, such as occurs with
the use of tobacco or coca leaves, gives rise to this condition. As such, most
changes are limited to the more superficial layers of keratinocytes.
There is acanthosis with little or no parakeratosis. The characteristic fea-
ture is the presence of degenerated and swollen cells in the superficial and
mid-epithelial layers, respectively, sometimes (but not always) with a layer of
compact cells sandwiched between (Fig. 11.30).9 The most superficial cells
have pale cytoplasm with many anucleate forms and prominent cell mem-
branes somewhat collapsed upon one another, forming a jigsaw puzzle pat-
tern (Fig. 11.31). The ballooned cells in the mid epithelium are large with
pale, watery cytoplasm; pyknotic nuclei are often present. There is usually no
inflammation in the lamina propria.
Ultrastructural studies show abnormal keratohyaline granules and loosely
dispersed tonofilaments with fragmented organelles in the superficial degen-
erated cells. The mid-level swollen cells contain abnormal swollen mito-
chondria.9,10 These features support the theory of limited cell damage with
Fig. 11.30
Leukoedema: note the
pale superficial cells and
acanthosis.
Morsicatio mucosae oris/Factitial keratosis 373
Fig. 11.31
Leukoedema: the
superficial cells
characteristically are
anucleate with a ‘jigsaw-
like’ pattern of cell
membranes.
swelling, possibly caused by failure of the sodium pump, but insufficient to
cause death and disintegration of the whole cell. Similar features have also
been reported in the sucking pads of neonates.11
Differential diagnosis
In morsicatio mucosae oris, there is papillary and shaggy parakeratosis asso-
ciated with many bacterial colonies also without inflammation; leukoedema
is often present beneath areas of such factitial keratosis (see below).
Smokeless tobacco keratosis presents with keratin chevrons and shows
a band of coagulated and degenerate cells with anucleation similar to leu-
koedema. The transition zone from normal to degenerate is often abrupt
in smokeless tobacco keratosis (see below). Hairy leukoplakia may exhibit
­leukoedema and concomitant morsicatio mucosae oris, but will also exhibit
viral cytopathic change.
Morsicatio mucosae oris/Factitial keratosis
Clinical features
In morsicatio mucosae oris (pathominia mucosae oris), cheek, lip or tongue
chewing habits occur either subconsciously at night or as a conscious para-
functional habit. It is usually seen in adults, is often bilateral and may involve
the buccal mucosa (most common), lateral tongue and lower labial mucosa.1–3
The site of injury exhibits shaggy white plaques that have a peeling, thready,
desquamative surface; erosions are often ­present, and occasionally ulcers are
seen (Figs 11.32, 11.33). Similar lesions have been noted in areca nut chew-
ers and glass blowers.4,5
Histological features,
There is hyperparakeratosis, which may be severe and acanthosis. Character-
istically, the keratin is thrown into papillations with fissures and clefts,
rimmed by bacteria (Fig. 11.34).2,6,7 Spongiosis or leukocyte exocytosis are
usually absent. Ballooned and swollen superficial keratinocytes typical for
leukoedema are present. Inflammation in the lamina propria is insignificant
unless there is erosion and ulceration. In betel nut chewers, there is a yellow-
brown pigment on the surface of the keratin and within epithelial cells, repre-
senting fragments of the betel quid.5,7 Interestingly, a biopsy of the linea alba
(the white line on the buccal mucosa bilaterally where the upper and lower
teeth meet) essentially reveals identical histological features.
374 Diseases of the oral mucosa

Differential diagnosis
Morsicatio mucosae oris may occur as a primary mucosal disorder such
as has been described above, or it may present as a secondary finding
related to chronic injury of protuberant plaques and nodules, such as
fibromas.
Hairy leukoplakia may show similar shaggy hyperparakeratosis and some-
times there is concurrent bite injury. However, the typical changes of ­chromatin
condensation, eosinophilic inclusions, and the presence of ­Epstein-Barr virus
easily afford their distinction.
Smokeless tobacco keratosis shows sharply demarcated coagulation of the
superficial cells, sometimes accompanied by hyalinized, amorphous eosino-
philic material in the lamina propria.
White sponge nevus exhibits perinuclear eosinophilic keratin condensations.

Benign alveolar ridge keratosis/Oral lichen

simplex chronicus
Fig. 11.32 Clinical features
Morsicatio mucosae oris (chronic bite keratosis): note the rough, shaggy plaques on
the buccal mucosa. These are white, often rough papules and plaques that occur on the crest of
the alveolar ridge, in particular in the area of extracted mandibular third
molars and adjacent retromolar pad (Fig. 11.35).1 They also occur in any
other part of the ridge where a previous extraction has occurred. They have
no malignant potential.
Lesions reported as alveolar ridge keratosis are any white lesion on the
alveolar ridge and gingiva with no histologic connotations and include both
benign and dysplastic/malignant keratotic lesions of the gingiva and alveolar
ridge; they are not synonymous with benign alveolar ridge keratosis, which
has the specific histologic appearance of lichen simplex chronicus.2

Pathogenesis and histological features

These lesions are caused by chronic frictional trauma to the ridge, not nec-
essarily by direct tooth-to-ridge contact, but by food being crushed by teeth
against the opposing edentulous ridge.
They have the typical histopathology of skin lesions of lichen sim-
plex chronicus. There is hyperorthokeratosis (often marked) with
­wedge-shaped hypergranulosis, surface papillomatosis and acanthosis
(Fig. 11.36 ). Rete ridges are tapered and generally uniformly elongated
and often confluent at the base. There is usually minimal to insignificant
Fig. 11.33 chronic inflammation in the lamina propria. Lesions from the retromo-
Morsicatio mucosae oris (chronic bite keratosis): note the macerated, shaggy lar pad often contain stellate-shaped fibroblasts, which are normal for
plaques on the buccal mucosa and lateral border of the tongue. that area.

A B

Fig. 11.34
Chronic bite injury: (A) there is marked shaggy hyperparakeratosis with acanthosis and leukoedema but little inflammation; (B) the characteristic fissures and clefts in the
parakeratin are rimmed by bacteria with little or no inflammation.

A A
B Fig. 11.36
Fig. 11.35
Benign alveolar ridge keratosis: (A) the site of a previous mandibular third molar
extraction is a typical location for this condition; (B) the crest of the alveolar ridge,
site of a previous tooth extraction, is another typical location for this condition.
Differential diagnosis
Verrucous hyperplasia may have a similar histology and often occurs on the
gingiva or alveolar ridge. However, the papillomatosis is usually more marked
and epithelial atypia is usually present, as well as bulky epithelial hyperplasia
and an endophytic growth pattern. Clinically, lesions of proliferative verru-
cous leukoplakia are extensive.
Benign migratory glossitis
Clinical features
Benign migratory glossitis (geographic stomatitis, stomatitis/erythema
areata migrans, geographic tongue, annulus migrans, erythema circinata)
occurs in 1–2% of the population (usually adults) although this figure
may be low because of the evanescent nature of the condition.1,2 Lesions
are recurrent, erythematous, and atrophic areas with a serpiginous white,
slightly raised border that may appear annular or scalloped (Fig. 11.37).2,3
These ‘map-like’ areas migrate and change in shape over the tongue dor-
sum as the condition resolves at one edge and involves another. Some
lesions, however, are stationary. Pain, in the form of a burning or sensitiv-
ity, may or may not be present. Twenty to 60% of patients have concurrent
fissured tongue.1–3
‘Ectopic geographic tongue’ or, more appropriately, geographic stom-
atitis, refers to a similar-appearing lesion at other sites, in particular the
Benign migratory glossitis 375
Benign ridge keratosis:
(A) there is hyperkeratosis,
wedge-shaped
hypergranulosis, and
acanthosis with minimal
to no inflammation;
(B) note the marked
hyperkeratosis,
B hypergranulosis, and
psoriasiform hyperplasia.
buccal and labial mucosae.4–6 The role of atopy in its pathogenesis is still
unsettled.3,7
Only 0.5% who present with benign migratory glossitis have psoriasis
but 5–14% of patients with psoriasis are affected by this condition.8–10 This
prevalence is likely higher in patients with pustular disease.11,12 The condition
also occurs in patients with Reiter's syndrome.13 Oral psoriasiform lesions
(excluding benign migratory glossitis) have a predilection for the palate.
Lithium carbonate (which can exacerbate psoriasis) has also been reported to
precipitate migratory glossitis.14
Human leukocyte antigen (HLA)-B15 (now Bw62 and Bw63) is seen
with higher frequency in affected patients and atopic individuals, as well
as in patients with associated type II diabetes mellitus lesions;15–17 how-
ever, the association with diabetes mellitus has been recently refuted.
There is also an increased incidence of HLA-Cw6 and HLA-B13 in addi-
tion to a reduced incidence of HLA-Cw4.18 Other authors have shown
increased incidences of HLA-DRw6, and -DR5 with reduced incidences
of -B51 and -DR2.19 There is also an increase in polymorphism in the
interleukin-1beta gene.20
376 Diseases of the oral mucosa

Fig. 11.37
Benign migratory glossitis: (A) note the erythematous
A B depapillated area rimmed by a white margin; (B) more
extensive involvement of the tongue which is fissured.

Histological features
The tongue dorsum exhibits loss of the filiform papillae (Fig. 11.38). There
are superficial spongiotic pustules and microabscesses (often involving up to
one-third of the thickness of the epithelium) in the absence of Candida infec-
tion (Fig. 11.39).2,4,21 The adjacent epithelium shows variable spongiosis and
leukocyte exocytosis. Additional features commonly present are psoriasiform
epithelial hyperplasia with broad rete ridges sometimes becoming conflu-
ent at their bases, edema of the lamina propria, and a variable lymphocytic
­infiltrate with conspicuous capillary dilatation.

Differential diagnosis
Candidiasis, which must always be excluded, more typically presents with
spongiotic pustules affecting only the top two to three layers of keratinocytes.
A PAS stain should routinely be performed for all pustular oral lesions. Median
rhomboid glossitis, a form of candidiasis, also enters the differential diagno-
sis since it may have a somewhat similar clinical presentation with ­atrophy of
­filiform papillae, although the area does not ‘migrate’ (see below).

Fig. 11.39
Benign migratory glossitis:
note spongiotic pustules
and neutrophilic exocytosis.

The epithelium at the edge of a healing ulcer often shows spongiotic

­pustules devoid of Candida and accompanied by neutrophilic exocytosis.
Oral lesions of patients with cutaneous psoriasis are histologically
­indistinguishable from lesions of benign migratory glossitis.22

Median rhomboid glossitis

Clinical features
Fig. 11.38 Median rhomboid glossitis is a form of oral candidiasis that occurs specifi-
Benign migratory glossitis: note the absence of filiform papillae (filiform papillary cally in the midline of the tongue just anterior to the circumvallate papillae
atrophy) and psoriasiform epithelial hyperplasia. (Fig. 11.40).1–3
 Smokeless tobacco keratosis 377

Fig. 11.42
Median rhomboid glossitis: Candida pseudo-hyphae are present with the PAS stain.
Fig. 11.40
Median rhomboid
glossitis: there is a typical
rhomboidal-shaped area
in the posterior midline of
the tongue.

Fig. 11.43
Median rhomboid
glossitis: note the
psoriasiform epithelial
hyperplasia and the dense
Fig. 11.41 median raphe just above
Median rhomboid glossitis: note the presence of spongiotic pustules.
the muscle fibers.

Histological features
Diagnosis depends on the presence of psoriasiform mucositis with spongiotic
pustules associated with candidal pseudo-hyphae (Figs 11.41, 11.42). The
identification of the median raphe, a densely hyalinized fibrous band within
the lamina propria, confirms that the tissue is from the midline of the tongue
(Fig. 11.43). It is unclear why this particular area of the tongue is predis-
posed to candidiasis.
of smokeless tobacco in contact with the mucosa.2 Discontinuation of use
usually results in resolution of oral lesions.5 Sudanese snuff (toombak) is a
mixture of tobacco and sodium bicarbonate and is high in tobacco-specific
nitrosamines.6
Early and mild lesions show slight wrinkling and pallor of the mucosa
while more advanced lesions show deep furrows and thickened white mucosa,
more typical of leukoplakia (Fig. 11.44).

Smokeless tobacco keratosis Pathogenesis and histological features

Clinical features
In smokeless tobacco keratosis (snuff dipper's keratosis), smokeless tobacco
is usually placed in the mandibular sulcus and its use is associated with the
development of white lesions at the site of contact in 13–46% of cases.1–4 The
severity of oral lesions is proportionate to the duration of use and the amount
Smokeless tobacco takes the form of snuff (moist or portion-packed) and
chewing tobacco. Scandinavian snuff, and particularly moist snuff which has
greater alkalinity (pH 8–9), has a greater propensity to cause lesions com-
pared with American snuff.1,2 In general, the risk of developing oral cancer
is less with smokeless tobacco than with cigarette smoking although this has
been disputed.7,8
378 Diseases of the oral mucosa

Fig. 11.44
Smokeless tobacco keratosis: note the grey white, pale, wrinkled mandibular
sulcular mucosa. Fig. 11.46
Smokeless tobacco
keratosis: note the keratin
The term ‘smokeless tobacco keratosis’ is a misnomer since early lesions chevrons and anucleate
are not markedly hyperkeratotic. Rather, the clinical appearance of whiteness and degenerate superficial
is a result of degeneration of the superficial keratinocytes from direct contact keratinocytes.
injury.
Lesions show a characteristic pale-staining surface layer of coagulated
and degenerate, often anucleate, cells occasionally covered by a thin layer
of parakeratin (Fig. 11.45). Typically, this superficial pale layer is sharply
demarcated from the underlying viable epithelium, which shows hyperplasia
and variable chronic inflammation. In addition, spires of keratin – ‘chevrons’ – ­are
usually present within this pale surface zone (Fig. 11.46).9–11 Keratin chev-
rons may also be seen in oral lesions associated with pipe smoking and the
use of other tobacco products.10 Sialadenitis of minor salivary glands has
been reported in up to 42% of cases.12 There is a reduction in the number of
intraepithelial Langerhans cells.13
Hyaline deposits may be seen as a dense homogenous, eosinophilic band
in the lamina propria in 8–17% of cases, usually located between the salivary
glands and the surface epithelium but also sometimes involving the gland
parenchyma and surrounding ducts (Fig. 11.47).12,14,15 This PAS-positive
material does not represent amyloid and is thought to be altered collagen
resulting from increased synthesis and/or reduced degradation of collagen.16

Fig. 11.47
Smokeless tobacco keratosis: the eosinophilic amyloid-like material is often seen
within underlying salivary gland parenchyma.

Epithelial atypia (generally mild) is present in up to 8% of cases, usually

in areas unassociated with chevrons and more often in areas of dense hyper-
keratosis.10 Squamous cell carcinoma is an infrequent complication of pure
smokeless tobacco usage in the absence of cigarette smoking and/or alcohol
consumption.3,4,9,10,15 The epithelial atypia is likely reactive since it resolves on
discontinuation of the habit.5,17
There is disturbed differentiation of keratin as evidenced by increased
expression of K13 and K14 in patients using toombak as compared with those
using Swedish snuff.18 Mutations in the p53 gene have been described.19

Differential diagnosis
Fig. 11.45 Hyaline deposits may also be seen in lesions of submucous fibrosis. The hya-
Smokeless tobacco keratosis: the superficial coagulated and degenerate cells are line material does not stain with Congo red and is not amyloid. Hyalinosis
sharply demarcated from the underlying acanthotic epithelium. mucosae et cutis has a different clinical presentation.

Fig. 11.48
Foreign body gingivitis: there is non-specific mild chronic inflammation in the lamina
propria.
Foreign body gingivitis
Clinical features
This condition occurs more often in females than in males (4:1), usually in
the fifth decade. The gingiva presents with multifocal or diffuse erythema that
is sore or painful in the majority of patients. Some lesions are ulcerated and/
or inflamed.1–3
Pathogenesis and histological features
Energy dispersive X-ray microanalyses have revealed Si, Al, Fe, Cu, and Ti in
the majority of cases and, in many lesions, the analyses match those of den-
tal abrasives. It is therefore thought that some of these cases result from such
abrasives forced into the gingiva during professional dental cleaning. Some
analyses also match those of amalgam.3,4
The epithelium is acanthotic or atrophic, and basal cell degeneration
is present in up to 50% of cases. The inflammatory infiltrate varies in
severity and is lichenoid (bandlike and lymphocytic) in half the cases
(Fig. 11.48). In one-quarter of cases, granulomatous inflammation may be
seen, sometimes accompanied by foreign body and/or Langhans-type giant
cells.1,2,5 Plasma cells may be abundant. Foreign bodies, ranging from 1 to
5 microns in ­diameter, are present in all cases, and 44% may be refractile
(Fig. 11.49).
Differential diagnosis
Plasma cell gingivitis exhibits an intense plasmacytic infiltrate, usually in
sheets, and foreign material is not identified although there is probably over-
lap between these two conditions.
Pyostomatitis vegetans
Clinical features
This is the oral counterpart of pyoderma vegetans. Men are twice as com-
monly affected as women.1 The most common associations are ulcerative
colitis (approximately 70%), Crohn's disease (10–15%), and liver ­disease
(21%).1–4 Patients present with numerous shallow ulcers and erosions,
­miliary abscesses, and pustules that coalesce to form ‘snail track’ lesions
(Fig. 11.50).5–7 These develop on erythematous mucosa in which ­vegetations
may be a feature. There is sometimes folding and fissuring of the buccal
mucosa. The dorsal surface of the tongue is usually spared.8,9 Peripheral
blood ­eosinophilia is present in 90% of cases.1
Pyostomatitis vegetans 379
Fig. 11.49
Foreign body gingivitis: small granules of foreign material that are refractile in polarized
light are present with mild surrounding chronic inflammation.
Fig. 11.50
Pyostomatitis vegetans: note the yellow pustular papules and linear lesions on the
buccal mucosa. By courtesy of B. Neville, DDS, Charleston, USA.
Histological features
There is epithelial hyperplasia, sometimes accompanied by papillomatosis,
and spongiosis. Suprabasilar clefting with acantholysis may also be seen
(Fig.  11.51). Characteristically, neutrophilic and eosinophilic abscesses are
present in the connective tissue papillae at the interface, and sometimes
within the epithelium itself (Fig. 11.52).1,5,8–10 Eosinophils and neutrophils
may permeate the epithelium and chronic inflammatory cells are abundant
in the lamina propria.
Direct immunofluorescence studies for IgG and C3 are generally negative.
When positive, the staining is usually weak and represents a secondary reac-
tion to epithelial inflammation and damage rather than a primary autoim-
mune phenomenon.1,11
Differential diagnosis
Pemphigus vulgaris may appear similar although typically there is more obvi-
ous acantholysis. In addition, neutrophilic and eosinophilic abscesses are
absent and papillary epithelial hyperplasia is not usually a feature. Pemphigus
vegetans shows considerable histological overlap although oral lesions are
rare. Distinction from both of these conditions is readily made by direct
immunofluorescence studies which show intercellular IgG deposition.
380 Diseases of the oral mucosa

Fig. 11.51
Pyostomatitis vegetans: note the intraepithelial clefting and abscesses.

Fig. 11.52
Pyostomatitis vegetans:
there is acantholysis and
an abscess is present
suprabasally.

Ulcerative conditions

Recurrent aphthous stomatitis

Clinical features
Recurrent aphthous stomatitis occurs in 15–20% of the adult population,
generally below the age of 40.1,2 It is a chronic, painful, relapsing, ulcer-
ative condition of the nonkeratinized mucosa (Fig. 11.53). There are three
­variants: minor, major and herpetiform.
• Ulcers of the minor form (the most common variant) are less than 1 cm,
last 7–14 days and heal without scarring.
• Ulcers of the major form are usually greater than 1 cm, last many weeks,
and heal with scarring.
• Ulcers of the herpetiform variety occur in small crops of 10–100 ulcers in
any one episode.2,3
Some conditions frequently associated with the minor variant include
Behçet's disease, anemia, inflammatory bowel disease, gluten-sensitive
enteropathy, food hypersensitivity, and neutropenia.4,5 Aphthous stomati-
tis presenting in association with rheumatological or mucocutaneous dis-
orders is sometimes referred to as complex aphthosis.6 There is also often
Fig. 11.53
a family history of aphthous ulcers but there is no evidence at present
Recurrent aphthous ulcer: a typical aphthous ulcer covered by yellow fibrin
that the condition is infectious in nature. More recent studies suggest that membrane with surrounding erythema on the upper labial mucosa.
Helicobacter pylori may play a role and they may reside in a reservoir
in the tonsils or dental plaque.7–9 In children, aphthous stomatitis may
be syndromic and associated with periodic fever, lymphadenopathy and destruction of the epithelium. Early lesions show a predominance of T-helper
pharyngitis (PFAPA syndrome, periodic fever syndrome).10–12 Interestingly, cells followed by an increase in T-suppressor cells during the ulcerative phase;
such patients often show complete response after tonsillectomy and/or T-helper cells re-emerge during the healing phase.16–18 Increased numbers of
adenoidectomy.13 peripheral gamma-delta cells have been noted, suggesting that antibody-
­dependent cell-mediated cytotoxicity may play a role in the immunopathogen-
Pathogenesis and histological features esis of this disease.19 Cell lysis may be mediated through tumor necrosis factor
Cross-reaction of antigens of Streptococcus mutans with a mitochondrial heat alpha (TNF-α).20
shock protein may play an important role in the pathogenesis of this condi- The histological appearances are non-specific. There is ulceration of the
tion.14 Expression of HLA class I and class II antigens on epithelial cells may mucosa with a thick fibrin clot enmeshed with neutrophils (Fig. 11.54).
result in targeting for cytotoxic attack.15 There is no evidence of increased The adjacent epithelium may exhibit reactive atypia; viral inclusions are not
circulating immunoglobulins or immune complexes. seen. The ulcer bed consists of granulation tissue with acute and chronic
The ulcerative process results from T-cell activation. Although the target ­inflammatory cells.21 Inflammatory changes and degeneration of superficial
antigens have yet to be clearly and consistently elucidated, the end result is skeletal muscle fibers may also be evident.
 Traumatic ulcerative granuloma 381

Fig. 11.54 Fig. 11.55

Recurrent aphthous ulcer: the mucosa exhibits non-specific ulceration. Traumatic ulcerative granuloma: this indurated ulcer had developed after a tongue
biopsy at that site.

Differential diagnosis
Traumatic ulcers and the ulcers of Behçet's disease are histologically indis-
tinguishable and their distinction is dependent upon clinicopathological
correlation. If there is inflammation of the muscle associated with a histio-
cytic mononuclear cell infiltrate and a significant number of eosinophils,
a diagnosis of traumatic ulcerative granuloma is more appropriate (see
below). If the fibrin clot and underlying granulation tissue contain few
neutrophils, neutropenia-associated ulceration – such as is seen in human
immunodeficiency virus (HIV) disease and cyclic neutropenia – must be
considered.

Traumatic ulcerative granuloma

Clinical findings
Traumatic ulcerative granuloma (traumatic ulcerative granuloma with
stromal eosinophilia, eosinophilic ulcer/granuloma of the tongue, Riga-Fede
disease) may present in two quite different ways. The less common form –
and one that is not usually biopsied – occurs in infants in the first year of life. Fig. 11.56
Painful ulcers that may be elevated occur on the ventral tongue or lower lip Traumatic ulcerative granuloma: this patient had bitten her tongue during a seizure
as a result of the child rubbing the mucosa against the developing lower ante- and the indurated mass developed over a few days.
rior deciduous teeth (Riga-Fede disease).1 The second presentation, and the
more common, is in the fifth and sixth decades of life. The lateral tongue (up
to 64% of cases), followed by the buccal mucosa, are most often affected.2–5
An ulcer or indurated area develops and persists for weeks or months (Figs
11.55, 11.56). The lack of pain, often a feature of this condition, raises the
clinical suspicion of squamous cell carcinoma.4 A history of trauma is elic-
ited in only 50% of cases.2,3 Lesions are often multifocal and up to 30% of
lesions recur.5

Pathogenesis and histological features

Lesions similar to but not identical with this condition can be experimentally
induced in animals by crush injury.6 It is thought that the inciting factor is
trauma, which leads to acute and chronic inflammation that for unknown
reasons becomes deep, penetrating, chronic, and exaggerated. It is possible
that cytokines released by activated lymphocytes recruit eosinophils. Whether
muscle degeneration is primary to the process or merely a secondary phenom-
enon is unclear.2,3 Infectious agents and foreign material have not been identi-
fied in these lesions.
There is loss of the surface epithelium with abundant granulation tis-
sue at the ulcer base accompanied by a polymorphous inflammatory infil- Fig. 11.57
trate of T lymphocytes and plasma cells, which penetrates into the deep Traumatic ulcerative granuloma: note the ulcerated surface and the penetrating
mucosa and underlying muscle (Figs 11.57, 11.58). The presence of many inflammation that separates muscle fascicles.
382 Diseases of the oral mucosa
Fig. 11.58
Traumatic ulcerative granuloma: there is prominent interfascicular inflammation and
muscle degeneration.
Fig. 11.59
Traumatic ulcerative granuloma: note the presence of histiocyte-like mononuclear
cells and many eosinophils.
­ ononuclear histiocyte-like cells accompanied by eosinophils and some-
m Atypical histiocytic granuloma: many lymphocytes, mononuclear cells, and
times mast cells is diagnostic (Fig. 11.59).2,3,7,8 Muscle fragmentation,
interfascicular inflammation with degeneration, and the presence of strap
cells are common additional features.6,9 In some cases, the granulation tis-
sue proliferation is so exuberant as to result in an exophytic pyogenic gran-
uloma-like mass.
The large histiocyte-like cells express either CD68 or factor XIIIa.7
Scattered CD30+ cells may be present in this lesion. 4,10
Differential diagnosis
In its most florid form, traumatic ulcerative granuloma shares histological
features with atypical histiocytic granuloma (pseudolymphoma).11–14 This
condition, which may or may not involve the underlying muscle, is character-
ized by a dense infiltrate of lymphocytes, including transformed variants and
centroblasts, often raising the suspicion of lymphoma (Figs 11.60, 11.61).12
Clonality and gene rearrangement studies are often necessary to differentiate
Fig. 11.60
Atypical histiocytic
granuloma: there is
a diffuse and dense
lymphohistiocytic infiltrate.
Fig. 11.61
eosinophils are present; there is a mitotic figure.
between these two conditions. Atypical histiocytic granuloma regresses spon-
taneously in the majority of cases. However, diffuse positivity for CD30 may
indicate T-cell lymphoma. 10
Angiolymphoid hyperplasia with eosinophilia may sometimes present in the
buccal mucosa or lip.15,16 Epithelioid endothelial cells stain for vascular markers.
Lymphocytes, plasma cells, and eosinophils are commonly seen and occasional
lymphoid follicles with germinal centers are p­ resent (Figs 11.62, 11.63).16,17
Histiocyte-like cells and eosinophils are a feature of Langerhans cell
­histiocytosis. However, Langerhans cells have the characteristic grooved
nuclei and can be identified with S-100 protein, CD1a and langerin
immunohistochemistry.
 Squamous papilloma 383

Fig. 11.62 Fig. 11.63

Angiolymphoid hyperplasia with eosinophilia: note the pale lobular areas with Angiolymphoid hyperplasia with eosinophilia: there are plump epithelioid endothelial
central vessels and prominent germinal centers. cells associated with many lymphocytes and eosinophils.

Papillary Lesions
Squamous papilloma
Clinical features
Squamous papilloma generally presents in adults in the second to fourth
decades. Sites of predilection include the soft palate–uvula complex and the
tongue, although any region in the oral cavity may be affected. Lesions may
be white or erythematous with a warty, finger-like or cauliflower-like appear-
ance (Figs 11.64, 11.65).1,2

Histological features
The epithelium is thrown into papillary folds and there may be prominent
or absent hyperparakeratosis or hyperorthokeratosis. In general, if the pap-
illoma arises from a nonkeratinized site (such as the uvula, soft palate, ven-
tral tongue or floor of mouth), it will often be non- or only thinly ­keratinized

Fig. 11.65
Squamous papilloma: there is a rough, white warty lesion of the lateral tongue.

but may exhibit keratinocyte edema (especially soft palate lesions) (Fig.
11.66).1 Koilocytes are not usually apparent. The epithelium may be thick-
ened but rete ridges are not bulbous. The connective tissue cores usually
contain congested vessels with perivascular hyaline cuffs. Depending on
whether the papilloma has been traumatized or not, there is variable inflam-
mation.1,2 In situ hybridization and polymerase chain reaction (PCR) stud-
ies have identified human papillomavirus (HPV) (usually -6 and -11) in up
to 67% of cases; HPV-2 is occasionally present.3,4

Differential diagnosis
Verruca vulgaris may occasionally occur in the oral cavity and, as in the skin,
it is characterized by marked hyperorthokeratosis with prominent coarse ker-
atohyaline granules and axial inclination of epithelial papillary projections.
HPV-2 is identified in up to 20% of cases of intraoral and up to 100% of lip
verruca vulgaris.5–7
Fig. 11.64 Oral condyloma acuminatum shows large, bulbous rete ridges and prom-
Squamous papilloma: there is a rough, warty lesion of the soft palate. inent koilocytosis; rare cases have an intrasalivary duct component and
384 Diseases of the oral mucosa

HPV-6 and -11 are often identified (Figs 11.67, 11.68).8–10 This condition
occurs most frequently in patients who are on long-term immunosuppres-
sion such as organ transplant recipients or those who have pre-existing
­genital lesions.
Irritated and inflamed papillomas often exhibit spongiosis. The condition
juvenile localized spongiotic gingival hyperplasia may represent such irritated
papillomas or be a distinct entity.11
Focal epithelial hyperplasia (Heck's disease), which is associated with
infection by HPV-13 and HPV-32, may show papillary epithelial hyperplasia
although this is not invariably present. Importantly, ‘mitosoid’ figures (cells
showing karyorrhexis) are a characteristic feature.
Rare cases of oral acanthosis nigricans have been reported and these are
generally associated with gastrointestinal malignancy.12,13

Verruciform xanthoma
Clinical features
Fig. 11.66 Verruciform xanthoma affects adults in the fourth and fifth decades with
Squamous papilloma: note the finger-like projections of epithelium keratinocyte
no significant sex predilection.1–3 It presents as a well-circumscribed rough,
edema is present.
­granular or pebbly, raised or depressed, yellowish, reddish or gray plaque
(Fig. 11.69). Seventy percent occur primarily on the keratinized attached
mucosa of the palate, gingiva or alveolar ridge mucosa. Lesions on the skin
(especially of the anogenital area) and other mucosal sites have also been
reported.4 Although there is one report of a patient with multiple lesions and
lipid storage disease, most patients do not exhibit hypercholesterolemia or
disorders of lipid storage.5

Pathogenesis and histological features

Fig. 11.67
Condyloma acuminatum: this larger warty lesion on the gingiva occurred in a
patient on long-term immunosuppression after lung transplantation.
It has been postulated that the epithelial cells are damaged and degener-
ate, releasing lipid that becomes engulfed by macrophages. Neutrophils
are also recruited to the area by the degenerating cells.4,6 The gingiva
and palate are constantly traumatized by mastication, in support of this
hypothesis. Verruciform xanthoma also occurs in association with other
conditions where epithelial damage occurs such as lichen planus, pemphi-
gus vulgaris, discoid lupus erythematosus, epidermolysis bullosa, follow-
ing bone marrow transplantation, and possibly graft-versus-host disease
(GVHD).7–12
Histologically, there is hyperparakeratosis with the parakeratin exhibit-
ing a bright orange hue. Loose keratin squames are present on the surface
or within epithelial crypts. The surface of a verruciform xanthoma generally

Fig. 11.68 Fig. 11.69

Condyloma acuminatum: unlike squamous papilloma, the rete ridges are large and Verruciform xanthoma: note the warty sessile lesion on the left hard palate.
bulbous and koilocytes are readily identified. By courtesy of C. Allen, DDS, Columbus, USA.
 Fibroma 385

Fig. 11.70
Verruciform xanthoma: there is marked hyperparakeratosis and papillomatosis with
confluence of rete ridges at the tips; note the unusually brightly stained keratin.
Fig. 11.72
Verruciform xanthoma:
the lamina propria
contains numerous foamy
macrophages.

has a papillary configuration although some lesions are flat.1 Rete ridges are
uniformly long and sometimes coalesce at their bases (Figs 11.70, 11.71).
Large, foamy, lipid-laden macrophages are found within the connec-
tive ­tissue papillae (Fig. 11.72); rarely, such cells extend beyond the
deepest portion of the rete ridges or are seen within the epithelium.13,14
Multinucleate forms are not a feature. Lymphocytes (primarily T cells)
are present at the base.15,16 Neutrophils may be present superficially and a
reduction of Langerhans cells has been noted in the affected epithelium.8,15
Rarely, nonmucosal cases may show a cystic and inverted, crateriform
configuration.4,17
Ultrastructurally, the xanthoma cells contain membrane-bound
­granules consistent with lysosomes, myelin figures, and fragments of des-
mosomes, the last supporting the theory of phagocytosis of epithelial cell
debris.6,13,18
Fig. 11.71 The xanthoma cells express CD68 and sometimes S-100 protein.15,16,19
Verruciform xanthoma: Most of the xanthoma cells represent reparative (RM3/1) and resident (25F9)
parakeratotic squames on foam cells. 20 Slight granular staining for cytokeratin within the foam cells also
the surface of the keratin supports the presence of epithelial fragments.4 HPV ­immunohistochemistry
and in the crypts are a is negative.4,16
characteristic feature.

Tumor-like conditions

Fibroma Histological features

Clinical features
Fibroma (fibrovascular polyp, fibroepithelial polyp, irritation fibroma, bite
fibroma) is the most common tumor-like (but non-neoplastic) condition in
the mouth. It is usually located at sites of trauma, namely the buccal mucosa
at or near the linea alba, the lateral borders and tip of the tongue and the
lower labial mucosa, as well as on the gingiva.1,2 It presents as a fleshy,
­pedunculated or sessile dome-shaped nodule that may be mucosal-colored,
ulcerated or hyperkeratotic (Figs 11.73, 11.74).
The fibroma consists of a proliferation of fibrocollagenous tissue with vari-
able vascularity and usually mild to insignificant inflammation unless there is
overlying ulceration (Figs 11.75, 11.76). On occasion, the lesion may resem-
ble a hypertrophic scar or keloid. Sclerotic fibroma (collagenous fibroma)
has been reported in the oral cavity and the collagen in these lesions has a
storiform appearance with clefts between the collagen and stellate or multi-
nucleated fibroblasts with dendritic processes. The cells sometimes stain for
CD34.3 Epithelium may be hyperkeratotic, acanthotic or atrophic. If adipose
tissue is present, the term ‘fibrolipoma’ is sometimes applied.
386 Diseases of the oral mucosa

Fig. 11.73 Fig. 11.76

Fibroma: there is a fleshy pink fibroma on the lower labial mucosa. Fibroma: often, the collagen in fibromas may be extremely hyalinized and almost
keloidal in appearance.

Giant cell fibroma

Clinical features
Giant cell fibroma occurs in the first three decades of life and the most com-
mon sites affected are the keratinized regions of the gingiva (44–49%), tongue
­(17–22%) and palate (15–18%).1,2 It often has a papillary or bosselated sur-
face configuration. It bears some resemblance to the fibrous papule of the
nose, angiofibroma, and the pearly penile papule. The retrocuspid papilla has
a similar ­histology and is located on the lingual mandibular gingiva in the
area of the cuspid.3,4

Histological features
The most characteristic feature of the giant cell fibroma is the presence of giant,
angulated and stellate-shaped fibroblast-like cells, usually clustered beneath
the epithelium (Figs 11.77, 11.78).1,2,5 Multinucleated giant fibroblast-like

Fig. 11.74
Fibroma: the lateral border of the tongue is a common site for a fibroma.

Fig. 11.77
Fig. 11.75 Giant cell fibroma: note
Fibroma: this fibroma from the buccal mucosa exhibits hyperkeratosis as compared the undulating surface and
to the base which is nonkeratinized. spiky rete ridges.
 Denture-associated fibrous hyperplasia 387

Fig. 11.79
Lipoma: note the yellowish nodule on the buccal mucosa.

Fig. 11.78
Giant cell fibroma: note
the stellate-shaped and
multinucleated cells.

cells (‘manta ray cells’) are common. The overlying epithelium is usually hyper-
plastic, forming spiky, saw-tooth-shaped rete ridges, and there may be surface
papillomatosis.
The cells express vimentin, occasionally factor XIIIa, but not S-100 pro-
tein or CD68.5,6

Differential diagnosis
The multinucleate cell angiohistiocytoma occurs rarely in the oral cavity
and contains multinucleated giant cells, branching capillaries, and a myxoid
stroma.7,8

Lipoma and atypical lipomatous tumor

Clinical features
This presents as a yellowish, soft and doughy, painless, sessile or pedun-
culated nodule that generally occurs on the buccal mucosa or sulcus (Fig.
11.79). It usually occurs in adults in the sixth and seventh decades.1–3 Other
sites include the tongue, lips, and floor of mouth. Infiltrating or intramus-
cular lipomas tend to occur two decades earlier and generally involve the
tongue.2,4,5
Some lipomas of the buccal mucosa are not true tumors but represent
­herniation of the buccal fat pad.
Histological features
Lipomas represent circumscribed proliferations of mature adipocytes iden-
tical to normal adipose tissue.3 Cartilaginous and osseous metaplasia has
occasionally been reported.6,7 Similar benign adipocytes are present within
skeletal muscle fibers in an infiltrating (intramuscular) lipoma.4 Oral spindle
cell lipoma has also been reported and this consists of spindle cells showing
slight nuclear pleomorphism within a myxoid stroma with ropey collagen
and mast cells.3
Differential diagnosis
Distinction must be made between a banal lipoma and an atypical lipoma-
tous tumor that generally occurs on the tongue of adults, and that represents
a superficial variant of well-differentiated liposarcoma. These are infiltrative
Fig. 11.80
Atypical lipomatous tumor:
the tumor has infiltrative
margins and cells with
variably sized vacuoles.
tumors containing lipoblasts (uni-, bi- or multivacuolated) with hyperchro-
matic and atypical nuclei (Figs 11.80, 11.81).7-9 Foci of spindled cells and
dedifferentiation have also been reported.
Denture-associated fibrous hyperplasia
Clinical features
Denture-associated fibrous hyperplasia (inflammatory fibrous hyperpla-
sia, epulis fissuratum, denture hyperplasia, papillary hyperplasia, inflam-
matory papillary hyperplasia) presents as a linear mass of tissue arising in
the mucobuccal sulcus around the flange of a poorly fitting denture. The
redundant tissue cushions the mucosa against ongoing trauma. The anterior
maxillary and mandibular sulci are the preferred sites of involvement (Figs
11.82, 11.83). There is a 3:1 female predisposition and most occur in the
sixth decade.1–3
388 Diseases of the oral mucosa

Fig. 11.81
Atypical lipomatous tumor: note the lipoblasts with atypical, hyperchromatic, and
indented nuclei. Fig. 11.84
Denture-induced papillary
hyperplasia of the palate:
note the typical pebbly
papillary structures on the
palate.

A clinically different form of denture-associated fibrous proliferation is

also referred to as papillary hyperplasia or inflammatory papillary hyperpla-
sia of the palate. The movement of a poorly fitting maxillary denture results
in the development of an erythematous, edematous and pebbly, multinodular
appearance to the mucosa of the hard palate (Fig. 11.84).4,5

Fig. 11.82
Denture-induced fibrous hyperplasia: there is an elongated mass of soft tissue in
the mandibular sulcus with a fissure running through it.
Histological features
Denture-associated fibrous hyperplasia is characterized by proliferation of
dense fibrous tissue with variable vascularity. Lymphocytes are generally dif-
fusely dispersed at the interface of epithelium and fibrous tissue; the epithe-
lium is hyperplastic and thrown into papillary folds (Fig 11.85). Pooling of
plasma on the surface of the mucosa indicates trauma. Osseous and chon-
droid metaplasia are seen in approximately 5% of cases, particularly in the
anterior maxilla.6 Salivary glands are present in 43% of cases.

Fig. 11.85
Denture-induced fibrous hyperplasia: there is papillomatosis and hyperplasia of
Fig. 11.83 epithelium and fibrous tissue. A cartilaginous rest is present in this lesion from the
Denture-induced fibrous hyperplasia: the denture flange (edge) fits into the fissure. anterior maxillary sulcus.
 Gingival fibroma 389

Fig. 11.86 Fig. 11.87

Denture-induced papillary hyperplasia: curettage specimens yield these fibrous Gingival nodule: note how the nodule arises from the gingival margin and hangs
nodules with chronic inflammation. down onto the tooth.

In palatal lesions, the histology is that of multiple small nodules of fibro-

vascular tissue containing chronic inflammatory cells that are typically
removed piecemeal (Fig. 11.86).4 If spongiotic pustules are present, Candida
superinfection should be excluded.7

Gingival nodules
Clinical features
The term ‘epulis’ refers to any mass or nodule on the gingiva or alveolar ridge
and should be confined to clinical usage only. The two exceptions are epu-
lis fissuratum and congenital granular cell epulis, referring to two particular
clinical and histological entities.
Most solitary gingival nodules represent one of the following conditions:
reactive tumor-like proliferations, odontogenic cysts, primary odontogenic
and nonodontogenic neoplasms, and metastatic neoplasms. The first are by
far the most common and consist of the following entities:
• fibroma or fibrous hyperplasia with or without inflammation,
• giant cell fibroma, Fig. 11.88
• pyogenic granuloma, Gingival nodule: such nodules may be located on the palatal aspect of the gingiva.
• peripheral ossifying fibroma,
• peripheral giant cell granuloma.
These lesions are located on the attached or marginal gingiva adjacent to
teeth. Depending on the degree of vascularity, inflammation, and/or ulcer-
ation present, they may be mucosal-colored, erythematous or ulcerated and Gingival fibroma
painful (Figs 11.87, 11.88).
It is thought that these fibrous and vascular reactive nodules develop Clinical features
as a response to irritation from dental plaque and calculus, often exacer- Some fibromas represent the scarred remnants of pyogenic granulomas. One
bated by the presence of defective restorations or other dental hardware. form of fibroma, the gingival fibrous nodule (also known as fibrous hyper-
Undifferentiated mesenchymal cells in the connective tissue proliferate and plasia, fibrovascular polyp, inflammatory fibrous hyperplasia, fibrous epu-
differentiate into cells that form native tissues in the area such as fibroblasts lis) occurs not on the free or marginal gingiva but on the attached gingiva as
(fibroma), endothelial cells (pyogenic granuloma), bone- and cementum- multiple mucosal-colored papules.1 Another variant is the giant cell fibroma,
producing cells (peripheral ossifying fibroma), or osteoclasts (peripheral which often has a papillary surface and may be clinically mistaken for a
giant cell granuloma). It is therefore not uncommon to see features of all papilloma.
four entities present to varying degrees within any one lesion. Unless the
source of irritation is removed completely, it is not unusual for these lesions
to recur. Histological features
Dental plaque is often present as clumps of Gram-positive filamentous Gingival fibroma is composed of a mass of densely or delicately collagenized
bacteria that morphologically resemble actinomycotic colonies. Unless sur- tissue with variable vascularity (Fig. 11.89).2 If there is significant chronic
rounded by a mantle of neutrophils, such colonies are surface colonizers and inflammation, the stroma may be edematous. The overlying epithelium is
do not represent Actinomycosis infection. sometimes hyperkeratotic and there may be continuity with crevicular epi-
Other gingival nodules and masses include the gingival and periodontal thelium, which generally shows spongiosis, neutrophilic exocytosis, and an
abscess and the parulis. underlying plasmacytic infiltrate (Fig. 11.90).
390 Diseases of the oral mucosa
Fig. 11.89
Inflammatory fibrous hyperplasia of the gingiva: the surface keratinized epithelium
is in continuity with the nonkeratinized crevicular epithelium, where inflammatory
cells are present.
Fig. 11.90
Inflammatory fibrous hyperplasia of the gingiva: note the crevicular epithelium with
spongiosis and the piece of dental plaque that morphologically resembles a mass
of actinomycotic organisms.
Pyogenic granuloma
Clinical features
These nodules tend to be dark red and bleed readily. One variant of this
lesion, the granuloma gravidarum, occurs during pregnancy, usually in the
second and third trimesters, probably as a consequence of the neovasculariz-
ing effects of estrogen (Fig. 11.91).1 The recurrence rate is 16%.2
Although the majority of intraoral pyogenic granulomas occur on the gingiva,
other sites including the lips, buccal mucosa, and tongue may be affected.3–5
Histological features
Gingival pyogenic granuloma is characterized by a diffuse (very common)
or lobular (more common on nongingival sites) proliferation of ­endothelial
Fig. 11.91
Granuloma gravidarum: this nodule occurred in an edentulous part of the
mandible.
Fig. 11.92
Pyogenic granuloma:
there is a typical lobular
proliferation of endothelial
cells and capillaries.
cells, many of which form canalized and congested capillaries (Figs 11.92,
11.93).5 Dilated, branching vessels are usually present in the center of
­lobules.3 The overlying epithelium is ulcerated in 75% of cases and there
is a variable neutrophilic, lymphocytic, and plasmacytic infiltrate.2 Some
­pyogenic granulomas become increasingly sclerotic and may eventuate in
gingival fibrous hyperplasias after the bulk of the vasculature is replaced by
fibrous tissue (Figs 11.94, 11.95).
There is no increase in the number of estrogen receptors on the endothelial
cells of such lesions compared with controls although they may express more
vascular endothelial growth factor and other angiogenesis-enhancing factors
and fewer inhibitory factors.6,7
 Peripheral ossifying fibroma 391

A B

Fig. 11.93
Pyogenic granuloma: (A) note benign-appearing endothelial cells and dilated capillaries; (B) normal mitoses are not uncommonly seen.

Peripheral ossifying fibroma

Clinical features
This tumor, also known as calcifying fibrous epulis or calcifying fibroblastic
granuloma, occurs in the second and third decades and women are affected
up to two times more often than men (1.5–2:1). Up to two-thirds occur in the
maxilla.1,2 The recurrence rate is 8–16%.1,2

Histological features
The lesion presents as a nonencapsulated cellular proliferation of plump,
fibroblast-like cells with fusiform-to-ovoid vesicular nuclei and indistinct
cell borders (Figs 11.96, and 11.97). Admixed are varying amounts of
osteoid, and woven and lamellar bone (Fig. 11.98). The more mature
the bone, the less cellular the stroma. The bone may be focally rimmed
by osteoblast-like cells. Droplet calcifications and (less commonly) broad

Fig. 11.94
Sclerosing pyogenic granuloma: note the break-up of the lobular architecture by
fibrous tissue.

Fig. 11.96
Peripheral ossifying
fibroma: there is a mass
Fig. 11.95 of cellular fibrous tissue
Sclerosing pyogenic granuloma: note marked sclerosis and corresponding reduction with calcifications and
in the number of vessels. overlying ulceration.
392 Diseases of the oral mucosa

Fig. 11.97 Fig. 11.99

Peripheral ossifying fibroma: note the plump fibroblasts and the marked cellularity. Peripheral ossifying fibroma: it is not uncommon to see clusters of osteoclast-like
giant cells in these lesions.

Histological features
Peripheral giant cell granuloma is characterized by a discrete but unencap-
sulated diffuse proliferation of osteoclast-like multinucleate giant cells and
mononuclear cells in a vascular stroma with abundant fresh hemorrhage and
hemosiderin deposition (Figs 11.100, 11.101). The giant cells may have
vesicular or hyperchromatic nuclei.7 The mononuclear cells have large vesicu-
lar nuclei with prominent nucleoli (Fig. 11.102). Mitoses are common.8
A Grenz zone often separates the giant cells from an overlying intact or ulcer-
ated epithelium.2 Chronic inflammation may be present. Myofibroblasts have
been demonstrated, supporting the reactive nature of this lesion.9 Foci of
peripheral ossifying fibroma are present in one-third of cases.8,10,11
The giant cells and mononuclear cells express vimentin, muramidase,
α1-antitrypsin, α1-,antichymotrypsin and CD68, suggesting that they are of
­monocyte–phagocyte lineage.7,12 Other studies have shown that the multinu­cle­
ated giant cells stain for MBI, an osteoclast marker.13 Estrogen but not proges-
terone receptors have been identified in both mononuclear and giant cells.14

Fig. 11.98
Peripheral ossifying fibroma: the bone may take the form of osteoid, woven and/or
lamellar bone, or calcified spherules.

anastomosing globular masses of cementum are sometimes seen.1,3 This

lesion is not a true neoplasm but rather a fibrous hyperplasia that forms
metaplastic bone and cementum. Even if calcifications are not clearly
identified, the cellular proliferation of such fibroblast-like cells should
raise the suspicion of this entity, and deeper sections will usually reveal the
presence of osteoid. Foci of osteoclast-like multinucleated giant cells are
occasionally present in addition to areas resembling pyogenic ­granuloma
(Fig. 11.99).1,2

Peripheral giant cell granuloma

Clinical features
This lesion usually occurs in the fourth and fifth decades of life and the
mandible may be two to three times more often involved than the maxilla.
Fig. 11.100
It often resides in a cup-shaped depression within the underlying bone.1–3 Peripheral giant cell
Some 19–22% occur in edentulous areas.4 The recurrence rate is up to granuloma: there is
22%.3 Examples of such peripheral lesions associated with hyperpara- generally a Grenz zone
thyroidism most likely represent gingival extension of central giant cell that separates the giant
granulomata.5,6 cells from the epithelium.

Fig. 11.101
Peripheral giant cell granuloma: note the marked vascularity of the lesion.
Fig. 11.102
Peripheral giant cell granuloma: giant cells, mononuclear cells and many siderophages
are present.
Parulis
Clinical features
The parulis (or gum-boil) is a red or pink, painless papule, sometimes with a
central punctum. It is located away from the gingival margin, usually overly-
ing the apex of a tooth, and represents the opening of a draining sinus from
an intraosseous odontogenic infection (Fig 11.103).
Histological features
The nodule consists of a proliferation of edematous granulation tissue contain-
ing many acute and chronic inflammatory cells and, in particular, microab-
scesses in a linear array – the sinus tract (Figs 11.104, 11.105).
Differential diagnosis
Although this lesion bears a superficial resemblance to a mucocele, no mucin
or muciphages are present. Mucoceles almost never occur on the gingiva since
salivary gland tissue is absent at this site.
Peripheral odontogenic fibroma 393
Fig. 11.103
Parulis: note the small papule located on the non-attached gingiva, at some distance
from the gingival margin.
Fig. 11.104
Parulis: the papule is composed of edematous granulation tissue; a tract leads from
deep in the tissues to the surface.
Peripheral odontogenic fibroma
Clinical features
The preferred site for this tumor is the mandibular premolar/cuspid and ante-
rior maxillary region.1 It mainly occurs in adults in the third decade with an
equal sex predilection. Recurrence varies from 3% to 39%.1,2
Histological features
The nodule consists of a proliferation of fibrous tissue that may be densely
or loosely collagenized and variably hypercellular or hypocellular. More typi-
cally, the stroma has a whorled, streaming or fasciculated pattern.2–4 Islands,
strands, and nests of odontogenic epithelium are present to a variable extent
(Figs 11.106, 11.107). Epithelial cells may appear clear or, rarely, squamous
and hyaline cuffs are sometimes seen around the epithelium (the so-called
‘inductive effect’). Calcifications are present in 33–50% of cases and take two
forms: as dentinoid or as dystrophic globular calcifications in the stroma.1,2,4,5
394 Diseases of the oral mucosa

Fig. 11.107
Peripheral odontogenic fibroma: strands of squamous epithelium show a hint of
palisading of the peripheral nuclei, typical for odontogenic epithelium.
Fig. 11.105
Parulis: note the natural
space formed by
neutrophils in a linear
array.

Fig. 11.108
Peripheral odontogenic fibroma: note the abundance of epithelium in this lesion.
By courtesy of T. Daley, DDS, Winnipeg, Ontario, Canada.

Fig. 11.106
Peripheral odontogenic fibroma: strands of odontogenic epithelium are present in a
fibrous stroma.

When epithelium is abundant, the term odontogenic gingival epithelial hama-

rtoma may be applied (Fig. 11.108).6 One variant contains stromal granular
cells.1,7 The presence of giant cells has also been reported.8

Differential diagnosis
Lack of significant atypia distinguishes this lesion from metastatic carcinoma
although it must be borne in mind that many malignant glandular and/or
adnexal tumors can sometimes show minimal pleomorphism.
Peripheral odontogenic fibroma is the most common peripheral odonto-
genic tumor and should also be distinguished from other odontogenic tumors
that may present on the gingiva.9 The peripheral ameloblastoma contains
many large islands of odontogenic epithelium with distinct palisading and Fig. 11.109
reverse polarization of the basal cell nuclei, resembling a basal cell ­carcinoma Peripheral ameloblastoma: islands of epithelium grow into the stroma from the
(Figs 11.109, 11.110).10 surface. By courtesy of C. Allen, DDS, Columbus, USA.
 Gingival cyst of the adult 395

Fig. 11.110 Fig. 11.113

Peripheral ameloblastoma: note the typical palisading of the basal cell nuclei. Calcifying epithelial odontogenic tumor: note the presence of epithelial cells and
By courtesy of C. Allen, DDS, Columbus, USA. amyloid.

Peripheral calcifying odontogenic tumor is lined by basaloid cells con-

taining ghost cells, sometimes with dystrophic calcification (Figs 11.111,
11.112).11 The counterpart of this lesion on the skin is the calcifying epi-
thelioma of Malherbe (pilomatrixoma). A solid variant called the odonto-
genic ghost cell tumor has a predominance of ghost cells and dentinoid or
osteoid.12
Peripheral calcifying odontogenic tumor consists of large polyhedral cells
with eosinophilic cytoplasm associated with amyloid deposits and ringlike
dystrophic calcification (Fig. 11.113).13

Gingival cyst of the adult

Clinical findings
This lesion occurs in the fifth decade with a roughly equal sex distribution.
Fig. 11.111 Three-quarters occur in the mandible, mainly in the cuspid/ bicuspid buccal
Odontogenic ghost cell tumor: note the basaloid cells and calcified material gingiva. It presents as a bluish nodule, usually measuring less than 1 cm in
adjacent to the epithelium. diameter.1–3

Pathogenesis and histological features

A variety of origins have been postulated. The gingival cyst may arise from
stimulated rests of dental lamina (a residuum of odontogenesis) or be derived
from epithelium in the gingival sulcus 2,4,5
The cyst is usually lined by nonkeratinized epithelium, either low cuboidal
or squamous, 1–3 cells thick (Figs 11.114, 11.115). Focal epithelial plaques
are present in approximately one-third of cases, some of which contain clear
cells.1–3 Occasional lesions resemble an intraosseous odontogenic keratocyst
with a thin epithelial lining, corrugated parakeratosis, and palisading of the
basal cells.6 This variant is sometimes referred to as a peripheral odontogenic
keratocyst.

Differential diagnosis
In children, dental lamina cysts of the newborn occur on the alveolar ridge
(especially maxillary) and are almost always filled with keratin, resembling
milia.7 If the cyst contains oncocytic cells, it is much more likely to be a sali-
Fig. 11.112 vary duct cyst. Salivary gland lesions do not occur in the gingiva (which does
Odontogenic ghost cell tumor: note the ghost cells and the foreign body reaction to not contain salivary gland tissue) although it may extend onto the gingiva
them. from the maxillary or mandibular sulcus.
396 Diseases of the oral mucosa
Fig. 11.114
Gingival cyst: note thinly lined cyst in the lamina propria.
Fig. 11.115
Gingival cyst: the cyst is lined by three to six layers of squamous or low cuboidal
cells.
Generalized gingival hyperplasia
Clinical features
In this condition, multiple and usually all quadrants of the upper and
lower gingiva are involved, initially by nodular hyperplasia in the inter-
dental areas, which then become coalescent to form diffuse nodular/papil-
lary masses. The gingiva may be edematous and boggy, or it can be firm,
fibrotic, and so ­proliferative as to reach the biting surfaces. Provoking fac-
tors include:
• poor oral hygiene (Fig 11.116),
• hormonal influences (during puberty and pregnancy),
• ingestion of medications, in particular phenytoin, valproic acid, calcium
channel blockers, and ciclosporin (Fig. 11.117).
Such overgrowths are rare in edentulous patients and if the teeth are
extracted, the lesions do not recur, pointing to plaque bacteria as playing an
important role in their pathogenesis.1–3 In general, good oral hygiene mea-
sures reduce the severity of disease.
Fig. 11.116
Generalized gingival hyperplasia: this overgrowth of gingiva was caused by poor oral
hygiene.
Fig. 11.117
Cyclosporin-induced gingival hyperplasia: this patient was taking cyclosporin to
prevent rejection of a renal allograft; he was also taking nifedipine, a calcium-
channel blocker.
Gingival hyperplasia occurs in approximately 50% of patients tak-
ing phenytoin,4,5 15–40% of patients taking nifedipine,3,6 and 25–70%
of patients on cyclosporin.7–9 Renal transplant patients taking both
cyclosporin and nifedipine show greater gingival overgrowth than those
taking cyclosporin alone.10 Of all calcium channel blockers, nifedipine and
those of the hydropyridine class are most likely to cause gingival hyperpla-
sia. Verapamil causes hyperplasia in 4% and amlodipine in 3% of cases,
which is probably not significantly different from patients not taking these
medications.11,12
Several cases of cyclosporin-induced fibrous hyperplasias/pyogenic gran-
ulomas of extragingival sites have been reported in patients treated for
chronic GVHD (Fig 11.118).13–15 It is, however, unusual to see significant
gingival hyperplasia in patients taking cyclosporin for treatment of chronic
GVHD.
One unusual form of gingival hyperplasia is associated with ligneous con-
junctivitis, an autosomal recessive disorder leading to functional plasminogen
deficiency and characteristic histological features in the conjunctiva and gin-
giva.16,17 The gingiva develops painless coalescent waxy nodules similar to those
on the conjunctiva.18,19 Other mucosal surfaces may also be involved.20 One case
occurred after systemic tranexamic acid (an antifibrinolytic agent) therapy.21
 Generalized gingival hyperplasia 397

In cyclosporin-induced nongingival lesions, the tumors are ­essentially

inflammatory fibrovascular polyps that are extensively ulcerated and ­composed
of edematous granulation tissue with a varying degrees of ­inflammation; some
resemble pyogenic granuloma (Figs 11.120, 11.121).13–15
Ultrastructural studies show an increase in cytoplasmic volume of fibro-
blasts with more extensive rough endoplasmic reticulum and Golgi com-
plexes, reflecting increased synthetic activity and concomitant reduction
in phagocytic activity of fibroblasts.27,28 Increased numbers of fibroblasts
­exhibiting secretory granules filled with sulfated mucopolysaccharides have
been noted.29 Myofibroblasts are present in increased numbers.30

Fig. 11.118
Cyclosporin-induced nongingival hyperplasia: this patient was taking ciclosporin
for treatment of chronic graft-versus-host disease after allogeneic bone marrow
transplantation

Pathogenesis and histological features

Gingival hyperplasia caused by cyclosporin (the most widely studied of all
the drugs) may result from accumulation of collagen and extracellular matrix
as a consequence of either increased production from susceptible subpopula-
tions of fibroblasts in the gingiva, or else, decreased degradation.22,23 Calcium
homeostasis is an important pharmacodynamic feature of these drugs and it
has been postulated that impairment of calcium-dependent mechanisms (such Fig. 11.120
as collagenase and metalloproteinase activity) may play an important etiolog- Cyclosporin-induced
ical role. Cyclosporin up-regulates the activity of TGF-β1, a potent cytokine nongingival hyperplasia:
involved in collagen homeostasis.24,25 these are essentially
Histologically, there is proliferation of fibrous tissue and ground substance polypoid masses of
granulation tissue similar
with variable hyperplasia of fibroblasts. The epithelium, which is paraker-
to pyogenic granuloma.
atinized, may also be hyperplastic and there is often a lymphoplasmacytic
infiltrate and vascular ectasia (Fig. 11.119). Straight-sided ‘test tube’ rete
ridges have been reported in such drug-induced gingival hyperplasias but
this is not a specific finding.6,7,26 There may also be foci that appear myxoid/
mucinous.

Fig. 11.121
Cyclosporin-induced
nongingival hyperplasia:
Fig. 11.119 note the edematous
Inflammatory fibrous hyperplasia: the histology is similar to that of the solitary granulation tissue and
gingival nodules of similar etiology. inflammation.
398 Diseases of the oral mucosa

Fig. 11.123
Varix: note the blue bleb on the lower labial mucosa.

Fig. 11.122
Ligneous gingivitis: there
is abundant fibrinous
eosinophilic material that
fills the lamina propria.

In ligneous gingival hyperplasia, the lamina propria is filled with eosino-

philic, PAS-positive amorphous material that stains with MSB phosphotung-
stic acid–hematoxylin and consists of fibrin (Fig. 11.122).17,18 Stains for
amyloid are negative. There may be associated epithelial hyperplasia with
acute and chronic inflammation and apoptosis. Early lesions show fibrin
deposits around blood vessels.

Differential diagnosis
Accumulations of eosinophilic material in the gingiva may be seen in lipoid
proteinosis (hyalinosis cutis et mucosae); these deposits do not stain for fibrin-
Fig. 11.124
ogen or fibrin and there is usually involvement of the skin and other sites.31,32
Varix: note the blue bleb on the buccal mucosa.
Amyloid deposits should also be excluded. Similar amyloid-like material may
sometimes be seen in the buccal mucosa (but not usually in the gingiva) of
patients who use snuff.

Varix
Clinical features
Varices (or venous lakes) are most common on the ventral surfaces of the
tongue (sublingual varicosities) and on the lower lip and buccal mucosa, usu-
ally in older individuals (Figs 11.123, 11.124).1,2 They are bluish-purple
blebs that may become firm if thrombosed.

Histological features
A varix represents a dilatation of an endothelium-lined blood vessel/venule
with a very thin muscular wall (Figs 11.125, 11.126).3 Some develop
thrombi, which on organization and canalization may present as a Masson
tumor (intravascular papillary endothelial hyperplasia) (Fig. 11.127).4

Differential diagnosis
The caliber-persistent labial artery (a pulsatile lesion of the lower lip) consists
of an artery that lies close to the surface epithelium with an artery diameter/ Fig. 11.125
depth ratio of less than 1.6 (Fig. 11.128).5,6 These putatively represent ­arterial Varix: there are grossly
branches from a main supplying labial artery that penetrate the ­superficial dilated venules in the
mucosa without loss of caliber.6 lamina propria.
 Hairy leukoplakia 399

Fig. 11.126
Varix: the grossly dilated venule has a very thin wall.

Fig. 11.128
Caliber-persistent artery:
this small artery is
typically superficially
located.

Fig. 11.127
Varix: there is intravascular papillary endothelial hyperplasia within this organizing
thrombus.

Infections
Hairy leukoplakia
Clinical features
Hairy leukoplakia is an Epstein-Barr virus infection of the oral epithelium
that was first described in the HIV-infected population.1 It may also be seen
in other immunocompromised patients who are susceptible to opportunistic
viral infections or reactivations, such as organ transplant recipients.2,3 Cases
have been reported in apparently healthy individuals.3,4 Although the term is
now entrenched in the scientific literature, ‘hairy leukoplakia’ as used in this
condition does not ever connote an increased incidence of cytological atypia
or propensity for development of squamous cell carcinoma such as is often a
feature of ‘leukoplakia’.
The majority of cases (> 70%) occur bilaterally on the lateral border of the
tongue as a white, corrugated (hence ‘hairy’) plaque that in early lesions has
vertical fissures running perpendicular to the long axis of the tongue (Figs
11.129, 11.130).5,6 Its appearance is associated with the development of
acquired immunodeficiency syndrome (AIDS) within 3 years in one-third of
patients.7
Pathogenesis and histological features
The oropharyngeal epithelia and lymphoid tissue are sites of persistent latent
Epstein-Barr virus infection.8 Reactivation of latent infected tongue mucosa
may be the cause of hairy leukoplakia.9
Oral hairy leukoplakia is characterized by hyperparakeratosis with a slightly
shaggy surface. Candida hyphae are present in 80% of cases, usually unassoci-
ated with spongiotic pustules.5,6,10,11 Beneath the keratin is a ­distinct band of
vacuolated and ballooned cells (Fig. 11.131). Pale cells contain Cowdry Type
A eosinophilic inclusions and characteristically exhibit ­condensation of chro-
matin against the nuclear membrane (‘beaded effect’) (Figs 11.132, 11.133).12
400 Diseases of the oral mucosa

Fig. 11.129
Hairy leukoplakia: the thick white plaque on the lateral border of the tongue has
vertical fissures. Fig. 11.131
Hairy leukoplakia: note
the thick parakeratin
and, importantly, the
vacuolated virally infected
cells just beneath.

Fig. 11.130
Hairy leukoplakia: this white plaque does not have the vertical fissures.

This morphology is readily seen even on exfoliative cytology.13,14 In situ
­hybridization localizes Epstein-Barr virus within keratinocyte nuclei (Fig.
11.134).
PCR-in situ hybridization studies demonstrated proteins that disrupt
Epstein-Barr virus latency in all layers of the epithelium including basal cells,
supporting the concept of reactivation of latent Epstein-Barr virus infection.
HIV has also been identified within the keratinocytes.9
Although HPV was identified in hairy leukoplakia in earlier studies, more
recent studies have disputed this observation.5,9,15
Differential diagnosis
Sometimes chronic bite injury is misdiagnosed as hairy leukoplakia. The
two conditions share in common shaggy hyperparakeratosis and cytoplas-
mic vacuolation. However, true hairy leukoplakia usually does not have the
fissures and clefts rimmed by bacteria seen in bite injury unless, of course,
there is ­concomitant secondary bite injury. The vacuolated cells in bite injury
­represent keratinocyte edema and not viral cytopathic effect. Identification of
Epstein-Barr virus establishes the diagnosis.
Fig. 11.132
Hairy leukoplakia: note condensation of chromatin in a beaded pattern against the
nuclear membrane.
Focal epithelial hyperplasia
Clinical features
Although any racial group may be affected, there is a predilection for focal epi-
thelial hyperplasia (Heck's disease, multifocal papillomavirus epithelial hyper-
plasia) in Native Americans of Central and South America, Inuits, and Africans.
Over 90% of cases occur in the first two decades of life and there is a prevalence
of 7–13% in predisposed populations.1–3 The condition tends to regress over
time. Focal epithelial hyperplasia also occurs in patients infected with HIV.4
Lesions are almost always multiple and multifocal, favoring the labial
mucosa, lips, buccal mucosa, and lateral tongue (Figs 11.135, 11.136).
They are mucosal-colored papules or nodules that sometimes may appear
papillary.2
 Focal epithelial hyperplasia 401

Fig. 11.133 Fig. 11.136

Hairy leukoplakia: ultrastructural confirmation of chromatin condensation; the center Heck's disease: typical multiple coalescent papules on the lateral tongue in this
of the nucleus is filled with herpes virus. native of East Africa.

Fig. 11.134 Fig. 11.137

Hairy leukoplakia: in situ hybridization reveals the presence of intranuclear Epstein– Heck's disease: there is epithelial hyperplasia with the formation of broad rete
Barr virus. ridges, somewhat similar to a condyloma.

Histological features
There is benign epithelial hyperplasia with slight keratinization and
broad anastomosing rete ridges (Fig. 11.137). Koilocytes are usually
present superficially (Fig. 11.138). ‘Mitosoid’ figures are a characteris-
tic finding in the mid and lower third of the epithelium (Fig. 11.139).
These represent ­degenerate and karyorrhectic nuclei showing aggregates
of coarsely clumped chromatin resembling mitoses. They may be identified
in up to 50% of original sections and are almost always present in further
levels.2,5,6
HPV-13 has been identified in 50–100% of cases while HPV-32 was found
in 60% of cases.3,6,7

Differential diagnosis
Condyloma acuminatum may appear similar clinically and histologically
but generally this lesion does not contain HPV-13 and HPV-32. Bowenoid
Fig. 11.135 ­papulosis may also exhibit similar ‘mitosoid’ figures, usually in a more florid
Heck's disease: the lesions are pale, fleshy papules. fashion and with more epithelial atypia.
402 Diseases of the oral mucosa

Fig. 11.139
Heck's disease: ‘mitosoid’ bodies represent human papillomavirus-induced nuclear
changes.

Fig. 11.138
Heck's disease: koilocytes
are readily identified.

Lichenoid and hypersensitivity reactions

Oral lichen planus and lichenoid stomatitis

Clinical features
Oral lichen planus is a chronic inflammatory condition of the mouth that occurs
in 1–2% of the population (range 0.08–4.0%).1 There is a 1.5 to 3-fold predilec-
tion for women and most patients are in the sixth decade.2,3 The buccal mucosa
is affected in 80–90% of cases, followed by the tongue and the gingiva.
While the older literature described between five and six different clinical
variants, they can be grouped simply into three main categories:
• Reticular and/or papular oral lichen planus presenting with classic lacy
white keratotic striations (Wickham's striae). Annular, papular, and
linear variants may also be seen. This variant tends to be non- or only
mildly symptomatic (Fig. 11.140).
• Erythematous (or erosive) oral lichen planus presenting as variably
symptomatic reddened mucosa. Because the mouth is a trauma-intense
environment, bullae or vesicles of bullous lichen planus are rarely seen.
Any blisters that develop soon rupture, giving rise to erythematous and
ulcerative lesions. Another erythematous variant presents clinically as
‘desquamative gingivitis’ (Fig. 11.141).4–6 Fig. 11.140
Oral lichen planus: Wickham's striae of reticular lichen planus with mild erythema.
• Ulcerative lichen planus, which presents with a yellow fibrinous exudate
on the surface and is almost always painful (Fig. 11.142).
Oral lichen planus often presents with a combination of the above clinical Plaque-type lesions resembling leukoplakia should be considered as con-
manifestations and may also change from one to another over time.7 From ventional leukoplakia arising in association with oral lichen planus. The rate
epidemiological studies, reticular lesions are the most common, especially on for malignant transformation varies from 0% to 12.5% but many reports
the buccal mucosa, whereas in studies from referral centers, the erythema- with the higher rate did not correct for tobacco usage as a confounding fac-
tous and ulcerative forms predominate because they tend to be symptomatic. tor.2,3,13,14 The true risk is probably in the order of 0.1–1%. Some authors
Similarly, the skin is reportedly involved in approximately 5% of cases in epi- believe that plaque-type disease has a higher association with malignancy
demiological studies and 20–40% at referral centers.2,3,8 Concurrent involve- while others believe erosive lesions are particularly susceptible. One reason
ment of the gingiva with erosive oral lichen planus and lesions affecting the for the confusion is that clinicians sometimes diagnose any red and white
female genitalia is known as the vulvovaginal-gingival syndrome although lesion as lichen planus while erythro-leukoplakia, also a red and white
men may also experience penile lesions. Other mucosal sites such as the lesion (see below), has a very high malignant transformation rate. Lesions of
esophagus may also be affected.9–12 Spontaneous remission occurs in approxi- ­proliferative leukoplakia and proliferative erythroleukoplakia have also been
mately 7% of cases.2 ­misdiagnosed clinically as lichen planus.
 Oral lichen planus and lichenoid stomatitis 403

Fig. 11.141 Fig. 11.143

Oral lichen planus: desquamative gingivitis may be a form of erythematous lichen planus. Oral lesions of discoid erythematosus: lichenoid reticulations in a patient with
systemic lupus erythematosus.

Fig. 11.142
Oral lichen planus: note the presence of some white papular areas, erythema, and
Fig. 11.144
ulcers.
Chronic oral graft-versus-host disease: lichenoid reticulations in a patient with
chronic oral graft-versus-host disease.
Pathogenesis and histological features
Local factors that may induce oral lichen planus or oral lichenoid lesions
include contact lichenoid reactions to mercury in amalgam restorations.
Between 16% and 91% of patients have a positive patch test to mercury,
especially those with lesions in direct contact with the restoration.15–17 These
lesions regress when the restorations are replaced. Similar reactions have been
reported to composite restorations, possibly representing a reaction to form-
aldehyde.18,19 In the Saudi Arabian population, chewing of deram has been
reported to cause oral lichen planus.20
Oral lichenoid drug eruptions and oral lichen planus are clinically and
histologically indistinguishable. The classes of drugs that have been impli-
cated include antihypertensive agents (in particular thiazides), antimalari-
als, gold, nonsteroidal antiinflammatory drugs (NSAIDs), hypoglycemic
agents, penicillamine and allopurinol.21,22 Patients previously diagnosed with
Grinspan syndrome (oral lichen planus, diabetes mellitus, and hyperten-
sion) were probably exhibiting a lichenoid mucosal reaction to their medica-
tions. Patients with autoimmune conditions such as lupus erythematosus and
chronic GVHD may present with oral lesions that are clinically and histologi-
cally indistinguishable from lichen planus (Figs 11.143, 11.144).23–25 There
is also an increased prevalence of oral lichen planus in patients with hepatitis,
in particular hepatitis C, and especially in Southern European and Japanese Fig. 11.145
populations associated with an increase in HLA-B6 (Fig. 11.145).26–28 Oral lichen planus: lichenoid reticulations in a patient with hepatitis C.
404 Diseases of the oral mucosa

Patients with oral lichen planus show an increased incidence of HLA-Bw57

in the white British population, HLA-DR9 in the Chinese and Japanese, and
HLA-DR3 in the Swedish, with a decrease in incidence of HLA-DQ1 in the
white British population.29–32 The Israeli population showed a significant
association with HLA-DR2 and a decrease in DR4.33 IFN-γ and IL-4 gene
polymorphisms influence disease susceptibility and progression of oral lichen
planus in a Chinese cohort.34
Because so many different conditions can lead to the clinical appearances
of oral lichen planus – contact phenomena, hypersensitivity to medications,
and autoimmune diseases – it is more appropriate to view oral lesions as the
final common pathway of expression of the mucosa to local or systemic anti-
gens. It represents a delayed-type hypersensitivity reaction characterized by a
T-cell reaction to altered epithelium and leading ultimately to basal cell lysis.
The pathogenesis of oral disease has been reviewed in several publi-
cations and only a summary, albeit somewhat simplistic, is presented
here.22,35,36 The initiating event is alteration of the keratinocyte either from
antigen bound or unmasked on the cell surface (e.g., drugs, major his-
tocompatibility complex (MHC) or viral antigens). Keratinocytes and
antigen-presenting cells secrete chemokines that attract lymphocytes.
Fig. 11.147
Antigen-presenting cells in the epithelium present antigens via MHC II mol-
Oral lichen planus: high-power view emphasizing the interface stomatitis; note the
ecules to CD4 cells while basal cells present antigens via MHC I molecules presence of colloid bodies.
to CD8 cells. A Th1 response mediated by CD4 cells results in secretion of
IL-2 and IFN-γ that bind receptors on CD8 cells that become activated and
trigger basal keratinocyte apoptosis.36 In the meantime, local mast cells
are activated and secrete TNF-α, which induces endothelial cell adhesion
molecule expression, priming the vasculature for lymphocyte adhesion and
transmigration.37
The reticular/papular type exhibits either hyperparakeratosis or hyper-
orthokeratosis with hypergranulosis, and variable acanthosis (Figs 11.146,
11.147). The erythematous form is non- or thinly keratinized and exhibits
epithelial atrophy or erosion (Fig. 11.148). In both cases, there is lympho-
cyte exocytosis, mild spongiosis, and increased numbers of Langerhans cells.
Common to all variants is destruction of the basal cell layer with blurring of
the epithelial–connective tissue interface, and a superficial bandlike lympho-
cytic infiltrate.35 Early lymphocytic infiltrates contain mainly CD4 cells while
older lesions consist predominantly of CD8 cells. Saw-toothed rete ridges and
apoptotic cells (cytoid or Civatte bodies) may be present, and the basement
membrane zone is sometimes thickly eosinophilic due to fibrinogen deposi-
tion. Subepithelial separation is occasionally present but may be artifactual
(albeit a reliable one) (Fig. 11.149). Although lymphocytes predominate,
plasma cells may be seen, particularly in hypersensitivity lichenoid reactions,
or if an ulcer or erosion is present. The term ‘lichenoid stomatitis/mucosi- Fig. 11.148
tis’ is sometimes used when a lesion has only some of the above features, in Oral lichen planus: erosive and ulcerative lichen planus without hyperkeratosis.

Fig. 11.146 Fig. 11.149

Oral lichen planus: typical features of hyperkeratosis, acanthosis, squamatization of Oral lichen planus: subepithelial separation occurs to varying degrees and is well
basal cells, and a lymphocytic band at the interface. demonstrated in this case.

­ articular, only focal basal cell degeneration or a sparse lymphocytic band at
p true dysplasia is the presence of basal cell hyperplasia and atypia rather than
the interface. Lesions of amalgam-induced oral lichen planus and banal lichen
planus are histologically indistinguishable.38
The chemokine RANTES and the adhesion molecule ICAM-1 are both
expressed in lesions of oral lichen planus and amalgam-induced lichenoid
reactions, but not IL-8.39
Although reactive epithelial atypia may be present, unequivocal epithelial
dysplasia should be reported as such. The term ‘lichenoid dysplasia’ was orig-
inally coined to denote dysplasia arising within histologic lichenoid stomati-
tis, which subsequently progressed to squamous cell carcinoma.40,41 These are
lesions that exhibit hyperparakeratosis or hyperorthokeratosis, epithelial dys-
plasia, and a bandlike lymphocytic infiltrate (Figs 11.150, 11.151). They are
no different from any other oral epithelial dysplasia and should not be classi-
fied separately. Rather, a diagnosis of ‘mild/moderate/severe dysplasia with a
lichenoid infiltrate’ is more appropriate. An important histological feature in
Fig. 11.150
Epithelial dysplasia with
lichenoid inflammatory
infiltrate: note the
atypical cells and bandlike
lymphocytic infiltrate.
Fig. 11.151
Epithelial dysplasia with lichenoid inflammatory infiltrate: note that there is basal
cell prominence and maturation disarray.
Oral lichen planus and lichenoid stomatitis 405
degeneration. In one report, dysplastic lesions with a lichenoid histologic
character were seen more commonly in clinically ‘lichenoid’ lesions rather
than reticulated oral lichen planus.42 Such lichenoid histologic and clinical
lesions (rather than typical histologic and clinical lesions of lichen planus)
also showed a higher rate of malignant transformation.43
Contact lichenoid hypersensitivity reactions to cinnamic aldehyde
show peri- and paravascular nodular lymphocytic infiltrates (Figs 11.152,
11.153).44,45 The absence of eosinophils does not rule out an oral hypersen-
sitivity reaction.
Direct immunofluorescence demonstrates fibrinogen at the basement mem-
brane zone, often in a fibrillar, shaggy ‘stalactite’ pattern with occasional C3
and IgM. Cytoid bodies also stain with IgM or C3.46 Indirect immunofluo-
rescence studies have shown that there may be circulating antibodies directed
against basal cells.47–49
Patients with chronic ulcerative stomatitis (an erosive–ulcerative condition
of the mouth that clinically resembles erosive oral lichen planus) have strati-
fied epithelium-specific antinuclear IgG in a speckled pattern primarily affect-
ing the lower epithelium (Fig. 11.154).50–52 Indirect immunofluorescence
Fig. 11.152
Cinnamaldehyde-associated contact stomatitis: erythematous area on the tongue
caused by cinnamon gum contact hypersensitivity reaction.
Fig. 11.153
Cinnamaldehyde-associated contact stomatitis: there is a lichenoid inflammatory
infiltrate at the interface with peri- and paravascular nodular lymphocytic aggregates;
in this case, the basal cells are intact.
406 Diseases of the oral mucosa
Fig. 11.154
Chronic ulcerative stomatitis: this presents with a vaguely reticulated mucosa.
By courtesy of L. Solomon, MD, SUNY, Buffalo, NY, USA.
using guinea pig esophagus demonstrates nuclear reactivity particularly well.
The putative antigen is deltaNp63alpha, an isoform of p63.53 Histologically,
chronic ulcerative stomatitis also resembles oral lichen planus and it is still
unclear what the relationship is between these two conditions.54
Loss of heterozygosity on chromosome arms 3p, 9p, and 17p is not a
­feature of oral lichen planus, a finding that supports the hypothesis that this
disease is not intrinsically premalignant; however, a high frequency of loss
was found in dysplastic lesions with a lichenoid infiltrate.55 Telomerase activ-
ity has been detected in up to 70% of patients.56 A high rate of TP53 muta-
tions has also been reported in oral lichen planus.57 The role of p53 in the
development of malignancy is still unclear.58
Differential diagnosis
Lesions of discoid lupus erythematosus may also show a lichenoid lympho-
cytic band at the interface and peri- and paravascular nodular lymphocytic
infiltrates (Fig. 11.155). Direct immunofluorescence studies are usually
­positive for the lupus band test in lesional tissue.
An intense chronic inflammatory infiltrate at the interface may also be
seen in plasma cell gingivitis although the cells in this condition are, of course,
predominantly plasmacytic. Rare cases of lichen planus pemphigoides have
been reported.59
Fig. 11.155
Oral lupus erythematosus: note the lichenoid inflammatory infiltrate.
Plasma cell gingivostomatitis
Clinical features
In the 1960s and early 1970s, patients presented with symptoms of soreness
and burning of the oral mucosa following the use of chewing gum. There was
angular cheilitis with fissuring, dry atrophic lips, and occasional desquama-
tion. The tongue was often fissured, edematous, and crenated (with scalloped
borders) and the gingiva (free and attached) was fiery red, often with exten-
sion onto the palatal mucosa.1,2 Some patients had drug allergies while others
had atopic states. The gingiva was sometimes the only site of involvement.3
Discontinuation of gum chewing led to resolution of lesions in most but
not all cases and it was postulated that this condition represented a hypersen-
sitivity reaction to some component of chewing gum or some other unidenti-
fied antigen.1,2 Since that cluster of cases and reformulation of chewing gum,
only occasional cases occur now in response to a variety of putative topical
irritants such as cinnamicaldehyde-flavored toothpastes and khat.4,5
Subsequent to these reports, patients were identified who not only pre-
sented with oral symptoms of pain but also with hoarseness, dysphagia, and
airway obstruction. On endoscopy, the larynx showed thickened, red, velvety,
and edematous mucosa; the lips were thickened and fissured with angular
cheilitis and fissured tongue.6–9 The soft palate and gingiva were sometimes
concurrently involved. Equivalent lesions have since been noted on the penis
(Zoon's balanitis) and the vulva.
It is unclear whether this widespread involvement of the mucosa of the
upper respiratory tract indicates a more severe and extensive form of plasma
cell gingivostomatitis. No obvious allergen has been identified.
Histological features
Plasma cell orificial mucositis and plasma cell gingivostomatitis have simi-
lar histology. There is psoriasiform epithelial hyperplasia with spongiosis,
spongiform pustules, and leukocyte exocytosis (Fig. 11.156). The suprapap-
illary epithelium is severely thinned.1,3 Dyskeratosis is often present in more
severe cases.6,8 Characteristically, the lamina propria is filled with sheets of
plasma cells with expression of both kappa and lambda light chains (Fig.
11.157). Russell bodies may be present but Dutcher bodies are not seen.
Occasional lymphocytes are also present.1,3
Differential diagnosis
An intense plasma cell infiltrate is characteristic of banal chronic gingivitis and
periodontal disease. However, in these lesions, the plasma cells are not generally
present in uninterrupted sheets but have a compartmentalized, slightly lobular
character (Fig. 11.158). Clinically, even though the gingiva may be hyperplastic
and edematous, gingivitis/periodontitis responds well to local therapy.
Fig. 11.156
Plasma cell gingivitis: there is a prominent inflammatory infiltrate at the interface
with epithelial hyperplasia and atrophy.

Fig. 11.157
Plasma cell gingivitis: the
lamina propria is packed
with plasma cells.
Fig. 11.158
Chronic periodontitis: note
the pockets of plasma
cells separated by bands
of collagen.
Plasma cell granuloma, a rare lesion in the oral cavity, is histologically
similar to plasma cell orificial mucositis except that the lesions are clinically
tumorous masses or nodules.10–13 Cases of plasma cell granuloma reported
from the periodontal space most likely represent chronic periodontitis or
banal inflammatory fibrovascular hyperplasias with the usual intense plasma
cell infiltrate.14
Lack of light chain restriction excludes plasmacytoma.
Orofacial granulomatosis 407
Fig. 11.159
Orofacial granulomatosis: there is diffuse rubbery swelling of the lower lip.
Orofacial granulomatosis
Clinical features
Orofacial granulomatosis (cheilitis granulomatosa, granulomatous cheili-
tis) is a chronic, non-necrotizing, granulomatous and inflammatory condi-
tion, likely a delayed-type hypersensitivity reaction. It is characterized by
nontender swelling and edema of the lips and/or face, often but not always
accompanied by swelling of the gingiva (usually around the anterior teeth),
and cobblestoning, folding, and erythema of the buccal mucosa. There may
be angular cheilitis, ulcerations, and prominent vertical fissures in established
lesions.1
In the Melkersson-Rosenthal syndrome, facial nerve palsy and fissured
tongue are additional findings.2,3
In general, the swelling of the lips is the most important clinical sign, and
is initially soft and relapsing (Fig. 11.159). However, swelling may involve
other sites such as the periorbital, zygomatic, or mental regions.4 Over the
years, it becomes persistent and rubbery. The gingiva is affected in 20–30%
of cases.5,6 Gingival swellings extend onto the alveolar mucosa and become
increasingly fibrotic over time (Fig. 11.160).6 Facial nerve palsy is pres-
ent in 13–47% of cases and may be due to either direct granulomatous
involvement of the nerve or edema leading to nerve compression. It predates
Fig. 11.160
Orofacial granulomatosis: note the thickened anterior maxillary gingiva.
408 Diseases of the oral mucosa

facial/lip swelling in 57–100% of cases.3,5,6 Fissured tongue is present in

40–50% of cases although its significance is uncertain since this is a relatively
common oral finding.3,5 Spontaneous improvement or resolution occurs in
approximately one-third of patients.5
Ten percent of patients have associated Crohn's disease while only 3%
have associated sarcoidosis.7 Vulval and eye lesions have been reported in
addition to more extensive neurological involvement. Of interest, patients
with orofacial granulomatosis but no gastrointestinal symptoms were found
on ileocolonoscopy and biopsy to have intestinal pathology and granulomata
in 54% of cases.8

Pathogenesis and histological features

Hypersensitivity to foods (such as eggs, chocolate, and dairy products),
­flavorings, antioxidants (such as octyl butylated hydroxyanisol and cinnam-
aldehyde), preservatives (such as benzoate and metabisulfites), and fragrances
have been demonstrated in up to 20% of cases; there is often a strong his-
tory of atopy.1,9–11 Elimination diet may result in significant improvement of
symptoms.12 Investigations targeting an infectious etiology with emphasis on
Saccharomyces cerevisiae, Mycobacterium tuberculosis, and Borrelia burg-
Fig. 11.162
dorferi have yielded variable results.13–15 Orofacial granulomatosis: typical subtle non-necrotizing granulomatous inflammation.
Orofacial granulomatosis is associated with increased HLA-A3, B7 and
DR2 expression.16 The cytokine profile (such as increased production of
interferon-gamma) suggesting a predominantly Th1 response, similar to that be larger and more conspicuous. Angioedema and hypersensitivity reactions
seen in gut lesions of Crohn's disease.17 may ­present with edema and vascular ectasia in the absence of granulomata.
Non-necrotizing granulomata are present in the lamina propria, sometimes Oral Wegener's granulomatosis is accompanied by pseudoepitheliomatous
adjacent to lymphatic vessels with associated lymphocytes and plasma cells hyperplasia and a mixed acute and chronic inflammatory infiltrate with
(Figs 11.161, 11.162).2,6 The granulomata may be subtle and poorly formed abscesses, necrosis, and eosinophils.
and often require serial sectioning to be identified with certainty. They may
bulge into and obstruct vessels.18 Edema and vascular dilatation has also been
reported but such features in isolation are insufficient for a diagnosis of oro-
facial granulomatosis. Foreign material within the granulomata effectively Oral Crohn's disease
excludes a diagnosis of orofacial granulomatosis. As with any granulomatous
infiltrate, special stains for microorganisms should always be performed. Clinical features
Crohn's disease usually presents in the second decade, with a male predomi-
Differential diagnosis nance.1,2 In one study, 37% of patients had asymptomatic gastrointestinal
Granulomata in this clinical setting are histologically indistinguishable from disease.3 There is usually swelling of the face or lips; additionally, there may
those of extragastrointestinal Crohn's disease; clinical differences help to dif- be linear vestibular aphtheiform ulcers, angular cheilitis, papulous and poly-
ferentiate between the two. In general, the granulomata of sarcoidosis tend to poid masses, mucosal tags, lip and gingival swelling, gingival erythema, and
cobblestoning of the mucosa (Figs 11.163, 11.164).1,3 Some patients present
with pyostomatitis vegetans and ‘snail-track ulcers’.4 In 22–60% of cases, oral
symptoms precede intestinal symptoms.1–3 Adhesions may lead to ­limitation
in mouth opening.2

Fig. 11.161
Orofacial granulomatosis:
this was the only
granuloma present in Fig. 11.163
the multiple sections Oral Crohn's disease: there is swelling of the lips and a reddened, indurated area of
examined. skin adjacent to the lower vermilion typical for skin involvement by Crohn's disease.

Fig. 11.164
Oral Crohn's disease: note the fissures and cobblestoning of the lower labial
mucosa.
Pathogenesis and histological features
It is believed that patients with the NOD2/CARD15 genes are predis-
posed to Crohn's disease and that the disease represents a dysfunctional
immune response and impaired defense to intracellular microbes such as
Mycobacterium avium subspecies paratuberculosis and/or adherent-invasive
Escherichia coli.5
Granulomata, which are seen in up to 88% of mucosal lesions, are typi-
cally noncaseating, often subtle, and usually located in the superficial lamina
propria, similar to orofacial granulomatosis.1–4 They are found within the
Autoimmune conditions
Desquamative gingivitis
Desquamative gingivitis is a chronic condition of adults, usually women (4:1),
affecting either the gingiva diffusely or multifocally. It presents as friable, fiery
red, painful, eroded, denuded attached gingiva, primarily on the facial or buccal
aspect, with occasional areas of ulceration.1,2 In approximately half the cases of
desquamative gingivitis, the gingiva is the only site affected by disease.
Desquamative gingivitis represents a distinct clinical manifestation of auto-
immune blistering diseases, hypersensitivity reactions or oral lichen planus.2,3,4
Large studies of desquamative gingivitis have shown that mucous membrane
pemphigoid and lichen planus together accounts for approximately 80%
of cases, with the rest representing pemphigus vulgaris and cases with non-
specific findings, some of which may represent hypersensitivity reactions.5–7
Occasional cases of epidermolysis bullosa acquisita present as desquamative
gingivitis. Cases of linear IgA confined to the mouth likely represent IgA type
mucous m ­ embrane pemphigoid.8
Mucous membrane pemphigoid
Clinical features
Mucous membrane pemphigoid is the most common autoimmune subepi-
thelial blistering disease presenting in the mouth. Several subsets of mucous
membrane pemphigoid exist, with variable antigenic characteristics but all
are characterized by predominant involvement of the mucous membranes by
a subepithelial blistering disorder. Cicatrization, however, is not a feature of
oral mucosal disease.1–3
Mucous membrane pemphigoid 409
Fig. 11.165
Oral Crohn's disease: there is involvement of the minor salivary glands of the lower
labial mucosa by non-necrotizing granulomata.
papulous folds, mucosal tags, and even ulcers. Salivary glands may also be
involved (Fig. 11.165).
Differential diagnosis
Granulomatous diseases associated with specific infections or for-
eign material must always be excluded. The histological features of oral
Crohn's disease are indistinguishable from those of idiopathic orofacial
granulomatosis.
Mucous membrane pemphigoid usually occurs in the sixth decade and
upward with a female predilection.1,4–11 The oral cavity is affected in 84–96%
of cases, and the conjunctiva in 52–81%.4–6,12 Other sites of involvement
in order of frequency are the upper airway (40–50%), skin (20–25%), and
(less frequently) genitalia (9–17%), anorectal area (3–4%), and esophagus
(3–4%).4–6,12 ‘High-risk’ patients are those showing involvement of eyes,
genitalia, nasopharynx, esophagus, and the larynx because of life-threatening
airway obstruction, and morbidity due to stricture and scarring. ‘Low-risk’
patients are those showing involvement of oral mucosa only or oral mucosa
and skin.3
The oral cavity is the only site involved in approximately 60% of cases
and is the first manifestation of the disease in 48–96% of patients.4,13,14
The gingiva is the most frequent site of involvement affecting from 64% to
94% of cases; this often takes the form of desquamative gingivitis.1,6,8,9,14
Desquamative gingivitis may be the sole manifestation of cicatricial pem-
phigoid in 60% of cases (Fig. 11.166).10 The buccal mucosa, labial mucosa,
and tongue are less often affected (Fig. 11.167). Lesions present as painful
areas of erosion, erythema, and ulceration. Intact blisters are rarely seen.
The collapsed blister roof may take the form of a yellow-white membrane
that readily peels off the mucosa. Unlike cases with ocular involvement,
cicatrization is an uncommon finding and was noted in only 9% of cases
in one series.4
Paraneoplastic pemphigoid has been reported in association with lym-
phoma and lung cancer and may represent paraneoplastic autoimmune mul-
tiorgan syndrome (see below).15,16
Oral and ocular pemphigoid is associated with increased frequency of
HLA-DQB1*0301.17–19
410 Diseases of the oral mucosa
Fig. 11.166
Mucosal pemphigoid: this typical case presented with erythematous gingiva and
white epithelial sloughs.
Fig. 11.167
Mucosal pemphigoid: there are large oral ulcers on the buccal mucosa.
Pathogenesis and histological features
Mucous membrane pemphigoid is characterized by separation of the mucosal
squamous epithelium from the underlying connective tissue with preservation
of the basal keratinocytes (Figs 11.168, 11.169 ).8–10 A variable lymphop-
lasmacytic infiltrate is usually present in the lamina propria. Unlike bullous
pemphigoid, eosinophils are rarely seen.
Direct immunofluorescence studies reveal basement membrane zone anti-
bodies in a smooth, continuous linear fluorescence pattern in 67–96% of
cases.12,20,21 IgG is present in 39–96% of cases, C3 in 43–97% of cases, and
IgA in 20–30% of cases.3,7,9,20,22
Indirect immunofluorescence studies for circulating autoantibodies (usu-
ally IgG) are present in approximately 20% of cases.9,12 However, one study
using oral mucosa as a substrate elicited a 36% positivity rate.20 There is no
consistent correlation between antibody titer and disease activity.
Indirect immunofluorescence studies in salt-split skin reveal circulating
IgG or IgA in 84–100% of cases.21,23,24 The majority (57–82%) show epi-
dermal binding with 9–22% showing dermal or both epidermal and dermal
localization. Those with both circulating IgG and IgA are virtually certain to
need systemic immunosuppressive therapy.21
Fig. 11.168
Mucosal pemphigoid: there is epithelial separation and preservation of the basal cells.
Fig. 11.169
Mucosal pemphigoid: the lamina propria contains many dilated small capillaries and
a lymphocytic infiltrate with scattered plasma cells.
Mucous membrane pemphigoid is now recognized to be a heterogeneous
condition. Thus a number of antigens have been implicated in ­immunoblotting
and immunoprecipitation studies. These include BPAg2 and to a lesser extent
BPAg1, laminin-332, beta4 subunit of alpha6 beta 1 integrin, and other less
well characterized molecules.3,12–33
Differential diagnosis
Oral lesions in mucous membrane pemphigoid must be distinguished
from other subepithelial and autoimmune bullous dermatosis and bullous
lichen planus. The latter, however, typically shows destruction of basal
cells and colloid body formation. In addition, the lymphocytic infiltrate
is usually denser.
Direct immunofluorescence studies are essential in helping to differentiate
between lichen planus and interface autoimmune stomatitides. Cases previ-
ously referred to as pure oral linear IgA disease should probably be reclassi-
fied as mucous membrane pemphigoid, IgA type.

Pemphigus
Clinical features
Oral pemphigus vulgaris typically begins in the sixth decade of life with a
female predilection. The mouth is involved in up to 87% of cases.1–4 Lesions in
the oral cavity precede those at other sites in up to 80% of cases.5 The mouth
is the only site of involvement in 25% of cases and the buccal mucosa, tongue,
palate, and floor of mouth are most often affected (Fig. 11.170).5 Pemphigus
vulgaris may present as desquamative gingivitis. Patients with pemphigus vege-
tans often show oral involvement.6 Mucous membrane involvement in pemphi-
gus foliaceus and pemphigus erythematosus is exceedingly rare. Paraneoplastic
pemphigus characteristically involves the oral ­cavity (see below).
Histological features
Biopsies of lesional tissue of pemphigus vulgaris reveal suprabasilar acantho-
lysis and clefting.4,7 Pemphigus vegetans in addition shows papillary epithelial
hyperplasia and eosinophilic abscesses.6
Direct immunofluorescence studies in pemphigus vulgaris and vegetans
reveal characteristic staining of the epithelial intercellular space with IgG in
all cases with active untreated disease.4,7 This differentiates pemphigus from
pyostomatitis vegetans which also shows suprabasilar acantholysis.
Paraneoplastic pemphigus
Clinical features
In paraneoplastic pemphigus, the oral mucosa is involved in all cases with
persistent, painful, treatment-resistant erosions of the oropharynx and
lips; the crusting vermilion lesions are reminiscent of Stevens-Johnson
­syndrome.1,2 More recently, the concept of paraneoplastic autoimmune
­multiorgan ­syndrome has been proposed.3 This syndrome is characterized by
an ­autoimmune blistering mucocutaneous disease with positive immunofluo-
rescence findings, characteristic immunoprecipitation findings, presence of
malignancy (most often lymphoproliferative in nature), and involvement of
other organ systems such as the lungs and kidneys. The mucocutaneous disor-
der may resemble pemphigus vulgaris, erythema multiforme or be lichenoid.
It is believed that either dysregulation of the immune system caused by the
neoplasm leads to production of autoantibodies or host antitumor response
produces antibodies that cross-react with native antigens.3
Pathogenesis and histological features
Histologically, there is suprabasilar acantholysis identical to pemphigus, in
addition to individual keratinocyte necrosis and vacuolar interface change,
suggestive of a lichenoid inflammatory process.1,3
Fig. 11.170
Pemphigus vulgaris: this presented as an ulcer on the lower labial mucosa.
Lupus erythematosus 411
Direct immunofluorescence shows deposition of IgG and/or complement in the
intercellular space, and along the basement membrane zone.1,4 Indirect immuno-
fluorescence is positive in a large number of cases if rat bladder is used.3 Antibodies
against envoplakin and periplakin are consistently present, although antibodies
against desmoglein and basement membrane zone antigens are also present.3,5
Linear IgA disease
Clinical features
Oral mucosal lesions associated with linear IgA disease occur in 26–100% of
cases and present as vesicles, bullae, erosions or ulcerations.1–3 They may be
located on the palate, buccal or labial mucosa, and oropharynx.3–6
Histological features
In linear IgA disease, there is a subepithelial vesicle or bulla with neutrophil
or eosinophil predominance.4,5 In many lesions, the infiltrate is mixed neutro-
philic and eosinophilic.
Direct immunofluorescence studies reveal homogeneous linear deposits of
IgA along the basement membrane zone.1,4,5 Currently, it is thought that cases
of desquamative gingivitis alone (without skin lesions) that are positive for
linear deposition of IgA represent mucous membrane pemphigoid.7
Dermatitis herpetiformis
Clinical features
Oral involvement in dermatitis herpetiformis, a condition associated with gluten-
sensitive enteropathy, presents as erythematous, pseudovesicular, purpuric or ero-
sive lesions in 70% of patients.1,2 Aphthous-like ulcers accompanied by mucosal
erythema and atrophic glossitis have been described in up to 22% of patients.3
Histological features
Mucosal biopsies may sometimes reveal neutrophil microabscesses at the
epithelial–connective tissue interface, occasional evidence of ­subepithelial
­blistering, and eosinophils and lymphocytes in the lamina propria.1,2
Extravasated erythrocytes are often conspicuous.
Direct immunofluorescence studies reveal granular deposits of IgA in the
basement membrane, particularly at the tips of the papillae.1,2,4
Epidermolysis bullosa acquisita
Clinical features
The oral mucosa is involved in from 53% to 64% of cases, although in many
reports the nature of the lesions is not documented.1,2 However, all 11 cases
of epidermolysis bullosa acquisita in children in one series had involvement of
the buccal mucosa, some taking the form of desquamative gingivitis.3
Histological features
The histological features are variable. In some lesions, there is a cell-free
subepithelial blister (classic variant) whereas in others, a neutrophil-rich or
eosinophil-rich lesion is seen.
Direct immunofluorescence studies show linear deposits of IgG and C3 at the
basement membrane zone similar to lesions of pemphigoid.4 Circulating anti-
basement membrane antibodies localize exclusively to the floor of the blister
in salt-split skin.5 Cases of paraneoplastic epidermolysis bullosa acquisita likely
represent ­paraneoplastic autoimmune multiorgan syndrome (see above).6
Lupus erythematosus
Clinical features
Oral involvement – mainly in the form of ulcers, erythema with or without
white striations, exfoliative areas, and discoid plaques – is seen in 26–45% of
patients with systemic lupus erythematosus, presenting primarily on the hard
412 Diseases of the oral mucosa
palate, buccal mucosa, and lips. Some lesions cause burning or soreness while
others are asymptomatic.1–4 Not surprisingly in bullous lupus erythematosus,
oral ulcers are occasionally seen.5,6
In patients with discoid lupus erythematosus, oral lesions in the form
of white plaques, papules, and striations associated with erosions and
ulcers are seen in 5–50% of cases.1,7,8 These often have a lichen planus-like
appearance.
Histological features
Oral lesions of both systemic and discoid lupus erythematosus exhibit hyper-
parakeratosis or hyperorthokeratosis, epithelial hyperplasia or atrophy,
­liquefactive degeneration of the basal cells, subepithelial PAS-positive depos-
its, perivascular inflammatory infiltrates (with some cases showing a bandlike
lichenoid infiltrate), and collagen degeneration.2,8–10
Direct immunofluorescence studies show deposition of IgG, lgM, IgA and/
or C3 in a band at the basement membrane zone; cytoid bodies stain for
IgM.8 As expected, T lymphocytes (CD4) predominate.11
Wegener's granulomatosis
Clinical features
Wegener's granulomatosis (one of the ANC vasculitides) in its complete form
is characterized by necrotizing vasculitis of small- and medium-sized vessels,
noninfectious granulomatous inflammation of the upper and lower respira-
tory tract, and glomerulonephritis. Approximately 5% of patients have oral
involvement. Although almost all patients show upper and/or lower airway
disease, some cases with isolated skin and mucosal disease have been reported
(limited Wegener's granulomatosis). In some patients, the disease runs a
protracted course limited to the upper airways before progressing to mul-
tiorgan involvement.1 The gingiva is hyperplastic, often with a friable, gran-
ular, erythematous-to-magenta appearance, so-called ‘strawberry gingivitis’
(Fig. 11.171). Ulcerated and necrotic masses may be present.2,3 The dentition
in the affected sites becomes mobile and extraction sockets heal poorly.
Pathogenesis and histological features
Patients' sera demonstrate the presence of antineutrophil cytoplasmic antibodies
(ANCA). There are two main immunofluorescent staining patterns for ANCA:
• cytoplasmic or c-ANCA staining (which is more specific for Wegener's
granulomatosis) targets proteinase-3, a 29-kD serine protease found in
the azurophilic granules of neutrophils,
• perinuclear or p-ANCA staining targets myeloperoxidase, another
constituent of neutrophilic granules.4,5 Other targets include lactoferrin
and human neutrophil elastase.
However, disease limited to the upper airway may be negative for such
antibodies.6 Proinflammatory cytokines prime neutrophils causing them to
express proteinase-3 and myeloperoxidase on the cell surface. ANCAs are
then able to activate such cells, leading to degranulation and the secretion of
additional cytokines, thus damaging endothelial cells and recruiting further
inflammatory cells to the region.7
Salivary gland disease
Reactive conditions
Mucocele
Clinical features
A mucocele (mucous escape phenomenon) caused by a tear in the excretory duct
and spillage of mucin into the connective tissue. This usually arises in children
and young adults and the most common locations are the lower labial mucosa
Fig. 11.171
Oral Wegener's granulomatosis: note the typical ‘strawberry gingivitis’. By courtesy
of S. Zunt, DDS, Indianapolis, USA.
Oral mucosal biopsies show marked pseudoepitheliomatous hyperplasia
with edema, a mixed acute and chronic inflammatory cell infiltrate, hem-
orrhage, and vascular dilatation; many eosinophils may also be present.
Granulomata are usually poorly formed or absent although scattered multi-
nucleated giant cells are sometimes present.2 Vasculitis with fibrinoid necrosis
is sometimes a feature.3,8 The typical geographic necrosis with palisaded gran-
ulomata is not usually a feature in the oral mucosa, although it is occasionally
evident in the major salivary glands.9
Direct immunofluorescence studies may show immune deposits of IgG or
IgA around blood vessels in skin biopsies.10
Differential diagnosis
Infectious processes must be excluded in the setting of a mixed inflamma-
tory infiltrate. The presence of pseudoepitheliomatous hyperplasia with
eosinophils and scattered giant cells raises the possibility of a fungal infec-
tion, such as blastomycosis. Other vasculitides should also be considered
although sole presentation in the oral cavity is rare. Microscopic polyarteritis
is indistinguishable from lesions of Wegener's granulomatosis but this does
not show immune deposition within vessel walls.11,12 Pyostomatitis vegetans
and ­pemphigus vegetans do not show vasculitis or granulomata and typi-
cally show acantholysis, although both may exhibit pseudoepitheliomatous
­hyperplasia and eosinophils.
Cocaine-induced midline destructive disease may resemble Wegener's granu-
lomatosis, particularly if obvious granulomas are not seen, and they can also be
ANCA positive.13 Wegener's granulomatosis is differentiated from nasal natural
killer (NK)/T-cell lymphomas of the palate and nasal cavity (‘midline destructive
disease’) by the absence of an atypical lymphocytic infiltrate (see below).
(59–73%), buccal mucosa (11–17%), floor of mouth (7–12%; referred to as
ranula), and ventral tongue (4%) (Fig. 11.172).1–3 It presents as a dome-shaped,
fluctuant, bluish, and sessile lesion, which often increases and decreases in size.
Salivary duct cyst or sialocyst results from dilatation of the excretory duct,
caused by a distal obstruction. Salivary duct cyst or sialocyst results from
dilatation of the excretory duct, caused by a distal obstruction and is there-
fore a retention cyst. The patients are older and the most common sites are the
floor of mouth (50%), buccal mucosa, and upper lip where the ­obstruction
is often a sialolith.2

Fig. 11.172
Mucocele: note the bluish sessile nodule on the lower labial mucosa, a typical site.
Fig. 11.173
Mucocele: the cyst-like
cavity filled with mucin
lies in the lamina propria.
Superficial mucoceles are distinctly vesicular or dewdrop-like, raising the
suspicion of a herpetic infection or autoimmune vesiculobullous disease and
occur in older adults, particularly on the palate, retromolar pad, and buccal
mucosa.4,5
Floor of mouth mucoceles, when large, are also called ranulas, and these
may extend below the mylohyoid muscle presenting extraorally as a ‘plung-
ing ranula’.6 There is recurrence in approximately 2% of cases.1
Histological features
Mucous escape mucoceles consist of pools of mucin containing muciphages
and often many neutrophils surrounded by condensed granulation tissue with
associated muciphages (Figs 11.173, 11.174).1,2 Some specimens consist only
of the collapsed wall of granulation tissue or even a solid mass of granulation
tissue containing muciphages (Fig. 11.175). Mucin may be dispersed in the
inter- and intralobular connective tissue. Portions of a metaplastic duct are
seen in 20% of cases.2 Occasionally, eosinophilic globular masses are present
within the mucin pools.7
Reactive conditions 413
Fig. 11.174
Mucocele: there is
no epithelium in the
lining, just condensed
granulation tissue.
Fig. 11.175
Mucocele: in areas of organization, there are sheets of muciphages with variable
amounts of granulation tissue.
Superficial mucoceles exhibit pools of mucin that are bordered superiorly
by surface squamous epithelium only that is often thinned.5,8
Salivary duct cysts are lined by cuboidal or columnar epithelium, often
with mucous cells or foci of squamous metaplasia; more than half may be
lined by oncocytic cells, sometimes with papillary projections (Figs 11.176,
11.177).4 These may also be referred to as oncocytic sialocysts.
The least common variant is the mucopapillary cyst,which is frequently
multiloculated and lined by stratified squamous or columnar epithelium with
pronounced mucous cell metaplasia and luminal papillary projections.4 The
associated minor salivary glands often exhibit varying degrees of acinar atro-
phy, ductal dilatation, and interstitial chronic inflammation with fibrosis.
Differential diagnosis
Parulides (gum-boils) of the gingiva can sometimes be mistaken for extrava-
sation mucoceles. However, neither pools of mucin nor muciphages is present
and microabscesses and sinus tracts are almost always evident.
414 Diseases of the oral mucosa
Fig. 11.176
Oncocytic sialocyst: this retention cyst consists of a grossly ectatic excretory
salivary duct; intraluminal papillary projections are evident.
Fig. 11.177
Oncocytic sialocyst: the lining cells are oncocytic.
The mucopapillary retention cyst is distinguished from mucoepidermoid
carcinoma by the lack of infiltration of the stroma and absence of discrete,
solid islands of neoplastic epidermoid and mucous cells.
Papillary cystadenomas are true tumors consisting of a proliferation of
salivary ductal cells in a cystic configuration (see below). In the major salivary
glands, papillary cystadenoma lymphomatosum (Warthin's tumor) shows a
prominent lymphoid component in addition to oncocytic lining cells.9
Sialolithiasis
Clinical features
In sialoliths (salivary gland calculi), affected patients are in their sixth or seventh
decade. The most common sites are the upper lip and buccal mucosa which
together account for 75–90% of all minor salivary gland lithiasis.1,2 They present
as deep masses, nodules, and swellings, sometimes associated with drainage.
Histological features
The calculi have a lamellated appearance with alternating eosinophilic and
basophilic bands and a generally homogeneous center.1,2 Globular and granu-
lar areas and cellular inclusions may be present. Such calculi generally reside
within a cystically dilated excretory duct that exhibits squamous metaplasia
and periductal inflammation (Fig. 11.178). Bacteria and inflammatory cells
may be present between the calculus and the duct lining, or between lamella-
tions. Rupture can lead to acute and chronic inflammation and/or a foreign
body reaction. Approximately one-quarter of calculi are unmineralized.1
Differential diagnosis
Phleboliths and calcified thrombi are generally not lamellated and occur
within vascular lumina lined by endothelial cells.
Necrotizing sialometaplasia
Clinical features
This is a self-healing inflammatory condition of salivary glands that may be
clinically and histologically mistaken for a malignancy because of its rapidly
progressive ulcerative nature and the lack of associated pain in a significant
proportion of cases.
Adults (2M:1F) are mainly affected with a mean age of onset in the fifth
decade. It usually presents as a painful or painless ulcer or (less often) as a
mass, with the majority (approximately 80%) occurring on the hard palate
(Fig. 11.179). Approximately 10% of cases affect the major glands and (less
often) the mucous glands of the nose, maxillary sinus, and larynx.1 One-third
Fig. 11.178
Sialolith: the sialolith is present within an ectatic salivary duct, the lining of which
exhibits squamous metaplasia.
Fig. 11.179
Necrotizing sialometaplasia: there is punched-out ulcer on the hard palate.
By courtesy of C. Allen, DDS, Columbus, USA.
 Reactive conditions 415

of patients give a history of recent surgery at the site. Other predisposing

factors include a history of trauma, injection of local anesthetics, or alcohol
and tobacco use, and there is sometimes an association with tumors.1 Cases
have been reported in bulimic patients and cocaine use.2,3, Generally, healing
occurs within several weeks of diagnosis.

Pathogenesis and histological features

The etiology is vascular compromise leading to infarction of the gland and
reactive squamous metaplasia of the ducts and acini. This has been experi-
mentally produced by ligation of salivary ducts and injection with local anes-
thetics.4,5 This hypothesis is supported by the development of necrotizing
sialometaplasia in a patient with Buerger's disease.6
One of the most important features in establishing this diagnosis and distin-
guishing it from a malignancy is preservation of the lobular architecture of the
gland with minimal distortion. Early lesions show infarction of acini resulting
in outlines of acinar units without viable acinar cells; more advanced lesions
show metaplastic changes with pseudoinvasive islands of benign-appearing
squamous epithelium (Figs 11.180, 11.181). There is generally a prominent
inflammatory infiltrate with granulation tissue formation in later stages.1,7,8
Fig. 11.181
Variable features include pseudoepitheliomatous hyperplasia, reactive epi- Necrotizing sialometaplasia: the squamous cells are benign and represent
thelial atypia, and vascular occlusion. Serous and mucoserous glands are less metaplastic ducts.
likely to show the necrosis and infarctive changes.1 Very early lesions may
show predominantly mucus spillage.

Differential diagnosis
The preservation of lobular architecture, lack of infiltration of the surround-
ing tissues by the epithelial elements, infarction necrosis, and generally bland
nuclear morphology of the metaplastic islands distinguish this condition from
squamous cell carcinoma. Mucoepidermoid carcinoma tends to have a sub-
stantial number of mucous cells and will often show obvious infiltration of
surrounding structures. The use of CK7 and myoepithelial markers may help
to differentiate between these three conditions.9
Subacute necrotizing sialadenitis characteristically develops in younger
patients (third decade), with an almost exclusive location on the palate.
Presentation, which is typically acute and over a matter of days, is character-
ized by a painful, nonulcerated mass, with rapid resolution within 2 weeks.10
Since most cases have been reported in the military, there is speculation that
this may represent a viral infection that is transmitted between individuals
living in close quarters. There is only focal necrosis with little ductal metapla-
sia. The glands are diffusely infiltrated by a mixed inflammatory infiltrate of
neutrophils, lymphocytes, histiocytes, and occasionally eosinophils.11,12 Some
contend that subacute necrotizing sialadenitis may fall within the spectrum
of necrotizing sialometaplasia but, in general, there are sufficient clinical and
histological differences to warrant treating them as two distinct entities.
Nicotinic stomatitis
Clinical features
Nicotinic stomatitis (stomatitis nicotina) is associated with pipe smoking and
its severity is proportional to the duration of the habit. It is reversible after
cessation of pipe smoking.1–3 It is caused by the heat from the pipe smoke,
and not the nicotine itself. The condition has also been noted in a patient who
consumed hot beverages.4
Early lesions appear as small red punctate areas sometimes associated with
whitening of the surrounding mucosa on the posterior half of the palate, a site
where many salivary glands are present. Involvement is usually ­symmetrical.
As the lesions progress, the palate may take on a cobblestone appearance
with raised white papules having slightly umbilicated central puncta (Fig.
11.182).1,3 The red puncta represent the inflamed ostia of the excretory
­salivary ducts.
Similar changes have been described in patients who practice reverse
­smoking (smoking with the lighted end of the cigarette in the mouth as is
common in parts of Asia).5,6

Fig. 11.180 Fig. 11.182

Necrotizing sialometaplasia: there are islands of squamous cells that are organized Nicotinic stomatitis: cobblestone, nodular appearance of the hard palate in a patient
in the usual salivary gland lobules, with inflammation. who reverse smokes. By courtesy of L. Lee, DDS, Toronto, Ontario, Canada.
416 Diseases of the oral mucosa

s­ uppurative condition of the minor salivary glands, usually of the lower lip.
Because salivary glands at other mucosal sites may be affected, the alternative
term ‘stomatitis glandularis’ has been proposed.1
Patients present with a painless or painful swelling and eversion of the lip,
often with a mucous or mucopurulent discharge through the duct ostia.1,2 The
lip may be dry, scaly, and nodular. Simple, deep, and deep suppurative forms
have been identified.

Pathogenesis and histological features

Fig. 11.183
Nicotinic stomatitis: the nodule consists of metaplastic excretory salivary ducts and
surrounding chronic inflammation.
Histological features
There is hyperparakeratosis or hyperorthokeratosis and acanthosis. The pap-
ules represent openings of the excretory salivary ducts that have undergone
squamous metaplasia and are usually surrounded by plasma cells and lym-
phocytes in an edematous stroma (Figs 11.183, 11.184).2,7 Lymphocytes are
often seen within the metaplastic ducts. Lobules of minor salivary gland may
be present depending on the depth of the biopsy.
Dysplasia or even invasive squamous cell carcinoma may be present in
patients who reverse smoke but in general malignant change is not a feature
in pipe smokers.3
Cheilitis glandularis (stomatitis glandularis)
Clinical features
Cheilitis glandularis (stomatitis glandularis, cheilitis glandularis apos-
tematosa) is a rare chronic, recurrent, inflammatory and, in some cases,
The etiology is unknown but the condition is likely to represent an inflamma-
tory response to a variety of local irritants. Cases of carcinomatous transfor-
mation have occurred in older male patients with outdoor occupations and
tobacco smoking; eversion of the lower lip increases its exposure to actinic
damage.3 Factitial injury such as repeated wetting and drying of the lips may
also play a role.4 Familial examples have been reported.5,6
There is dilatation and metaplasia (squamous, mucous cell or oncocytic)
of the excretory ducts with variable surrounding acute and chronic inflamma-
tion. Intraluminal suppuration may be present.1,2,7,8 The minor salivary glands
exhibit non-specific inflammatory changes of acinar atrophy, ductal ectasia,
interstitial fibrosis, and interstitial inflammation (Fig. 11.185).2,8
Differential diagnosis
Similar histological changes are seen in glandular obstruction such as occurs
in glands draining into a mucocele and, in particular, in glands that have
been plugged by thick mucinous secretions or by small calculi, a common
phenomenon in the upper lip. The clinical presentation separates this condi-
tion from mucocele or sialolithiasis, both of which are localized and discrete
phenomena.
Salivary gland neoplasms
Clinical features
Any salivary gland neoplasm of epithelial differentiation, benign or malig-
nant, that occurs in the major salivary glands may also occur in the intraoral
minor glands (which are predominantly mucous secreting). Here, only the
more common salivary gland neoplasms affecting the minor glands will be dis-
cussed. Approximately half of intraoral salivary gland neoplasms are benign
and half are malignant and there is a female predilection.1–4 The most com-
mon sites are the hard and soft palate, lips, and buccal mucosa, although
any site may be involved. As expected, lesions present as a swelling at the
site. Benign lesions tend to have a long history of gradual enlargement while
malignant lesions tend to grow more rapidly and ulcerate.

Fig. 11.184
Nicotinic stomatitis: there
is chronic inflammation in
the surrounding fibrous
tissue and lymphocyte Fig. 11.185
exocytosis through the Cheilitis glandularis: there are grossly dilated excretory ducts with mucous cell
duct epithelium. metaplasia, intraluminal suppuration, and surrounding chronic inflammation.
 Reactive conditions 417

The ensuing discussion will focus on the histopathology of only five lesions
which present with some frequency in the oral cavity:
• pleomorphic adenoma
• canalicular adenoma
• mucoepidermoid carcinoma.
• polymorphous low-grade adenocarcinoma
• adenoid cystic carcinoma.
There may be some variation in prevalence of some tumors over others
based on racial differences.3,4
Pleomorphic adenoma (together with its variant, myoepithelioma) and
canalicular adenoma comprise the two most common benign neoplasms.1,3,4
The canalicular adenoma has a particular predilection for the upper lip in
females and lesions are often multifocal.
The most common malignant neoplasm is mucoepidermoid carcinoma
(the second most common tumor overall after pleomorphic adenoma).1,3,4
The polymorphous low-grade adenocarcinoma (originally referred to as lob-
ular carcinoma because of its resemblance to lobular carcinoma of the breast,
and terminal duct adenocarcinoma) was recognized as a distinct entity only in
the 1980s.5–7 Prior to that, it was likely diagnosed as pleomorphic adenoma,
adenoid cystic carcinoma or adenocarcinoma, not otherwise specified, and Fig. 11.186
Pleomorphic adenoma.
is even today a challenging diagnosis for many. Genetic markers for these
tumors have been reviewed recently.8
A condition known as adenomatoid hyperplasia of the minor glands con-
sists of proliferation of normal-appearing mucous acini. This condition is
often seen adjacent to, and possibly as a reaction to, an adjacent salivary
gland neoplasm and should prompt a search for the primary tumor.

Pleomorphic adenoma
This term is preferable to the old term of ‘benign mixed tumor’. It is believed
to arise from intercalated duct reserve cells that can be differentiated into
ducts, acini or myoepithelial cells. In its classic presentation, it comprises a
discrete although not usually entirely encapsulated proliferation of ductal,
myoepithelial, and mesenchymal elements forming ducts and cysts, as well as
sheets, strands, and trabeculae of tumor cells.9 Ducts are lined by eosinophilic
cuboidal cells and surrounded by a cuff of epithelioid myoepithelial cells
(Figs 11.186, 11.187). From these periductal locations, they may blend
into spindled or stellate myoepithelial cells in the stroma which is hyalinized
and/or myxochondroid, sometimes with bone or adipose tissue formation
(Fig. 11.188).10 Keratin pearl formation, although unusual, should not be
misinterpreted as a sign of malignancy and neither should focal capsular inva-
sion. Many variations of this classic histology may be seen including cellular
Fig. 11.187
and myxoid variants and, importantly, the myoepithelial predominant vari- Pleomorphic adenoma: the ducts are lined by uniform cuboidal cells and there is a
ant, or myoepithelioma.2–4 surrounding myoepithelial layer.
Myoepitheliomas are believed to be a variant of pleomorphic adenoma
where the myoepithelial element predominates and where ductal structures
may be minimal or altogether absent. Most lesions occur on the palate
and consist of spindled cells, plasmacytoid or ‘hyaline’ cells (large cells
with abundant eosinophil cytoplasm and eccentric nuclei) or a combina-
tion of both (Fig 11.189).11 Clear and epitheloid myoepithelial cells may
also be present. Plasmacytoid myoepithelial cells can exhibit variation
in shape and size of the nuclei but mitoses are not seen. Pockets of such
plasmacytoid myoepithelial cells may be seen in banal pleomorphic ade-
noma. Differentiation of myoepitheliomas from plasmacytoma is based
on the myoepithelial cells not exhibiting a zone of Hopf, the lack of a
clumped chromatin pattern, and negative staining for B-cell markers or
monoclonality.
Myoepithelial cells stain consistently for cytokeratin, S-100 protein, and
vimentin. They also stain for calponin, p63, and glial fibrillary acidic pro-
tein while staining for muscle-specific actin and smooth muscle actin are less
consistent.9,12,13
Malignant transformation in intraoral pleomorphic adenomas occurs but
it is uncommon.9
Adenomatoid hyperplasia of the salivary glands, a benign lobu-
lar proliferation of acini and ducts resembling normal glands is often
seen adjacent to both benign and malignant salivary gland tumors (Fig Fig. 11.188
11.190).14,15 Pleomorphic adenoma: in this example there is a focal chondroid stroma.
418 Diseases of the oral mucosa

Fig. 11.189 Fig. 11.191

Myoepithelioma: high-power view showing plasmacytoid myoepithelial cells. Canalicular adenoma: the tumor is encapsulated and composed of well-defined
trabeculae and interlacing strands of basaloid cells.

Fig. 11.190
Salivary gland adenomatoid hyperplasia: note the lobular growth pattern. The acini Fig. 11.192
resemble those seen in normal salivary gland. Canalicular adenoma: the trabecular are two cells thick and form small ductal
structures; stroma is myxoid with little collagen and dilated capillaries.

Canalicular adenoma
The canalicular adenoma generally has a thick capsule. There is a prolif-
eration of strands and anastomosing trabeculae of basaloid cells, often in a
double layer. Solid and trabecular forms are also recognized.16 The nuclei are
fusiform with inconspicuous nucleoli and no atypia. The stroma is generally
myxoid and contains small blood vessels but is not particularly ­collagenized.
Multifocality is not uncommon and should not be mistaken for infiltra-
tion (Figs 11.191, 11.192). Tumors stain for S-100 protein but not smooth
­muscle actin, calponin or c-kit.9,17

Mucoepidermoid carcinoma
The mucoepidermoid carcinoma, as its name suggests, consists of a proliferation
of mucous, epidermoid cell, and intermediate cells with variable duct and cyst
formation (Figs 11.193, 11.194).9,18 The epidermoid cells have ample, palely
eosinophilic cytoplasm and medium-sized nuclei with dispersed chromatin while
intermediate cells have less cytoplasm. Cystic structures are often lined by all
three cell types, often with luminal proliferation of the same cells forming ducts
and complex architecture. Some tumors have a preponderance of clear cells. Fig. 11.193
Invasion of the stroma occurs as small islands of cells and these may not always Mucoepidermoid carcinoma: medium-power view showing ducts and cystic spaces
be readily identified. lined by mucous cells with stroma infiltration.
 Reactive conditions 419

isomorphism of the cells themselves (Figs.11.195, 11.196).7,9,25 The cells are

ovoid to spindled with medium-sized nuclei with finely dispersed chroma-
tin, small nucleoli, and pale cytoplasm. There may be clear or oxyphilic cells.
Mitotic activity and necrosis are infrequent. A helpful feature is the presence of
cells ‘in single file’ at the periphery or near the mucosal surface of the tumor.
The stroma is hyalinized and/or myxoid but cartilaginous and osseous elements
are not seen. Perineural invasion is common in spite of the tumor being of low
grade. It may be difficult to identify areas of true stromal invasion in curet-
ted specimens. Immunohistochemistry studies for glial fibrillary acidic protein,
S-100, actin, bcl2, and p53 have shown variable results and do not distinguish
between this tumor and pleomorphic adenoma or adenoid cystic carcinoma.25
Differentiation of this tumor from a pleomorphic adenoma can be difficult
if there is no evidence of perineural invasion since it shares many features with
pleomorphic adenoma such as variable pattern, bland cytology, and myxoid
stroma. The presence of plasmacytoid myoepithelial cells in clusters and the cuff-
ing of ductal structures by a layer of myoepithelial cells are features of pleomor-
phic adenoma and not seen in polymorphous low-grade adenocarcinoma. Cells
A positive for glial fibrillary acidic protein are seen often in stromal cells in pleo-
morphic adenomas but not in polymorphous low-grade adenocarcinomas.26
The tumor may also resemble adenoid cystic carcinoma although the
latter tends to have more nuclear pleomorphism, hyperchromatism, and atypia.
Both stain for p63 but CD43 may be less often expressed in polymorphous
low-grade adenocarcinoma than in adenoid cystic carcinoma.27,28

Adenoid cystic carcinoma

This tumor takes three forms: the classic type that has a prominent cribriform
pattern, the tubular type, and the solid type which forms few ductal or cribri-
form structures and carries the worst prognosis.9,16,29
Adenoid cystic carcinoma is an invasive tumor and consists of a prolif-
eration of basaloid cells that have large, oval or irregularly shaped, angu-
lar, hyperchromatic nuclei (Figs 11.197 to 11.199). Cells have less cytoplasm
than is seen in polymorphous low-grade adenocarcinoma. A cribriform pat-
tern (so-called ‘swiss cheese’ appearance) is the most reliable feature seen usu-
ally in combination with a tubular pattern. The stroma is variable myxoid or
hyalinized and perineural invasion is a frequent finding. Perineural invasion
B of major nerves is associated with higher local recurrence and lower survival
rates as are tumors with >30% solid component.30
Fig. 11.194 It may be difficult to differentiate this tumor from a polymorphous low-
Mucoepidermoid carcinoma: high-power views of (A) mucous and epidermoid cells;
grade adenocarcinoma that may also have focal areas with a cribriform
(B) focal squamous differentiation.
configuration although this tumor tends to stain with c-kit and CD43 more
strongly.28 In general, the cells in an adenoid cystic carcinoma exhibit more
nuclear atypia, hyperchromatism, and mitotic activity.
For many decades, grading into low, intermediate, and high grades was
based on the presence of cystic spaces and the proportion of mucous to epi-
dermoid cells. However, more recently, two studies have proposed grad-
ing schemas using point systems based on the presence of cystic structures,
mucous cell population, anaplasia, stromal and bone invasion, neural and
vascular invasion, and mitotic activity.19,20 Grade I to III in both systems cor-
relate with recurrence and prognosis. Expression of p27 and high Ki-67 index
may impact prognosis.21,22
Acinic cell carcinomas may look similar but they lack significant numbers of
mucous cells and more than 90% of them contain zymogen granules that are
PAS positive and diastase resistant. Cystic lesions are easily mistaken for pap-
illary cystadenomas (which do not generally contain mucous cells), especially
since the cytology of these tumors is bland with little evidence of mitotic activ-
ity.9,23 Luminal proliferation of mucous and epidermoid cells, complex ductal
architecture, and invasion of the surrounding stroma are important features.
It may also share similarities with a papillary cystadenocarcinoma which
has prominent luminal papillae, shows hobnailing of cells in the lumen and
more cytologic atypia and mitotic activity.24

Polymorphous low-grade adenocarcinoma

Fig. 11.195
This unencapsulated but often well-circumscribed tumor is characterized by Polymorphous low-grade adenocarcinoma: at low power, this tumor can be readily
two features: a marked variation in the pattern of the tumor cells with solid, confused with pleomorphic adenoma. Note the solid areas, ductal differentiation,
ductal, cribriform, cordlike, trabecular, cystic or fascicular patterns; and bland and focal myxoid stroma.
420 Diseases of the oral mucosa

Fig. 11.198
Adenoid cystic carcinoma: myoepithelial cells surrounding myxoid stroma forming
cribriform pattern.

Fig. 11.196
Polymorphous low-grade adenocarcinoma: (A) the tumor cells appear uniform with
vesicular nuclei and prominent nucleoli. Clear cell forms are evident. There is a
myxoid stroma, (B) in this field, cystic spaces are evident.

Fig. 11.199
Adenoid cystic carcinoma: tubular structures with ductal and myoepithelial cells in
hyalinized stroma.

Papillary ductal lesions

Three conditions deserve mention: intraductal papilloma, inverted papil-
loma, and sialadenoma papilliferum.1 They are all likely reactive papillary
and metaplastic lesions and not true neoplasms.
The intraductal papilloma and inverted papilloma present as mucosal nod-
ules or masses. The intraductal papilloma occurs within a cystically dilated
salivary duct as a result of papillary proliferation of columnar epithelium,
usually with many mucous cells overlying fibrovascular cores.1 The inverted
papilloma presents as an endophytic papillary proliferation of epithelium
forming large lobular structures with crypts.2 The epithelium is columnar on
the luminal aspect and basaloid within the lobules. Mucous cells and micro-
cysts are present. There is minimal mitotic activity and usually no atypia.
Human papillomavirus 6/11 have been identified in rare cases.3
Sialadenoma papilliferum is the mucosal counterpart of syringocystade-
noma papilliferum.4,5 These lesions are usually located on the palate and clini-
cally present as an exophytic papillary growth. Microscopically, there is an
exophytic proliferation of squamous cells and an endophytic proliferation of
ductal and cystic structures with a complex branching architecture and also
Fig. 11.197 luminal papillary projections of columnar and mucous cells. Positive staining
Adenoid cystic carcinoma: low-power view showing characteristic cribriform growth for cytokeratin, S-100, glial fibrillary acidic protein, vimentin, and smooth
pattern. muscle actin suggests that myoepithelial cells play a role in these tumors.4

Premalignant conditions
Leukoplakia, erythroplakia and
epithelial dysplasia
Clinical features
Leukoplakia, a clinical term, is defined as a white plaque that does not wipe
off and cannot be characterized clinically or pathologically as any other dis-
ease and is not associated with any physical or chemical agent except tobacco;
it excludes all frictional keratoses.1,2 Its prevalence is 1.5%.3 There is a strong
association between the appearance of leukoplakia and the use of tobacco
products.4,5 Conversely, of all patients who have leukoplakia, 70–90% have
a tobacco history.6,7 Prevalence increases with age.6 Clinically, lesions may
appear homogeneous (in color and texture) or nonhomogeneous; if the lat-
ter, they may be referred to as erythroleukoplakia (or speckled leukoplakia),
verrucous leukoplakia or nodular leukoplakia (Figs 11.200 and 11.201).1,2,8
The most common sites are the buccal mucosa, commissure, tongue, gingiva/
alveolar mucosa, and the palate, although the nature of oral habits may affect
the location of leukoplakia.4,8–10 However, sites associated with dysplasia and
Fig. 11.200
Leukoplakia: nonhomogeneous sharply demarcated and fissured white plaque on
the buccal mucosa. This exhibited moderate dysplasia.
Fig. 11.201
Leukoplakia: erythroleukoplakia on the lateral tongue. This exhibited moderate
dysplasia.
Leukoplakia, erythroplakia and epithelial dysplasia 421
carcinoma – so-called ‘high-risk’ sites – are the floor of mouth, tongue, and
soft palate (Fig 11.202).8,9,11
Dysplasia, carcinoma-in-situ or invasive squamous cell carcinoma is
present in 20–34% of leukoplakias overall.6,10 However, in subcontinental
Indians, the rate is generally less than 1%, suggesting alternative factors or
that different diagnostic criteria may be at play.8 The malignant transforma-
tion rate of leukoplakia is 3–5%.12 If epithelial dysplasia is present, the rate
increases to 12–19%;13–15 one study had a rate of 37%.6
Verrucous leukoplakia most likely represents a precursor lesion of ver-
rucous carcinoma or papillary squamous carcinoma. Clinically, this variant
presents as a rough white plaque on the gingiva or alveolar mucosa in patients
more than 50 years old, with a roughly equal sex distribution.16 More exten-
sive lesions are referred to as proliferative verrucous leukoplakia. This is a per-
sistent and progressive form of leukoplakia that tends to affect women (3:1),
with a tobacco habit present in approximately one-third of cases.17–20 It starts
as an innocuous leukoplakia that subsequently spreads or develops multifo-
cally, becoming increasingly verrucous and sometimes erythematous over the
roughly two decades that it often takes to be recognized (Figs 11.203, 11.204).
Fig. 11.202
Leukoplakia: this red and white plaque exhibited severe epithelial dysplasia.
Fig. 11.203
Proliferative verrucous leukoplakia: this patient had been aware of this progressive
lesion for approximately 10 years. This was a verrucous carcinoma arising from
proliferative verrucous leukoplakia.
422 Diseases of the oral mucosa

These  lesions, although clinically extensive, are often cytologically bland

and patients have had multiple biopsies without a diagnosis of ­dysplasia
or ­carcinoma. Malignant transformation to squamous cell or verrucous
­carcinoma occurs in 60–100% of cases.20
Erythroplakia (similar to erythroplasia) presents as a velvety red papule
or plaque that is usually painless. It is much less common than leukoplakia
(Fig. 11.205). Dysplasia, carcinoma-in-situ or invasive carcinoma is present
in 69–91% of cases at the time of biopsy.21–23

Pathogenesis and histological features

All leukoplakias are characterized by hyperparakeratosis or hyperorthok-
eratosis with varying degrees of acanthosis and chronic inflammation.
Unlike in other mucosae, architectural features of dysplasia are particu-
larly important, especially for evaluating lesions of proliferative verrucous
leukoplakia. Architectural features of dysplasia include marked papilloma-
tosis and exophytic growth, such as is seen in verrucous hyperplasia, and
endophytic growth;24 these are often bulky lesions. Rete ridges are frequently
bulbous if there is prominent epithelial hyperplasia, or tear-drop or drop
shaped. Cytological features are similar to those used for other epithelia: loss of
Fig. 11.206
normal stratification and polarity, dyscohesion, dyskeratosis, basal cell hyper- Epithelial dysplasia: there is budding of the rete ridges; dysplastic cells involve less
plasia, increased nuclear-to-cytoplasmic ratio, mitoses in the mid and upper than one-third of the thickness of epithelium.

epithelium, and anaplasia.2,13,25 By convention, the terms mild, moderate, and

severe dysplasia are applied if less than one-third, between one- and two-
thirds, and greater than two-thirds of the epithelium is affected (Figs 11.206–
11.208). Full- thickness involvement represents carcinoma-in-situ.
Extension and spread of dysplastic cells from the surface epithelium down
excretory salivary ducts (particularly in floor of mouth dysplasias) without
evidence of stromal invasion is accompanied by the same recurrence rate
as for invasive squamous cell carcinoma (Fig. 11.209).26 This may, in part,
explain recurrences in the floor of mouth after superficial excision or laser
ablation.
Squamous intraepithelial neoplasia is a term used for dysplasia and car-
cinoma-in-situ of the upper aerodigestive tract, analogous to the concept of
cervical intraepithelial neoplasia.27 Squamous intraepithelial neoplasia con-
notes not only histomorphological features of malignant change (albeit of
a noninvasive lesion) but also molecular and genetic changes of neoplastic
transformation.

Fig. 11.204
Proliferative verrucous leukoplakia: this is the same patient depicted in Figure
11.203, showing palatal involvement.

Fig. 11.207
Epithelial dysplasia:
dysplastic cells involve
Fig. 11.205 greater than one-third but
Erythroplakia: this innocuous-appearing red macule on the lateral tongue was an less than two-thirds of the
invasive squamous cell carcinoma histologically. epithelium.

Fig. 11.208
Carcinoma-in-situ:
dysplastic cells involve
the full thickness of the
epithelium.
Fig. 11.209
Carcinoma-in-situ: dysplastic cells involve the excretory salivary duct, also in an in
situ pattern; this has important prognostic implications.
The use of molecular markers to help predict malignant transformation is
rapidly evolving.28 Loss of heterozygosity in 3p, 9p, and 17p are associated
with dysplasia but not consistently so.29,30 There is increased expression of
p53 in moderate and severe dysplasia and carcinoma-in-situ.31,32 The presence
of p53 in suprabasal cells correlates with the development of oral squamous
cell carcinoma even when clear evidence of dysplasia is not present.33 The use
of microarrays for the identification of specific gene expression products may
prove important in further defining the progression potential of dysplastic
lesions.34 Other studies include those that have investigated ploidy status, and
proliferation and differentiation markers. However, the current ‘gold stan-
dard’ for the evaluation of dysplasia is still routine histology.
A histological diagnosis of verrucous hyperplasia is made for those lesions
exhibiting marked hyperorthokeratosis or hyperparakeratosis with the epi-
thelium thrown into exophytic papillary projections, sometimes bulbous rete
ridges and an endophytic growth pattern.24 This corresponds clinically to ver-
rucous ­leukoplakia. ‘Blunt’ and ‘sharp’ papillary projections are identified,
Leukoplakia, erythroplakia and epithelial dysplasia 423
Fig. 11.210
Verrucous hyperplasia: note the exo- and endophytic squamous proliferation with
marked hyperkeratosis; normal epithelium is present at one edge.
Fig. 11.211
Verrucous hyperplasia:
there is hyperorthokera-
tosis, normal-sized rete
ridges, and minimal
cytological atypia.
with the blunt ones being usually non- to thinly keratinized and the sharp
ones being markedly hyperkeratotic (Figs 11.210, 11.211).12 Cytological aty-
pia may be minimal. If there is hyperparakeratosis and the papillary folds of
epithelium push endophytically and assume frondlike rete ridges, a diagnosis
of verrucous carcinoma should be made (Figs 11.212, 11.213).24,35 Between
20% and 30% of verrucous hyperplasias have been found to harbor human
papillomavirus.36,37
The histological features of proliferative verrucous leukoplakia are vari-
able and usually those of verrucous hyperplasia. They all show hyperorthok-
eratosis or hyperparakeratosis and papillomatosis. Epithelial dysplasia may be
absent to mild in early lesions. As they spread relentlessly over the mucosa,
lesions may show increasing cytological evidence of dysplasia, more marked
exophytic papillomatosis and, finally, an endophytic and/or frankly invasive
growth pattern of conventional squamous cell or verrucous carcinoma.20 In
one series, 77% of cases were positive for HPV-16.38 DNA aneuploidy has also
been reported.39 Cases may also develop aneuploidy as the lesions progress and
become dysplastic.40
424 Diseases of the oral mucosa
Fig. 11.212
Verrucous hyperplasia/early verrucous carcinoma: note the exo- and endophytic
squamous proliferation with bulbous pushing rete ridges.
Fig. 11.213
Verrucous hyperplasia/
early verrucous carcinoma:
there is parakeratin
plugging, minimal atypia,
and a broad endophytic
front.
Differential diagnosis
The use of a sanguinaria-containing dentrifice may lead to a leukoplakia in
the maxillary vestibule that exhibits hyperorthokeratosis, atrophy, papillo-
matosis, and usually mild cytological atypia/dysplasia (Fig. 11.214).41,42 No
cases have resulted in carcinomatous transformation although discontinua-
tion of the dentifrice has not always led to resolution.
Bowenoid papulosis, a condition of young adults, occurs uncommonly on
the lips, tongue, and buccal mucosa. In addition to koilocytes, there are atypi-
cal, dyskeratotic, apoptotic cells with peculiar fragmented chromatin simulat-
ing arrested mitoses involving the full thickness of the epithelium, while the
surrounding epithelium exhibits varying degrees of epithelial dysplasia (Figs
11.215, 11.216).43–46 Seventy percent of cases may be HPV positive by in situ
hybridization and most are positive for high-risk HPV-16/18.42 The authors of
another series consider that the term bowenoid papulosis should not be used
if dysplasia is present, and recommend that the term ‘koilocytic dysplasia’ be
used instead. In their series, 68% of cases were positive for HPV-16/18.45
Fig. 11.214
Sanguinaria-induced leukoplakia: the maxillary gingiva and sulcus is a typical
location for these sharply demarcated, rough plaques.
Fig. 11.215
Koilocytic dysplasia: there is carcinoma-in-situ.
The term ‘lichenoid dysplasia’ has been used to denote epithelial dyspla-
sia associated with a band of lymphocytes at the interface. In such instances,
it may be less confusing to use the term ‘epithelial dysplasia with lichenoid
inflammatory infiltrate’ because the lymphocytic band is likely a host response
to dysplastic cells.
Submucous fibrosis
Clinical features
This condition affects adults of usually Asian descent (subcontinental
Indians in particular) who chew areca nut as a component of betel quid or
paan.1 Patients develop progressive pallor, fibrosis, and a marble-like rigid-
ity of the tissues usually beginning in the soft palate and fauces, and then
involving the buccal mucosa, lips, and tongue, not dissimilar to progressive
systemic sclerosis. Palpable fibrous bands run vertically down the buccal
mucosa in advanced lesions and lead to reduction in mouth opening. Ulcers,
areas of erythema, and symptoms of burning are common.2 This is a prema-
lignant condition, as squamous cell carcinomas develop in a large number
of cases.3,4

Fig. 11.216
Koilocytic dysplasia:
nuclear fragmentation is
a characteristic feature of
this condition.
Pathogenesis and histological features
Arecoline (areca nut alkaloid) and areca nut flavonoids stimulate collagen
synthesis and are carcinogenic. Increased collagen synthesis and reduced
matrix degradation mediated through transforming growth factor-beta leads
to fibrosis and this condition may be considered a collagen metabolic dis-
ease.5,6 Destabilized chromosome loci and loss of heterozygosity at loci asso-
ciated with oral squamous cell carcinoma have been identified in almost half
of cases of submucous fibrosis in one study, as well as inhibition of p53 and
DNA repair and impairment of T-cell function.7–9
The epithelium is hyperkeratotic and atrophic with loss of rete ridges.
The subepithelial connective tissue first shows edema, vascular dilatation,
and chronic inflammation. Progressive thickening of the collagen bundles
occurs with increasing degrees of hyalinization (Fig. 11.217). In severe
cases, hyalinized bands of collagen are devoid of cells.2,10,11 Half of cases
may show a lichenoid pattern of inflammation.11 Epithelial dysplasia was
noted in 8% of cases.11
Malignant lesions
Squamous cell carcinoma
Clinical features
Squamous cell carcinoma is the most common malignancy in the oral cavity,
accounting for more than 90% of all oral cancers. In the USA, it constitutes
approximately 3% of all malignancies and accounts for 20 000–25 000 cancer
cases diagnosed annually.1,2 The two most significant risk factors are cigarette
smoking (by far the most important) and excessive alcohol consumption.3–5 In
Asian countries, tobacco use and areca nut chewing in its various forms are
a major cause of oral cancer.5 Oral cancer is the most common form of can-
cer among men in India where such habits are prevalent;5 these tumors often
develop within submucous fibrosis. Other risk factors include a history of a
previous oral squamous carcinoma, history of cancer elsewhere in the body,
history of immunosuppression, family history of cancer and age.6,7 Lip carci-
noma is generally not included in the discussion on oral lesions because of its
Squamous cell carcinoma 425
Fig. 11.217
Submucous fibrosis:
there is epithelial atrophy
and dense fibrosis that
surrounds skeletal muscle
fibers.
Early ultrastructural studies showed abnormal collagen fibrils that were
fragmented, angulated, and degenerate.12 Other studies have shown the pres-
ence of type I and type III collagen in a normal distribution with normal fiber
morphology but with increased density.13 A further study has shown reduced
amounts of type III procollagen and type VI collagen in fibrotic areas.14
Differential diagnosis
The eosinophilic bands of collagen do not stain for amyloid. Smokeless tobacco
keratosis may exhibit similar eosinophilic bands of altered collagen but, in
addition, there is surface coagulation and keratin chevrons, as well as epithe-
lial hyperplasia rather than atrophy as is typically seen in submucous fibrosis.
Involvement of the oral mucosa by systemic sclerosis is an important differential
diagnosis that can be excluded on clinical grounds and with serological tests.
Lichen sclerosus is a rare oral condition. In addition to the hyalinized
eosinophilic subepithelial band, there is basal cell degeneration and a
­lymphocytic band beneath the area of hyalinization.15–17
different etiology (sunlight) and its better prognosis. HPV is identified infre-
quently in carcinomas of the oral cavity proper but is found in approximately
25% of squamous cell carcinomas of mucosa associated with the tonsils and
Waldeyer's ring and carries a better prognosis; the vast majority are of HPV-
16 subtype.8,9
The tumor may present initially as plaque lesions of leukoplakia,
erythroplakia, and proliferative verrucous leukoplakia, or as nonheal-
ing ulcers, masses or nodules (Fig. 11.218). As with leukoplakia, the
premalignant condition, the most common sites are tongue and floor of
mouth.1,2 Patients are usually in the sixth decade of life or older, although
more recent data reveal a rise in these tumors in younger patients, often
unassociated with tobacco use. Up to 25% of patients present with syn-
chronous or metachronous tumors of the upper aerodigestive or digestive
tract.10 Overall 5-year survival is 58% with stage I and II tumors showing
85% survival and stage III and IV tumors with distant metastases, 25%
survival.1
426 Diseases of the oral mucosa

Fig. 11.218
Squamous cell carcinoma: there is a fungating mass on the buccal mucosa.

Pathogenesis and histological features Fig. 11.219

Squamous cell carcinoma:
The development of oral squamous cell carcinoma is a multistep process invasive well-differentiated
involving allelic imbalance and loss of heterozygosity involving chromosomes tumor.
3p, 9p, and 17p especially, as well as 11q, 13q, and 17p; although these are
the most common, genetic aberrations involving practically every gene have
More recently, sentinel node biopsy in patients without clinical evidence
been identified.11,12 A history of tobacco and alcohol use is associated with a
of cervical metastases has disclosed metastatic disease in approximately
high frequency of p53 mutations.5 With molecular techniques, p53 overex-
25–50% of cases.23
pression has been found in histopathologically benign margins. Local recur-
An important variant is the papillary squamous cell carcinoma, which pre-
rence has been noted in 38% of patients with such p53-positive margins and
dominantly occurs on the alveolar ridge, buccal mucosa, larynx, pharynx, floor
metastatic nodal disease identified in 21% of clinically negative lymph nodes.
of mouth, and tongue. The literature regarding this entity is somewhat confus-
Diploid tumors are associated with lower incidences of recurrence and lymph
ing. There are two subtypes, both characterized by a papillary growth pattern:
node metastasis.13
Histologically, these tumors are similar to squamous cell carcinoma aris-
• One occurs in the larynx and upper respiratory tract and consists of an
invasive papillary proliferation of minimally to nonkeratinizing epithelium
ing at other sites (Fig 11.219). The overlying epithelium shows varying
with highly atypical epithelial cells and numerous mitoses overlying a
degrees of dysplasia. Tumor cells exhibit dyskeratosis and keratin pearl for-
fibrovascular core (Figs 11.220, 11.221).24–26 The in situ portion of
mation and vary in degree of pleomorphism and mitotic activity. The cells
the tumor resembles a squamous papilloma with ­carcinoma-in-situ.
are usually large with abundant eosinophilic cytoplasm, and intercellular
bridges are often readily identified. Tumors in the nasopharyngeal and ton-
sillar areas that are minimally keratinizing with basaloid morphology are
generally positive for high risk HPV and p16 is a reliable marker for that.8
The tumor may invade the stroma as large islands and fronds of epithe-
lium on a pushing front (bluntly invasive type), often connected to the sur-
face epithelium, or it may infiltrate the stroma as smaller irregular islands
and nests of tumor cells or as single cells. Keratin pearl formation associ-
ated with microabscesses at the tips of rete ridges are often seen in bluntly
invasive lesions. Immunolocalization of type IV collagen and laminin reveals
that basement membrane is generally preserved in bluntly invasive patterns of
growth and lost in infiltrative tumors.14 The infiltrative pattern is associated
with a significantly higher incidence of lymph node metastasis compared to
bluntly invasive tumors.15,16 Thicker tumors such as those 5 mm or greater are
more likely to metastasize; however, a figure as low as 1.5–2 mm is quoted for
lesions of the tongue and floor of the mouth, both being high-risk sites.17–21 A
recent tumor scoring system is based on seven parameters:22
• vascular invasion,
• tumor size,
• grade of differentiation,
• tumor thickness,
• degree of inflammation,
Fig. 11.220
• shape of invasion, Papillary squamous cell
• perineural spread. carcinoma: the papillary
This has shown good correlation for prediction of cervical lymph node projections of malignant
metastasis. Although tumors are often graded well, moderately, or poorly dif- epithelial cells are
ferentiated depending on the amount of keratin produced, the degree of kera- nonkeratinized and there
tinization is unlikely to be related to prognosis. is stromal invasion.
 Sarcomatoid carcinoma 427

Fig. 11.221 Fig. 11.222 Fig. 11.223

Papillary squamous cell carcinoma: there is marked Papillary well-differentiated squamous cell carcinoma: Papillary well-differentiated squamous cell carcinoma:
pleomorphism and koilocyte-like cells. note the abundant keratin formation and papillary and the cells in this tumor are keratinizing.
crypt-like formations.

These tumors are HPV positive in approximately one-third of cases and
the presence of p53 correlates with poor survival.26
• In contrast, oral papillary squamous cell carcinomas are well keratinized
and generally well differentiated, although they usually show varying
degrees of dysplasia in contrast to the bland histology typical of
verrucous carcinoma (see below) (Figs 11.222, 11.223).27
Intraoral so-called keratoacanthomas are rare and may resemble verru-
cous carcinoma.28,29 They typically have a crateriform architecture with the
cup-shaped depression filled with keratin. Cells have ‘glassy’ cytoplasm and
the underlying stroma is usually infiltrated by cells exhibiting cytological aty-
pia. Keratoacanthoma is best regarded (and treated) as a variant of well-
­differentiated squamous cell carcinoma.
the main body of the tumor.1 Tumor cells are seen to ‘drop off’ or stream
from the surface epithelium as spindled cells into the underlying stroma.
The spindled cells may form streaming fascicles and storiform patterns, and
have a prominent myxoid stroma (reminiscent of granulation tissue) (Fig.
11.224).1,2,5 The cells sometimes have bipolar processes or appear stellate-
shaped and epithelioid; nuclei may be pleomorphic with prominent nucle-
oli (Fig. 11.225). There are usually abundant mitoses, and pleomorphic
tumor giant cells as well as osteoclast-like giant cells are sometimes pres-
ent. Osteoid is present in 7% of cases and malignant cartilage has been
reported.1,4,6
Cytokeratins such as AE1/AE3 and CAM 5.2 are present in the spin-
dled cells in 50–62% of cases; spindled cells may also coexpress vimentin

Sarcomatoid carcinoma
Clinical features
Sarcomatoid carcinoma (carcinosarcoma, sarcomatoid squamous carci-
noma, spindle cell carcinoma, metaplastic carcinoma) is a tumor of the sixth
to eighth decades with an equal sex distribution.1 The most common sites to
be affected are the lower lip, tongue, and alveolar ridge. A polypoid, exo-
phytic configuration is the most common presentation.1,2 A history of radia-
tion to the site has been noted in 13–67% of cases.1–3 Oral cavity tumors
tend to be deeply invasive and associated with low survival rates; polypoid
lesions may have a better prognosis.2,4

Histological features
The tumor, which is typically ulcerated, is biphasic with a malignant epi-
thelial component (squamous cell carcinoma) usually present at the base or Fig. 11.224
peduncle of the polypoid lesions, and a malignant spindle cell component in Sarcomatoid carcinoma: note the streaming, fasciculated pattern.
428 Diseases of the oral mucosa

Fig. 11.225 Fig. 11.226

Sarcomatoid carcinoma: note the large, pleomorphic spindled cells. Basaloid squamous cell carcinoma: there is comedo-necrosis and lobules of
malignant basaloid cells.

­ iffusely.4,7 Epithelial membrane antigen (EMA) is seen in less than 10% of

d
cases. S-100 protein and GFAP are typically negative.3,7
Ultrastructurally, desmosomes may be well or poorly developed and kera-
tin filaments are variably present. Dilated rough endoplasmic reticulum and
the presence of tropocollagen suggest secretory activity.3–5

Differential diagnosis
Sarcomatoid carcinoma is the most common spindle cell malignancy in
the oral cavity.8 The diagnosis is not usually difficult when a spindle cell
malignancy is present in association with typical squamous cell carcinoma
although the ­latter may be only evident focally at the base of polypoid lesions.
Important differential diagnoses include nodular fasciitis, spindle cell mela-
noma, sarcoma, and malignant myoepithelioma. In difficult cases, immunep-
eroxidase studies will usually enable distinction.

Basaloid squamous cell carcinoma

Clinical features
Fig. 11.227
This is an aggressive variant of squamous cell carcinoma that primarily Basaloid squamous cell carcinoma: there are many mitotic figures and trabeculae of
affects men (M:F = 7:1) in the sixth and seventh decades with a predilec- hyalinized material.
tion for the tongue and floor of mouth; 60–80% develop local and/or distant
metastases.1–3

Histological features
This unusual tumor is characterized by well to moderately differentiated
squamous cell carcinoma coexisting with a malignant lobular proliferation
of basaloid cells. The tumor lobules often exhibit comedo-like ­necrosis and
microcystic spaces filled with PAS-positive material (Fig. 11.226). A cribri-
form pattern is evident and hyalinized material surrounding tumor islands
is an occasional feature; there may be peripheral palisading of tumor cells
(Fig. 11.227).1,4 True ductal differentiation or a focal spindle cell morphol-
ogy is sometimes seen.5 The basaloid cells have dark hyperchromatic nuclei
and indistinct nucleoli. Mitoses are often abundant and perineural invasion
is frequently conspicuous.3
Recognizable squamous cell carcinoma must be identified to establish this
diagnosis. Dysplasia of overlying epithelium is present in 85% of cases and
transition between the squamous and basaloid patterns may be subtle or even
absent.2,4
The cells express cytokeratin (in particular AE1/AE3, CAM 5.2, and
34betaE12), EMA, and NSE (weakly). Carcinoembryonic antigen (CEA)
and S-100 protein are present in approximately 50% of cases.2 Others
report vimentin in a perinuclear rim in the basaloid cells, the absence of NSE
and S-100 (and present only within dendritic cells).3,4,6 Chromogranin and
s­ ynaptophysin are absent.2,3 Approximately 50% of tumors are aneuploid
although this may not have prognostic significance.7,8 These tumors show
marked proliferative activity (PCNA studies) and expression of p53 protein
and Bax.9,10,11
Differential diagnosis
Nonkeratinizing HPV-associated squamous cell carcinoma of the oropharynx
appears very similar but does not have an associated conventional squamous
cell carcinoma.12 Salivary gland carcinomas such as adenoid cystic carcinoma
and basal cell adenocarcinoma (uncommon in minor salivary glands) con-
tain basaloid cells but do not contain a recognizable conventional squamous
cell carcinoma. Adenoid cystic carcinoma also exhibits diffuse cytoplasmic
vimentin expression, whereas in the basaloid squamous carcinoma it is peri-
nuclear when present. One study showed that basaloid cell carcinoma almost
always stains for 34betaE12 keratin while small cell undifferentiated carci-
nomas are negative.13 Merkel cell carcinoma has a trabecular or solid growth
pattern and is generally NSE positive. Keratin expression is characterized by
paranuclear punctate dots and the tumor cells contain typical neurosecre-
tory ­granules.14 Adenosquamous carcinoma has true ductlike structures and
­produces ­epithelial mucin.

Adenoid squamous cell carcinoma
Clinical features
In adenoid squamous cell carcinoma (acantholytic squamous cell carcinoma,
pseudoglandular squamous cell carcinoma, adenoacanthoma) the major-
ity of tumors present on the lower lip with a fivefold male predilection.1,2
Approximately 21% occur on the upper lip, an unusual site for conventional
usual squamous cell carcinoma.3 While lip lesions generally have a good prog-
nosis, intraoral tumors have a mortality of up to 75% for stage 4 lesions.2–4
Histological features
Conventional squamous cell carcinoma must be identified. Pseudoglandular
structures with central ‘lumina’ lined by two to three layers of atypi-
cal squamous epithelium are seen within the tumor islands (Fig 11.228).
Typically, these contain rounded acantholytic tumor cells within the ‘lumina’
(Fig 11.229).1–5 In most lesions, the acantholysis appears to begin in the
immediate suprabasal cells.6 In lip lesions, there is typically a background
of solar elastosis, and sometimes acantholytic solar keratosis is present,
supporting the association with sun damage.7 Clear cell change may also
be seen.8 The epithelial cells stain for cytokeratins and EMA but not for
mucin.2,3,8
Fig. 11.228
Acantholytic squamous cell carcinoma: note the pseudoglandular structures.
Fig. 11.229
Acantholytic squamous cell carcinoma: note the atypical acantholytic cells.
Verrucous carcinoma 429
One variant of this tumor is the pseudovascular adenoid squamous cell
carcinoma that exhibits anastomosing pseudovascular spaces lined by epi-
thelioid cells, mimicking angiosarcoma.9 The lining cells exhibit cytokeratin
staining and do not express vascular antigens.
Differential diagnosis
These lesions must be differentiated from adenosquamous carcinoma in
which true glandular differentiation occurs. See below.
Adenosquamous carcinoma
Clinical features
Only a few cases have been reported in the oral cavity although the larynx
and paranasal sinuses are common sites for this tumor.1,2 It occurs in older
men with a predilection for the tongue and floor of mouth. At least half the
cases show metastasis to regional and distal sites.1,3,4
Histological features
Two distinct components are present: there is a moderately to poorly differentiated
squamous cell carcinoma, a mucin-secreting adenocarcinoma, and transitional
areas (Figs 11.230, 11.231). Mucin is present within lumina or intracellularly.1,3
Ductal carcinoma-in-situ may be present and the adenocarcinoma may show
tubular, alveolar, and ductal structures.1,5 High molecular weight keratins are
present in the squamous cell carcinoma component and low molecular weight
keratins in the adenocarcinoma.3 Carcinoembryonic antigen and CAM 5.2 are
often present in glandular areas but not in the squamous areas.6
Differential diagnosis
High-grade mucoepidermoid carcinomas tend to have a prominent malig-
nant epidermoid component and inconspicuous cystic and mucous cell com-
ponent and may be mistaken for adenosquamous carcinoma. In ­general, the
­malignant epidermoid component does not show the degree of pleomorphism,
­atypia, and keratinization of a conventional squamous cell carcinoma.
Verrucous carcinoma
Clinical features
Verrucous carcinoma presents in older individuals (usually seventh decade)
with a predilection for the buccal mucosa and gingiva (more than 70% of cases)
and is strongly associated with the use of smokeless tobacco or ­cigarettes.1–4
The tumors are white, fungating, cauliflower-like masses, ­generally several cen-
timeters in size, and have usually been present for several years before patients
Fig. 11.230
Adenosquamous carcinoma: low-power view of a poorly differentiated tumor with
intracytoplasmic lumina.
430 Diseases of the oral mucosa

A B

Fig. 11.231
Adenosquamous carcinoma: (A) note the atypical squamous cells; (B) there are intracytoplasmic lumina resembling signet-ring cells.

are finally diagnosed (Fig. 11.232). There may be destruction of underlying

bone and other structures on a broad advancing front. Reactive lymphade-
nopathy is often present and nodal metastases are distinctly unusual except in
irradiated tumors.1,4 Between 17% and 20% of patients may have associated
leukoplakia (most likely verrucous leukoplakia or proliferative verrucous leu-
koplakia) and up to 38% have a second ­primary carcinoma.1,4

Histological features
Verrucous carcinoma is characterized by marked hyperparakeratosis with
keratin plugs between papillary projections of benign-appearing epithelium.
The epithelium forms large, bulbous, frond-like rete ridges that are bluntly
invasive on a broad advancing front (Fig. 11.233). Although there may be
slight epithelial atypia, pleomorphism or anaplasia is lacking (Fig. 11.234).
Some of the rete ridges exhibit central degeneration and abscess formation.
Foreign body granulomas may develop secondary to keratin spillage.1,2,4
Lymph node dissection does not usually reveal metastatic disease.5
Foci of more typical infiltrative squamous cell carcinoma may be seen in
one-fifth of tumors, the so-called ‘hybrid tumor’. These foci may be respon-
sible for a higher recurrence rate (approximately 30%) and subsequent Fig. 11.233
­anaplastic transformation, independent of radiation treatment.4 Strictly, Verrucous carcinoma: there is an endophytic proliferation of squamous epithelium
such tumors probably should be diagnosed as papillary well-differentiated with a broadly invasive front; note the normal gingival epithelium at the periphery.
squamous cell carcinoma rather than verrucous carcinoma.

Differential diagnosis
Strict criteria must be adhered to for the diagnosis of verrucous carcinoma.
Papillary squamous cell carcinoma usually seen in the larynx, which is gen-
erally minimally if at all keratinized, is composed of convoluted ribbons of
highly atypical squamous cells, with dysplastic cells involving the full thickness
of the epithelium.6 These are distinct from the papillary well-differentiated
squamous cell carcinoma that resemble verrucous carcinoma but can be dis-
tinguished by the presence of significant atypia, pleomorphism, dyskeratosis,
keratin pearl formation, and infiltration of the stroma (even if the invasion is
of the ‘blunt’ type). Cases of verrucous carcinoma exhibiting perineural inva-
sion by ‘nests of well-differentiated squamous epithelium’ may also ­actually
represent papillary well-differentiated squamous cell carcinoma.7

Midline destructive disease

Fig. 11.232
Verrucous carcinoma: there is a warty mass in the mandibular buccal mucosa and sulcus.
Clinical features
Midline destructive disease (also known as midline lethal granuloma, cen-
trofacial malignant granuloma, polymorphic reticulosis) presents with deep
ulceration and necrosis of the midline of the face, nasal septum, and palate.
Although once thought to represent a distinct entity, it is now recognized that
 Amalgam tattoo 431

Fig. 11.234
A B Verrucous carcinoma (A, B): there is minimal cytological
atypia and no single cell infiltration.

the features may be caused by a wide range of conditions, including infections
(particularly deep fungal, treponemal, and mycobacterial), chronic cocaine
use, Wegener's granulomatosis, malignancy and, in particular, NK/T-cell lym-
phoma of the sinonasal tract.1–4 T-cell lymphomas constitute 60% of all such
midline lesions.1 These lymphomas (also previously referred to as malignant
­ istiocytosis and angiocentric lymphoma) consist of small, cleaved, and large
h
atypical lymphocytes dispersed in a polymorphic infiltrate of neutrophils, reac-
tive lymphocytes, histiocytes, and plasma cells, and showing invasion of vessels
with consequent necrosis.4–7 There is a strong association with Epstein-Barr
virus and presentation in native South Americans and Asians.5,8,9

Pigmented lesions

Amalgam tattoo
Clinical features
These are asymptomatic gray, bluish, black or slate-colored macules that gen-
erally occur on the gingiva/alveolar ridge (approximately 50%), the buccal
mucosa (approximately 25%) or the floor of mouth (approximately 10%)
(Figs 11.235, 11.236). However, they can occur anywhere in the oral c­ avity
of adults.1

Pathogenesis and histological features

Particles of amalgam restorations may be traumatically implanted into the
mucosa by the dentist during placement or removal of a restoration, by
the patient from bite injury, from leakage and disintegration of a restora-
tion (or root canal filling material), from a restoration falling into a tooth
socket after extraction or after endodontics surgery and an amalgam retro-
fill. Dental amalgam is a mixture of mostly silver and tin and other metals in
smaller amounts, and mercury. The silver stains agryrophilic fibers within the Fig. 11.235
connective tissue. It is believed that metallothioneins (low molecular weight Amalgam tattoo: there are slate-gray macules on the left buccal mucosa
proteins that bind metals) are also present within tattoos and bind metals, corresponding to some large amalgam restorations.
preventing local and systemic toxicity.2
Amalgam in the tissues takes two main forms: as large dense dark-brown
to black fragments that are often macroscopic, and as fine golden- or dark- itself may sometimes be stained a golden color. In approximately 50% of
brown dusty granules (Fig. 11.237).1 The fine granules characteristically are cases, a lymphocytic and/or histiocytic and foreign body granulomatous reac-
dispersed along connective tissue fibers since the silver deposits on reticu- tion is seen around the larger particles, some of which are present within the
lin. They particularly outline the basement membrane of the epithelium and cytoplasm of macrophages and giant cells.1 Scarring is generally present, con-
blood vessels and stain nerve and muscle sheaths (Fig. 11.238). The ­collagen firming its traumatic etiology in many cases.
432 Diseases of the oral mucosa
Fig. 11.236
Amalgam tattoo: there is a blue-black macule on the attached gingiva superior to a
semilunar scar; this tattoo is caused by a root canal-related surgical procedure.
Fig. 11.237
Amalgam tattoo: there are coarse and fine granules of amalgam associated with
foreign body granulomata; there is also a golden stain to the collagen fibers.
Fig. 11.238
Amalgam tattoo: note the typical staining of the vessel basement membrane.
Ultrastructurally, the metal particles are located in the lamina densa of the
basal lamina beneath the epithelium and around blood vessels, and on elastic
fibers.3 They contain silver, copper, and other metals typical for amalgam.
Differential diagnosis
Graphite (pencil lead) can present as clumps of black particles. These tend to
be coarse and they do not localize to the connective tissue fibers (Fig.11.239).
Aluminum and silicon (hardeners for graphite) may be identified using dis-
persive X-ray microanalysis.4
Silver tattoos of nonamalgam derivation have been reported in patients
following silver nitrate cautery.5
Oral melanocytic lesions
Four conditions are of particular importance: melanotic macule, melanoacan-
thosis, melanocytic nevus, and melanoma.
Oral melanotic macule
Clinical features
These are the most common melanocytic lesions in the oral cavity. Originally,
these were labeled ‘labial melanotic macule’ since most of them are found on
the lips (Fig. 11.240).1,2 However, subsequent reports identified similar-appearing
Fig. 11.239
Graphite tattoo: there are large deposits of black granular material.
Fig. 11.240
Oral melanotic macule: note the typical dark brown-to-black macule on the vermilion.

lesions intraorally (especially on the palate) and at other mucosal sites such as on
the genitalia. The preferred term for such oral lesions is ‘oral melanotic macule’.3
These are often solitary (two-thirds solitary, one-third multiple), well-
defined, brown-to-black macules measuring less than 1.5 cm and occurring
on the lips (usually lower), palate, gingiva or buccal mucosa in adults, with a
female predilection (2:1).1,4,5 The intensity of pigmentation is usually constant
unlike in ephelides, which tend to darken with sun exposure. The lesion has
often been present for months to years and 14–25% give a history of increase
in size.1,4,6 Biopsy is usually performed to exclude a melanoma. Oral melan-
otic macules tend not to recur except in those associated with HIV infection.7
This may because these particular lesions are ­medication-induced or repre-
sent post-inflammatory hyperpigmentation.
Pathogenesis and histological features
The melanocytes may be functionally hyperactive as suggested by melanin incon-
tinence and the presence of heavily melanized melanosomes seen ultrastructur-
ally although the cause for such activity is unclear.8 Since 14% of patients with
labial melanotic macules give a family history, there may be a genetic predisposi-
tion. Some melanotic macules may represent a drug-induced hypermelanosis, an
unusual distribution of physiologic/racial pigmentation, a manifestation of endo-
crine disorder, a postinflammatory hypermelanosis, or represent an idiopathic con-
dition. Oral melanotic macules are also associated with longitudinal pigmented
bands in the nails (melanonychia striata), pigmentation of the genitalia and other
skin and mucosal sites in the Laugier-Hunziker syndrome.9,10 Correlation with
clinical data is essential in helping to arrive at a definitive diagnosis.
The oral melanotic macule is characterized by increased melanin pigmen-
tation in the basal cell layer of the epithelium, usually localized to the tips
of the rete ridges with no or only minimal melanocytic hyperplasia (Fig.
11.241).1,3,8 One study, however, found that melanocytic hyperplasia is a
constant feature.11 There are usually increased numbers of melanophages in
the lamina propria that correlate with the degree of chronic inflammation
present. There may be associated mild hyperkeratosis and acanthosis.
Ultrastructurally, stage III and stage IV heavily melanized melanosomes are
clustered in complexes within melanocytes, keratinocytes, and melanophages.8
Differential diagnosis
Postinflammatory hypermelanosis exhibits increased melanin in the basal kera-
tinocytes without concentration at the rete ridges. In addition, there is melanin
deposition within the lamina propria, with increased numbers of ­melanophages,
Fig. 11.241
Oral melanotic macule:
there is increased
melanization of the basal
cells in the absence of
melanocytic hyperplasia or
inflammation.
Oral melanocytic lesions 433
Fig. 11.242
Postinflammatory
hypermelanosis: there is
increased melanization
of the basal cells,
vascular ectasia, chronic
inflammation, and many
melanophages in the
lamina propria.
a more intense lymphoplasmacytic infiltrate and vascular ectasia (Fig. 11.242).
These features are particularly prominent in resolving lesions, such as may be
seen in lichenoid mucositis and oral lichen planus, and in smokers.12
Ephelides occur on sun-exposed areas and the darkness of pigmentation
increases with sun exposure. Lentigo shows epithelial and melanocytic hyper-
plasia in addition to increased melanin pigmentation. Rare cases of oral len-
tigo simplex have been reported where epithelial and melanocytic hyperplasia
have been identified.13
Syndromes associated with melanotic macules such as Peutz-Jegher's
syndrome, Albright's disease, neurofibromatosis, and Laugier-Hunziker
syndrome are differentiated primarily by clinical features since they are his-
tologically identical. Minocycline-induced pigmentation usually shows a
­combination of melanin and iron deposits in the lamina propria.
Melanoacanthosis
Clinical features
Melanoacanthosis (oral melanoacanthoma, mucosal melanotic macule)
should not be confused with cutaneous melanoacanthoma. It occurs in young
black females (greater than 70%), and typically presents in areas that are
susceptible to trauma such as the buccal mucosa, lower lip, palate, and gin-
giva.1–4 The macules have a slightly rough surface and are brown, black or
bluish (Fig. 11.243). The lesion may be well or poorly demarcated. Most
lesions are solitary although rare cases are multifocal.5 A history of trauma is
present in only 50% of cases. Lesions may grow rapidly to several centimeters
in size. Complete resolution occurs within weeks to months.
Pathogenesis and histological features
It is likely that oral melanoacanthosis is a reactive lesion, most probably pre-
cipitated by trauma with subsequent inflammation resulting in stimulation of
dendritic melanocytes and transepithelial elimination of melanocytes.
There is slight parakeratosis and acanthosis; spongiosis is also usually evi-
dent (Fig. 11.244). Numerous dendritic melanocytes and their melanin-laden
processes are found insinuating between keratinocytes throughout the full
thickness of the epithelium (Fig. 11.245).1–6 Such transmigration of melano-
cytes should not be overdiagnosed as melanoma since there is no cytologic
atypia. Melanophages, a mild lymphocytic infiltrate, and vascular ectasia
may also be seen in the lamina propria. Sometimes the spongiosis may be so
434 Diseases of the oral mucosa
Fig. 11.243
Melanoacanthosis: there is a blue-black macule on the buccal mucosa that enlarged
rapidly over a few weeks.
Fig. 11.244
Melanoacanthosis: there is parakeratosis, acanthosis, and spongiosis.
severe as to form spongiform vesicles. Stains for melanocytes such as S-100,
7 melanomas.1–3 It is particularly common in the Japanese.4 Tumors are most
Melan-A, and HMB-45 are positive.3,8
Differential diagnosis
Melanoacanthosis differs from a nevus by the absence of any junctional ­activity.
The benign cytology readily distinguishes this lesion from oral melanoma.
Oral melanocytic nevus
Clinical features
Oral melanocytic nevi are generally diagnosed and biopsied in the third and
fourth decades of life, with a female predilection (2:1). Approximately 85%
are clinically pigmented (gray, brown, blue or black, or a combination thereof)
and almost all are raised, being nodular or papular lesions.1,2 The hard pal-
ate and buccal mucosa are the favored sites, followed by the labial mucosa,
gingiva, and vermilion. Seventy-five percent of all intraoral blue nevi occur as
macules on the palate followed by the labial mucosa, whereas intramucosal
banal nevi occur on the palate and buccal mucosa equally.3
Histological features
Melanocytic nevi in the oral cavity are histologically identical to those found
on the skin. The intramucosal nevus (counterpart of the dermal nevus) is the
Fig. 11.245
Melanoacanthosis: benign
dendritic melanocytes
are present throughout
the full thickness of the
epithelium.
most common (63–66%), followed by the blue nevus and compound nevus
(3–5%).1,3,4 Epithelial hyperplasia is seen in association with intramucosal
nevi in approximately 50% of cases, sometimes associated with benign len-
tiginous melanocytic hyperplasia. Approximately 13% may be histologically
nonpigmented. Nevus cells are also sometimes seen within the underlying adi-
pose tissue and muscle.1 The spindled cells of blue nevi are usually separated
from the overlying epithelium by a Grenz zone. Intramucosal and oral blue
nevi stain for S-100 protein and HMB-45.5
Combined nevi (blue and intramucosal) have been reported.3 Spitz and
congenital nevi have also been described, albeit rarely.6,7
Oral melanoma
Clinical features
Primary oral melanomas comprise up to 20–40% of mucosal head and neck
often seen in older adults, with an equal sex distribution. The hard palate
mucosa and maxillary gingiva are affected in more than 70% of cases. The
lesions are usually pigmented and macular and, less commonly, nodular with
surrounding macular melanosis.2,4–6 Between 20% and 40% of patients pres-
ent with lymph node metastases.1–3
Overall, the prognosis for oral tumors is much worse than for cutane-
ous melanoma, the 5-year survival rate being varying from 8% to 10%,1,2
although rates of 40% have been reported.3,7 A high rate of nodal metastasis,
thick tumor at presentation, extensive tumor spread, and the complicated
anatomy of the maxillary complex make it difficult to completely excise the
majority of these lesions.
Histological features
Most oral melanomas arise from pre-existing intraepithelial melanocytic dys-
plasia that is either lentiginous or pagetoid, similar to cases of acral ­lentiginous
­melanoma.8 Invasive tumors consist of malignant epithelioid and spindled mela-
noma cells, which are only rarely amelanotic. High clinical stage, tumor thick-
ness greater than 5 mm, presence of vascular invasion, absence of melanin in
histological sections and the development of nodal and distant metastases pre-
dict a worse prognosis.3,9 Furthermore, survival of patients with stage I disease
correlates with depth of invasion, as would be expected.9 Desmoplastic mela-
noma has been reported in the oral ­cavity;10,11 cartilaginous metaplasia has been

reported (metaplastic melanoma).12 Results of immunohistochemistry studies
are identical to those for cutaneous melanomas.
One other intraoral tumor that presents with melanotic pigmentation
is the melanotic neuroectodermal tumor of infancy. This occurs as an
intraosseous lesion that usually breaks through the cortical bone into the
soft tissues.13
Medication-induced oral pigmentation
Clinical features
These present as slate-blue macular pigmentation usually of the hard palate
and gingiva. The cutaneous tissues may or may not be involved. The medica-
tions involved include minocycline, antimalarial agents, clofazamine, birth
control medications, amiodarone, and drugs that contain heavy metals.1–6
Tetracycline becomes incorporated into hydroxyapatite crystals of bone and
teeth. It is common for the pigmented bone to show through the mucosa as
grey macular areas.7 Extracted teeth also have a grayish-green cast.
Other tumors
Granular cell tumor
Clinical features
The granular cell tumor presents at a variety of sites, most commonly the
skin (38% of cases), the tongue (23–28%), the breast (16%), and the larynx,
especially the true cord (8%).1–3 Females are affected twice as often as males
and the mean age at presentation is in the fourth decade. However, cases have
also been reported in the first two decades of life.4 In the mouth, the major-
ity of cases (> 80%) occur in the tongue, with the lips, buccal mucosa, and
floor of mouth being other sites of involvement.5 Approximately 8% of cases
are multiple.1 The lesions are yellowish-white, firm and indurated, painless
masses or plaques generally measuring less than 2 cm in greatest dimension
(Fig. 11.246). There is little tendency to recur even after ­incomplete excision.
Pathogenesis and histological features
Although many theories of histogenesis have been proposed over the years,
including myoblastic, neural, fibroblastic, and undifferentiated mesenchymal
cells, the consistent staining of the tumor cells with S-100 protein supports
schwannian differentiation with degenerative changes.6,7
Fig. 11.246
Granular cell tumor: note the yellowish deep mass in the tongue.
Granular cell tumor 435
Pathogenesis and histopathological features
The metabolites of these medications are either themselves pigmented or chelate
to hemosiderin and melanin to form these discernible granules of pigment.
There is deposition of small, 1–3 micron, brown spherical granules in the
superficial lamina propria that are disposed often in a linear fashion along
connective tissue fibers. Some granules are present within macrophages.
Importantly, there is usually no increased melanin deposition within the
basal keratinocytes. However, the granules often stain for melanin (Fantama
Massan) and iron (Prussian blue).
Differential diagnosis
Many medication-induced hyperpigmentary states are not caused by metabo-
lites of the medication, but rather represent postinflammatory hypermelani-
nosis. This is particularly common if the medications cause a lichenoid or
interface stomatitis. In such cases, the lesions almost always show increased
melanin pigment within the basal keratinocytes (even if a lymphocytic band
at the interface is not present), and the stain for iron will be negative.
The overlying epithelium exhibits pseudoepitheliomatous hyperplasia in
one-third to two-thirds of cases, which in some tumors is so marked as to
result in a misdiagnosis of invasive squamous cell carcinoma.3,4,6,7 The tumor
is unencapsulated and presents as nests, cords, and sheets of granular cells
that commonly abut the epithelium, often but not invariably filling the entire
lamina propria and infiltrating into the underlying muscle (Fig. 11.247).4
There is usually close association between the tumor cells and skeletal muscle,
nerves, and blood vessels.4,7,8 Cells are large and ­polygonal with either distinct
or indistinct cell borders and a small nucleus (Fig. 11.248).4 The cytoplasm
contains granules that are PAS positive and diastase resistant, although this is
far from an invariable finding and is of limited diagnostic value.
S-100 protein is invariably positive and immunohistochemistry for muscle
and histiocytic markers is consistently negative.7–9 Stains for CD68 and PGP
9.5 are often positive.10–13
Fig. 11.247
Granular cell tumor:
granular cells fill the
lamina propria and
insinuate between the
muscle fibers of the
tongue.
436 Diseases of the oral mucosa

Fig. 11.248
Granular cell tumor: the cells are polyhedral with pale granular cytoplasm and small
nuclei. Fig. 11.249
Ectomesenchymal
chondromyxoid tumor of
the tongue: the tumor is
discrete and myxoid, with
Ultrastructurally, the granular cells contain autophagic granules and vesic- many cleft-like spaces.
ular bodies.14 Membrane-bound angulate bodies represent angular lysosomes.
A basal lamina is sometimes seen around the cells, supporting a schwannian
derivation.
Malignant granular cell tumors are rare and exhibit pleomorphism, mito-
ses, necrosis, and spindling of cells with a similar staining pattern. They may
metastasize.15,16

Differential diagnosis
There is a variant of the granular cell tumor that does not stain with S-100
protein – the ‘primitive polypoid granular cell tumor’. This lesion is poly-
poid with an epithelial collarette, and the granular cells exhibit slight nuclear
­atypia.17–19 The congenital granular cell tumor is also S-100 negative and has
a delicate arborizing vasculature. Granular cell change may also be observed
focally in many other tumors.18

Ectomesenchymal chondromyxoid tumor

Clinical features
Fig. 11.250
This unusual nodular tumor of the anterior tongue dorsum occurs in the third Ectomesenchymal chondromyxoid tumor of the tongue: note the epitheloid cells and
to sixth decades of life.1,2 trapping of muscle fibers.

Histological features
The tumor is a well circumscribed but unencapsulated, lobular ­proliferation
of tumor cells in the superficial tongue musculature, arranged in sheets,
strands, and cords in a chondromyxoid stroma with cleft-like spaces
(Fig. 11.249).1–3 Cells are polygonal, ovoid, and fusiform with small nuclei
and faintly ­basophilic cytoplasm. There may be focal nuclear hyperchroma-
tism and bi- or multinucleation. The myxoid nature of the stroma often gives
the tumor a reticular appearance and pseudocyst formation is seen in 50%
of cases (Fig. 11.250). Muscle fibers are often trapped at the periphery of
the tumor.4
The tumor cells stain for vimentin, GFAP, and S-100 protein, and often
cytokeratin.1–3 Staining for CD57, smooth muscle actin, and Leu-7 is ­variable.
Tumors are negative for desmin and EMA 1,2 Stains typical for myoepithelial
cells such as calponin, smooth muscle myosin, and p63 have been reported
as negative.5
Ultrastructurally, basal lamina is focally present, but desmosomes and
dense bodies are absent.1
It is likely that this tumor arises from a pluripotential mesenchymal cell.
Differential diagnosis
Myoepitheliomas may resemble this tumor because of a similar cytomorphol-
ogy and immunohistochemistry. The chondromyxoid matrix is also shared by
both. The distinction can be readily made, however, by the absence of duc-
tal differentiation and plasmacytoid cells. In addition, myoepithelioma typi-
cally arises in close proximity to a salivary gland and does not extend into
or entrap adjacent skeletal muscle. While the tumor stains for glial fibrillary
acidic protein and S-100 protein, it does not stain for other markers of myo-
epithelial cells.
 Chapter

See
www.expertconsult.com
for references and
additional material
Diseases of the anogenital skin
Eduardo Calonje, Sallie Neill, Chris Bunker,
Nick Francis, Alcides Chaux and Antonio C Cubilla
12
Introduction  438 Penile necrosis  459 Penile horn  489
Spontaneous scrotal ulceration  460 Pseudoepitheliomatous, keratotic and
Normal female anatomy  438 Scrotal fat necrosis  460 micaceous balanitis  489
Labia majora and perianal skin   438
Labia minora and clitoral prepuce   439 Associations with systemic disease  460 Genital intraepithelial neoplasia, and
Glans clitoris  439 Crohn’s disease  460 squamous cell carcinoma   490
Vestibule  439 Acute hemorrhagic edema of Squamous cell carcinoma of the genital
childhood  461 epithelia  492
Normal male anatomy  439 Necrotising vasculitis   461 Verrucous carcinoma  493
Embryology  440 Penile squamous cell carcinoma  494
Infectious diseases  461
Invasive squamous cell carcinoma  498
Pubic hair  441 Erythrasma  461
Usual squamous cell carcinoma  498
Tinea  461
Anogenital ‘sweat’ glands  441 Subtypes of squamous cell carcinoma  499
Trichosporosis  463
Normal variants   443 Condyloma acuminatum   463 Cloacogenic carcinoma  509
Pigmentation  443 Syphilis  465
Adnexal tumors  510
Circumcision  443 Granuloma inguinale  472
Papillary hidradenoma (mammary-like
Acrochordons  443 Chancroid  474
gland adenoma of the vulva)   510
Pearly penile papules  443 Lymphogranuloma venereum  475
Benign tumors of Bartholin’s gland  511
Vestibular papillomatosis  443 Schistosomiasis  476
Adenoma of minor vestibular glands  512
Sebaceous gland hyperplasia  443 Amebiasis cutis  478
Bartholin’s gland carcinoma  512
Demodecidosis   478
Inflammatory dermatoses  444 Malacoplakia  479 Basal cell carcinoma  512
Intertrigo and balanoposthitis  444 Fournier’s gangrene  479
Non-specific balanoposthitis   444 Metastatic tumors  513
Eczema  445 Miscellaneous conditions  479
Vulvodynia  479
Lymphoma and leukemia  513
Infantile gluteal granuloma  445
Lichen simplex chronicus  445 Idiopathic calcinosis  480 Juvenile xanthogranuloma  513
Seborrheic dermatitis  445 Dermatitis artefacta  480
Sclerosing lipogranuloma  480 Langerhans cell histiocytosis  513
Psoriasis  446
Reiter's syndrome   446 Pilonidal sinus  480 Soft tissue tumors  513
Genital lichen planus  449 Pigmented lesions  481 Keloid  513
Lichen nitidus  452 Genital melanosis  481 Fibroepithelial stromal polyp  513
Lichen sclerosus  452 Genital melanocytic nevi  482 Lymphedematous fibroepithelial
Zoon’s balanitis  456 Melanoma  484 polyp of the glans penis
Zoon’s vulvitis  457 and prepuce  514
Granuloma annulare  457 Epithelial lesions  486 Prepubertal vulval fibroma  515
Vesiculobullous conditions  457 Benign mucinous metaplasia and mucinous Angiomyofibroblastoma  515
Genital papular acantholytic syringometaplasia  486 Aggressive angiomyxoma  516
dyskeratosis  457 Endometriosis and endosalpingiosis  486 Cellular angiofibroma  516
Penile acne  457 Median raphe cyst  486 Genital leiomyoma  517
Hidradenitis suppurative   458 Bartholin duct cyst  487 Leiomyosarcoma  518
Aphthe  459 Mucinous cyst  487 Vulvar leiomyomatosis  518
Lipschutz ulcer  459 Mesonephric cyst  488 Myointimoma  518
Sclerosing lymphangitis of the penis  459 Mesothelial cyst  488 Postoperative spindle-cell nodule  519
Pyoderma gangrenosum  459 Periurethral cyst  488
438 Diseases of the anogenital skin

Introduction 4
1
This section concerns itself principally with dermatological disorders ­specific
to the anogenital skin. Conditions that are properly the preserve of the
­gynecologist (or urologist) are not discussed. 5
Many of the dermatological conditions that present in the skin 2
­elsewhere sometimes affect the anogenital area although this site may
be one of ­predilection. Clinical and histological features can be modified
by the ­chronicity of the problem and the occlusive effect of this natural
6
flexural site.
Over the years, various unsatisfactory classifications have been devised
for vulval disorders.1 Terms such as squamous cell hyperplasia are clinically 3
meaningless and at best histologically descriptive. There is probably no need
1. Glans clitoris
for a separate classification for cutaneous disorders that affect the vulval
2. Labium majus
skin and mucosa. The terminology for vulval intraepithelial neoplasia (VIN) 3. Posterior labial commissure
and penile intraepithelial neoplasia (PIN) are discussed later. Extramammary 4. Prepuce of clitoris Fig. 12.1
Paget’s disease and in situ melanoma are no longer included in the spectrum 5. Labium minus Normal vulva showing the
of VIN. 6. External orifice of urethra major anatomical landmarks.
The anogenital area is covered by both skin and mucous membrane, i.e.,
keratinized and nonkeratinized stratified squamous epithelium. The transi-
tion from skin to mucosa is characterized by a subtle modification in the Labia majora and perianal skin
properties of the epithelia at their junctions. It is therefore critically impor-
tant that the site sampled for histological analysis always be specified so as to Histological features
avoid confusion and misinterpretation. These sites most closely resemble skin from other regions of the body since the
epithelium is keratinized and stratified and adnexal structures are represented.
The epithelium of the labia majora normally contains occasional lymphocytes,
which are found in very small numbers around the superficial dermal vascula-
Normal female anatomy ture. In the labia majora, sebaceous glands are present in association with hair
The vulva comprises the mons pubis, the labia majora and minora, the vesti- follicles and both eccrine and apocrine glands are typically present. On the
bule, the clitoris (including the prepuce and frenulum), the glands of Bartholin medial aspect of the labia majora the hair follicles become modified and there
and Skene, the hymen, posterior commissure, fossa navicularis, introitus and is often no hair seen although sebaceous glands are still present (Fig. 12.2).
the external urethral orifice (Fig. 12.1). Some may open directly onto the epithelium (Fordyce spots, see below). In the
deep dermis, a layer of smooth muscle known as the tunica dartos labialis is
seen. The subcutaneous tissue of the labia majora tends to be prominent in
Histological features women of reproductive age but decreases in amount after the menopause. The
The anogenital region, as with other mucocutaneous sites, is characterized by labia majus contains a long smooth muscle called the cremaster. The skin of
a gradual transition from skin to a mucosal surface. the perianal area shows numerous terminal hairs with sebaceous glands.

Fig. 12.2
(A, B) Normal vulva: medial aspect of labium majus. The
A B epidermis is keratinized. The dermis is richly vascular. Hair
follicles are absent.
 Normal male anatomy 439

Labia minora and clitoral prepuce
Histological features
The labia minora represent the female equivalent of the penile corpus
­spongiosum. They are located lateral to the vaginal vestibule, medial to
the labia majora and are covered by stratified, often pigmented, squamous
­epithelium. In most females, adnexal structures are absent, as is ­subcutaneous
tissue. The stroma is richly vascular and contains abundant erectile tissue and
elastic fibers.
The pilosebaceous unit is incomplete, as the sebaceous gland is not ­usually
associated with a hair follicle and opens directly onto the surface. Sweat
glands are sparse and subcutaneous fat is not seen.
Glans clitoris
Histological features
The epithelium is stratified and keratinized. No adnexal structures are
present. The glans clitoris, unlike its male counterpart, does not ­contain
a corpus spongiosum. The frenulum and the prepuce originate from
the labia minora and contain abundant sebaceous and mucus-secreting
glands.
Vestibule
Histological features
The epithelium is stratified and nonkeratinized, i.e., it is a mucosa (Fig. 12.3).
Both the vagina and the urethra open into the vestibule. Bartholin’s glands
are located deep to the posterior part of the labia majora. They represent the
equivalent of Cowper’s glands or the bulbourethral glands in the male. The
ducts of Bartholin and Skene’s glands and the minor vestibular glands open
into the vestibule
that the penile urethra does possess a true mucosa, while the glans of the
­circumcised male does not; the glans and inner prepuce of the uncircumcised
male probably does not display mucosa but the outer prepuce does. There are
several epithelial transition zones.7 The proximal (pre-prostatic and prostatic)
urethra is lined by transitional epithelium, the membranous spongy penile
urethra by pseudostratified columnar epithelium. The distal penile urethra is
lined by stratified or pseudo-stratified squamous epithelium incorporating a
single layer of columnar cells at the surface and contains Littre’s glands, the
distal 5–6 mm of penile urethra, which includes the navicular fossa ­manifests a
6–10 cell layer of nonkeratinizing squamous epithelium, contains no ­adnexae
and is continuous with the epithelium of the uncircumcised glans (which may
show some thin keratinization, although some accounts state that the glans
is not keratinized in the uncircumcised) and inner preputial epithelium; the
outer preputial epithelium is identical to skin.7 Just as there is wide ­variability
in the size and shape of the navicular fossa, the site of the epithelial transition
zones and probably the degree of keratinization of the glans and the dispo-
sition of adnexa may vary. Presumed multipotential, mucous secreting cells
have been described in the perimeatal epithelium8 and ­mucinous metaplasia
of glans and foreskin have also been observed.9,10 Also, the final ­transition
will depend on the length of the foreskin: it is our ­experience that male genital
lichen sclerosus has a greater predilection for the male with a longer ­foreskin
(as does penile cancer11). The wide spectrum of differentiation of the male
urogenital tract is accompanied by changes in the expression of epithelial
cytokeratins, but this is relatively unexplored territory.12 Normal regional
­histology is illustrated in Figures 12.4–12.9.

Normal male anatomy

The penis, as well as being essential for sexual intercourse, is also the conduit
for urinary excretion. The scrotum is an extracorporeal sac which contains
the testes at an ideal ambient temperature for spermatogenesis. The natal cleft
and the inguinal (crural) folds are special sites of importance because they are
areas where two layers of skin come into close apposition. They constitute the
flexural junctions between the lower limbs and the trunk and also surround
A
the mucocutaneous junctions of the anus and genitalia. The perineum lies
between the anus and the scrotum and the skin at this site is tightly tethered
to the underlying tissues.
The prepuce has been present in primates for at least 65 million years and
indeed this may be an underestimate, 100 million years having been suggested.
The female counterpart is the clitoral hood. Only 4% of boys have a ­retractable
foreskin at birth, 15% at six months, 50% at 1 year and 80–90% at 3 years.1
The separation of the mucosa of the prepuce and glans is usually complete by
17 years.2–4 The prepuce is composed of specialized protective and ­erogenous
tissue. The protection it affords is both physical and immunological.4 Its
­structures (e.g., the penile dartos muscle and the corpuscular ­receptor-rich
ridged band) and secretions are held to be important for normal function. The
foreskin is of variable length and retractability in uncircumcised men.
The anatomical position, when one considers the features of the normal
penis, is that of full penile erection. Thus the dorsal aspect of the penis is the
surface that is in direct contiguity with the abdomen, being the ventral sur-
face of the body.

Histological features
The pattern of keratinization of the epithelium varies throughout the anogen-
ital area most markedly in the transition from true urothelium to true skin.
There is controversy over the definition of ‘mucosa’ 5,6 but there is no doubt
B
Fig. 12.3
Vestibule: (A) the epithelium is nonkeratinizing and rich in glycogen. Cutaneous
appendages are absent at this site; (B) the epithelium is strongly PAS positive.
440 Diseases of the anogenital skin

F
CC
CC
F

CS

S
Fig. 12.6
Normal histology of the penis, balanopreputial sulcus. Histologic components of
Fig. 12.4 both glans and penile body are present. This specimen from a circumcised person
Penis: This transverse section of the human penis shows the arrangement of the shows the mucosa at top, lamina propria below, then dartos, or smooth muscle
erectile tissues, which exist in the form of three columns. The two dorsal columns layer and Buck’s fascia. H&E. Courtesy of and reproduced with permission from
are called the corpora cavernosa CC and the single ventral column is the corpus Sternberg, SS, ed. Histology for Pathologists, 2nd edition. Philadelphia: Lippincott,
spongiosum CS, through which runs the penile urethra U. At its distal end, the Williams and Wilkins, 1997.
corpus spongiosum expands to form the glans penis. The erectile corpora are
enclosed within, and separated by, a fibrocollagenous capsule F. The erectile
centre of the penis is enclosed in a sheath of skin S to which it is connected by a
loose subcutis containing prominent blood vessels. Reproduced with permission
from Young B. et al., Wheater’s Functional Histology, 5th edition. © Churchill
Livingstone, 2006.

Fig. 12.5
Normal histology of the
penis. Foreskin. Full
thickness of prepuce
shows all five layers:
keratinized stratified
squamous epithelium,
dermis with sebaceous
glands, dartos, submucosa
and squamous mucosa.
H&E. Courtesy of
and reproduced with
permission from
Sternberg, SS, ed.
Histology for Pathologists,
2nd edition. Philadelphia:
Lippincott, Williams and
Wilkins, 1997.
Embryology
The anatomical position, the arrangement of all of the structures in the area,
the normal histology and some of the histopathology are explained by the
embryology (Figs 12.10, 12.11).1,2 Around the third week of fetal develop-
ment, mesenchymal cells derived from the primitive streak form ridges of tis-
sue around the cloacal membrane. These cloacal folds are joined anteriorly
Fig. 12.7
Normal histology of the penis. Glans penis. The three layers of glans are noted:
nonkeratinized stratified mucosa, lamina propria and corpus spongiosum. H&E.
Reproduced with permission from Sternberg, SS, ed. Histology for Pathologists,
2nd edition. Philadelphia: Lippincott, Williams and Wilkins, 1997.
and cranially and form the genital tubercle. Posteriorly and caudally, they
are partially joined to form an annulus. The underlying cloacal membrane is
now subdivided into urogenital and anal membranes craniocaudally by about
6 weeks. During the same period, lateral genital swellings develop that will
form either the scrotum or labia majora.
From this point differentiation of the external genitalia occurs in a
­gender-specific manner, driven in the male by fetal testicular androgens. The
­genital tubercle lengthens, creating a urethral groove. This eventually becomes
the urethral canal when the folds fuse at about 12 weeks. The penile urethra
has an epithelium derived therefore from endoderm. It is incomplete ­cranially
where the glans has developed from the genital tubercle. The glandular ­urethra,
the navicular fossa and the meatus are derived from an invading cord of ecto-
derm that eventually becomes canalized. There is wide variability in the size

Fig. 12.8
Anal transitional zone (ATZ). Transition from ATZ epithelium (left) to squamous zone
(right). H&E. Reproduced with permission from Sternberg, SS, ed. Histology for
Pathologists, 2nd edition. Philadelphia: Lippincott, Williams and Wilkins, 1997.
Fig. 12.9
Perianal skin. Keratinized
squamous epithelium and
an underlying apocrine
gland. H&E. Reproduced
with permission from
Sternberg, SS, ed.
Histology for Pathologists,
2nd edition. Philadelphia:
Lippincott, Williams and
Wilkins, 1997.
and shape of the navicular fossa in men, testifying to the variable conse-
quences of this embryological process. The scrotal swellings fuse posteriorly
at about 14 weeks. They are not occupied by the testes until about the time
of birth. The cloacal membrane is where ectodermal and endodermal tissues
are in direct apposition caudally. The separation into urogenital membrane
and anal membrane with the formation of the perineum at about 7 weeks is
due to the separation of the cloacal portion of the hindgut by the urorectal
septum growing caudally between the allantois anteriorly and the hindgut
and partitioning the cloaca into the urogenital sinus anteriorly and the ano-
rectal canal posteriorly. The anal membrane disintegrates at about 9 weeks to
open into an ectodermal anal pit formed in the posterior cloacal (anal) folds.
The prepuce 3,4 is formed by a midline collision of ectoderm, neuroectoderm
and mesenchyme, resulting in a pentalaminar structure consisting of (inner)
Anogenital ‘sweat’ glands 441
Allantois Allantois
Future
bladder
Definitive
urogenital
sinus
Cloaca Rectum Future
pelvic urethra
Fig. 12.10
Development of the primitive urogenital sinus. Between 4 and 6 weeks, the
urorectal septum splits the cloaca into an anterior primitive urogenital sinus and
a posterior rectum. The superior part of the primitive urogenital sinus, continuous
with the allantois, forms the bladder. The constricted pelvic urethra at the base of
the future bladder forms the membranous urethra in females and the membranous
and prostatic urethra in males. The distal expansion of the primitive urogenital
sinus, the definitive urogenital sinus, forms the vestibule of the vagina in females
and the penile urethra in males. From Bunker C: Male Genital Skin Disease.
Saunders Ltd./Elsevier 2004.
squamous mucosal epithelium, lamina propria, dartos muscle, dermis and
glabrous skin (outer). The preputial fold progressively extends but there is
also an ingrowth of a cellular lamella. It then fuses with the mucosa of the
glans. At birth, the prepuce is still developing histologically and it is usually
incompletely separated from the glans.
Pubic hair
Pubic hair appears during puberty as vellus hair that is focally replaced by
terminal hair. Men have a different pattern of pubic hair than women but
in practice it is one of degree. The distribution of hair and pubic hair varies
widely between men.1 Generally, the abdominal wall, pubic mound, groins,
scrotum and perineum are hairy but the natal cleft, perianal skin, distal penile
shaft, prepuce and glans are hairless.
Anogenital ‘sweat’ glands
The anogenital area posseses numerous eccrine and apocrine (some function-
less) sweat glands. Also plentiful are (holocrine) sebaceous glands, usually
in association with hair follicles (pilosebaceous units), but also occurring as
free glands at some sites such as the anal rim or around the coronal sulcus
(Tyson’s glands). Their secretions lubricate the hinge between limb and torso,
hair, mucocutaneous junctions to assist in the voiding of excreta and protect
the epithelia from irritation and the penis for sexual activity (the retraction
of the foreskin).
Anogenital ‘sweat’ glands, which were first described by Van der Putte,
are found in anogenital skin, mainly in the interlabial sulci.1,2 They share
morphological and histological features of eccrine, apocrine and mammary
glands, making categorization difficult (Fig. 12.12). Superficially, an excre-
tory duct opens directly onto the skin. A deeper coiled or a long straight
duct gives rise to several sac-like invaginations forming small glands, which
typically extend deeper than the apocrine or eccrine glands. The anogenital
sweat glands are lined by simple columnar epithelium surrounded by a layer
of myoepithelial cells (Fig. 12.12). It has been suggested that adnexal tumors
arising in the genital skin derive from or show differentiation towards the
anogenital glands and, in a number of cases, lesions are very similar to tumors
occurring in the breast.3,4
442 Diseases of the anogenital skin

Genital
tubercle
Urogenital Urogenital
fold Urogenital membrane
Cloacal membrane
fold Labioscrotal breaks
Cloacal swelling down
membrane Anal Perineum
membrane Anal fold

A 6th week Early 7th week 7th week

6th to 7th week 14th week

Endoderm

Urethral Urethral Urethral Penile

groove plate fold urethra

3rd month

Fig. 12.11
Formation of the external genitalia in males and females. (A) The external genitalia form
a pair of labioscrotal folds, a pair of urogenital folds and an anterior genital tubercle. Male
and female genitalia are morphologically indistinguishable at this stage. (B) In males, the
urogenital folds fuse and the genital tubercle elongates to form the shaft and glans of the
penis. Fusion of the urogenital folds encloses the definite urogenital sinus to form most
of the penile urethra. A small region of the distal urethra is formed by the invagination
Epithelial of ectoderms covering the glans. The labioscrotal folds give rise to the scrotum. From
B invagination Bunker C: Male Genital Skin Disease. Saunders Ltd./Elsevier 2004.

A B

Fig. 12.12
Anogenital mammary-like glands. (A) Medium-power view showing glands with focal cystic dilatation; (B) high-power view showing a double layered cell wall. Focally, there
is a suggestion of apocrine differentiation. By courtesy of D Kazakov, Charles University Medical Faculty Hospital, Pilsen, Czech Republic.
 Normal Variants 443

Normal Variants
Pigmentation
The commonest variation is constitutive pigmentation due to race.
­Sun-induced facultative pigmentation is rarely relevant in the genital area, but
­postinflammatory hyperpigmentation is common. Linear hyperpigmentation
of the ventral penile shaft, along the median raphe, is often seen.

Circumcision
The commonest variation is the presence or absence of the foreskin.
Circumcision is the oldest elective operation, with evidence of its prac-
tice in Ancient Egypt between 2400 and 3000 bc.1 The operation has been
­performed for religious, cultural or medical reasons throughout history.2 It
has been ­estimated that globally 25% of men have been circumcised.3 The
prevalence of circumcision in any population reflects racial, religious, cultural
and ­medical differences. The risks and benefits of neonatal circumcision have
been the focus of much debate.4–6 Importantly, circumcision protects men from Fig. 12.13
cancer of the penis, urinary tract and sexually transmitted ­infections includ- Pearly penile papules. Glans penis, coronal rim. From Bunker C: Male Genital Skin
ing HIV and genital dermatoses.7 However, the incidence of penile ­cancer is Disease. Saunders Ltd./Elsevier 2004.
low in Japan and Denmark where circumcision is rare,8 and ­therefore other
factors are important in its pathogenesis .
Circumcision is indispensible in the management of diseases of the penis
Vestibular papillomatosis
and foreskin, including dermatological conditions, and is being investigated
for the control of HIV infection. Although the long-held consensus is that Clinical features
there is little evidence of significant adverse effects on health, including Vestibular papillomatosis is not due to human papillomavirus infection and
­psychosexual function, circumcision does have side effects and complications is a common finding of no significance.1,2 It is asymptomatic and is the female
including bleeding, postoperative and other infections, adhesions, fistulae and equivalent of penile pearly papules (hirsutoid papillomas). Individual lesions
keloid.5 are dome shaped or filiform and arise on a solitary base. They are found on
the inner aspect of the labia minora and vestibule (Fig. 12.14).
Acrochordons Histological features
There is a normal or thickened epidermis overlying a central fibrovascular core.
Clinical features
Skin tags (acrochordons) are common in the groins, especially in the obese.
They may catch on clothing, bleed and get infected. Fibrosed hemorrhoids
Sebaceous gland hyperplasia
can result in perianal skin tags, but larger, fleshier, more edematous skin
tags should arouse the suspicion of Crohn’s disease: they can predate
Clinical features
gastrointestinal disease by several years.1 These lesions are particularly The sebaceous glands of the inner labia majora, the labia minora and clito-
­relevant in young patients with diarrhea, abdominal pain and/or growth ral prepuce do not usually have an associated hair follicle. The glands open
retardation.1 directly onto the surface and may be very prominent and numerous at these

Histological features
The histology of a skin tag at this site is identical to that of those occurring
elsewhere. The presence of granulomata in anal skin tags is often a clue to the
diagnosis of Crohn’s disease.2

Pearly penile papules

Clinical features
Pearly/pink penile papules1 may be found in 15–50% of men.2–5 They ­manifest
as flesh-colored, smooth, rounded papules (1–3 mm) occurring predomi-
nantly around the coronal margin of the glans, rarely on the glans. Often
there are rows or rings of papules (Fig.  12.13). Ectopic lesions, for exam-
ple on the penile shaft, have been reported,6 including in children.7 They are
frequently mistaken for warts and Tyson’s or ectopic sebaceous glands. The
lesion is analogous to other acral angiofibromas such as adenoma sebaceum,
­subungual and periungual fibromas, fibrous papule of the nose, acquired acral
angiofibroma and oral fibroma. These lesions may regress with ­circumcision
and old age.8
Fig. 12.14
Vulval papillomatosis: numerous pale papillomata are present in the vestibule and
Histological features on the labia minora. These are a normal finding and are particularly common in
The histology is that of angiofibroma.9 HPV DNA is absent.10,11 pregnancy. By courtesy of the Institute of Dermatology, London, UK.
444 Diseases of the anogenital skin
sites. The yellow uniform papules (Fordyce spots) are often seen best if the
skin is stretched (Fig.  12.15). Sebaceous gland hyperplasia may sometime
be associated with pruritus and pain if they enlarge and the contents rupture
into the dermis.
In the male, sebaceous gland prominence, Tyson’s glands, sebaceous
hyperplasia and ectopic sebaceous glands (Fordyce’s condition) are all virtu-
ally synonymous and are common, normal variants of the skin of the scrotal
sac and penile shaft (very rarely the glans) but may cause concern to patients
even amounting to dysmorphophobia (Fig. 12.16).1, 2
Histological features
One or more enlarged sebaceous glands, each composed of numerous
lobules, surround a central duct that opens directly into the epidermis
(Fig. 12.17).
Inflammatory dermatoses
Intertrigo and balanoposthitis
Clinical features
These are non-specific terms.1 Intertrigo is the name given to any dermato-
sis occurring in skin folds: any scale is usually rapidly removed by frictional
abrasion, and a degree of epithelial loss may result in erosion that renders
the site especially susceptible to secondary infection, e.g., with Candida
(see below).
Balanitis denotes inflammation of the glans penis while posthitis is inflam-
mation of the prepuce. Balanoposthitis means inflammation of the glans and
prepuce and is regarded as a special form of intertrigo. By definition, there-
fore, balanoposthitis cannot occur in the circumcised male, but balanitis
might.
Fig. 12.15 Fig. 12.16
Fordyce spots: hyperplastic sebaceous glands Sebaceous hyperplasia (Fordyce’s condition). Penis,
presenting as conspicuous yellow papules. Similar prepuce. From Bunker C: Male Genital Skin Disease.
lesions may be seen on the inner lip and oral Saunders Ltd./Elsevier 2004.
mucosa. By courtesy of the Institute of Dermatology,
London, UK.
Pathogenesis and histological features
Generally, dermatologists feel that balanitis, posthitis and balanoposthitis
are probably more commonly due to inflammatory and precancerous derma-
toses, while genitourinary physicians teach that most cases are due to infec-
tion, usually with Candida.1 However, Candida is a ready opportunist so
its presence may not always indicate primary infection as the cause of the
genital inflammation. Bacteria have increasingly been implicated in the eti-
ology of the ­disease, particularly Staphylococcus aureus.2 In cases in which
Streptococcus pyogenes is isolated it has been suggested that the ­disease
may be sexually transmitted by penile–oral intercourse.3 Diabetes may be an
important predisposing factor to Candida and other infective causes or com-
plications of balanoposthitis.1
The histological features are non-specific.
Non-specific balanoposthitis
Clinical experience and histological evidence indicate that non-specific
balanoposthitis is a real entity.1–3 However, in practice it is a diagnosis of
exclusion, because sexually transmitted diseases, eczematous dermatoses,
psoriasis, Zoon’s balanitis, lichen planus, lichen sclerosus, mucous membrane
pemphigoid and penile carcinoma in situ must be excluded. Non-specific
balanoposthitis is a manifestation of a dysfunctional foreskin. Patients
generally complain of pain during intercourse and may have variable signs,
including eczematous, lichenoid and Zoonoid inflammation, and even
scarring. Candida and other organisms can be identified, but they probably
represent opportunistic infection. Diabetes should be excluded. In severe
cases, medical treatments fail and the only cure is by circumcision. A prior
clinical diagnosis may be reversed at this stage by foreskin histology showing
lichen sclerosus, lichen planus or carcinoma in situ. However, experience
shows that even where the most thorough histological examination of the
excised prepuce is undertaken, nothing more than non-specific chronic
­inflammation is found.
Fig. 12.17
Fordyce spot: this small sebaceous gland can be
seen communicating directly with the epidermis.

Eczema
Clinical features
Seborrheic dermatitis is the commonest form of eczema affecting anogenital
skin, followed by irritant contact eczema. Eczema, particularly ­seborrheic
dermatitis, is more common than many other inflammatory dermatoses in
uncircumcised males.1 Allergic contact eczema is rare at genital sites and
occurs more typically in a perianal distribution. Involvement of genital skin
with atopic eczema is very uncommon.
In infants, eczematous reactions are often seen in the napkin area. Most
of these represent a primary irritant dermatitis. Seborrheic dermatitis and a
psoriasiform napkin rash can also occur. Some but not all of the patients with
the latter condition develop psoriasis later in life.2
Histological features
The histological features are identical to those seen in eczema affecting other
areas of the skin. Psoriasiform napkin rash shows histological features that
overlap with psoriasis.
Infantile gluteal granuloma
Clinical features
Infantile gluteal granuloma (papuloerosive dermatitis of Jacquet and Sevestre)
is a rare condition that has been described mainly in the newborn and infants
in the napkin area. It frequently develops in a background of an irritant nap-
kin rash.1–4 A similar condition has been described in incontinent elderly
women with lesions developing on the labia majora (Fig. 12.18).5–7 Oval or
round papulonodular lesions present on the convex areas of the perineum,
which are in direct contact with the napkin or incontinence pad. They tend to
regress spontaneously over a few weeks and occasionally leave scars.
Pathogenesis and histological features
The etiology of the process is unclear but occlusion, Candida infection and
fluorinated corticosteroids have been implicated. The last, however, does not
seem to be of importance in the incontinent elderly patient.
The histology is fairly non-specific and includes superficial ulceration,
focal necrosis and a prominent mixed inflammatory cell infiltrate with
Fig. 12.18
Papuloerosive dermatitis:
there are multiple
ulcerated papules and
nodules predominantly
affecting the labia majora.
By courtesy of the
Institute of Dermatology,
London, UK.
Inflammatory dermatoses 445
g­ ranulomata and numerous lymphocytes and plasma cells. Hemorrhage and
hemosiderin deposition can sometimes be present.
Differential diagnosis
In the elderly variant and, when appropriate, Crohn’s disease and infective
granulomatous conditions may have to be excluded
Lichen simplex chronicus
Clinical features
The clinical features of lichen simplex chronicus presenting on genital and
anal skin are identical to those seen at other sites of the body. The mons pubis
or labium majus, scrotum and perianal skin are the usual sites affected. Giant
forms (of Pautrier) occur, e.g., on the scrotum, giving a pineapple appearance
(Fig. 12.19).
Histological features
The histological features are discussed in detail elsewhere but lichenifica-
tion is characterized by hyperkeratosis, hypergranulosis, uniform acanthosis,
fibrosis of the papillary dermis and an unremarkable low-grade perivascular
infiltrate of mononuclear leukocytes in the superficial dermis. At mucosal
sites hyper- and orthokeratosis create a cornified layer, resulting in the ­clinical
appearances of leukoplakia.
Seborrheic dermatitis
Clinical features
Seborrheic dermatitis is a very common pattern of eczematous disease
a­ ssociated with an abnormal hypersensitivity to the normal commensal
cutaneous yeast, Pityrosporum ovale. It is discussed elsewhere. In addition
to the classical sites, e.g., scalp (pityriasis capitis, dandruff), ears, glabella
and brows, nasolabial folds, axillae, chest and back, the groin and penis
can be involved. Indeed, this may be the sole site, leading to the patient
presenting, with pruritus ani or balanoposthitis, to a dermatologist. Some
patients may also have a tendency to psoriasis (‘sebopsoriasis,’ ‘seboriasis’).
On the scalp, on the face, in the flexures and at anogenital sites, seborrheic
dermatitis and psoriasis may be indistinguishable. Seborrheic dermatitis is
very common in HIV infection. Diagnosis is achieved on clinical grounds
and it is not usually necessary to do a biopsy. Pityrosporum spp will be seen
in large numbers.
Histology is identical to seborrheic dermatitis occurring elsewhere.
However, spongiosis can be more prominent.
Fig. 12.19
Lichen simplex chronicus. Scrotum. Giant ‘pineapple’ lesion. From Bunker C: Male
Genital Skin Disease. Saunders Ltd./Elsevier 2004.
446 Diseases of the anogenital skin

Psoriasis
Clinical features
Flexural psoriasis is the most common pattern seen in the anogenital region,
with extension into the genitocrural folds and natal cleft (Figs 12.20–12.23).
There are often difficulties clinically in distinguishing between psoriasis
and seborrheic dermatitis. Genital and flexural disease may reflect koeb-
nerization and is relatively common.1 In the circumcised male the signs
on the glans and distal penile shaft are similar to those of psoriasis at
extragenital sites, whereas the appearances in the ­uncircumcised male are
of balanoposthitis similar to flexural psoriasis.2

Histological features
Histology is often unhelpful, as the changes can be quite non-specific. The
typical features of psoriasis are rarely evident and the presence of secondary
spongiosis may be very misleading.

Fig. 12.22
Psoriasis: in this example a slight scale is apparent. By courtesy of the Institute of
Dermatology, London, UK.

Fig. 12.20
Psoriasis: note the symmetrical, intensely erythematous eruption involving the
groins, vulva and perineum. Scaling is typically absent in flexural disease. The sharply
demarcated border is characteristic. By courtesy of the Institute of Dermatology,
London, UK.

Fig. 12.23
Psoriasis: note the
erythematous and slightly
scaly plaque affecting the
perineum. By courtesy
of the Institute of
Dermatology, London, UK.

Reiter’s syndrome
Clinical features
Reiter’s disease or syndrome is part of the same continuum as psoriasis in
genetically predisposed individuals.1 Reiter’s syndrome is defined by the triad
of arthritis, urethritis and conjunctivitis. The eponym is gradually ­losing favor
in the face of more descriptive nomenclature and the term reactive arthritis is
frequently used. It is precipitated by non-specific urethritis, bacillary or ­amebic
dysentery and associated with HIV infection and the ­immunogenotype HLA
B27.2–6 The classical triad may occur together or develop in sequence, and a
range of other symptoms may also be present. It has a ­worldwide ­distribution.
Fig. 12.21 Reiter’s syndrome most commonly affects men 20–30 years of age; the male
Psoriasis: there are erythematous plaques on the glans penis. By courtesy of the to female sex ratio is approximately 10:1.1 The syndrome is characterized by
Institute of Dermatology, London, UK. a relapsing course.4

The condition may follow an enteric or a urogenital infection.7,8 Shigella
dysentery was the first associated enteric infection to be recognized and the
causative organisms were either Shigella flexneri or S. dysenteriae.9 Recently,
Salmonella, Yersinia and Campylobacter have been reported preceding
Reiter’s syndrome.10–14
Sexually transmitted Reiter’s syndrome may occur with a nongonococ-
cal or ‘non-specific’ urethritis.7 Chlamydia trachomatis is isolated from the
genitourinary tract in 40–60% of male cases; isolation is ­variable, ­however,
and an indirect immunofluorescence test detects chlamydial infection in
90% of patients.15,16 Mycoplasma infection and Streptococcus ­viridans
have also been implicated.17–19 The condition has also been linked to the
acquired immunodeficiency syndrome (AIDS).20–22 Rare associations include
Cyclospora, Cryptosporidium, intravesical bacillus Calmette-Guérin (BCG)
­immunotherapy, Gardnerella vaginalis, hepatitis B immunization and ­systemic
interferon-alpha (IFN-α) treatment.23–28
Reiter’s syndrome is more likely to occur in predisposed individuals.
Human leukocyte antigen (HLA)-B27, which is thought to occur in up to
90% of patients, increases the risk of developing Reiter’s syndrome by 25
times; the disease is also more severe in HLA-B27-positive individuals.4,29
HLA-B27 in patients with Reiter’s syndrome correlates with ankylosing spon-
dylitis.4 Reiter’s syndrome develops in 20% of HLA-B27-positive individuals
after a specific infective episode.30 HLA-B27 is found in approximately 10%
of the normal population. Recently, an association with HLA-B51 has been
reported.31 Rarely, familial instances have been documented.30 Therefore it
appears that the disease is triggered in genetically predisposed individuals by
an unknown mechanism precipitated by infection.
The genitourinary tract is virtually always involved in the form of urethri-
tis, prostatitis, seminal vesiculitis and hemorrhagic cystitis. Urethral strictures
also sometimes occur and females may develop cervicitis.
Bilateral mucopurulent conjunctivitis is the usual form of eye involvement
occurring in up to 35% of patients, but occasionally iritis, iridocyclitis, kera-
titis or blindness occurs.32
Weight-bearing joints and the larger ones (knees, ankles, feet and wrists)
are involved by the arthritis, often together with sacroiliitis. Radiological
Fig. 12.24 Fig. 12.25
Reiter’s syndrome: there are bilateral keratotic Reiter’s syndrome: in addition to keratotic papules
papules and plaques affecting the soles of the feet. there are pustular lesions, many of which have
By courtesy of R.A. Marsden, MD, St George’s ruptured – keratoderma blenorrhagicum. By courtesy
Hospital, London, UK of the Institute of Dermatology, London, UK.
Inflammatory dermatoses 447
changes include osteoporosis, erosions and loss of joint space, with multiple
joints usually affected.4,30 Periostitis often affects the metatarsals, the pha-
langes of the feet and the tarsal bones; occasionally, ankylosis develops in
the small bones of the hands and feet. Ankylosing spondylitis, which is an
important manifestation, correlates with a high erythrocyte sedimentation
rate (ESR).30
In the initial stages of the arthritis the clinical picture resembles that of an
acute joint infection, settling to subacute involvement. Although the arthritis
in Reiter’s syndrome usually recovers completely, chronic manifestations can
sometimes occur; it is important to remember that arthritis may be the only
symptom in recurrent episodes.
Skin lesions in Reiter’s syndrome may be similar to those of psoriasis.
Cutaneous manifestations include hyperkeratotic cobblestone lesions on
the palms and soles and occasionally affecting the trunk and extremities
(Fig. 12.24). The lesions initially present as erythematous macules; over the
course of several days these become hyperkeratotic waxy papules, with an
erythematous halo covered by dry hyperkeratotic material. The papules are
numerous and eventually coalesce to form thickened horny plaques. Pustular
lesions of the palms and soles may also be evident (keratoderma blenorrhagi-
cum) (Fig. 12.25).
Circinate balanitis, presenting as a moist superficial erosion, 2–4 mm
across, may affect the glans penis and meatus (Figs 12.26–12.28). Superficial
ulceration of the oral mucosa may also occur, together with reddening and a
granular appearance of the surrounding mucous membrane.4,5
Stomatitis and nail dystrophy (indistinguishable from that of psoriasis)
may be additional features.4 Weight loss is common.20 Aortic incompetence is
an important late complication and IgA nephropathy has been described in a
number of patients.4,33
As stated before, Reiter’s syndrome is very rarely reported in females, and
the majority of cases recognized are in males.34–38 Vulvitis has been described
in a small number of case reports.34–38 and in one case cervical lesions were
seen.37 The vulval lesions are erythematous and may be ulcerative, eroded or
scaly, and often resemble mucocutaneous candidiasis. The cervical lesions
were recorded as white papules.37 There may be accompanying oral lesions.
Fig. 12.26
Circinate balanitis. Glans penis. Psoriasiform lesions.
From Bunker C: Male Genital Skin Disease. Saunders
Ltd./Elsevier 2004.
448 Diseases of the anogenital skin
Fig. 12.27
Reiter’s syndrome: there
are multiple erosions
on the glans penis. By
courtesy of The Institute of
Dermatology, London, UK.
Fig. 12.28
Reiter’s syndrome: in this
patient there are scaly
lesions on the glans penis.
By courtesy of the
Institute of Dermatology,
London, UK.
Reiter’s syndrome may resolve spontaneously, but more often it is
c­ haracterized by chronicity and recurrences.4 Rarely, it may prove fatal.4
Causes of death include aortic incompetence, atrioventricular block, terminal
cachexia, systemic amyloidosis and iatrogenic effects.39
Histological features
Essentially, just as the skin lesions of Reiter’s syndrome have psorias-
iform ­morphology (Fig.  12.29), they have the same histopathology and
­ultrastructure as pustular psoriasis.40
The epidermis is acanthotic with elongation and hypertrophy of the epider-
mal ridges and parakeratosis. The suprapapillary plates are thinned and there
Fig. 12.29
Reiter’s syndrome: there is parakeratosis overlying a macropustule. The squamous
epithelium shows psoriasiform hyperplasia. These features are indistinguishable
from pustular psoriasis.
Fig. 12.30
Reiter’s syndrome: high-power view showing parakeratosis and a pustule.
is infiltration of the epidermis by neutrophils, associated with vacuolation of
superficial keratinocytes, together with the formation of spongiform pustules
and microabscesses (Fig.  12.30). The inflammation extends into the adja-
cent underlying dermis where it is predominantly mononuclear. The histol-
ogy is essentially identical to that seen in pustular psoriasis.2 Therefore, close
clinicopathological correlation is critical to establish a diagnosis. Occasional
biopsies from typical lesions of patients with Reiter’s syndrome may disclose
an underlying leukocytoclastic vasculitis.41
A small number of patients presenting with skin lesions that histologi-
cally showed sterile neutrophilic folliculitis with perifollicular vasculopathy
have been documented.42 The authors suggested that this histological ­pattern
may be a marker of systemic disease. Associations may include Reiter’s
­syndrome, inflammatory bowel disease, Behçet’s disease, hepatitis B ­infection,
­scrofuloderma, connective tissue diseases and hematological dyscrasias.
Patients present with systemic symptoms and variable skin lesions ­including
folliculitis, vasculitis, acneiform eruptions, vesiculopustules and erythema
nodosum-like features.
Early joint lesions are characterized by a neutrophil polymorph inflam-
matory cell infiltrate with little if any synovial changes. Older lesions show
features suggestive of rheumatoid arthritis, including lymphoid aggregates, a
perivascular chronic inflammatory cell infiltrate and synovial hyperplasia.30

Differential diagnosis
Periodic acid-Schiff (PAS) and/or silver stains should always be ­performed
to exclude a fungal infection which can show similar histological
features.
Genital lichen planus
Clinical features
Anogenital lesions may be found in up to 40% of patients with generalized
disease. In some, however, the disease is restricted to the lower genital tract
and/or the perianal region, and in these instances the diagnosis may be dif-
ficult to establish.1,2 Lichen planus (LP) manifests the Koebner phenomenon
which may partly explain the orogenital predilection.3 Genital lichen planus
in children is exceptional.4
The lesions are typical, violaceous or white patches or areas of erythema
and erosions. Wickham’s striae (frequently seen in oral involvement), although
sometimes visible, are less often found on anogenital skin (Fig. 12.31). The
erosive form of LP is commoner at anogenital sites and can lead to scarring
and distortion of the architecture (Figs 12.32–12.34). The vulval vestibule
and vagina and cervix may also be involved and sometimes the vagina and or
the cervix are affected alone.5–7 Perianal disease can lead to deep, painful fis-
suring and it is often the hypertrophic variant that involves this site. Women
with oral lichen planus often have genital disease and they frequently have
asymptomatic lesions.8,9
The clinical variants of lichen planus affecting the anogenital skin are usu-
ally squamopapular with areas of erosion, hypertrophic and hyperpigmented
flexural disease (Figs 12.35–12.39). In the male genital, LP can present as
phimosis.10,11 Adhesions are seen in the uncircumcised male, both transcoro-
nal and subcoronal.
There is also an unusual variant of erosive LP in women that involves
the oral gingivae, vulval vestibule and vagina, known as the vulvovaginal-
­gingival syndrome (Figs 12.40–12.42).12,13 This can lead to severe ­vulval
and vaginal scarring with vaginal adhesions, constriction bands and, in some
cases, ­complete stenosis.14 A male equivalent to the ­vulvo-vaginal syndrome
Fig. 12.31 Fig. 12.32
Lichen planus: perineal lesions showing conspicuous Erosive lichen planus: bilateral erosions are present.
striae. By courtesy of the Institute of Dermatology, By courtesy of the Institute of Dermatology,
London, UK. London, UK.
Inflammatory dermatoses 449
of Hewitt with chronic erosive gingival and genital lesions ­(genito-gingival
syndrome) has been described.15,16 Patients with genital lesions may have
anal, oral, aural, conjunctival and esophageal ­involvement.17–24 Those
patients with predominantly mucosal disease clinically mimic mucous
membrane pemphigoid but immunofluorescence studies are invariably
negative. A case of paraneoplastic lichen planus with orogenital involve-
ment and cicatrizing conjunctivitis in association with thymoma has been
described.25
Lichen planopilaris has also been described on the vulva.26
Anogenital lichen planus carries a small increased risk of malignancy, usu-
ally squamous cell carcinoma (SCC) (Fig.  12.43).27–30 Hypertrophic lichen
planus of the glans penis should be regarded as having potential sinister bio-
logical behavior.28,31
Pathogenesis and histological features
Studies of oral LP have supported an immunological basis with activated­
T cell to an unidentified antigenic stimulus.32 The histological features of
anogenital lichen planus are often more difficult to recognize than those of
LP presenting on nonmucosal surfaces. The epidermis may be effaced or
thickened and there is a dense, band-like infiltrate hugging the dermoepider-
mal junction (Fig. 12.44). Many genital lesions are mucosal and the inflam-
matory cell infiltrate is often rich in plasma cells, in contrast with lesions of LP
at other sites where lymphocytes and histiocytes predominate (Fig. 12.45).
The basal layer is often disrupted with some cytological atypia as regen-
eration takes place. Cytoid bodies may be seen but tend not to be promi-
nent. Sometimes there is focal accentuation of the granular zone of mucous
membrane lesions. This is accompanied by parakeratosis. Focal secondary
spongiotic changes are not uncommon, particularly in mucosal surfaces.
In longstanding disease the dense, band-like infiltrate may be replaced by
a patchy, scant infiltrate with small foci of lichenoid inflammation. Many
cases of male genital lichen planus are misdiagnosed as Zoon’s dermatitis or
lichen sclerosus.
Immunofluorescence studies may show fibrinogen and IgM along the
basement membrane zone and more rarely IgG or IgA.19 Cytoid bodies may
also be labeled.33
Fig. 12.33
Erosive lichen planus: there is extensive erosion
of the glans penis. By courtesy of the Institute of
Dermatology, London, UK.
450 Diseases of the anogenital skin

Fig. 12.34 Fig. 12.35 Fig. 12.36

Vulval lichen planus: reticulated lesions of lichen Vulval lichen planus: in this example of resolving Perineal lichen planus: typical papules with
planus extending into the perineum. By courtesy of disease there are linear hyperpigmented lesions. Wickham’s striae are present. By courtesy of the
the Institute of Dermatology, London, UK. By courtesy of the Institute of Dermatology, Institute of Dermatology, London, UK.
London, UK.

Fig. 12.37 Fig. 12.38 Fig. 12.39

Hypertrophic perianal lichen planus: chronic scratching Penile lichen planus: there is involvement of the Penile lichen planus: the proximal shaft shows post
has resulted in superimposed lichenification. By shaft and glans. From Bunker C: Male Genital Skin inflammatory hyperpigmentation. From Bunker C: Male
courtesy of the Institute of Dermatology, London, UK. Disease. Saunders Ltd./Elsevier 2004. Genital Skin Disease. Saunders Ltd./Elsevier 2004.
 Inflammatory dermatoses 451

Fig. 12.40 Fig. 12.43
Vulvovaginal-gingival syndrome: there is extensive vestibular erythema and erosion with a Lichen planus: chronic penile lesion complicated by an ulcerated squamous cell
surrounding delicate white scale. By courtesy of the Institute of Dermatology, London, UK. carcinoma. By courtesy of the Institute of Dermatology, London, UK.

Fig. 12.41
Vulvovaginal-gingival syndrome: there is ulceration of the vagina and cervix.
By courtesy of the Institute of Dermatology, London, UK.
Fig. 12.44
Lichen planus: there is hyperkeratosis, acanthosis and a band-like inflammatory cell
infiltrate.

Differential diagnosis
The clinical differential diagnosis includes psoriasis, Zoon’s balanitis in the
male, lichen sclerosus, viral warts, bowenoid papulosis and porokerato-
sis. Lichen planus is in the differential diagnosis of pruritus ani. A biopsy is
­frequently necessary for diagnostic purposes but is more importantly done
in the follow-up of the rare cases of chronic anogenital disease where the
development of ulcero-erosive or verrucous features leads to concern about
the development of squamous cell carcinoma. Lichen planus often overlaps
with the features of lichen sclerosus, and in some patients the two disorders
may coexist. Hyalinization of the papillary dermis or the superficial lamina
propria is indicative of the latter condition. In patients suffering from such
a chronic overlap syndrome, particular care should be taken to recognize
­dysplastic areas or SCC.
Fig. 12.42 Sometimes drugs can precipitate a generalized lichenoid eruption. A case
Vulvovaginal-gingival syndrome: note the intense erythema with erosion of the of a lichenoid drug eruption confined to the penis due to propranolol has
gum. By courtesy of the Institute of Dermatology, London, UK. been reported.34
452 Diseases of the anogenital skin

There are two peaks of incidence; in females there is one in the premenar-
chal years and the other in the menopause, and in prepubertal and young to
middle-aged adult males. When the disease arises in childhood it tends to per-
sist, regression being uncommon.5 In girls, the condition can present at a very
early age with hemorrhagic perianal lesions (Figs 12.46, 12.47). Constipation
can occur as a complication of the painful fissuring of the anal canal. If there
is marked anogenital involvement, the condition may be mistaken for sexual
abuse.2 Perianal disease does not occur in males but in boys genital LS is
the most common cause of phimosis. Extragenital lesions occur in 11% of
women with genital lichen sclerosus.6 Such involvement occurs on the upper

Fig. 12.45
Lichen planus: (A) note
the hyperkeratosis,
hypergranulosis and
basal cell hydropic
degeneration; (B) in
contrast to cutaneous
disease, plasma cells as
shown in this field are
A often present in genital
lesions.

Fig. 12.46
Lichen sclerosus: severe
bilateral and symmetrical
disease with atrophy and
virtual loss of the labia
minora. Vulval lesions
are intensely pruritic. By
courtesy of the Institute of
Dermatology, London, UK.

Lichen nitidus
Clinical features
This disease has an affinity for the penis.1 It can be difficult to diagnose
because the signs may be subtle even when the lesions are widespread, and
when itchy the signs due to excoriation and eczematization may eclipse those
due to the lichen nitidus.

Histological features
Histologically, the appearances are the same as lichen nitidus occurring
elsewhere.

Lichen sclerosus Fig. 12.47

Lichen sclerosus: perianal
Clinical features disease is often present
in addition to vulval
Lichen sclerosus (LS) is a lymphocyte mediated dermatosis of unknown eti- involvement, giving rise
ology.1–3 It has a predilection for the anogenital skin in women and genital to the so-called hourglass
skin in men. Women are more frequently affected than men (10:1) and it is distribution. By courtesy
more common in white than nonwhite patients. It almost never affects men of the Institute of
circumcised at birth.4 Dermatology, London, UK.

trunk, groins, upper extremities, neck, lower trunk and lower extremities in
decreasing order of frequency (Figs 12.48, 12.49). Involvement of the scalp
and face is rare and can be associated with alopecia.7–9 An exceptional case
with plantar involvement has been documented.10 Extragenital lesions may
occur in the absence of genital lesions. The Koebner phenomenon is frequent
and LS has been described in association with scars, at the sites of radio-
therapy, and insulin injection and in association with a tattoo.11–14 Lesions
can also develop or recur in skin or myocutaneous grafts.15 Oral involvement
including lip lesions as an isolated phenomenon or in association with genital
lesions has been described.16–18 The exact incidence of the latter is unknown,
as suspected cases are not often confirmed by histological examination.19
Lichen planus can coexist with LS and this may account for some of the
oral lesions.20 Coexistence of LS with morphea has also been documented.21
A single case of multiple genital and extragenital lesions in a patient receiving
imatinib mesylate has been reported.22 A further case in association with allo-
geneic stem cell transplantation and another of genital disease developing in
scrotal skin used in a case of male-to-female gender reassignment have been
documented.23,24
The typical lesions of LS are porcelain-white papules and plaques with a
crinkled surface. They can coalesce to form plaques. There are often associ-
ated ecchymoses and areas of hyperkeratosis. The latter occurs in relation to
the appendage ostia, which are dilated, giving rise to the physical sign of del-
ling. Bullae only rarely occur. Common symptoms in women include pruritus,
burning and dyspareunia, and in men coital and urinary ­difficulties. Although
anogenital LS is intensely pruritic, lichenification is often not conspicuous.
Female anogenital involvement is typically symmetrical and bilateral, and is
described as having a figure-of-eight (hourglass) distribution when it affects
the perianal as well as vulval skin. In men the involvement is ­‘tulip-like’
­symmetrically affecting the distal penile shaft, glans and foreskin (not the peri-
anal skin) (Fig.  12.50). On the other hand, the presentation may be with
complete phimosis (Fig.  12.51). Lesions on the vulva predominantly affect
the inner aspect of the labia majora, the labia minora, the prepuce of the
­clitoris, the fossa navicularis and the posterior commissure (Figs 12.52, 12.53).
Fig. 12.48 Fig. 12.49
Lichen sclerosus: irregular white plaque. It should be Lichen sclerosus: healing lesion with a typical
noted that extragenital lesions sometimes occur in ‘wrinkled tissue paper’ appearance. By courtesy
the absence of genital lesions. By courtesy of R.A. of R.A. Marsden, MD, St George’s Hospital,
Marsden, MD, St George’s Hospital, London, UK. London, UK.
Inflammatory dermatoses 453
Penile disease can affect the glans, and distal foreskin, the frenulum and ven-
tral ­subcoronal sulcus is a particular target. Lichen sclerosus is a scarring dis-
order and in women there may be marked anatomical changes with loss of
the labia minora, burying of the clitoris, and ­urethral perimeatal stenosis. The
vagina is unaffected. Urethral involvement is very rare.25 In men there may be
complete phimosis, constrictive posthitis due to a sclerotic band (‘waisting’),
transcoronal and subcoronal adhesions, erosion, ulceration and destruction
or obliteration of the frenulum, effacement of the coronal sulcal architecture
and definition (e.g., loss of pearly penile papules), meatal ‘pin hole’ narrow-
ing. The involvement of the anterior urethra can be serious: 29% of patients
undergoing urethroplasty for urethral stricture had pathological evidence of
lichen sclerosus.
In a single case of vulval LS in a child, a melanoma developed later.26
An important complication of genital LS is the development of dysplasia
and SCC. The latter only very exceptionally has been reported in association
with extragenital lesions.27 In the vulva (Figs 12.54, 12.55), dysplastic foci
may appear as hyperkeratotic adherent, gray–white areas, ice pick ­erosions or
fixed areas of erythema.3 Such changes must be examined histologically. Less
than 4% of patients with vulval LS will develop a squamous cell carcinoma.3
It has recently been shown that an important number of cases diagnosed
as lichen sclerosus with progression to squamous cell carcinoma actually
represent differentiated vulvar intraepithelial neoplasia and not lichen scle-
rosus.28 The main reason for the high number of misdiagnosed cases is prob-
ably the difficulty in diagnosing differentiated vulval neoplasia on histologic
grounds. These patients tend to have a more rapid progression to invasive
squamous cell carcinoma. In the group of patients with true lichen sclerosus
and ­progression, a number of histologic features are seen which are absent
in cases without progression. It has been suggested that these criteria can
be used to identify patients at risk. They include parakeratosis, dyskerato-
sis, hyperplasia and basal cell atypia.28 In the male, the published risk of
SCC complicating LS is between 4% and 8%.29–32 When excision specimens
of penile squamous cell carcinoma are examined, lichen sclerosus has been
found in between 32% and 50% of cases.32–34 The type of penile squamous
Fig. 12.50
Lichen sclerosus: in males, lesions of the foreskin
and glans may be complicated by urethral stricture
(so-called balanitis xerotica obliterans). By courtesy
of the Institute of Dermatology, London, UK.
454 Diseases of the anogenital skin

of patients, suggesting that a number of cases have a genetic component.40

Fig. 12.51
Lichen sclerosus: a more advanced case showing severe phimosis. By courtesy of
the Institute of Dermatology, London, UK.
cell ­carcinoma associated with lichen sclerosus is not usually associated with
HPV.35 Chronicity, asymmetry, erythema, zoonoid or erythroplasia, erosions,
ulcers and verrucous change must be regarded with a very high index of
­suspicion and a low threshold for biopsy.
Pathogenesis and histological features
The etiology of LS is unknown. It has been suggested that genetic, hor-
monal and autoimmune factors may be of importance. Familial cases are
well ­recognized and have been described in both sexes and in identical and
nonidentical twins.36–39 A recent study found a family history in up to 12%
About 21% of patients with LS have an associated autoimmune disease
including alopecia areata, vitiligo, hyperthyroidism, hypothyroidism, perni-
cious anemia and diabetes mellitus.41,42 Patients and first-degree relatives may
have circulating autoantibodies including those to thyroid, gastric parietal
cell and smooth muscle in addition to antinuclear factor.43 A significant asso-
ciation between LS and the presence of class II antigens including HLA-DQ7,
-DR7, -DQ8 and -DQ9 (alone or in combination) has been reported.44 It has
also been suggested that HLA-A2 possibly exerts a protective role, as it tends
to be absent in patients with extensive extragenital lesions. Also, linkage of
HLA-DR4 with -DQ8 is commoner in patients with marked structural dam-
age to the anogenital area. Circulating IgG antibodies to the glycoprotein
extracellular matrix protein1 have been found in the sera of 75% women
with genital LS.45 In a few otherwise healthy children with vulval lichen scle-
rosus, IgG autoantibodies against the BP180 antigen have been detected.46
In a recent study, women with genital lichen sclerosus were found to have
a higher incidence of psoriasis (predominantly extragenital) compared with
the general population.47,48
LS developing in premenopausal women has been linked to the use of oral
contraceptives, particularly those with antianodrogenic properties.49
Additional proposed etiological factors include absence of collagenase,
an increase in collagen inhibitor enzyme and decreased elastase activity.1
Reduced dihydrotestosterone levels have been described in some patients and
there is one report documenting the histological presence of variably ­acid-fast
bacilli.50,51 As with morphea and atrophoderma, a causal relationship to
Borrelia burgdorferi has been proposed but this putative connection derives
from cases in Europe and not the USA.52 There is no serological evidence in
British men with genital LS for an association with Borrelia.53 Borrelia has
only exceptionally been demonstrated by nested PCR in LS.54 The ­variable
results may be due to techniques employed to detect Borrelia and it has been
suggested that focus floating microscopy should be the gold standard for detec-
tion.55 HPV (types 6, 16 and 18) has been reported in 70% of cases of child-
hood penile lichen sclerosus and in 17.4% of adult cases (types 16, 18, 45)

Fig. 12.52 Fig. 12.53 Fig. 12.54

Lichen sclerosus: symmetrical white lesions with
gross atrophy and hemorrhage. By courtesy of the
Institute of Dermatology, London, UK.
Lichen sclerosus: there is extensive vulval disease with
involvement of the perineum and atrophy. By courtesy
of the Institute of Dermatology, London, UK.
Lichen sclerosus: long-standing disease with
complete loss of the vulval architecture complicated
by the development of an ulcerated squamous
cell carcinoma. By courtesy of the Institute of
Dermatology, London, UK.

Fig. 12.55
Lichen sclerosus: an
ulcerated squamous cell
carcinoma has destroyed
much of the left side
of the vulva. Note the
background of ulcerated
lichen sclerosus. By
courtesy of the Institute of
Dermatology, London, UK.
compared with 8.7% of normal males in one study and in 33% of adult cases
(types 16, 18, 33, 51) in another.56–58 Topical steroid treatment of lichen scle-
rosus may lead to HPV reactivation.59 HPV, however, has not been found in
other studies of vulva LS.60 EBV was reported in 26.5% of samples in the
same study.60 However, the epidemiology and clinical tenor of lichen sclerosus
is not that of an infectious or sexually transmitted disease.
In males, anatomical abnormality and trauma seem to be contributing fac-
tors.4,25,61 LS has been specifically related to hypospadias and its repair.25,62
The presence of histopathological features of lichen sclerosus in a percentage
of acrochordons (skin tags) has led to the suggestion that occlusion of ­flaccid
skin is a pathogenic factor.63 In men, at least, all the evidence points to LS
being due to chronic intermittent occluded contact with urine.
The histological changes are identical irrespective of the site involved
(Figs 12.56–12.59).64–66 However, genital lesions, as opposed to those ­occurring at
extragenital sites, often show absence of atrophy, lichen simplex ­chronicus-like
changes, spongiosis and dermal eosinophils.67 Extragenital LS, on the other hand,
Fig. 12.57
Lichen sclerosus: this example shows the characteristic features of lichen
sclerosus. Note the hyperkeratosis, epidermal atrophy and a broad band of dermal
hyalinization. Telangiectatic vessels are prominent.
Inflammatory dermatoses 455
Fig. 12.56
Lichen sclerosus: early lesion showing epidermal atrophy and marked basal cell
hydropic degeneration. There is a narrow zone of papillary dermal hyalinization and a
band-like infiltrate is present.
seems to be associated in a number of cases with elastophagocytosis, a ­feature
not reported in genital LS.68 Occasionally, pseudoxanthoma elasticum-like fibers
may be seen in patients without pseudoxanthoma ­elasticum.69 Fully developed
lesions of LS show a thinned, effaced epidermis with interface change and a
wide band of hyalinization in the upper dermis and a lymphohistiocytic infil-
trate below the hyalinized area. Marked hyperkeratosis, often associated with
follicular plugging on hair-bearing skin, is frequently seen. Subepidermal edema
is sometimes present and may be ­sufficient to cause subepithelial vesiculation
(Fig. 12.60). Telangiectasia is common and purpura may be an additional fea-
ture. Angiokeratoma-like lesions can also develop.70 A similar phenomenon is
that of lymphangiectasia.71 Early lesions and the periphery of fully developed
lesions display lichenoid changes ­similar to lichen planus (see differential diag-
nosis). Some cases may be associated with foci of marked and highly irregu-
lar acanthosis, often with a very ­jagged lower border (so-called squamous cell
hyperplasia). Such cases should be carefully scrutinized for evidence of epithe-
lial dysplasia (differentiated intraepithelial neoplasia) or adjacent carcinoma.
Fig. 12.58
Lichen sclerosus: close-up
view of basal cell hydropic
degeneration.
456 Diseases of the anogenital skin
Fig. 12.59 Fig. 12.60
Lichen sclerosus: in this view the lymphohistiocytic Lichen sclerosus: occasionally, intense edema may
infiltrate is present deep to the zone of hyalinization. result in subepidermal vesiculation.
There is telangiectasia with hemorrhage.
Differentiated intraepithelial neoplasia is by far the most common type of dys-
plasia found in squamous cell carcinoma associated with lichen sclerosus.72
Currently, there is no evidence to suggest that oncogenic human papillomavirus
(HPV) is associated with LS-related SCC.
The occasional observation of endarteritis in LS led originally to the usage
of the term ‘obliterans’. In two cases in boys, a dermal lymphohistiocytic and
granulomatous phlebitis was found, and one also had evidence of HPV.73 An
exceptional case of LS with associated eosinophilic spongiosis representing
superimposed bullous pemphgioid has been reported.74
Ultrastructural studies of LS show fragmentation, reduplication and forma-
tion of gaps in the basal lamina.66,75 Langerhans cells appear to pass through
these gaps. The mononuclear infiltrate in LS is composed of an admixture of
T-helper and suppressor lymphocytes. Expression of p53 by epidermal cells
has been reported in lichen sclerosus.67,76 The latter is more often seen in cases
associated with squamous cell carcinoma.77
Differential diagnosis
Most cases of genital lichen sclerosus can be diagnosed clinically. Lichen
planus and the much rarer mucous membrane pemphigoid are in the differ-
ential diagnosis. A biopsy should be performed if there is clinical doubt or if
the lesion is eroded or verrucous. Anogenital LS, particularly early lesions,
may be difficult to distinguish from lichen planus (LP). Changes present in the
early stages of LS, and absent in LP, include a psoriasiform lichenoid pattern,
exocytosis of lymphocytes affecting the basal cell layer, basement membrane
thickening, foci of epidermal atrophy and loss of papillary dermal elastic
fibers.65 The histological features may simulate mycosis fungoides.78,79
Zoon’s balanitis
Clinical features
Zoon’s plasma cell balanitis (ZB) is a disorder of middle-aged and older
uncircumcised males, although an analogous condition has been reported to
afflict the vulva, mouth, lips and epiglottis.1–7 Exceptionally, the disease may
present in a circumcised male.5
Fig. 12.61
Zoon’s balanitis: there is involvement of the glans,
prepuce and shaft of the penis. From Bunker C: Male
Genital Skin Disease. Saunders Ltd./Elsevier 2004.
The presentation is classically indolent and asymptomatic. ­Well-demarcated,
glistening, moist, bright red or brown patches involve the glans and visceral
prepuce with sparing of the keratinized penile shaft and foreskin (Fig. 12.61).
The navicular fossa may be involved. Other signs include dark red stippling –
‘cayenne pepper spots’ – and purpura with hemosiderin deposition, ­solitary or
multiple lesions of differing sizes (guttate or nummular), characteristically
symmetrical about the axis of the coronal sulcus and ‘kissing’. Although
­vegetative and nodular presentations have been recorded, ­atypical or unusual
morphology should be viewed with great suspicion and ­biopsied.8,9 The ­clinical
differential diagnosis includes erosive lichen planus, psoriasis, ­seborrheic
dermatitis, contact dermatitis, fixed drug eruption, ­secondary syphilis,
­histoplasmosis, erythroplasia of Queyrat and Kaposi’s sarcoma.10,11 As such,
a confident clinical diagnosis is not always possible or safe.12,13 Therefore a
biopsy is advisable, and the pathologist should actively seek concomitant dis-
ease. Overt cases of lichen sclerosus, lichen planus, bowenoid papulosis and
penile cancer often appear to have ZB-like changes both on clinical examina-
tion and on ­histology:9,13–16 the signs of ZB may be secondary to underlying
preputial disease.8 Probably some of the clinical and histological variants that
have been reported, and the idea that ZB might be a premalignant condition,
reflect this ­phenomenon. ZB indicates a dysfunctional foreskin, potentially
concealing a more sinister dermatosis.10,17,18
Pathogenesis and histological features
Since Zoon’s original reports there have been many accounts in the literature,
but the etiology remains uncertain. The evidence suggests that ZB is a chronic,
reactive, principally irritant dermatosis brought about by a ­dysfunctional
­prepuce. Retention of urine and squames and excessive frictional trauma (ZB
is often located on the dorsal aspect of the glans and/or the adjacent prepuce,
sites of maximal friction on foreskin retraction) create the irritation. There is
no evidence of an infectious cause, and immunohistochemical findings sug-
gest that ZB represents a non-specific polyclonal tissue reaction, consistent
with an irritant dermatosis.6,7
Classically the epidermis shows attenuation with absent granular and
horny layers, and diamond- or lozenge-shaped basal cell keratinocytes
 Inflammatory dermatoses 457

with sparse dyskeratosis and spongiosis (Figs 12.62, 12.63). In the der-
mis, there is a dense band of infiltration with plasma cells of variable
density.13 Other signs include extravasated erythrocytes, hemosiderin and
vascular proliferation. Zoon stressed the presence of the plasma cell infil-
trate in this condition, but in practice the plasma cell density can be very
­variable 9,13,19
Zoon’s vulvitis
This variant of Zoon’s is the female counterpart of the more common
Zoon’s balanitis and was also described by Zoon after it had been noted by
Garnier.1–3
Clinical features
Lesions in females are exceedingly rare and affect the vestibule and the
labia minora.4–8 Few lesions have been described on the clitoris. The con-
dition probably is not a single entity but a pattern of inflammation that is
seen on a mucosal surface in other chronic dermatoses, particularly lichen
planus.9 The lesions are bright red with a varnished appearance and some-
times there is cayenne pepper-like speckling. There may also be areas of
purpura.
Alternative names proposed for these inflammatory changes include
chronic vulval purpura10 and persistent purpuric dermatitis.11 Similar lesions
have been described in the oral cavity and other mucosal surfaces, including
the epiglottis, under such names such as plasma cell orificial mucositis and
atypical gingivostomatitis.12

Histological features
The histology is the same as described above under Zoon’s balanitis. An
exceptional case of Zoon’s vulvitis with prominent mucinous metaplasia has
been described.13

Granuloma annulare
A few cases of granuloma annulare affecting the penis have been reported,
mainly in children and adolescents.1–4 Erythematous smooth, round and
­linear nodules are described. The histology is identical to that seen elsewhere,
and often lesions tend to represent deep granuloma annulare.

Vesiculobullous conditions
Subepidermal autoimmune blistering diseases including bullous pemphi-
goid and mucous membrane pemphigoid are discussed elsewhere. Other
blistering disorders including pemphigus, Darier’s disease and Hailey–
Fig. 12.62 Hailey disease are discussed elsewhere. Pemphigus can involve the penis
Zoon’s balanitis: note the epidermal thinning, spongiosis and a dense superficial (the glans is the usual site) but very rarely in isolation. Pemphigus veg-
inflammatory cell infiltrate. etans presenting with a 4-year history of indolent tender balanitis, where
the glans penis was involved with a moist vegetative plaque with beefy red
erosions separating irregular ­hyperkeratotic mounds, has been reported.1
Involvement of the penis in mucous membrane pemphigoid is very uncom-
mon and may cause blisters, erosions, ulcers, transcoronal adhesions, scarring
and phimosis.2
The histology of bullous disorders in genital skin is the same as that seen
in lesions presenting elsewhere.

Genital papular acantholytic dyskeratosis

This term has been used to describe a condition where papules and nodules
develop on the genital skin and may be mistaken for warts.1,2 Histologically,
lesions demonstrate changes similar to Darier’s disease and Hailey–Hailey.
disease.3,4 It has been proposed that some cases may be a forme fruste of
the latter.5 Another term used for this entity is acantholytic dyskeratosis.6
Immunofluorescence studies are negative, although one case with ­positive
immunofluorescence consisting of intercellular IgG and C3 has been
reported.7

Penile acne
Clinical features
This is not an entity that is well recognized in the literature but it is
occasionally encountered in clinical practice. Young men complain of
Fig. 12.63 spots, boils or blackheads and on examination have comedones, papules,
Zoon’s balanitis: there pustules, inflammatory nodules and scars of the proximal penile shaft
is ‘lozenge-shaped’ (Figs 12.64, 12.65). An important differential diagnosis of acneform dis-
spongiosis and an intense ease presenting at any site is chloracne, due to occlusion of the skin with
plasma cell infiltrate. machine oil.
458 Diseases of the anogenital skin

encountered in men (Fig 12.66). In classical hidradenitis, bridged comedones,

folliculitis and furunculosis, deep discharging sinuses, nodules, cysts, and scars
in the groins (Fig.  12.67), the natal cleft and buttocks2 may all be present
(and in the axillae and under the breasts) and the patient may have conglobate
acne. It is commoner in black individuals and affects the axillae preferentially
in women and the perineum in men. A urethral cutaneous fistula and phimosis
has been reported.3 It is a cause of dorsal perforation of the penis.4,5 Scarring
from the disease and its treatment can be extensive (Fig. 12.68). The morbid-
ity of hidradenitis may be appalling, interfering with sitting, sleeping, walking,
defecation and sexual activity. Depression is common.
Hidradenitis suppurativa can be considered to be a form of ‘apocrine acne’.
The role of endocrine factors is uncertain as is the primary part played by
bacteria. Chronicity and tissue destruction lead to the classical physical signs.
Disease that has persisted for more than 20 years carries a significant risk of
progression to squamous cell carcinoma and rarely verrucous carcinoma.6–9
Hidradenitis is usually a clinical diagnosis. Swabs should be taken for
bacteriological analysis. Rarely, a biopsy may be necessary to exclude carci-
noma or Crohn’s disease. Perineal Crohn’s disease mimics hidradenitis with
Fig. 12.64 its granulomatous inflammation, ulceration and fistula formation but it is less
Penile acne: comedones, painful. Also, the disease is absent from the axillae and it is rare for patients
cysts and healing inflamed to be free of overt gastrointestinal symptoms. Very florid perianal disease can
lesions are present on be seen in myeloma and leukemia in homosexual men and AIDS.10–12
the proximal shaft of
the penis. From Bunker
C: Male Genital Skin
Disease. Saunders Ltd./
Elsevier 2004.

Fig. 12.66
Pili incarnati: lesion from the groin showing and inflamed follicular lesion. From
Bunker C: Male Genital Skin Disease. Saunders Ltd./Elsevier 2004.

Fig. 12.65
Penile acne: comedones,
papules and nodules are
evident. From Bunker
C: Male Genital Skin
Disease. Saunders Ltd./
Elsevier 2004.

Histological features
The histology is identical to that of acne at classical sites.

Hidradenitis suppurativa
Clinical features
Hidradenitis suppurativa (termed chronic perianal pyoderma in Japan)
­represents a clinical spectrum overlapping with chronic folliculitis, e.g., of
Fig. 12.67
the buttocks and penile acne.1 Pili incarnati (ingrowing hairs) and ­secondary
Hidradenitis suppurativa: there is extensive involvement of the groin. From Bunker
folliculitis is a common problem in the ‘bikini’ area in women but rarely C: Male Genital Skin Disease. Saunders Ltd./Elsevier 2004.
 Inflammatory dermatoses 459

The microscopic appearance has not been described in detail but there
is non-specific superficial ulceration with a mixed inflammatory cell
infiltrate.

Sclerosing lymphangitis of the penis

Clinical features
Sclerosing lymphangitis of the penis (Mondor’s disease) is a rare condi-
tion which presents as a serpiginous cord-like thickening of the skin near
the coronal sulcus.1–4 Rarely, there is involvement of the dorsal aspect
of the shaft. There may be some inflammation and local tenderness.
The condition is usually self-limiting and resolves spontaneously after
a few weeks. Only occasional cases are persistent and may require sur-
gery.5 There does not appear to be a female equivalent to this disorder
but there has been a report of the disease involving the upper lip and the
labium minus.6
Fig. 12.68
Hidradenitis suppurativa: Pathogenesis and histological features
there is extensive
scarring as a result of the The etiology is unknown but vigorous or traumatic sexual activity is an
disease and also from important precipitant.7,8 In general, there does not seem to be any relation-
surgery. Courtesy of Prof. ship to venereal disease although cases have been reported following genital
Tim ­Allen-Mersh, London, herpes and Chlamydia infection.9,10 A case developing after coadministration
UK. From Bunker C: Male of tadalafil and fluconazole has been documented.11
Genital Skin Disease. The histological features are characterized by a thrombosed vascu-
Saunders Ltd./Elsevier 2004. lar channel, thought to be of either lymphatic or venous derivation. Some
authors separate sclerosing lymphangitis from Mondor’s disease based on
Histological features the ­involvement of lymphatics in the former and veins in the latter.12 Focal
Masson-like changes may be seen. Later in the course of the disease, the
The histology is identical to that of hidradenitis suppurativa occurring
thrombus is replaced by fibrous tissue and a few scattered mononuclear
elsewhere.
inflammatory cells are also seen. The wall of the affected vessel later becomes
thickened and sclerotic.
Aphthe
Clinical features Pyoderma gangrenosum
Aphthous ulceration of the penis and scrotum does occur but this is not an This is a rare genital affliction, including the variant superficial granulomatous
acceptable diagnosis in the perianal skin or genitalia without overt exclu- pyoderma1 that involves the penis and scrotum in adults and children. In chil-
sion of sexually transmitted diseases, and culture is reasonable practice.1 The dren the anogenital area is a site of predilection in addition to the head and
causes of aphthae are obscure. neck. Genital pyoderma gangrenosum may occur following local trauma such
The impression is that aphthe and idiopathic orogenital ulceration are as urological surgery1,2 or treatment for cancer.3 It may complicate ulcerative
commoner in HIV infection and worse, symptomatically and morphologi- colitis4 or chronic lymphocytic leukemia, or may be idiopathic.5–8 In idiopathic
cally. Giant lesions may occur. In HIV, all mucocutaneous ulcers must be cases, diagnosis is frequently delayed because it is not included in the differen-
biopsied and cultured; several pathologies may coexist.1 tial by the clinician in pursuit of a diagnosis of cancer or infection. Pathologists
may receive biopsies without this possibility being mentioned to them.9
Histological features
The histology of idiopathic aphthous ulceration is entirely non-specific. Histological features
The histological features are identical to those seen in lesions elsewhere.
Lipschutz ulcer
Penile necrosis
Clinical features
This condition is seen in teenage girls who present with vulval ulceration of Clinical features
sudden onset. Lesions may be solitary or multiple.1–7 The initial lesion is a This serious situation has a number of causes and a wide clinical differen-
tender purpuric or hemorrhagic papule that rapidly enlarges and ulcerates. tial diagnoses. Many of the causes are discussed in this and other chapters,
The ulcers are deep, painful and have sharply delineated erythematous mar- for example decubitus ulcer, the strangulation and tourniquet syndromes and
gins. There may be an accompanying fever, malaise and cervical lymphade- other autoerotic misadventures and causes of artifact (priapism), ­pyoderma
nopathy. However, in most cases, other signs and symptoms are absent or not gangrenosum, infections such as herpes simplex, ecthyma gangrenosum and
­prominent, and confirmation of the diagnosis requires serological tests. Other Fournier’s gangrene, and as a complication of serious illness (e.g., mucormy-
associated infections have included typhoid and paratyphoid, mycoplasma cosis in acute myeloblastic leukaemia).1 Necrosis can be the result of dia-
and cytomegalovirus.5–7 betic small vessel and end-stage renal disease2,3 and chronic renal failure
An analogous situation in males is not recognized. with secondary hyperparathyroidism and calciphylaxis,4 and can compli-
cate polycythemia, thrombocytopenia and leukemia, cryoglobulinemia and
Pathogenesis and histological features ­vasculitis. Inferior vena caval thrombosis as part of disseminated intravas-
The condition is a toxic reaction to a systemic infection. The most ­commonly cular ­coagulation can lead to necrosis and gangrene of the penis.5 Heparin
associated infection is Epstein-Barr virus (EBV) infection (infectious ­necrosis is a coagulopathy due to heparin-induced thrombocytopenia. Warfarin
mononucleosis).1–7 ­necrosis is a state of acquired protein C dysfunction .6,7
460 Diseases of the anogenital skin
Histological features
The histological features consist of extensive necrosis of the skin and deeper
tissues and more specific changes may be found depending on the etiology of
the process.
Spontaneous scrotal ulceration
Five cases of spontaneous scrotal ulceration in young, previously fit men
have been described by Piñol Aguade.1 Histology showed non-specific vas-
culitis, and spontaneous resolution occurred. This entity may be related to
idiopathic scrotal panniculitis and fat necrosis. Idiopathic scrotal necrosis in
a 2-month-old boy has been documented by Sarihan;2 trauma, extreme cold
and Fournier’s gangrene were excluded.
Scrotal fat necrosis
This condition is distinct from other causes of acute scrotum in prepubertal
boys.1 It presents as acute tender, sometimes painful, swelling (classically, but
not always, after swimming in cold water). Masses may be palpable in the
scrotal wall. The patient is otherwise well, with no fever or leukocytosis.2,3
In adults, one case of idiopathic scrotal panniculitis has been reported4 and
another associated with pancreatitis.5
Associations with systemic disease
Crohn’s disease
Clinical features
Anogenital lesions occur in about 30% of patients with intestinal Crohn’s
disease, either by direct extension of active intestinal disease or as a
­manifestation of so-called ‘metastatic disease’ (Figs 12.69–12.72).1–7 Skin
Fig. 12.69 Fig. 12.70
Vulval Crohn’s disease: there is intense erythema and Vulval Crohn’s disease: in this patient there is
multiple vestibular erosions are present. By courtesy of marked edema with erythema and conspicuous
the Institute of Dermatology, London, UK. granulomatous lesions. By courtesy of the Institute
of Dermatology, London, UK.
i­nvolvement is more common in patients with colonic disease (up to 80%).
In ‘metastatic disease’ the affected areas are not contiguous with the involved
bowel and may occur in distant cutaneous sites including the face and
limbs.8–12 Anogenital disease may present years before there is evidence of
gastrointestinal disease.13–16 Vulval edema can be the only manifestation and
occasionally it is unilateral.17,18 Crohn’s disease may involve the penis and
scrotum, presenting as penoscrotal lymphedema.19–21 More usually, how-
ever, the ­disease is associated with erosions, ulceration, abscesses, skin tags,
sinus and fistula formation.22 Lesions can exceptionally mimic hidradenitis
suppurativa and pyoderma gangrenosum.23 Unilateral hypertrophy of the
vulva has also been reported.24 Deep fissures (‘knife-cut’ sign) along the
skin creases are a characteristic feature. Patients of any age with Crohn’s
disease including children may present with anogenital involvement.25 Oral
involvement includes edema, fissuring and mucosal ‘cobblestoning’. One
patient presented with ‘metastatic’ Crohn’s disease and oral intraepithelial
IgA pustulosis.26
Crohn’s disease is not uncommonly associated with pyoderma gangrenosum
and erythema nodosum. Other links include leukocytoclastic vasculitis, ery-
thema elevatum diutinum, granulomatous vasculitis, Sweet’s syndrome, epider-
molysis bullosa acquisita, polyarteritis nodosa, pyostomatitis ­vegetans, vitiligo,
psoriasis, erythema multiforme, lichen nitidus, hidradenitis ­suppurativa and
acne fulminans.27–43
The condition runs a chronic course. Development of Bowen’s disease in
a case of vulvovaginal Crohn’s disease has been reported.44 Rarely, squamous
cell carcinoma may develop in long-standing disease.45–47
Histological features
The histology may show only edema, dilated lymphatics or lymphangiecta-
sia. More commonly, there are dermal or rarely subcutaneous noncaseating
granulomata (Fig. 12.73). The latter may have a perivascular distribution.45
The histological diagnosis can only be made after careful clinicopathological
correlation.
Fig. 12.71
Vulval Crohn’s disease: note the erythema, edema
and erosions. By courtesy of the Institute of
Dermatology, London, UK.
 Infectious diseases 461

necrosis has been reported.1 Rubio et al.2 describe a case of isolated penile
ulceration due to a necrotizing vasculitis, with no evidence of ­systemic
­vasculitis that responded to systemic steroids. Fournier’s gangrene may
show ­histological evidence of necrotizing vasculitis,3 and priapism has been
­documented as a manifestation of isolated genital vasculitis.4

Infectious diseases
Erythrasma
Clinical features
Erythrasma is a superficial infection of the skin at flexural sites, particularly
in the inguinal and genitocrural folds (Fig. 12.74).1–7 The skin between the
toes and natal cleft may also be involved. The affected areas are covered
in red–brown scaly plaques with well-demarcated edges. The rash is usually
asymptomatic or mildly itchy. The affected areas fluoresce coral pink under
Wood’s light. This feature is due to the presence of porphyrin and may be
absent in some cases.5 Very rare cases present with generalized involvement.6
Fig. 12.72 The disease may appear concomitantly with a dermatophytosis and this often
Perianal Crohn’s disease: makes the diagnosis difficult.7
multiple skin tags showing
massive edema are Pathogenesis and histological features
present. By courtesy The organism involved is an aerobic, Gram-positive corynebacterium,
of the Institute of C. minutissimum,3 which is a normal skin commensal. Overgrowth and
Dermatology, London, UK. ­dermatitis are encouraged by the damp and warm conditions of a flexural
zone. Obesity, friction, diabetes and immunosuppression are all contributory
factors.4
The characteristic clinical picture and the presence of fluorescence under
Wood’s light obviate the need for biopsies in most cases. A biopsy shows
the presence of rods and filamentous organisms in the stratum corneum
(Figs 12.75, 12.76). Inflammation is minimal.

Tinea
Tinea (or ‘ringworm’) refers to superficial dermatophytosis. Tinea is a com-
mon disease of the pelvic girdle, especially of the groins (Figs 12.77–12.79)
and is usually due to Trichophyton rubrum. It is not always spread from the
nails or feet although people with tinea manuum or unguium can spread it
to the groins or perianal skin because they are common sites of chronic itch.
Tinea cruris is itchy, and diagnosed by the presence of red–brown, scaly
patches with raised, deeper red edges extending from the groins onto the
abdomen (Fig.  12.80), buttocks (Fig.  12.81) and thighs. Annular lesions
are not always obvious. Diagnosis is not always easy because many patients

Fig. 12.73
Vulval Crohn’s disease: there is an ill-defined granulomatous infiltrate with
conspicuous giant cells in the deep reticular dermis.

Acute hemorrhagic edema of childhood

Clinical features
This is an unusual variant of leukocytoclastic vasculitis of infants and young
children that may present as tenderness, redness and swelling of the penis and
scrotum with the development of more widespread hemorrhagic lesions.1,2

Pathogenesis and histological features

Streptococci, staphylococci and adenoviruses have been implicated. The
­histology shows a leukocytoclastic vasculitis.

Necrotizing vasculitis
Peniloscrotal ulceration due to necrotizing vasculitis in association with Fig. 12.74
Wegener’s granulomatosis, systemic lupus erythematosus, systemic ­vasculitis, Erythrasma: the flexural distribution and sharply demarcated border are characteristic
polyarteritis nodosa and hereditary spherocytosis with recurrent ­vascular features. By courtesy of the Institute of Dermatology, London, UK.
462 Diseases of the anogenital skin

Fig. 12.75 Fig. 12.76 Fig. 12.77

Erythrasma: bacilli are just visible in the upper Erythrasma: PAS stain showing elongated bacilli. Tinea cruris: there is a large erythematous lesion
stratum corneum. involving the inner thigh. From Bunker C: Male
Genital Skin Disease. Saunders Ltd./Elsevier 2004.

Fig. 12.78 Fig. 12.79 Fig. 12.80

Tinea cruris: note the acute margin. From Bunker C: Tinea cruris: close up view. From Bunker C: Male Tinea cruris: in this patient, there is extensive
Male Genital Skin Disease. Saunders Ltd./Elsevier 2004. Genital Skin Disease. Saunders Ltd./Elsevier 2004. involvement. From Bunker C: Male Genital Skin
Disease. Saunders Ltd./Elsevier 2004.

have been previously misdiagnosed and/or partially treated with topical
­corticosteroids or topical antifungal agents. This presentation is called tinea
incognito (Fig. 12.82) in the previously topical corticosteroid-treated patient
where the symptom of itch and the signs of inflammation, including ­redness,
the scale and the well-demarcated often scalloped, elevated active ­margins,
have been suppressed, although there is often subtle ­postinflammatory
hyperpigmentation.
Tinea of the penis or scrotum1 is not common and when it occurs it is
­usually associated with crural disease. Rarely encountered is tinea on the
glans penis with an itch or pain and producing an erythematous patch or a

Fig. 12.81
Tinea cruris: note the bilateral involvement of the buttocks.
Fig. 12.82
Tinea incognito: there is extensive involvement of the abdomen, groins, thighs and
scrotum. This followed injudicious use of topical steroids. From Bunker C: Male
Genital Skin Disease. Saunders Ltd./Elsevier 2004.
crop of scaly papules. Pandey et al.2 associated penile tinea (in India) with
occlusion due to the wearing of a langota – described as a T-shaped bandage
tied over the genitalia.
Trichosporosis
Clinical features
Trichosporosis due to Trichosporon beigelii is a common form of ­genitocrural
and perianal intertrigo in India.1 Predominant symptoms are itching or ­burning.
Scaly papules can accompany the intertrigo. Coexisting ­dermatophyte,
Candida, trichomycosis and erythrasma infection may be found. Infection
rarely occurs elsewhere, including the scalp.2,3
Histological features
The infection involves the hairs but not the surrounding skin. Microscopic
examination of hair shafts shows white or brown soft nodules of varying size
that can easily be removed.2 The diagnosis is suspected by a KOH ­preparation
to identify variable-sized arthrospores and is confirmed by culture.
Infectious diseases 463
Condyloma acuminatum (genital warts,
human papilloma virus( HPV) infection)
Clinical features
Genital warts (condyloma acuminatum) are usually caused by HPV types
6, 11, 16, 18, 30–32, 42–44 and 51–55.1–5 HPV-7, usually associated with
warts in butchers, can exceptionally be the cause of condylomas.6 HPV-6
and 11 account for approximately 90% of these lesions.2,7 However, more
than one HPV type can be isolated from a single lesion.8 They occur on the
glans penis and prepuce or shaft as soft, fleshy (sometimes filiform) plaques
and may extend into the meatus (Figs 12.83, 12.84). On the shaft, they are
less exophytic. Vulval lesions may be bulky and macerated, and can extend
into the introitus (Figs  12.85–12.87). Often, lesions are difficult to detect
on clinical examination.1,9,10 Vulval condylomata usually involve the labia
minora, interlabial sulcus or the area around the introitus. Similar fleshy
and filiform soft masses may occur perianally and in the anus, more often
in males (Fig.  12.88).11 Anal and cervical squamous carcinomas have also
been shown to contain HPV types 6, 16 and 18 in a significant proportion of
cases.4 Genital warts in children always raise the possibility of sexual abuse
but can occur with close nonsexual contact.12 However, nonvenereal viral
warts (verruca vulgaris) mainly caused by HPV type 2 can occur in both
young girls and less frequently in adult women, so HPV typing can be very
­important.13 Young sexually active adults are the most frequently affected
(second and third decades), and often in association with other sexually
acquired infections.2,5,14
Rarely, condyloma acuminatum presents in the oral cavity.15 Recently,
­condylomata have been reported in the abdominal pannus fold of a few obese
patients.16
It is important to recognize that a significant proportion of genital HPV
infections are asymptomatic.1,17 The female partners of male patients with
genital warts have been shown to have an increased risk of cervical HPV
infection and intraepithelial neoplasia.18 Cervical neoplasia associated with
pre-existent vulval warts has also been related to immunosuppression, at
least in some patients.19 Up to 80% of invasive cervical squamous ­carcinomas
have been shown to contain HPV DNA. Types 16, 18, 31–33, 35, 39, 42
and 51–54 are most commonly associated with cancer of the cervix, vulva
and penis.4,5,20 Malignant transformation of genital warts is rare but may be
found in association with penile bowenoid papulosis and vulval intraepithe-
lial n
­ eoplasia (VIN) usual type (undifferentiated).3,21–24
A large, exuberant and locally destructive variant of condyloma (Buschke-
Löwenstein tumor) may rarely be encountered.25,26 This is associated with
HPV-6, 11 or 16. It is considered by many to be a variant of verrucous
Fig. 12.83
Condyloma acuminatum: multiple erythematous, velvety plaques are present on
the glans penis. By courtesy of the Institute of Dermatology, London, UK.
464 Diseases of the anogenital skin

Fig. 12.85
Condyloma acuminatum:
multiple gray lesions
are evident on the labia
minora and around the
vestibule. By courtesy
of the Institute of
Dermatology, London, UK.

Fig. 12.84
Condyloma acuminatum:
(A) in this patient the
lesions have a typical
filiform appearance;
(B) multiple condylomata
are present on penis and
scrotum. By courtesy
of the Department of
Genitourinary Medicine,
B St Thomas’ Hospital,
London, UK.

c­ arcinoma, a subtype of well-differentiated squamous carcinoma (see below).
However, the issue still remains controversial and other authors regard it
as a distinctive entity. Juvenile laryngeal papillomata containing HPV-6 and
11 can be seen in children born to mothers with condylomata acuminata.1
They may show malignant progression if irradiated. The condition has been
described in an HIV-positive patient.27
Histological features
Condylomata acuminata are characterized by marked acanthosis with a solid
or trabecular pattern and a broad, rounded, exophytic growth (Figs 12.89,
12.90). There is a sharp, fairly regular, deep margin. The surface of the
lesion is hyperkeratotic and parakeratotic. Superficial vacuolated keratino-
cytes (koilocytes) are characteristic (Fig. 12.91). The vacuolated epithelium
is often most marked in the declivities. Care must be taken not to confuse
­koilocytes with the vacuolated, glycogenated keratinocytes of mucosal
­epithelia. Distinction can be made fairly readily as koilocytes have an enlarged,
­wrinkled, ­hyperchromatic nucleus.
Care should be taken in the histological interpretation of lesions that
have previously been treated with podophyllin (although this treatment is
­seldom used nowadays since the advent of imiquimod).28,29 These can ­display
Fig. 12.86
Condyloma acuminatum:
in this patient the
condylomata are
pedunculated and have
extended onto the thighs.
By courtesy of the
Institute of Dermatology,
London, UK.
­ rominent degenerative changes with cytoplasmic vacuolation, nuclear
p
enlargement and metaphase arrest. The changes, however, tend to be more
focal, and abnormal mitotic figures are not seen. Immunohistochemical stains
for papillomavirus common antigen have been used to confirm the diagnosis
but this is only positive in about 60% of cases.30 More recently, in situ hybrid-
ization in paraffin-embedded tissue has become available.
Giant condyloma acuminatum (Buschke-Löwenstein tumor) occurs most
frequently on the genitalia, and is larger and more cauliflower-like.24,25,31 It
shows some tendency to endophytic growth, but without any suggestion
of frank infiltration. It can recur locally. Anal condylomata may develop
bowenoid features, and occasionally invasive tumors supervene.3,4
 Infectious diseases 465

Fig. 12.87
Condyloma acuminatum:
there is very extensive Fig. 12.89
disease. The patient Condyloma acuminatum: there is focal parakeratosis, slight papillomatosis and very
is at considerable risk marked acanthosis. The lower border is sharply demarcated.
of developing cervical
disease. By courtesy
of R.A. Marsden, MD,
St George’s Hospital,
London, UK.

Fig. 12.90
Condyloma acuminatum: this is a much more florid example. Note the gross
papillomatosis and very marked acanthosis.

Fig. 12.88
Condyloma acuminatum: perianal involvement is likely to be associated with
homosexual activity. By courtesy of R.A. Marsden, MD, St George’s Hospital,
London, UK.
Syphilis
Clinical features
The incidence of syphilis fell dramatically after the introduction of penicillin
in the 1940s. In recent years the incidence has been rising annually largely due
to the increased number of cases of human immunodeficiency virus (HIV)
infection. Drug abuse and high-risk sexual behavior are also contributory
factors.1–3 ‘Prostitution for drugs’ is particularly important.2 The increase in
the incidence of syphilis continues, especially in HIV-infected patients with
predilection for young homosexual black males.4
In the sixteenth century, syphilis carried a high mortality associated
with a chronic disfiguring and disabling disease. The disease currently
appears less aggressive, even in untreated cases. It is highly infectious, with
the risk of transmission from an infected partner ranging from 30% to
51%.5,6 The chance of acquiring the disease depends upon the number of
­exposures, type of sexual practice and the location and number of the part-
ner’s lesions.2 There is a close relationship between syphilis and HIV infec-
tion and both diseases can be acquired together.7–9 It is recognized that
diseases such as syphilis that induce genital ulceration increase the risk of
acquiring HIV infection.9
The causative organism is Treponema pallidum, a spirochete with fastidi-
ous growth requirements. Transmission is primarily sexual. An endemic form
known as bejel, caused by an identical organism, occurs in children living in
conditions of poor hygiene and is transmitted by cutaneous inoculation.10
Other endemic forms have been associated with shared drinking vessels when
some members of the community have oral or labial syphilitic lesions.
The typical initial lesion, a chancre, deveops 20–30 days after exposure
to the organism at the site of inoculation. This can be anywhere on the
­anogenital skin, more often on the glans penis (especially the coronal sulcus),
the shaft or prepuce, or on the labia majora or minora (Figs 12.92–12.96).5
At least 5% of primary chancres arise at extragenital locations, most com-
monly oral but virtually every other part of the skin surface may be affected
including the tonsils, fingers, eyelids and nipples (Figs 12.97, 12.98).2,5,11,12
Lesions in the vagina or cervix may go undetected. The chancre appears as an
indurated, punched-out, painless ulcer. It is usually accompanied by painless
lymphadenopathy. This resolves without scarring after 1–5 weeks.
466 Diseases of the anogenital skin

Fig. 12.93
Primary syphilis: painless lymphadenopathy is often present. By courtesy of C. Furlonge,
Fig. 12.91 MD, Port of Spain, Trinidad.
Condyloma acuminatum:
there are conspicuous
koilocytes with irregular
nuclei and vacuolated
cytoplasm.

Fig. 12.94
Primary syphilis: in this patient the chancre has a punched-out appearance. By courtesy
of the Institute of Dermatology, London, UK.

Fig. 12.92
Primary chancre: the chancre is a painless ulcer with an indurated edge. The base is
yellow and harbors large numbers of spirochetes. By courtesy of F. Lim, MD, King’s
College Hospital, London, UK.

The secondary cutaneous lesions (syphilids) are highly infectious and may
mimic virtually any skin disorder. They present 6–8 weeks after the appear-
ance of the chancre.13 They develop insidiously (in up to 80% of patients),
with a roseolar, macular–erythematous rash, on the head, face and neck fol-
lowed by a polymorphic papular eruption.5 The macules measure 5–10 mm
in diameter, are not pruritic and particularly occur on the trunk, abdomen
and limbs, especially the palms and soles (Figs 12.99–12.104).13 The papular
lesions are characteristically coppery red in color and 3–10 mm in diameter.
Hypopigmentation of the neck is known as the ‘collar of venus’.13
Other manifestations described include condylomata (in intertriginous
areas), annular, lichenoid, papulosquamous lesions (psoriasiform), arcuate
lesions, corymbose brownish-red papules (Gr. korymbos, clusters of ivy ­flowers), Fig. 12.95
bullous, erythema multiforme like follicular and pustular variants on the skin, Primary syphilis: a typical chancre is present on the left labium majus. By courtesy
with erosive ulcers (mucous patches), often of ‘snail track’ type, and the (highly of R.N. Thin, MD, St Thomas’ Hospital, London, UK.

Fig. 12.96
Primary syphilis: typical ‘kissing ulcers’ are present within the vestibule. By courtesy
of D. Barlowe, MD, St Thomas’ Hospital, London, UK.
Fig. 12.97
Primary syphilis: oral chancres are most often located on the lip. By courtesy of
R.N. Thin, MD, St Thomas’ Hospital, London, UK.
Fig. 12.98
Primary syphilis: a chancre is present at the edge of the anal ostium. By courtesy of
R.N. Thin, MD, St Thomas’ Hospital, London, UK.
Infectious diseases 467
Fig. 12.99
Secondary syphilis:
the face is commonly
affected. Note the
numerous papules.
By courtesy of R.N. Thin,
MD, St Thomas’ Hospital,
London, UK.
Fig. 12.100
Secondary syphilis: this patient shows a widespread hyperpigmented
maculopapular eruption. By courtesy of C. Furlonge, MD, Port of Spain, Trinidad.
i­nfectious) condylomata lata affecting the mucosae (Figs 12.105–12.108).14–21
Keratoderma can also be seen.22 Large hypertrophic condylomata are known
as framboiseform syphilids.12 Other variants described are acneform, varioli-
form and, rarely, necrotic (Fig. 12.109). Lesions tend to be widely disseminated
and often symmetrical in distribution.5 Papular involvement of the scalp may
result in nonscarring, patchy alopecia (Fig.  12.110).23 The alopecia induced
by ­secondary syphilis is known as alopecia syphilitica and has a characteris-
tic, moth-eaten appearance.24,25 The beard, eyebrows and eyelashes may also be
affected.5 Telogen effluvium has also been described.13
Rare ‘malignant’ forms of syphilis present with rapid progression, pap-
ulopustular lesions, much ulceration and rupial lesions (Gr. rhypos, filth;
necrotic lesions covered by dirty, lamellated encrustation resembling oyster
shells) mainly affecting the face and limbs.13,26,27 Patients can also present with
fever, eye involvement, myalgia, lymphadenitis, and hepatosplenomegaly.28
This form of syphilis has been described in association with HIV infection
and is characterized by necrotic and ulcerative lesions.29–31
468 Diseases of the anogenital skin

Fig. 12.101
Secondary syphilis: note the widespread papules and nodules many of which have
a hypertrophic appearance. By courtesy of C. Furlonge, MD, Port of Spain, Trinidad.

Fig. 12.103
(A, B) Secondary syphilis:
erythematous and scaly
papules involving the
palms and soles are
present in this patient
with secondary syphilis.
(A) By courtesy of R.A.
Marsden, MD, St George’s
Hospital, London, UK; (B)
by courtesy of R.N. Thin,
Fig. 12.102 MD, St Thomas’ Hospital,
B
Secondary syphilis: the palms are almost invariably affected. By courtesy of the London, UK.
Institute of Dermatology, London, UK.

Secondary syphilis manifestations have typically been described as

­ onpruritic, but this is not always the case.2,5,32 Indeed, in the series of 105
n
patients with secondary syphilis published by Chapel, 42% complained of
pruritus.33 Resolution may be accompanied by hypo- or hyperpigmenta-
tion.5 Lymphadenopathy, which may be widespread and is painless and rub-
bery, occurs in 50–85% of patients.5 The cutaneous manifestations are often
accompanied by pyrexia, headache, weight loss and non-specific muscle and
joint aches.13 Periostitis can rarely occur.34 Ocular involvement including
uveitis and retinitis can occur at any stage of the disease.35 Untreated lesions
of syphilis resolve in 2–10 weeks.13 When syphilis is treated with antibiotics,
there may be a self-limited febrile reaction known as the Jarisch–Herxheimer
reaction associated with systemic symptoms.
Atypical clinical forms of syphilis have been reported in HIV-positive
patients,36,37 and multiple genital ulcers may occur in primary syphilis as well
as concomitant ulcer with secondary syphilis.38
Secondary syphilis is followed by a latent phase, which may precede a
change to: Fig. 12.104
• seronegativity and cure, Secondary syphilis: in this patient, typical copper penny macules with surrounding
• persistent seropositivity without further lesions, annular scale (Biette’s collarette) contrast with confluent exfoliation on the palms.
• development of tertiary lesions. By courtesy of the Institute of Dermatology, London, UK.

Fig. 12.105
Secondary syphilis: this is a typical corymbose eruption. Note the circumscribed,
confluent, erythematous scaly papules. By courtesy of the Institute of Dermatology,
London, UK.
Fig. 12.106
Secondary syphilis: pustular lesions, as seen on this patient’s face, are a rare
manifestation. By courtesy of R.N. Thin, MD, St Thomas’ Hospital, London, UK.
Fig. 12.107
Secondary syphilis: note the symmetrically distributed ‘snail track’ ulcers. By courtesy
of R.N. Thin, MD, St Thomas’ Hospital, London, UK.
Infectious diseases 469
Fig. 12.108
Secondary syphilis: early perianal condylomata lata. By courtesy of R.N. Thin, MD,
St Thomas’ Hospital, London, UK.
Fig. 12.109
Secondary syphilis: in
this patient the lesions
greatly resemble pityriasis
lichenoides. By courtesy
of R.A. Marsden, MD,
St George’s Hospital,
London, UK.
These late lesions involve mainly the cardiovascular (aortic incompetence)
and central nervous system (tabes dorsalis and general paresis of the insane),
but cutaneous lesions are seen as noduloulcerative lesions and gummata that
tend to break down with central necrosis and suppuration. Gummata may
occur up to 15 years after the initial infection. They are painless, frequently
ulcerated, firm subcutaneous nodules that show a predilection for the scalp,
face, chest and legs (Fig. 12.111).35,39 Noduloulcerative late syphilitic lesions
present as superficial nodules that extend peripherally and heal centrally to
form ulcerated serpiginous plaques.40,41 Lesions of tertiary syphilis can be
seen in internal organs and may clinically mimic cancer.42
Infants born to infected mothers may have widespread lesions reflect-
ing a systemic infection (congenital syphilis). Development of the disease is
mainly associated with lack of antenatal screening.43 These include fibrosis
in many organs, with inflammatory changes seen particularly in bones and
lungs. Vesicular skin lesions and maldevelopment of teeth and bone are also
sometimes evident. Later changes of congenital syphilis are classically frontal
470 Diseases of the anogenital skin

produced by host inflammatory cells. A hyaluronidase is associated with the

surface of T. pallidum and may facilitate dissemination in tissues.45
After the first inoculation of the spirochete through mucosa or abraded skin, the
organism becomes systemically distributed before the primary c­ hancre develops at
the site of inoculation and numerous spirochetes can again be identified.
The chancre is characterized histologically by initial epidermal hyperpla-
sia with an intense lymphohistiocytic and neutrophil infiltrate in the dermis
(Figs 12.112–12.114). Plasma cells are present, but may be more numerous
in papular and papulosquamous secondary lesions (see below). The ­overlying
epithelium becomes ulcerated, and the adjacent epidermis often shows pseu-
doepitheliomatous hyperplasia and infiltration by neutrophils. The indura-
tion of the primary lesion is due to a large amount of mucoid substance.
Vascular endothelial cell swelling is often prominent. The organisms can be
­demonstrated by dark-field examination of a smear taken from the primary
lesion. A silver stain such as Warthin-Starry or more recently immunohis-
tochemistry are also useful in demonstrating the organisms in tissue sections.
By electron microscopy, the spirochetes are often found in macrophages,
endothelial cells, plasma cells and in the ­intercellular space close to small
blood vessels.46 Resolution of the chancre, while appearing to coincide with
Fig. 12.110 immunity to further infection and ­demonstration of antibodies, neverthe-
Secondary syphilis: scalp involvement is not uncommon. Note the scaling and hair
less does not impede the widespread dissemination and ­proliferation of the
loss. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK.
treponeme. This leads to its ­recrudescence in the ­secondary phase, a paradox
that is not understood.

Fig. 12.111
Syphilis: the presence of
gummatous cutaneous Fig. 12.112
lesions as seen in this Primary syphilis: biopsy from a chancre on the penis. Note the typical punched-out
elderly male is now a appearance.
very rare manifestation.
By courtesy of M.M.
Black, MD, Institute of
Dermatology, London, UK.

bossing, a short maxilla, a high arched palate, chronic interstitial kerati-

tis, notched (Hutchinson’s) incisors, Mulberry’s molars, VIII cranial nerve
deafness and saddle nose.44 Other manifestations include painless hydroar-
throsis, perforation of the nasal septum and palate, and cardiovascular and
­neurological changes, as seen in late-stage adult disease.

Pathogenesis and histological features

T. pallidum is a slender, coiled organism, 6–16 μm long, capable of an undulat-
ing, corkscrew-like motion. The organisms are readily visualized in material
from a primary chancre with dark-field illumination, but have only recently
been grown in culture. The usually nonpathogenic spirochetes, which live as
commensals around the gingiva, although still termed Treponema, are quite
different, not least in that they have a right-handed spiral in contrast to the
left-handed spiral of T. pallidum and other pathogenic spirochetes.
T. pallidum produces a nonantigenic mucin coat, which may be protective Fig. 12.113
in early infections. This mucoid element may be increased by a component Primary syphilis: note the marked endothelial swelling.
 Infectious diseases 471

Fig. 12.114 Fig. 12.116
Primary syphilis: the infiltrate consists of lymphocytes, histiocytes and conspicuous Secondary syphilis: the infiltrate contains large numbers of plasma cells. This
plasma cells. specimen comes from a condyloma lata.

Secondary lesions show variable appearances depending to some extent

upon the clinical morphology (Figs  12.115–12.122).47–50 Purely macular
lesions are not distinctive and show a rather sparse perivascular lymphohistio-
cytic infiltrate with few, if any, plasma cells.13 The epidermis is normal. As the
lesions develop a papular morphology, superficial and deep perivascular infil-
trates develop, which may also adopt a band-like distribution. Involvement
of the subcutis is rare. Plasma cells become more numerous and parakerato-
sis, acanthosis, spongiosis and exocytosis may be evident. Thick-walled blood
vessels with swollen endothelial cells are characteristic. A prominent infiltrate
is often present around hair follicles and sweat glands. Early lesions showing
perivascular neutrophils and a heavy neutrophilic infiltrate mimicking Sweet’s
syndrome has been reported.51 Psoriasiform syphilids show parakeratosis and
acanthosis with extended (psoriasiform) epidermal ridges. The inflammatory
cell infiltrate is both perivascular and superficial, and band-like in distribu-
tion. Spongiform pustulation and neutrophil exocytosis may be evident, and
focal cell hydropic degeneration can sometimes be present.14,50 Keratinocyte
necrosis may occasionally be seen.50 Leukocytoclastic vasculitis is very rare.52

Fig. 12.117
Secondary syphilis: in this example, there is hyperkeratosis, irregular acanthosis
and a very dense dermal infiltrate.

Fig. 12.115
Secondary syphilis:
there is very marked
hyperkeratosis and
parakeratosis. The
epidermis shows
psoriasiform hyperplasia.
A dense inflammatory
cell infiltrate is present in
the lamina propria. This
specimen comes from a Fig. 12.118
condyloma lata. Secondary syphilis: spongiosis is evident.
472 Diseases of the anogenital skin

Fig. 12.119 Fig. 12.122
Secondary syphilis: in this field, there is marked interface change. Secondary syphilis: numerous spirochetes are present (Warthin-Starry stain).

Erythrocyte extravasation may be a feature of both papular and papu-

Fig. 12.120
Secondary syphilis: note the marked endothelial cell swelling.
losquamous variants. A granulomatous element has been described in both ­papular
and papulosquamous eruptions, but this is not a constant ­feature.50 In addition to
a dense dermal infiltrate, large numbers of plasma cells and ­occasional giant cells
are seen in corymbose syphilis. The number of organisms in secondary syphilis
varies. Traditionally, they have been ­identified by the use of silver stains, mainly
Warthin-Starry. However, the ­latter method is time consuming and ­difficult to
interpret. The organisms can also be identified by PCR and a ­polyclonal antibody
against Treponema pallidum is available for immunohistochemistry.53–56 Both
PCR and immunohistochemistry are much more ­specific than ­histochemistry in
the diagnosis of syphilis.55–57 In primary syphilis, the organisms are found both
within the ­epidermis and around blood vessels, while in ­secondary syphilis organ-
isms are mainly found within the epidermis, suggesting that these patterns can
be used as an aid in distinction between the two stages of syphilis.56 The ­bacteria
have also been identified in vivo in the epidermis by the use of reflectance confocal
microscopy.58 In a case of malignant syphilis, a ­surprisingly very low number of
organisms was found in the lesions.59 Spirochetes have been ­demonstrated within
hair follicles in a case of alopecia syphilitica.60
The nodular variants of secondary syphilis may be associated with granu-
lomatous or pseudolymphomatous histology.61–63 Some lesions can contain
an impressive number of CD30-positive atypical T cells.64 The granulomata
can mimic those of sarcoid and may rarely have a palisaded distribution
resembling granuloma annulare.61,65 The rupial and condylomatous forms
are characterized by marked epidermal hyperplasia, spongiosis and a neutro-
phil infiltrate. The dermis contains a very heavy inflammatory cell infiltrate
including numerous plasma cells. Vascular changes are marked.
Late secondary lesions are typified by histiocytic granulomata.40 These are
not well circumscribed and do not usually include multinucleated giant cells.
They can be distinguished from tuberculosis by the presence of numerous
plasma cells peripherally and the swollen endothelia of small blood vessels.
Gummata are characterized by central necrosis similar to caseation, but
with a visible suggestion of residual cell outlines (Fig. 12.123). The necrosis
is surrounded by a lymphohistiocytic and plasma cell infiltrate with fibrosis.
Spirochetes are very scanty and very difficult to find with the use of silver
stains. Endarteritis is often evident.
Noduloulcerative lesions are granulomatous and typically there is no
­significant necrosis. Plasma cells are said to be inconspicuous, which may
therefore cause considerable diagnostic difficulty.41,66

Granuloma inguinale
Clinical features
Granuloma inguinale (donovanosis) occurs in people with poor hygiene in
Fig. 12.121 tropical regions, mainly in India, Brazil, the West Indies, South China and West
Secondary syphilis: innumerable plasma cells are present. Africa; it was formerly seen in southern USA, but is now rare.1–7 The disease

Fig. 12.123
Gumma: high-power view reveals ghost outlines of cells and connective tissue.
is still seen in Australia in the Aboriginal population.8 The organism is of low
infectivity and is presumed to be spread by sexual contact, probably through
abraded skin. It occurs most often in the third to fifth decades.1 The incubation
period is uncertain and may range from 2 to 3 weeks to several months.9
The initial presentation in females is usually of one or more indurated
­papules or nodules on the inner aspect of the labia, the fourchette or around
the clitoris (Fig.  12.124).10 In males, the glans, prepuce, coronal sulcus or
shaft is affected (Fig. 12.125). Dorsal perforation of the prepuce can occur
as a late complication.11 The perianal and inguinal regions and the cervix
may also be involved.12–15 In one case involving the cervix there was associ-
ated malacoplakia.15 The papules ulcerate irregularly and extend widely if
untreated. The base of the ulcer is ‘beefy’ and the margins are undermined
and indurated. Spread to contiguous ‘kissing’ areas may sometimes occur.
Variants include verrucous, necrotic and scarring lesions.1 Primary infection
of the lymph nodes does not occur, but painful lymphadenopathy is ­common
due to secondary infection. Rarely, primary extragenital lesions may be
Fig. 12.124
Granuloma inguinale:
early lesion showing an
ulcerated papule adjacent
to the clitoris. By courtesy
of J. Lawson, MD,
University of Newcastle-
upon-Tyne, UK.
Infectious diseases 473
Fig. 12.125
Granuloma inguinale: in this patient there is extensive ulceration of the glans penis.
Note the typical ‘beefy’ appearance. By courtesy of C. Furlonge, MD, Port of Spain,
Trinidad.
seen (mainly mouth or lips but also at unusual sites such as the foot).12,16–18
Exceptionally, presentation as a psoas abscess and as a pelvic mass mimicking
ovarian cancer has been described.19–21
Very occasionally, there is a systemic infection with involvement of
many organs including the liver, and osteolytic lesions in bone.22 The lat-
ter may particularly relate to a primary cervical lesion.1 Spinal compression
has also been reported.23 Later complications include strictures of the ure-
thra, vagina or anus, destruction of the penile shaft with autoamputation
and pseudoelephantiasis.1,24–27 As with other sexually transmitted diseases,
patients with granuloma inguinale are often HIV positive and may also have
syphilis.9,28 Genital squamous cell carcinoma is an uncommon but important
­complication.1,29,30 Infection in children has rarely been reported and occurs
as a result of transmission from an infected mother at birth.31 Rare manifes-
tations of the disease in children include a mass in the neck, otitis media and
mastoiditis.32,33
Pathogenesis and histological features
Granuloma inguinale is caused by Calymmatobacterium ­granulomatis
­(formerly Donovania granulomatis), an encapsulated short (1–2 μm)
­Gram-negative rod with characteristic bipolar staining. It is transmitted by
sexual contact, but it is of low infectivity.1 The organism is found in feces and
this may act as a reservoir of infectivity or, in occasional cases, be the source
of genital infection. The higher incidence of infection in homosexuals may
­support this concept.
The lesion is characterized by a very intense inflammatory infiltrate
in which plasma cells are predominant (Fig.  12.126). Focal forma-
tion of neutrophilic microabscesses is frequent. Pathognomonic mac-
rophages contain cytoplasmic cyst-like vacuoles in which bacteria can
be demonstrated by staining with Giemsa or the Warthin-Starry reaction
(Figs 12.127, 12.128).34 The bacteria can also be seen extracellularly. In
most cases there is associated acanthosis, which sometimes amounts to
­pseudoepitheliomatous hyperplasia. Ulceration is common. A recent large
study has ­demonstrated frequent transepidermal elimination of organ-
isms.35 It is likely that this phenomenon may be an important mechanism
in the spread of the disease.
Diagnosis is confirmed by the identification of typical organisms
(Donovan bodies) on a scraping from an ulcer or in a biopsy stained with
Giemsa or Warthin-Starry. More recently, polymerase chain reaction (PCR)
has been used successfully to confirm the diagnosis.36 Dark-field illumination
­microscopy should be performed to exclude syphilis. By electron ­microscopy,
the ­encapsulated microorganisms can be demonstrated within the ­phagosomes
of macrophages.9,37
474 Diseases of the anogenital skin

Fig. 12.126
Granuloma inguinale: biopsy from the penis. Note the pseudoepitheliomatous
hyperplasia. There are intense inflammatory changes.
Chancroid
Clinical features
Chancroid (soft chancre, genital ulcer disease) is very common in some tropi-
cal areas of Africa, Southeast Asia, Central America and the Pacific.1–4 Poor
hygiene is a feature of communities where the disease is endemic.5 It is associ-
ated with an increased risk of transmission or acquisition of HIV.6,7 Genital
ulcers including chancroid appear to develop more commonly in HIV-positive
women during the first month of antiretroviral therapy.8 It has also been diag-
nosed more frequently in Western Europe and North America in association
with increased travel, immigration and prostitution. Chancroid was endemic
in New York City and southern Florida in the 1980s.6 It represented 3% of
genital ulcers in a sexually transmitted disease clinic in Paris.9 The disease is
acquired almost always by sexual contact and has a short incubation period
of 3 days to 2 weeks (median 7 days). Exceptionally, nonsexually transmitted
lower limb chancroid ulcers have been reported in patients from Papua New
Guinea and Samoa, in both adults and children.10,11 Concurrence with other
sexually transmitted d ­ isease including gonorrhea can be seen.12
The initial lesion is usually a transient vesicular tender papule, which
rapidly ulcerates with copious suppuration. The ulcer is sharply circum-
scribed with an undermined edge and is typically not indurated.2 These
lesions appear much more commonly in the male, usually on the penis
(Fig. 12.129). The prepuce, coronal sulcus, frenulum and glans are the most
favored sites.6 Circumcised males are at lower risk of developing the dis-
ease.13 Lesions in the female are seen on the fourchette, labia majora and
minora, and ­periclitorally. The perineum and perianal area may also be
affected. Multiple ulcers can be present, which have an irregular ragged edge
and slough-covered bases. Cervical and vaginal involvement is uncommon.
Variants of primary chancroid ulcers include giant and serpiginous forms,
follicular, transient and dwarf lesions; occasionally a condyloma lata-like pre-
sentation may occur.2
The ulcers are tender and especially painful when in contact with urine.
Lymphadenitis occurs in about 50% of cases approximately 1 week after the
genital lesion and, in 50% of these, suppuration (bubo formation) ­usually
­follows. Sometimes rupture may occur, resulting in inguinal ulceration. In
other cases the course is variable, some resolving without treatment in a
few days while others go on for several weeks, developing phimosis or even
­gangrene. Systemic infections do not occur.2

Pathogenesis and histological features

Fig. 12.127 Chancroid is caused by Haemophilus ducreyi, a Gram-negative coccobacil-
Granuloma inguinale: the infiltrate consists of lymphocytes, neutrophils, plasma lus, which grows in chains sometimes arranged in parallel. It is transmitted
cells and conspicuous pale-staining histiocytes. through minor abrasions during sexual intercourse. The subsequent lesion
comprises:

Fig. 12.128 Fig. 12.129
Granuloma inguinale: the histiocytes contain characteristic Donovan bodies Chancroid: irregular ulcer extending along the coronal sulcus of the penis. By courtesy
(Warthin-Starry stain). of R.A. Marsden, MD, St George’s Hospital, London, UK.
 Infectious diseases 475

Fig. 12.130 Fig. 12.131
Chancroid: (A) biopsy Chancroid: note the coccobacilli growing in chains.
through an ulcer on the
glans penis; (B) note the
conspicuous plasma cells. homosexuals and in the context of HIV infection.1–5 It is less common in
By courtesy of S. Lucas, women.6–10
A MD, St Thomas’ Hospital, The disease evolves in three stages:
London, UK. • In stage 1 disease the primary lesion develops 3–30 days after contact
and is a small, transient, frequently asymptomatic papulovesicle
or ulcer on the penis, scrotum, rectum, vulva, vagina and/or cervix
(Figs 12.132,12.133).11 The most commonly affected site on the vulva
is the fourchette.6 Primary lesions have been described on the fingers
and tongue.12 Rarely, lymphogranuloma venereum has been reported
presenting with a psoas abscess.13 Cat scratch disease may clinically
simulate this disease.14
• Stage 2 develops within a few weeks of the primary lesion and consists
of enlargement of the regional lymph nodes; the inguinal nodes in the
male, and, in the female, the inguinal and/or pelvic lymph nodes. The
lymphadenopathy is severe and initially painless and hard; later the
nodes (buboes) soften and discharge viscous pus. The tissue around
the nodes becomes involved in the inflammatory process so that they

• a superficial zone of neutrophils, red cells, bacteria and cell debris,

• a middle zone of edematous granulation tissue,
• an underlying infiltrate of histiocytes, lymphocytes and plasma cells
(Figs 12.130, 12.131).
The enlarged lymph nodes show central necrosis with a surrounding mixed
inflammatory response of neutrophils and macrophages.
Diagnosis is confirmed by isolation of the organism by culture in a blood-
enriched medium containing vancomycin at 33°C. The bacterium may be
identified by its chain-like growth in scrapings from the margin of the ulcer,
but secondary organisms are often present and it is more helpful to identify
the organism in an aspirate from a necrotic lymph node. DNA in situ hybrid-
ization and polymerase chain reaction for H. ducreyi has been developed.14,15
DNA from the organism has been detected by polymerase chain reaction in
esophageal lesions of HIV-positive patients.16

Lymphogranuloma venereum Fig. 12.132

Lymphogranuloma
venereum: note the ulcer
Clinical features on the right labium majus.
Lymphogranuloma venereum is endemic in Asia, Africa and South America By courtesy of S. Lucas,
and was considered to be rare in developed countries until several outbreaks MD, St. Thomas’ Hospital,
were reported in a number of European countries and the USA, mainly in London, UK.
476 Diseases of the anogenital skin
Fig. 12.133
Lymphogranuloma venereum: there is an ulcer on the penile shaft covered with
necrotic debris. By courtesy of the Institute of Dermatology, London, UK.
become matted together. Along with lymphadenopathy, the patient may
also experience malaise, joint pains and hepatosplenomegaly. Erythema
nodosum, light-sensitive eruptions and erythema multiforme may
complicate this phase and are more common in women.
• Stage 3 disease consists of complications of the early inflammatory
changes. Involvement of the deep iliac and perirectal lymph nodes
resulting from drainage from a high vaginal, posterior urethral, cervical
or rectal primary lesion may be complicated by a stricture of the rectum
5–10 cm from the anus.15 This is associated with periproctitis and
proctocolitis, which sometimes fistulates.16,17 Rectal carcinoma is an
occasional late complication.18 In both sexes, genital lymphedema and
even elephantiasis can develop after the lymphadenopathy. This may be
a continuing problem and can be associated with secondary cutaneous
erosions and ulceration.
Systemic lesions are rare, and include cardiac and pulmonary ­involvement,
keratoconjunctivitis, episcleritis, uveitis, papilledema and retinal ­hemorrhages,
meningitis, hepatitis and cutaneous manifestations such as erythema ­nodosum
and erythema multiforme.7,19
Pathogenesis and histological features
Lymphogranuloma venereum is caused by strains L1, L2 and L3 of the
­bacterium Chlamydia trachomatis.20,21 The C. trachomatis species is divided
into 15 prototypic serovars according to analysis of their outer membrane pro-
tein.22 Only serovars L1 to L3 are associated with lymphogranuloma venereum.
Most cases of lymphogranuloma venereum are caused by C ­trachomatis
L2. Chlamydiae are nonmobile, coccoid, obligate intracellular parasites.23,24
They depend upon their host cells for ATP metabolites and multiply within
­membrane-bound vacuoles in the host macrophage cytoplasm.20 They
stain faintly blue with hematoxylin and eosin, Gram-negative with the
Brown-Hopps tissue Gram stain and black with the Warthin-Starry ­silver
impregnation technique.25 On the rare occasions that the primary lesion is
viewed histologically, the base of the ulcer is lined by intensely inflamed
fibrous granulation tissue. Plasma cells and microabscesses are present.
The lymphadenitis has a characteristic picture of stellate central necrosis
with ­neutrophils and a surrounding palisaded granulomatous reaction with
­occasional giant cells.
The central necrosis is slowly absorbed and replaced by fibrosis. As a
consequence, lymphedema develops distally. The lymphatics are typically
inflamed and granulomata may be seen.
Diagnosis is supported by complement fixation tests (rising titers) or
monoclonal antibodies.24 PCR may also be used to confirm the diagnosis.24–26
The Frei skin test is no longer performed. Confirmation of the diagnosis is
best established by isolation of the organism in tissue culture and by lymph
node biopsy.27
Schistosomiasis
Clinical features
Schistosoma hematobium and Schistosoma mansoni are both found exten-
sively in Africa. S. mansoni also occurs in the West Indies and in parts of
South America. S. japonicum is present in China, Japan and Southeast Asia.
These trematodes (blood flukes) do not often cause major disease of the skin,
but skin lesions do occur at various stages of infestation.1–13
Invasion of the human host by the aquate cercarial stage may be associated
with dermatitis (swimmer’s itch).3,9,11 This rash is erythematous, pruritic and
urticarial, but eventually resolves to leave a pigmented spot. It is more often
encountered with invasion of avian species.3
In schistosomiasis (bilharziasis) the mature worms may be associated
­non-specifically with erythematous itching macules at the time of release of large
­numbers of eggs. This probably represents a systemic reaction to antigen libera-
tion. A more severe reaction seen particularly with S. japonicum is Katayama
disease or Yellow River fever. In addition to erythema, macules and pruriginous
lesions, patients may also have fever, malaise, chills, sweats, arthralgias, headache,
­lymphadenopathy, hepatosplenomegaly and peripheral blood eosinophilia.3
Specific skin lesions are seen, usually around the genitalia and most often
in women mainly before puberty, when ova are deposited there (Fig. 12.134).
They appear as grouped solid papules, which subsequently become warty
and vegetative, resembling condyloma acuminatum (Fig. 12.135). The labia
majora are often involved first. Occasionally, progression to squamous cell
carcinoma occurs. Periurethral granulomata due to schistosomes may be asso-
ciated with thrombosis and necrosis, sometimes resulting in fistula formation
in the perineum (‘watering can perineum’).3 In late lesions prominent ­scarring
may occur. More rarely, entrapped ova are seen in other areas of skin, but
the means of their migration to those sites is not understood. Extragenital
lesions of schistosomiasis have been described in the trunk (mainly periumbil-
ical but also in the axilla, back and inframammary area), face and proximal
lower limbs.4,6,8,14 Facial lesions may be associated with ocular involvement.8
Extra-anogenital schistosomiasis, also known as extra-anogenital bilharzia-
sis cutanea tarda, is very rare and its recognition is extremely important as
it is usually a sentinel as well as a potential external marker of recurrent
­visceral disease.14 Interestingly, it has been noted that this type of disease often
occurs in ­pre-existing cutaneous pathology including a squamous ­papilloma,
squamous cell carcinoma, scarring and hidradenitis suppurativa.14
Fig. 12.134
Schistosomiasis: early
lesion showing labial
erythema and swelling.
These features are
a response to ova
deposition. By courtesy of
P. Dowd, MD, Middlesex
Hospital, London, UK.

Fig. 12.135
Schistosomiasis: this warty pale nodule has almost completely replaced the left
labium majus; other vulval manifestations include schistosomal condylomata, ulcers
and rarely, vitiligo. By courtesy of the late M.S.R. Hutt, MD, St Thomas’ Hospital,
London, UK.
Pathogenesis and histological features
Part of the life cycle of schistosomes takes place in water snails. After their
release from the snails, the cercaria penetrates the skin of humans and migrate
as schistosomes to the portal veins where they mature into adult male and
female worms. Adult females then migrate to the mesenteric plexus (S. mansoni
and S. japonicum) or vesical plexus (S. haematobium). Ova are deposited
in the venules, and the clinical and pathological sequelae are a direct conse-
quence of the immunological response to their presence.
Eggs are released into the urine or feces where they hatch, releasing
miracidia, which enter the snail host. Involvement of the female genital tract
is usually due to S. hematobium and occurs as a consequence of worms being
transported via anastomoses between the vesical and uterovaginal venous
plexuses.
Histologically, adult worms are occasionally seen within the lumina of
dilated deep dermal veins and lymphatics (Fig.  12.136). Viable ova may
be present with a recognizable miracidial structure (Fig.  12.137). These
are ­usually located within abscesses containing numerous ­neutrophils
Fig. 12.136
Vulval schistosomiasis: adult worms within a dilated lymphatic; the male
characteristically embraces the female in the gynecophoric canal.
Infectious diseases 477
Fig. 12.137
Schistosomiasis: these ova are surrounded by a heavy infiltrate with conspicuous
eosinophils.
and ­variable numbers of eosinophils. Poorly formed granulomata with
Langhans giant cells are also sometimes a feature. S. hematobium is
­recognized by its terminal spine (Fig.  12.138). S. Mansoni has a lateral
spine and S. ­japonicum has no spine. The dead ova typically calcify and
provoke a chronic, ­frequently granulomatous, inflammatory response.
The ­overlying epidermis is usually acanthotic, sometimes to the point of
­pseudoepitheliomatous hyperplasia and may occasionally contain intra-
epidermal ova undergoing transepidermal elimination (Fig.  12.139).15,16
Smearing crushed biopsies between two glass slides with 0.5% tryptan blue
in saline helps to highlight the ova.17 Adult parasites can sometimes be iden-
tified in ­anogenital and extragenital lesions.14
Identification of the type of schistosoma can be made by molecular
methods.18
Fig. 12.138
Schistosoma hematobium:
the terminal spine is
characteristic of this
species.
478 Diseases of the anogenital skin

Fig. 12.139 Fig. 12.140
Schistosomiasis: there is marked acanthosis. Ova are present within a breach in the Amebiasis: biopsy from a vulval ulcer, which developed as a result of direct spread
epidermis. from the anus.

Amebiasis cutis
Clinical features
Cutaneous lesions of Entamoeba histolytica are rare and more likely to occur
in adults,1–3 although cases in children have been described.4–6 These are most
commonly seen after surgical treatment of intestinal or hepatic amebiasis, but
may also occur by direct extension, perianally from the bowel or from hepatic
involvement, and by direct inoculation of the skin from other infected lesions.
Penile amebiasis may follow anal intercourse or vaginal intercourse if the
female has amebic vaginitis. HIV infection should be suspected.7 Cutaneous
lesions have been recorded on the trunk, buttocks, face (including the eyelid
and the orbit), genitalia, perineum and on the legs.3,8–12 The cervix is often
affected in genital lesions.13 Subcutaneous swellings called amebomas have
been described.9 Patients with deep tissue involvement tend to have associ-
ated contiguous disease and the prognosis tends to be worse. In HIV/AIDS
the outcome is associated with coexisting systemic diseases and death may
ensue in patients with extensive internal involvement.14
Lesions present as cutaneous ulcers with a central necrotic zone covered by a
purulent exudate, an undermined margin and an erythematous halo. The ulcers
Fig. 12.141
are irregular, but sharply defined. They spread and do not heal spontaneously.
Amebiasis: the floor of the ulcer is covered by a dense fibrinous exudate.
They are extremely painful and may be destructive. Presentation can also be
with fistulae, fissures, abscesses and polypoid or warty lesions.14 Occasionally
the latter are large and resemble ulcerating tumors. Sometimes they mimic
squamous cell carcinoma.15,16 Cases of amebiasis presenting as balanitis have
been described.17 Although painful swelling and ulceration are the principal
clinical features, frequency, dysuria and retention may be complications

Histological features
Lesions are characterized by prominent ulceration, necrosis and a mixed
inflammatory cell infiltrate composed of lymphocytes, histiocytes, plasma
cells and neutrophils. The trophozoites of E. histolytica are found within
the purulent ulcer exudate and are best identified with PAS staining
(Figs 12.140–12.142).13,18 They are distinguished by their tendency to phago-
cytose red blood cells. Trophozoites and cysts are usually found in the patient’s
feces. The organisms are surrounded by neutrophils, with some lymphocytes
and plasma cells. The adjacent epidermis appears acanthotic and this may be
marked or pseudoepitheliomatous in verrucous forms. In some cases there is
thrombosis or vasculitis with intravascular amebic trophozoites.13

Demodecidosis
The pathological role of the mite Demodex folliculorum in human cuta- Fig. 12.142
neous diseases such as rosacea is controversial. However, Hwang et  al.1 Amebiasis: there are numerous trophozoites present. Note the ingested red
have described a man with a long-standing pruritic eruption of multiple, blood cells.

­ onomorphic, match-head sized, flesh-colored papules on the penis and
m
scrotum. Histology demonstrated intrafollicular mites and the patient was
cured with topical crotamiton.
Malacoplakia
Clinical features
Malacoplakia (soft plaque) is a result of impaired macrophage function in the
inflammatory response to bacterial pathogens, most notably Escherichia coli
but other organisms, including Staphylococcus aureus, Proteus, Pseudomonas,
Klebsiella and mycobacteria can be involved. Primary or acquired immuno-
deficiency has been found in 40% patients.1 The latter include HIV and solid
organ transplantation, mainly renal and, very rarely, heart transplant.2–4
It is most frequently described affecting the urinary tract, but it can involve
many other organs including the gastrointestinal system, lymph nodes, lower
genital tract, brain, bone, lungs, adrenals and skin.5–13 Cutaneous lesions may
be dermal and/or subcutaneous and are most common around the genitalia
(particularly the vulva) or perineum in about 41% of cases, but can be seen
at other sites including the trunk in 20% of patients, head and neck in 20%,
limbs in 10% and axilla in 10%.7 Multiple cutaneous sites can be involved
and in an exceptional case there was involvement of the skin with extension
into the calvarium and the brain parenchyma.7 Involvement of Bartholin’s
gland has also rarely been reported.14 Cutaneous manifestations are variable
and include papules, plaques, polyps, ulcers and sinuses. Vaginal bleeding
may occur. There may be associated malacoplakia at other sites.
Underlying or related conditions, which are usually associated with immu-
nosuppression, include carcinoma, rheumatoid arthritis, systemic lupus
erythematosus, hepatitis C, sarcoidosis, leukemia, lymphoma and transplan-
tation.5,8,15 The skin lesions are nonprogressive, but are typically persistent.
Pathogenesis and histological features
Malacoplakia is characterized by confluent sheets of histiocytes with eosinophilic
granular cytoplasm and small, usually eccentric, nuclei. There are characteris-
tic cytoplasmic, calcified, von Kossa-positive inclusions known as Michaelis-
Gutmann bodies (Figs 12.143, 12.144). These are sometimes laminated and
this can be accentuated with PAS staining. They may also be positive on staining
with Perl’s reaction for iron. The Michaelis-Gutmann body is sufficiently distinc-
tive to allow cytological distinction of malacoplakia in a preparation from a skin
scraping.16,17 The histiocytic infiltrate may be mixed with neutrophils, lympho-
cytes and plasma cells, with associated granulation tissue. Electron microscopy
of malacoplakia shows the histiocytes to contain ­numerous ­phagolysosomes,
sometimes with intact and/or partly digested ­bacteria. It appears that the
­phagolysosomes accumulate in response to chronic bacterial infections.
Fig. 12.143
Malacoplakia: the infiltrate consists of histiocytes with eosinophilic cytoplasm. Note
the pale blue, laminated Michaelis-Gutmann bodies.
Miscellaneous conditions 479
Fig. 12.144
Malacoplakia: the Michaelis-Gutmann bodies can be highlighted with the von Kossa
reaction.
Fournier’s gangrene
Fournier’s gangrene is analogous to necrotizing fasciitis and Meleney’s gan-
grene. The disease begins with urethral or appendageal polybacterial infection.
Most of the organisms isolated are resident urethral or lower gastrointestinal
flora, and most patients have mixed infections. In children, staphylococci and
streptococci are most commonly isolated.1 A necrotizing vasculitis is initiated
that involves skin, subcutis, fascia and muscle. Classically painful erythema-
tous swelling of the genitals occurs (particularly the scrotum 2, where a dark
red or a black spot may appear) that spreads to perianal or lower abdominal
skin and there may be urnary retention.3 There is crepitus but no suppura-
tion.4 In adults there is systemic toxicity but this may be absent in children.3
Necrosis of skin and deeper tissues can occur rapidly, and there is a very
high mortality unless the diagnosis is made promptly and radical manage-
ment undertaken. Preceding surgery and instrumentation in patients with the
listed risk factors is particularly important.
In adults, the mortality is approximately 25% but it is lower in
children.3,5
The clinical differential diagnosis of Fournier’s gangrene includes trauma,
herpes simplex, cellulitis (streptococcal, staphylococcal), streptococcal necro-
tizing fasciitis, gonococcal balanitis and edema, ecthyma gangrenosum, aller-
gic vasculitis, polyarteritis nodosa, necrolytic migratory erythema, vascular
occlusion syndromes and warfarin necrosis.
Miscellaneous conditions
Vulvodynia
Vulvodynia is the term used to describe a burning or soreness of the vulva in
the absence of any visible cause. It is a sensory disorder and has now been
divided into two categories: touch provoked (vestibulodynia) and spontane-
ous vulvodynia. It is a clinical and not a histological diagnosis but it is worthy
of a mention as it is in the older textbooks under the heading of vestibulitis.
The term vestibulitis is a misnomer as it is not an inflammatory dermatosis
as was once thought.1 The inflammatory changes reported on biopsies from
women with this sensory disorder were non-specific and could also be found
in healthy normal vestibular epithelium.2–4 Vestibulitis, now termed touch
provoked vulvodynia (vestibulodynia), is characterized by a constellation of
symptoms and signs which include secondary dyspareunia and point tender-
ness in the vulval vestibule (particularly at 5 and 7 o'clock over the openings
to the greater vestibular glands of Bartholin) and variable erythema at these
sites (Fig. 12.145).5 In a study to validate these criteria, erythema was found
to be an unreliable clinical sign.6 There is no relationship to HPV infection or
chronic candidal infection.7,8
480 Diseases of the anogenital skin

Fig. 12.146
Fig. 12.145 Scrotal calcinosis: (A)
Vestibulitis: there is marked vulval erythema. By courtesy of C. Furlonge, MD, Port characteristic yellow
of Spain, Trinidad. papules and nodules are
present; (B) close-up view
of the lesions.
Idiopathic calcinosis By courtesy of the
A Institute of Dermatology,
London, UK.
Clinical features
Genital calcinosis is uncommon. It occurs much more frequently in the scro-
tum than in the vulva, where it has only seldom been reported.1–8 Very rarely,
idiopathic calcinosis may develop in the penis or areola of the nipple.9,10
Lesions present as single or multiple hard nodules in children and young
adults (Fig. 12.146). Occasionally nodules break down and discharge chalky
material. Some lesions are polypoid and in this setting the clinical diagnosis is
difficult if only a single lesion is present.11–13 Very young children can excep-
tionally present with single or multiple calcified scrotal lesions secondary to
meconium periorchitis.14,15

Pathogenesis and histological features

Although originally thought to represent an idiopathic condition, it more
likely that this disorder develops from dystrophic calcification of epidermoid
cysts or the contents of cystically dilated eccrine ducts.16–22 It has also been
suggested that the condition can result from dartos muscle degeneration.23
Scrotal calcinosis is characterized by single or multiple dermal nodules of
dystrophic calcification (Fig. 12.147). In some cases, there is histological evi- B
dence of a pre-existing and partially destroyed cyst.
in Japan and have predilection for the genitourinary system but can occur
Dermatitis artefacta elsewhere including the rectum.6–8 Granulomatous penile nodules (Tanko’s
Dermatitis artefacta localized to the anogenital area is sometimes encoun- nodules) have been described due to the insertion of glass spheres under
tered (Figs  12.148–12.150). At this site the injuries may be sustained in the penile skin.9
the course of sadomasochistic sexual gratification1 due to algolagnia (love
of pain). A biopsy is usually obtained to exclude penile cancer but it is Histological features
important also to consider pyoderma gangrenosum; although rare, it is There is a foreign body-type granulomatous reaction in the dermis. ‘Lipid’
­frequently omitted from the differential diagnosis of anogenital ulceration vacuoles are surrounded by dense fibrous tissue. Rare extensive necrosis in a
by nondermatologists. case of primary sclerosing lipogranuloma has been documented.8

Sclerosing lipogranuloma Pilonidal sinus

Clinical features
Sclerosing lipogranuloma (paraffinoma) may involve the scrotum, penis
and exceptionally the epididymus.1–3 It usually represents a tissue response
to ­exogenous material (usually paraffin, silicone and even mineral oil and
Vaseline) and is seen most commonly in the paratesticular area second-
ary to the injection of size-enhancing materials.4,5 A very small number of
cases of sclerosing lipogranuloma appear to be primary, are more common
Clinical features
This condition mainly occurs in the sacrococcygeal region and has only rarely
been reported as occurring in the penis.1–8 Only about 20 cases have been
reported in the literature. Lesions present in uncircumcised adults with a pre-
dilection for the dorsal aspect of the coronal sulcus. It has been postulated that
penile pilonidal sinus develops because the coronal sulcus acts as a cleft where
hairs can accumulate and eventually penetrate the shaft and the foreskin as a
 Pigmented lesions 481

Fig. 12.147 Fig. 12.148 Fig. 12.149

Scrotal calcinosis: the calcium deposits stain purple
with hematoxylin and eosin. Sometimes a pre-
existent epidermoid cyst can be identified.
Dermatitis artifacta: there is gross destruction of
the penile shaft. From Bunker C: Male Genital Skin
Disease. Saunders Ltd./Elsevier 2004.
Dermatitis artifacta: note the circumferential
ulceration. Reproduced with permission from
Bunker CB and Mallon E, Management of penile
erosions and ulcers, Postgraduate Doctor Middle
East, 1998;21:163–168. Copyright © Professional
Managerial and Healthcare Publications Limited.
From Bunker C: Male Genital Skin Disease. Saunders
Ltd./Elsevier 2004.

result of friction between these two surfaces. The symptoms are those of chronic
inflammation and abscess formation. Pilonidal sinus has been associated with
actinomycosis, squamous cell carcinoma and verrucous carcinoma.1,8–10

Histological features
The histopathology is identical to that of pilonidal sinus occurring at the usual site.

Pigmented lesions
Melanocytic lesions are not the only cause of genital pigmentation.
Postinflammatory hyperpigmentation following an inflammatory dermatosis
such as lichen planus is much more commonly encountered. However, only
melanocytic genital lesions are discussed in this section.

Fig. 12.150
Dermatitis artifacta: this
is a view of the natal
cleft. Note the central
ulceration and surrounding
lichenification. From
Bunker C: Male Genital
Skin Disease. Saunders
Ltd./Elsevier 2004.
Genital melanosis
Clinical features
This condition of the genital skin is characterized by pigmentation with no
overt evidence of a preceding inflammatory dermatosis.1–5 However, in men
the clinical suspicion is usually raised of past or chronic low-grade lichen
sclerosus, lichen planus, Zoon’s balanitis or non-specific balanoposthitis. The
pigmentation may vary in its intensity and is typically irregular. The problem
usually affects several sites including cutaneous and mucosal surfaces. The
pigmentation develops slowly and can be very extensive.
Unifocal lesions can also sometimes occur. Small discrete single or multiple
lesions are usually described as genital melanotic macules.4 The commonest sites
are the glans and shaft of the penis and the inner aspects of the vulva including the
vestibule (Figs 12.151, 12.152). Lesions may also affect the vagina and cervix.6,7
482 Diseases of the anogenital skin
Fig. 12.151
Penile melanotic macule: there is a small irregular pigmented macule on the glans
penis. By courtesy of the Institute of Dermatology, London, UK.
Fig. 12.152
Vulval melanosis: there
are multiple irregular
pigmented macules on
the vulva and adjacent
skin. By courtesy of the
Institute of Dermatology,
London, UK.
The condition is considered benign but there are rare anecdotal reports
of melanoma ensuing in areas of melanosis.8,9 This, however, has only been
described in penile melanosis. Melanoma rarely occurs in the context of
­vulval melanosis and this is likely to be due to the fact that in the latter con-
dition there is no increase in the number of melanocytes but only basal cell
layer hyperpigmentation. Penile lesions, on the other hand, often display an
increase in the number of basal melanocytes. Single lesions are very difficult
to distinguish on clinical grounds from either a lentigo or an early junctional
nevus.
Cases of multiple genital lesions associated with oral pigmentation
have been described as Laugier-Hunziker disease (idiopathic lenticular
mucocutaneous pigmentation).10,11 It is worth remembering that rare cases
of Carney's complex may present with lentigines in genital skin and the
­correct diagnosis will only be possible if close attention is paid to the
­ resence of other markers of this disease.12,13 Dowling Degos may also
p
present with genital melanosis.
Histological features
Genital melanosis is characterized by increased pigmentation of basal
­keratinocytes and melanocytes (Fig.  12.153). By definition, there is no
increase in melanocyte number. If, however, melanocytes are present in
increased numbers, the term ‘genital lentiginosis’ may be more appropriate.14
In real terms, the difference is academic. There is no evidence of junctional
activity or cytological atypia. Pigment-laden macrophages may be conspicu-
ous in the underlying dermis. An important pitfall is the presence of coexis-
tent lichen sclerosus, as the dermal changes may mimic a completely regressed
melanoma.15
Genital melanocytic nevi
Clinical features
Acquired melanocytic nevi in the genitalia have been estimated to affect the
various races in the following proportions: whites 9.5%, Latins 21.5% and
blacks 3.5%.1 The prevalence of vulval melanocytic nevi has been reported as
2.3% in one series.2 Junctional, compound and dermal nevi can all occur and
may demonstrate worrisome histological features, often raising the possibil-
ity of malignancy.2–6 Melanocytic lesions presenting in flexural areas (atypical
genital nevi, atypical flexural nevi, milk-line nevi, atypical melanocytic nevi
of genital type), including the axillae, umbilicus, inguinal creases, pubis, scro-
tum and perianal area, similarly may show identical disturbing histological
features.6
In women, the presentation is in young girls or adults and lesions vary in
size from a few millimeters to up to 1 cm (Fig. 12.154). Lesions are typically
located on the labia minora, mucosal surface of the clitoris or labia majora.
Atypical genital nevi should not be confused with dysplastic nevi, which
may also present on the external genitalia, particularly the labia majora.4
Melanocytic lesions on male genital organs are possibly less common than
in females.
Pathogenesis and histological features
Both ordinary and atypical genital nevi can show BRAF V600E mutations
as do nevi and melanomas occurring elsewhere.7 In cases with BRAF muta-
tions, expression of IGFBP7 is maintained, offering a possible explanation as
to why these lesions do not have aggressive behavior even harboring BRAF
mutations.
Banal (ordinary type) and dysplastic nevi are identical to their nongenital
counterparts and are discussed elsewhere.
Fig. 12.153
Vulval melanosis: there is marked basal cell pigmentation.
 Pigmented lesions 483

Fig. 12.154 Fig. 12.156
Atypical vulval nevus: there is an irregular darkly pigmented lesion on the perineum. Atypical genital-type nevus: this is a shave biopsy from the labium majus showing
By courtesy of the Institute of Dermatology, London, UK. a compound melanocytic nevus. The papillomatosis and obvious retraction artifact
around the junctional nests are typical features.

Atypical genital nevi can be a source of considerable diagnostic difficulty

and sometimes alarm which is unfounded as lesions there do not ­usually
­progress to melanoma.8–12 Flexural nevi at other sites are often similar
although the changes are usually less marked. They may be junctional or
compound, symmetrical or asymmetrical, and are typically fairly small, mea-
suring only a few millimeters to 1.0 cm in diameter. The associated epidermis
is typically hyperplastic, and papillomatosis can be marked (Figs.  12.155,
12.156). The junctional component is usually lentiginous and nested and
commonly involves the adnexae in addition to the epidermis. The nests are
often large, surrounded by a retraction artifact and, unlike banal nevi, are
situated along the sides in addition to the tips of the rete; they may also be
located overlying the dermal papillae (Fig.  12.157). Transepidermal elimi-
nation of nests is commonly present and some degree of pagetoid spread
may be a feature.13 The nevus cells are epithelioid in type and often atypical
(Figs 12.158–12.160). The dermal component is composed of morphologi-
cally similar nevus cells, which mature with depth. The cytological atypia can
affect both junctional and dermal components and in some cases is severe.
These features, in addition to dermal mitoses, which are commonly present,
may be extreme and raise the possibility of melanoma. Genital melanoma
is, however, generally a condition of elderly women. The biologic potential

Fig. 12.157
Atypical genital-type
nevus: high-power view
highlighting the retraction
artifact.

of these lesions is benign. Nevertheless, incompletely excised nevi or lesions

Fig. 12.155
Atypical vulval nevus: scanning view of a polypoid lesion from a 17 year old female.
Note the heavily pigmented nests at the top of the field. By courtesy of the Institute
of Dermatology, London, UK.
which extend very close to the radial margin would be best re-excised.
Although there may be some overlap with genital dysplastic nevus, the
latter can be distinguished by the presence of elongation of the rete ridges, a
more lentiginous distribution of the melanocytes, and the induction of lamel-
lar and eosinophilic fibrosis in the papillary dermis in association with a vari-
able mononuclear inflammatory cell infiltrate and pigmentary incontinence.
Any other type of nevus may occur on genital skin including Spitz nevus,
Reed nevus, deep penetrating nevus and blue nevus. Recently, a small series of
epithelioid blue nevi of genital skin in patients with no evidence of Carney’s
complex was reported.14 These lesions were described on the foreskin and
labium minus. Cases of divided or ‘kissing’ nevus (Fig. 12.161) have been
reported affecting the penis, analogous to the situation in the eyelid.15–17
Congenital ‘bathing trunk’ nevi may involve the anogenital area and pose
significant management problems as they carry a very high risk of multifocal
malignant transformation.
484 Diseases of the anogenital skin

A A

Fig. 12.160
(A, B) Atypical genital-type
B nevus: this example from
the vulva of a 20-year-
Fig. 12.158 old female shows severe
(A, B) Atypical genital-type nevus: in this example the junctional nests are large cytological atypia. The
and due to fine melanin pigmentation; the cytoplasm has a grayish hue. Note the biological behavior of this
nuclear hyperchromatism. nevus variant is uncertain
although the likelihood of
malignancy is very low.
B It should, however, be
completely excised.

Melanoma
Clinical features
Female genital melanoma is rare and accounts for around 3% of all female
melanomas and 2–10% of female genital tract malignancies.1–16 Mucosal
female tract melanomas account for 18% of all mucosal melanomas.17 The
vulva is the most frequently involved site followed by the vagina and much
less often the cervix (Fig.  12.162).5,6,8,10,11,18 The labia majora and the cli-
toris are the most commonly affected sites.18 Most patients present in the
sixth and seventh decades of life.19 Less than one-third of cases occur in
patients younger than 50 years of age. Melanoma of the vulva in children
has been very exceptionally reported and in some cases reported in associa-
tion with lichen sclerosus.20,21 An association with melanosis is very rare and
a tumor in a young woman, a frequent user of tanning parlors, has been
documented.22,23
Fig. 12.159 Clinical presentation varies from flat to raised polypoid brown to black
Atypical genital-type nevus: in this field, there is nuclear hyperchromatism and mild lesions. Ulceration may be present. Less commonly, patients complain of
pleomorphism. pruritus and/or bleeding. Amelanotic melanomas are reported to be rare,

Fig. 12.161
Divided or ‘kissing’ nevus: note the pigmented lesions on the shaft and the glans
penis. From Bunker C: Male Genital Skin Disease. Saunders Ltd./Elsevier 2004.
Fig. 12.162
Vulval melanoma: tumors
at this site are very rare.
They are commonly
thick at presentation
and therefore generally
associated with a poor
prognosis. By courtesy of
M. Ridley, MD, Institute of
Dermatology, London, UK.
but they represented 27% of all cases in a large Swedish series.18,24,25 They
may clinically mimic squamous cell carcinoma or extramammary Paget’s
disease.
Some tumors arise within a pre-existing nevus.18 A recent study found the
latter to occur in around 5% of cases.18 Most of these are of the superficial
spreading type.
The 5-year survival varies enormously, ranging from 15% to 54%.4–13,26
A study of 219 vulval melanomas reported a 5-year survival rate of 47%.27
As with melanomas presenting elsewhere, tumor thickness is the best
­predictor of survival.1,27 Staging has also been found to be an ­independent
predictor of survival.27 In addition, in stage I disease only, ulceration and the
presence of clinical amelanosis were found to be independent ­predictors of
survival.27 Radical surgery for vulval melanoma does not seem to ­influence
outcome. A multivariate analysis of 644 patients with vulval melanoma
Pigmented lesions 485
Fig. 12.163
Penile melanoma: note the large size, irregular border and variable pigmentation.
By courtesy of the Institute of Dermatology, London, UK.
found that young age, localized disease and negative lymph nodes were
independent prognostic factors.28 The 5-year disease-specific survival was
75.5%, 38.7% and 22.1% for patients with localized, regional, and distant
disease, respectively.28
Melanoma of the male genital skin is very rare, as are those arising around
or on the anus (Fig. 12.163).29–32 Penile metastasis of cutaneous melanoma
elsewhere is exceptional.33 The commonest site in men is the glans but rare
cases may present elsewhere, including the shaft and the scrotum.34–36 The
diagnosis can be delayed because of the patient’s reluctance to seek medi-
cal help.37 Exceptional cases complicating penile melanosis, penile nevi, have
been reported, also a penile melanoma which developed simultaneously with
squamous cell carcinoma.38–40 Because of the rarity of the disease, estimation
of prognosis is difficult. In the few cases reported, the prognosis appears poor
but this seems to be related to late presentation, delay in diagnosis and prob-
lems in achieving complete clearance because of the site. A study of a series
of 19 primary mucosal penile melanomas and a review of 47 cases reported
in the literature found 2- and 5-year survival rates of 63% and 31%, respec-
tively.40 All patients presenting with nodal and/or distant metastasis died of
disease within 2 years.41 The prognosis is similar in patients who present
with metastatic disease on the penis from a primary tumor elsewhere.42 Poor
prognosis was associated with ulceration, Breslow thickness of more than
3.5 mm and a tumor diameter of more than 15 mm. The behavior of mucosal
penile melanoma appears to be the same as cutaneous melanoma elsewhere
of s­ imilar thickness.
Pathogenesis and histological features
An important number of mucosal melanomas have shown mutations in c-kit
as opposed to melanomas arising in skin exposed intermittently to the sun, in
which BRAF mutations are frequently found.43,44 The presence of c-kit muta-
tions offers the possibility of targeted therapy to those melanomas harbor-
ing the mutation. A study of vulvar and vaginal melanomas detected HPV-3
and epidermodysplasia verruciformis-associated types of HPV in a number of
lesions.45 Since these HPV types are not usually found in the vulva or vagina,
it has been suggested that they may play a role in the pathogenesis of mela-
nomas at these sites.
Histological features of genital melanoma are identical to melanomas else-
where. Until recently, there was no consensus as to the most common type of
genital melanoma. Recently, however, a large study found that 57% of vulval
melanomas were mucosal lentiginous, 22% nodular, 12% unclassified and
4% superficial spreading.16 Desmoplastic and neurotropic variants may also
occasionally be encountered. Multiple in situ penile melanomas have been
documented.46
486 Diseases of the anogenital skin

Epithelial lesions
Benign mucinous metaplasia and mucinous
syringometaplasia
Benign mucinous metaplasia of the penis and vulva is exceptionally rare.1,2
It has been reported on the labia and foreskin. The clinical features are non-
distinctive, and histologically benign mucus-containing cells are found within
the epidermis with a predilection for the upper layers. Distinction from extra-
mammary Paget’s disease is difficult but the cells in benign mucinous meta-
plasia lack cytological atypia and contain nuclei with basal orientation.1
Mucinous syringometaplasia is very rare in genital skin and can be distin-
guished from benign mucinous metaplasia because the cells in the former are
not confined to the epidermis but extend into adnexal structures.3

Endometriosis and endosalpingiosis

Clinical features
Cutaneous endometriosis is uncommon, is predominantly seen in young
females and usually develops in a scar following an abdominal operation
such as a cesarean section.1–5 On occasion, it appears to develop spontane-
ously in the integument (e.g., in the umbilicus, the inguinal region and the
perineum). Endometriosis of the vulva is rare and may occur in an episiotomy
scar or after curettage.6,7 Clinically, it presents as a bluish nodule, which is
often painful, and sometimes shows cyclical variation in size and symptoms.8
Rarely, it may bleed during menstruation. Malignant transformation in cuta-
neous endometriosis is extremely rare.9
Cutaneous endosalpingiosis is a similar condition in which cysts lined by
tubal epithelium develop as a consequence of salpingectomy.10 It is exceed-
ingly rare in the skin and most cases have presented in an abdominal scar
and occasionally in the umbilicus.11,12 One case was associated with severe
abdominal pain.13
Histological features
The diagnosis of cutaneous endometriosis depends upon the detection of both
endometrial glands and stroma (Figs 12.164, 12.165).2 Endometrial glands
are lined by tall columnar epithelium with basophilic cytoplasm and basally
located oval vesicular nuclei. All types of metaplastic changes of the müllerian
epithelium can be seen including tubal, oxyphilic, hobnail, mucinous and pap-
illary syncitial.14 Mitotic activity may sometimes be marked and rarely a­typical
mitotic figures are identified.14 The stroma is composed of small ­spindle cells
and is usually edematous. Occasionally, decidualization is evident. When the
Fig. 12.165
Vulval endometriosis: in this example, there is stromal decidualization.
latter is seen, decidual cells are positive for CD30, the latter being a poten-
tial pitfall in diagnosis.15 Other stromal changes include smooth muscle meta-
plasia, lipoblast-like cells some with intranuclear inclusions, myocytes with
degenerative changes and exceptionally elastosis and perineural invasion.14
Menstrual bleeding into the deposits often leads to hemosiderin deposition,
scarring and chronic inflammation.
Histologically, in endosalpingiosis, the cyst (which is unilocular) is lined by
an admixture of ciliated columnar, nonciliated mucus-secreting columnar and
intercalated dark cells.10 In contrast to endometriosis, there is no associated
stroma and foci of hemorrhage and/or hemosiderin are not seen.
Median raphe cyst
Clinical features
Median raphe cyst (urethroid cyst) is a rare lesion that usually presents on
the ventral aspect of the penis of young adults, with a predilection for the
glans (Fig. 12.166).1–4 Perineal and scrotal lesions may occasionally be seen

Fig. 12.166
Median raphe cyst: there
is a translucent cystic
swelling on the glans
penis. From Bunker
Fig. 12.164 C: Male Genital Skin
Vulval endometriosis: endometrial glands with edematous stroma are present in Disease. Saunders Ltd./
the reticular dermis. Elsevier 2004.
 Epithelial lesions 487

and are rarely polypoid.5–7 Some lesions present as a cordlike induration.8

The cyst is usually congenital but tends to become visible only in adult life,
often after trauma or infection. Exceptional development after orchiopexy
has been documented.9 Lesions are most commonly solitary, asymptomatic
and measure only a few millimeters in diameter. Large lesions are very rare.10
Exceptional cases present with multiple cysts and spontaneous regression has
also been reported.11 Pigmented cysts are due to the presence of melanocytes
in the ­lining.10,12,13 Simple excision is curative.

Pathogenesis and histological features

It is likely that the cyst originates not as a result of defective closure of the
median raphe but secondary to anomalous budding and separation of the
urethral columnar epithelium from the urethra.3
The cyst is lined by pseudostratified columnar epithelium (Figs 12.167,
12.168). Rarely, mucin-containing cells or ciliated cells are seen.14,15
Immunohistochemical stains show that the cells lining the cyst are positive
for cytokeratin 7, cytokeratin 13 and CAM 5.2, and negative for cytokeratin
20. It has been suggested that this pattern of keratin expression supports the
theory that the cells lining the cyst represent a columnar mucinous epithelium
Fig. 12.168
that has undergone immature urothelial metaplasia.16 Scattered melanocytes Median raphe cyst: the cyst is lined by pseudostratified epithelium. By courtesy of
and neuroendocrine cells (positive for chromogranin and synaptophysin) may C. Gulmann, MD, Beaumont Hospital, Dublin, Republic of Ireland.
also be identified.16 Although this lesion may mimic an apocrine ­cystadenoma,
this line of differentiation is unlikely, as the cells in the cyst are ­negative for
human milk fat globulin 1.17

Bartholin duct cyst

Clinical features
These lesions present in women of reproductive age as a result of obstruction
of the main duct of Bartholin’s gland.1 They are relatively uncommon and
occur in the posterior aspect of the labium majus. Size varies from 1 cm to
several centimeters in diameter. Cysts are usually asymptomatic but the devel-
opment of a Bartholin’s gland abscess is a relatively common complication as
the retained glandular secretions become infected.

Histological features
The cyst is lined by transitional epithelium, which frequently undergoes
squamous metaplasia (Figs 12.169, 12.170).2 Very rarely, a papilloma has

Fig. 12.169
Bartholin duct cyst: low-power view of the cyst. By courtesy of C. Crum, MD, Brigham
and Women’s Hospital and Harvard Medical School, Boston, USA.

been reported developing within a cyst.3 The exceptional development of a

high-grade squamous cell carcinoma associated with HPV 16 within a cyst
has also been described.4

Fig. 12.167
Median raphe cyst: low-
power view of cyst.
By courtesy of C.
Gulmann, MD, Beaumont
Hospital, Dublin, Republic
of Ireland.
Mucinous cyst
Clinical features
These are rare lesions in men that present as small flesh-colored, midline,
translucent, mobile, papules (2 mm) to nodules (25 mm), usually easily deter-
mined to be cystic on clinical grounds.1,2 They do not have a punctum. Either
they are asymptomatic or they become infected or interfere with sex. They
have usually been present from birth or childhood and are common near the
glans penis or on the foreskin but may occur anywhere from the urethral
meatus to the anus and present at any age in life. The assessment of such cysts
should involve the exclusion of secondary infection, for example gonorrhea.
Vulval lesions are mainly seen adult women and presents as a solitary
or, less often, multiple lesions in the vestibule.3–5 Rare cases are found in
­adolescents. This cyst arises as a result of obstruction of the duct of a minor
vestibular gland. Simple excision is curative.
488 Diseases of the anogenital skin

Fig. 12.170 Fig. 12.172
Bartholin duct cyst: the Mucinous cyst: the cyst is lined by mucin-secreting epithelium. By courtesy of C. Crum,
cyst is lined by transitional MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
epithelium. By courtesy
of C. Crum, MD, Brigham
and Women’s Hospital and
Harvard Medical School,
Boston, USA.

Pathogenesis and histological features

Lesions in women were thought to be derived from müllerian epithelium.
It is more likely, however, that lesions in both men and women derive
from ­ectopic urogenital sinus epithelium.2,6,7 The cyst is lined by a layer
of ­mucinous ­epithelium with occasional focal squamous metaplasia
(Figs 12.171–12.173).3–5 Myoepithelial cells are not identified.

Mesonephric cyst
Clinical features
This lesion presents in the lateral part of the vulva as a small, asymptomatic,
blue–red cystic lesion containing clear fluid. It is thought to be derived from
remnants of the mesonephric duct. Simple excision is curative.
Fig. 12.173
Mucinous cyst: the mucin stains bright red with mucicarmine. By courtesy of C. Crum,
MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.

Histological features
The cyst is lined by a single layer of cuboidal or columnar nonciliated cells
surrounded by a layer of smooth muscle.1

Mesothelial cyst
Clinical features
Mesothelial cyst (cyst of the canal of Nuck) presents as a lesion varying in size
from less than 1 cm to 5 cm or more. It arises on the upper and lateral aspect
of the labium majus at the level of the insertion of the round ligament. Some
cases are associated with an inguinal hernia. Simple excision is curative.

Histological features
Fig. 12.171
Microscopic examination reveals a unilocular cavity lined by a single layer of
Mucinous cyst: low-power
view of mucin-containing flattened mesothelial cells.1
cyst. Note the
nonkeratinizing surface Periurethral cyst
epithelium. By courtesy
of C. Crum, MD, Brigham
and Women’s Hospital
Clinical features
and Harvard Medical This cyst presents as a small or, exceptionally, large swelling lateral to the
School, Boston, USA. urethral meatus.1,2

Histological features
Histological examination shows a cavity lined by transitional epithelium
(Figs 12.174, 12.175).
Penile horn
Cutaneous horn (Fig. 12.176) is a type of verrucous lesion marked by exces-
sive and increasing keratosis, and a penile horn is a rare lesion with only
a handful of reported cases.1–6 The hyperkeratosis of the cutaneous horn
may derive from numerous dermatological lesions including burns, nevi,
angiomas, Bowen’s disease, condylomata, seborrheic keratoses/basal cell
papillomas, basal cell carcinoma, pseudoepitheliomatous hyperkeratotic and
micaceous balanitis, verrucous carcinoma and squamous carcinoma.1,7–10
Chronic inflammation and recent circumcision for long-standing phimosis
are important predisposing factors. The lesion is premalignant or, in one-
third of cases, malignant at presentation with squamous cell carcinoma as
the underlying pathology. Precise diagnosis is achieved by adequate excision
and histology of the whole lesion, with follow-up because recurrence may
occur.11
Fig. 12.174
Periurethral cyst: low-power view of unilocular cyst. By courtesy of C. Crum, MD,
Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
Fig. 12.175
Periurethral cyst: the cyst is lined by transitional epithelium. By courtesy of C. Crum,
MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
Epithelial lesions 489
Fig. 12.176
Penile horn: this lesion arose from an underlying squamous cell carcinoma. Courtesy
of Dr. J. Ponce de Leon, Barcelona, Spain. Reproduced by kind permission of
Blackwell Science from Ponce de Leon J et al. Cutaneous horn of glans penis.
Br J Urol 1994;74:257–8. From Bunker C: Male Genital Skin Disease. Saunders Ltd./
Elsevier 2004.
Pseudoepitheliomatous, keratotic and
micaceous balanitis
Clinical features
Pseudoepitheliomatous micaceous and keratotic balanitis (PEMKB) is a rare
penile condition that was first described by Lortat-Jacob and Civatte.1,2 It
­presents as thick, scaly, micaceous patches3–6 on the glans penis of older
uncircumcised men. Clinically, white, hyperkeratotic and crusted ­‘micaceous’
plaques develop on the glans penis. These lesions are resistant to treatment
and a verrucous (penile horn) or erosive tumor may emerge from them
(Figs. 12.177, 12.178). It has been misdiagnosed as Reiter’s disease. Some
­consider that PEMKB is a form of locally invasive verrucous ­carcinoma,7 ­others
that it is a variant of lichen sclerosus.8 Metastatic spread has not occurred
except where there was a penile horn9 and in one patient who ­developed an
aggressive soft tissue sarcoma of the penis.10 There is no ­association with
human p ­ apillomavirus infection.11
Fig. 12.177
Pseudoepitheliomatous micaceous and keratotic balanitis: verrucous plaques are
present on the glans penis. Courtesy of B. Kumar, MD, Chandigarh, India. From
Bunker C: Male Genital Skin Disease. Saunders Ltd./Elsevier 2004.
490 Diseases of the anogenital skin
Fig. 12.178
Pseudoepitheliomatous micaceous and keratotic balanitis: note the verrucous
plaque. There is underlying lichen sclerosus. Courtesy of B. Kumar, MD, Chandigarh,
India. From Bunker C: Male Genital Skin Disease. Saunders Ltd./Elsevier 2004.
Histological features
Biopsies from early lesions show mild to moderate epidermal hyperpla-
sia with no cytological atypia and a variable focal lichenoid mononuclear
­inflammatory cell infiltrate. Larger lesions display pseudoepitheliomatous
hyperplasia and often there is transition to verrucous carcinoma.
Genital intraepithelial neoplasia and
squamous cell carcinoma
In this text, the term intraepithelial neoplasia is restricted to squamous intra-
epithelial neoplasia and does not include extramammary Paget’s ­disease or
melanoma in situ. The terminology used for premalignant vulval epithelial
lesions has been confusing and unsatisfactory for many years. In 1986, older
terms such as Bowen’s disease, erythroplasia of Queyrat, bowenoid papulo-
sis, multifocal pigmented Bowen’s disease, severe dysplasia and carcinoma in
situ, which represented full-thickness atypia, were abandoned in favor of a
grading system into three categories similar to that used for cervical intraepi-
thelial neoplasia.1–3 VIN grades 1, 2 and 3 represent the degree, in thirds, that
the epithelium is atypical (Table 12.1). This terminology has been extended
to include other perineal sites, for example perianal ­intraepithelial neoplasia
(PaIN 3) and the penis (­ discussed elsewhere).
Furthermore, unique to the vulval skin, ‘VIN 3 differentiated’ was intro-
duced to describe a variant where the neoplastic cells do not extend throughout
the full thickness of the epidermis, which remains well differentiated. However,
this terminology does not compare like with like, since the cervix is covered
by mucosa and most of the epithelium covering the vulva is skin, the only
area that is a mucosa being the vestibule. This newer terminology did not take
into account the clinical and biological differences between the cervix and the
vulva and there was also a misconception that there was a natural progression
through grades 1–3 to invasive squamous cell carcinoma (SCC). In addition,
there were problems with interobserver variation, particularly with VIN 2 and
3, and also poor correlation clinically with some lesions that were histologi-
cally VIN 1 and 2.4 Changes similar to VIN 1 are often found in states where
Table 12.1
Classification of vulval intraepithelial neoplasia
• VIN 1 – mild dysplasia
• VIN 2 – moderate dysplasia
• VIN 3 – severe dysplasia or carcinoma in situ (differentiated and
undifferentiated VIN)
abnormal basal cytology is a result of epithelial reparation (e.g., lichen planus
or basal hyperplasia arising from HPV infection). A newer classification has
therefore been proposed to remove this grading system and replace it with two
types of VIN: VIN undifferentiated (usual type) and VIN differentiated.5
Undifferentiated usual type VIN: This is atypia involving two-thirds to full
thickness of the epidermis of the vulva, previously known as VIN 2 or VIN
3, respectively. This type of VIN is usually associated with the oncogenic type
HPV infection. Changes previously described as VIN 1 are now regarded as
flat condyloma (HPV-associated).5
Differentiated VIN (or carcinoma in situ): This is atypia confined to the
basal area of the epidermis, previously termed VIN3 differentiated. This often
occurs on a background of LS either surrounding an SCC or just prior to the
development of malignant change. This type of VIN does not appear to be
associated with HPV infection. Differentiated VIN has a higher risk of pro-
gression to invasive squamous cell carcinoma.6
This terminology is still far from perfect, particularly as differentiated VIN
may mistakenly be thought of as having a better prognosis than undifferenti-
ated VIN. Contrariwise, differentiated VIN developing against a background
of lichen sclerosus is much more likely to be associated with progression to
invasive tumor and aggressive behavior than HPV-associated undifferentiated
lesions. Most often, it is seen in vulvectomy specimens from women with SCC
arising in a background of lichen simplex or lichen planus.
Clinical features
Clinical lesions of undifferentiated VIN (usual type) may be unifocal and dis-
crete or multifocal and diffusely distributed about the external genitalia and
perineum, where the anus may also be affected. Multiple small papules at this
site were for many years described as bowenoid papulosis due to the mistaken
belief that these lesions could be histologically distinguished from Bowen’s
disease. It is now appreciated that histologically the two conditions are indis-
tinguishable. The majority of young healthy patients have only a small risk of
progression to invasive disease but the immunocompromised are at a much
greater risk, particularly in the setting of perianal disease.7 Similarly, pigmented
multifocal Bowen’s disease is now classified within the spectrum of VIN.
The morphology of the lesions ranges from papules to plaques, which may
be skin-colored, white, erythematous or pigmented (Figs  12.179–12.181).
The surface often has a warty texture; less commonly, lesions are papil-
lomatous, particularly around the anus where they may become polypoid
(Fig. 12.182). The main presenting symptom is pruritus.
Fig. 12.179
Intraepithelial neoplasia:
intensely erythematous
ulcerated lesion.
By courtesy of the
Institute of Dermatology,
London, UK.
 Epithelial lesions 491

Fig. 12.180
Intraepithelial neoplasia:
there are numerous scaly
papules accompanied
by condylomata. In the
older literature, the former
was known as bowenoid
papulosis. Pigmented Fig. 12.182
lesions are also present. Intraepithelial neoplasia: perianal lesions presenting as multiple small papules
These were once known (bowenoid papulosis). By courtesy of the Institute of Dermatology, London, UK.
as multicentric pigmented
Bowen’s disease. The terms warty and basaloid undifferentiated VIN refer to histological
By courtesy of the variants and are not biologically distinct entities. In some lesions there may
Institute of Dermatology, be a mixture of the two.
London, UK.
Clinical lesions of differentiated VIN (simplex) are not often recognized
and are poorly described. Since invasion can develop rapidly, any suspicious
areas should be biopsied. It is usually a small hyperkeratotic white papule
or plaque or a punched-out ulcer or erosion with a firm border. The lesion
invariably arises in a background of a chronic atrophic dermatitis such as
lichen sclerosus (with associated epidermal acanthosis) or other conditions
associated with squamous hyperplasia.

Histological features
Undifferentiated VIN (usual or classic type)
In this major subtype, there is complete loss of cellular stratification ­thr­oughout
the epidermis with large hyperchromatic cells, dyskeratosis, multinucleated
cells and numerous typical and atypical mitoses.13
Two distinct types of undifferentiated VIN have been described but are
clinically and biologically the same:
• warty, characterized by individual cell keratinization and premature
cellular differentiation; pleomorphism may be marked and abnormal
mitoses are often conspicuous (Fig. 12.183),

Fig. 12.181
Intraepithelial neoplasia:
there is an erythematous
plaque with focal scaling.
By courtesy of the
Institute of Dermatology,
London, UK.

Multifocal vulval and perianal lesions are strongly associated with the
oncogenic papilloma viruses, particularly HPV-16 and -18, and almost exclu-
sively occurs in smokers.8,9 HPV-16 is found more frequently than HPV-18.10
It is believed that there is a failure of the host to mount an immune response
to HPV and that patients who are immunocompromised are at particular
risk. However, many of the patients do not have an identifiable immune defi-
ciency. Anogenital intraepithelial neoplasia, in addition to being multifocal,
can be multicentric and there is a history in two-thirds of female patients of
current or past cervical intraepithelial neoplasia.11
Vaginal involvement is very uncommon. The morphology of the lesions Fig. 12.183
is quite variable, some resembling typical warts, others islands of erythema, Undifferentiated VIN: there is full-thickness dysplasia with very marked nuclear
erosion or white patches.12 pleomorphism. Note the abnormal mitosis.
492 Diseases of the anogenital skin

• basaloid, with atypical parabasal cells extending throughout the full term ‘VIN 3 differentiated’ was coined by the ISSVD. However, this change
thickness of the epithelium (Fig. 12.184). is poorly recognized by many pathologists and there is a ­significant risk of a
The two variants often overlap histologically and are, as mentioned before, report of VIN 1 being issued, with potentially d ­ isastrous consequences.
part of the same spectrum. It is important to note that occasional cases of differentiated VIN negative
Two cases of VIN associated with HPV16 and with prominent mucinous for HPV display complete replacement of the epidermis by basaloid, homo-
differentiation have been reported.14 geneous undifferentiated keratinocytes.16
Undifferentiated VIN tends to be diffusely positive for p16 and negative Differentiated VIN can be associated with p53 mutations and p53 is often
for p53. positive not only in the basal cell layer but also in upper layers of the epi-
dermis.15 A similar staining pattern can be seen in inflammatory conditions
Differentiated VIN (simplex) including lichen sclerosus.17 It has recently been shown that high levels of p53
In some cases of vulval lichen sclerosus there is an associated basal keratino- expression in differentiated VIN correlates with DNA aneuploidy.18 p16 is
cyte cytological atypia with dyskeratosis and normal differentiation through- usually negative in cases of differentiated VIN.
out the overlying epithelium (Fig. 12.185).15 The rete ridges may be long and
forked with keratin pearls. This change may reflect invasive disease or herald Squamous cell carcinoma of the genital
its imminent onset. To reflect the seriousness of this epithelial change, the
epithelia
Vulval squamous cell carcinoma
There are two main etiologies for vulval squamous cell carcinoma (SCC):1–3
• The majority (> 60% of cases) arise in elderly women against a
background of a chronic scarring dermatosis, usually lichen sclerosus
but less often lichen planus. In these patients, the tumors develop directly
within the background dermatosis and may be preceded by differentiated
VIN. They are not usually associated with HPV.4–11 Squamous cell
carcinoma arising in the background of differentiated VIN appears to
have a higher tendency for local recurrence.12
• The second group consists of younger women with a background
of undifferentiated VIN (usual type) which is associated with HPV-
16 and -18, smoking and a previous or current history of squamous
intraepithelial lesion (SIL/CIN). HPV-16 is the most common type of
HPV found in association with vulval squamous cell carcinoma.13
Interestingly, a recent study of human papillomavirus genotypes in inva-
sive vulval squamous cell carcinoma found HPV in 70% of cases (mainly
HPV-16) and the average age of the patients was 65. Patients with no evi-
dence of HPV were older than those with proven HPV but these differences
were not statistically significant.14
Fig. 12.184 In addition, much more rarely, vulval carcinoma has been described in
Basaloid VIN: there is full-thickness replacement of the epidermis by a fairly
association with chronic granulomatous disease, hidradenitis ­suppurativa,
uniform population of small cells with densely basophilic nuclei and imperceptible
Fanconi’s anemia, and the genodermatosis Netherton’s syndrome.15–19
cytoplasm.
A tumor in a young woman with Cohn’s disease and one developing within
a localized vulvar lesion of Hailey-Hailey disease after tacrolimus therapy
have been documented.20,21
Patients with the warty and basaloid histological subtypes of vulval SCC
tend to be younger than those with conventional keratinizing SCC and in
one series there seems to be a predominance of black patients with this his-
tological subtype.22 The majority of vulval SCCs develop on the inner aspect
of the labia majora and periclitorally.23 Patients present with a mass that is
sometimes associated with pruritus, ulceration, bleeding, discharge or pain
(Fig. 12.186). Multifocal tumors are very rare.24 Vulval SCC usually spreads
via lymphatics to inguinal, femoral and pelvic lymph nodes. Midline tumors
are often associated with bilateral lymph node spread.25
The overall 5-year survival for patients with vulval SCC depends on the
depth of stromal invasion and the presence or absence of lymph node metas-
tasis.26–32 A study has found that patients with stromal invasion of more than
9 mm had higher risk of local recurrence.33 In the absence of lymph node
spread, the 5-year survival is up to 90% but this rate falls to less than 70% in
patients with inguinal lymph node metastasis and to less than 25% in those
with pelvic lymph node spread.27 The presence or absence of lymph node
Fig. 12.185 metastasis is the single most important factor determining prognosis.34 Other
Differentiated VIN: there is factors that have been found to be independently associated with prognosis
basal dysplasia associated
include older age, advanced stage, size of the tumor, positive margins and
with dyskeratosis and
degree of differentiation. It has been suggested that HPV-positive tumors have
normal differentiation.
By courtesy of C. Crum, a worse prognosis than those that are HPV negative.35,36 Warty and basaloid
MD, Brigham and SCCs of the vulva are often associated with HPV infection and there is some
Women’s Hospital and suggestion that the prognosis of the basaloid subtype may be worse than that
Harvard Medical School, of conventional SCC (see below).6,22 Warty squamous cell carcinoma of the
Boston, USA. vulva is more often associated with high risk HPV other than HPV-16.14

Fig. 12.186
Vulval squamous cell carcinoma: this tumor arose against a background of
long-standing carcinoma in situ (Bowen’s disease). By courtesy of the Institute
of Dermatology, London, UK.
Tumors with less than 1-mm stromal invasion do not require lymph node
dissection and the appropriate surgery is curative.
Verrucous carcinoma
Clinical features
Verrucous carcinoma is a low-grade, slow-growing squamous cell carcinoma
(SCC) first described in 1948.1 The precise incidence of verrucous carcinoma
is difficult to assess accurately because of the confusing number of different
terms that have been applied to this tumor in the past. There has been some
debate as to whether verrucous carcinoma, well-differentiated epidermoid
SCC, epithelium cuniculatum and giant condyloma of Buschke-Löwenstein
are all one and the same or separate entities. It is now generally accepted that
they are identical lesions.2,3
The tumor presents as a warty exophytic plaque and usually occurs at
three anatomical sites: the oropharynx, sole of the foot and the anogenital
skin (Figs 12.187, 12.188).2,4–6 Verrucous carcinoma of the vulva may arise
on a background of lichen sclerosus or lichen planus.7–9 Oral and lower limb
neoplasms may be associated with various types of HPV.10–13 Similarly, genital
Fig. 12.187
Verrucous carcinoma: note the keratotic warty tumor mass. By courtesy of the
Institute of Dermatology, London, UK.
Genital intraepithelial neoplasia and squamous carcinoma 493
Fig. 12.188
Verrucous carcinoma: this
tumor arose in the gluteal
cleft of an elderly female.
Note the characteristic
sharply demarcated lower
border.
verrucous carcinoma may be associated with human papillomavirus albeit in
a minority of cases.14 The benign histological appearances of this tumor often
lead to an incorrect histological report of condyloma or squamous papilloma,
with resulting undertreatment. Vulval verrucous carcinoma can coexist with
ordinary squamous cell carcinoma.15 A case of vulval verrucous carcinoma in
an HIV-positive patient has been documented.16
Histological features
Verrucous carcinoma is characterized by an exophytic and endophytic
growth pattern.17,18 The latter, which may extend deeply into subcutaneous
tissues or beyond, has a bulbous and sharply delineated lower border, lacking
the infiltrative characteristics of conventional SCC (Figs  12.189–12.191).
The epithelium is well differentiated, showing no appreciable cytological
atypia; mitoses, which are generally sparse, are confined to the lower layer.
Intraepithelial neutrophil abscesses are commonly present. In some tumors,
koilocytes may be seen, supporting an HPV-associated etiology. One study
describes a distinctive triad of marked epithelial acanthosis, loss of the granu-
lar cell layer with superficial epithelial cell pallor, and multilayered parak-
eratosis.19 It has been suggested that this could be a precursor to verrucous
carcinoma and is designated vulvar acanthosis with altered differentiation.
Fig. 12.189
Verrucous carcinoma:
low-power view showing
the characteristic growth
pattern comprising deeply
penetrating, blunt, finger-
like processes.
494 Diseases of the anogenital skin

• squamous intraepithelial lesion of low and high grade,

• dysplasia,
• penile intrepithelial neoplasia grade 3.
Taking into account similarities in morphology and pathogenesis between
vulval and penile carcinoma, we have recently proposed a new ­nomenclature
for penile preinvasive lesions.7,8 In this section, we present a simplified ­version
taking into account the etiopathogenetic correlation of precursor HPV and
non-HPV-related lesions with their invasive counterparts.9 The term penile
intraepithelial neoplasia (PeIN) is preferred over older terminology.10–13
PeIN is classified into differentiated (non-HPV-related), undifferentiated
­(HPV-related) and mixed differentiated–undifferentiated categories.
Undifferentiated PeIN may be further subclassified into warty, basaloid,
mixed warty/basaloid and other variants. PeIN may be solitary or ­multifocal,
and may or may not be associated with infiltrative SCC. PeIN unassociated
with invasive cancer occurs in younger patients and tends to be of the undif-
ferentiated type, positive for HPV. Patients with HPV may also develop
warty or basaloid PeIN. Conversely, when PeIN is associated with invasive
SCC, the predominant histological subtype is the differentiated variant, pre-
senting in 65% of the cases and usually negative for HPV. The explanation
for this apparent paradox may be the clinical and pathological underrecogni-
tion or underdiagnosis of differentitated PeIN. Differentiated PeIN tends to
Fig. 12.190 affect the foreskin of older patients whereas undifferentiated PeIN generally
Verrucous carcinoma: the
affects the glans of younger patients.
epithelium is uniformly
well differentiated and The gross appearance of PeIN is heterogeneous and does not allow a
often displays a ground- clear distinction between the two main types. Differentiated PeIN tends to
glass cytoplasmic pallor. be white, whereas undifferentiated PeIN is typically reddish or darkly pig-
mented. Lesions vary from flat to slightly elevated, and can be pearly white or
moist erythematous, dark brown or black and present as macules, papules, or
plaques. They may be warty, granular or villous (Figs. 12.192–12.195). The
contours are sharply delineated or subtle and irregular.

Histological features
Microscopically, differentiated PeIN is characterized by hyperkeratosis,
parakeratosis, variable hypergranulosis and acanthosis with elongated and
anastomosing rete ridges. There is subtle abnormal maturation (enlarged
keratinocytes with abundant eosinophilic cytoplasm) (Fig. 12.196), whor-
ling and keratin pearl formation (usually in deep rete ridges), prominent
intercellular bridges (spongiosis) and sometimes acantholysis. Atypical
basal or prickle layer cells are present and a prominent nucleolus may
be seen (Fig.  12.197). At low power, the atypia may seem to be pres-
ent only in lower levels of the epidermis; however, at higher magnifica-
tion, there is subtle but abnormal maturation in all levels of the epithelium
(Figs 12.198–12.200).

Fig. 12.191
Verrucous carcinoma:
intraepithelial neutrophil
abscesses are often
present.

Penile squamous cell carcinoma

Penile intraepithelial neoplasia (PeIN)
In this text, penile intraepithelial neoplasia refers to purely squamous lesions
and excludes Paget’s disease and melanoma in situ. There is a wide spec-
trum of morphological lesions reflecting the diverse pathogenesis of penile
squamous cell carcinoma (SCC). Historically, there has been variable nomen-
clature and multiple classifications of penile precursor lesions have been
proposed:1–6
• Bowen’s disease, Fig. 12.192
• erythroplasia of Queyrat, Intraepithelial neoplasia: multiple eroded lesions are present. By courtesy of the
• carcinoma in situ, Institute of Dermatology, London, UK.
 Genital intraepithelial neoplasia and squamous carcinoma 495

Fig. 12.193 Fig. 12.196
Intraepithelial neoplasia: in this example, viral warts are present in addition to multiple Differentiated PeIN: with acanthosis, hyperkeratosis, retained squamous maturation,
small papules on the glans (bowenoid papulosis). By courtesy of the Institute of and minimal atypia.
Dermatology, London, UK.

Fig. 12.194
Fig. 12.197
Intraepithelial neoplasia: this patient presented with multiple ulcerated lesions and
Differentiated PeIN: with marked atypia, more prominent at the bottom layers.
a thick, scaly plaque. By courtesy of the Institute of Dermatology, London, UK.

Fig. 12.195
Intraepithelial neoplasia: there is intense erythema of the glans penis and the distal Fig. 12.198
shaft. This lesion is also referred to as Bowen’s disease and in the older literature as Differentiated PeIN: atypia are seen throughout the epithelium; note the presence
erythroplasia of Queyrat. By courtesy of the Institute of Dermatology, London, UK. of dyskeratosis.
496 Diseases of the anogenital skin

Fig. 12.199 Fig. 12.201
Differentiated PeIN: squamous hyperplasia (left field ) merging into differentiated PeIN Differentiated PeIN: with underlying lichen sclerosus characterized by dense
(center field ), the latter in continuity with invasive squamous cell carcinoma (right field). hyalinized subepithelial tissue.

In basaloid PeIN, the epithelium is replaced by a monotonous population

of small or intermediate-sized immature cells with high nuclear:cytoplasmic
ratio (Figs  12.202–12.205). Short spikes or spindle-shaped cells may be
noted. Apoptosis and mitotic figures are numerous. Basaloid PeIN should
be distinguished from transitional cell urethral carcinoma in situ, which may
secondarily involve the penile meatal region.15
In the warty variant, the epithelium has an undulating/spiky surface with
atypical parakeratosis. There is cellular pleomorphism and koilocytosis
(multinucleation, nuclei with irregular contours, perinuclear halos and dysk-
eratosis) (Figs 12.206–12.208). Mitosis may be numerous.
Basaloid lesions are monotonous and flat, whereas warty lesions are spiky
and pleomorphic with prominent koilocytosis. Frequently, lesions show over-
lapping features of both, namely mixed warty–basaloid PeIN. These mixed
lesions have an irregular surface with koilocytic changes while the lower
half of the epithelium is predominantly composed of small basaloid cells.
This is not a surprising finding, taking into consideration that warty and
­basaloid carcinomas are both HPV-related tumors. Warty PeIN should be
­distinguished from the common condyloma which does not display atypia
Fig. 12.200 except at the level of the upper koilocytotic layer.
Differentiated PeIN: the presence of nuclear atypia (right field) allows the distinction
of differentiated PeIN from squamous hyperplasia (left field)

The differential diagnosis is squamous hyperplasia which, by definition,

shows no atypia. In the absence of specific penile dermatological conditions
which may be associated with hyperplasia, it is likely that most acanthotic
squamous lesions represent differentiated PeIN.
It is not surprising that the precursor lesions of well-differentiated invasive
tumors show such a high degree of differentiation. It is important to recog-
nize this lesion because it appears to be the most frequent precursor lesion of
penile carcinoma, especially of the keratinizing and well-differentiated vari-
ants. Unfortunately, most studies on differentiated PeIN are retrospective and
have been based on penectomies performed for invasive carcinoma.
There is a preferential association for differentiated PeIN and lichen scle-
rosus (Fig. 12.201).14 It is therefore important to maintain a high index of
suspicion when dealing with hyperkeratotic/hyperplastic epidermal lesions
with subtle keratinocytic atypia arising in the setting of long-standing lichen
sclerosus.
Undifferentiated PeIN (the HPV-related type) shows distinctive morpho-
logical features. Lesions can be subclassified into basaloid, warty and mixed
warty–basaloid PeIN. In accordance with their common pathogenesis, it is
frequent to find mixtures of warty and basaloid patterns in the same speci-
men. We classify a lesion as either warty or basaloid when there is more than Fig. 12.202
90% predominance of one type over the other. Basaloid PeIN: with acanthosis, parakeratosis, and slightly irregular surface.
 Genital intraepithelial neoplasia and squamous carcinoma 497

Fig. 12.203 Fig. 12.206
Basaloid PeIN: with epithelial thickening, parakeratosis, and an overall ‘blue’ appearance Warty PeIN: with prominent parakeratosis and abundant koilocytes, more prominent
due to altered squamous maturation. at upper layers.

Fig. 12.207
Fig. 12.204
Warty PeIN: showing its characteristic spiky, parakeratotic surface.
Basaloid PeIN: the epithelium is replaced by a monotonous proliferation of small to
medium-sized cells with basal-like features

Fig. 12.208
Fig. 12.205 Warty PeIN: nuclear atypia is discernable throughout the epithelium, with conspicuous,
Basaloid PeIN: with abundant mitoses and apoptotic figures throughout the epithelium. sometimes pleomorphic koilocytosis (right field ) and marked parakeratosis.
498 Diseases of the anogenital skin
Rarely, a mixed lesion composed of differentiated and undifferentiated
PeIN is encountered. If an associated invasive cancer is present it also shows
mixed morphology of more than one subtype of invasive squamous cell
carcinoma.
Other exceptional and less well-studied morphologic patterns of pre-
cursor lesions include pleomorphic, spindled cell, clear cell, pagetoid and
small cell. All of these are likely to represent variants of the undifferenti-
ated group.
With few exceptions there is good correlation between the microscopic
appearance of the preinvasive lesion and the associated invasive carcinoma.
Usual and differentiated subtypes of SCC are associated with differenti-
ated PeIN while warty and basaloid invasive carcinomas are associated with
warty or basaloid PeIN. These observations further support the concept of a
bimodal pathway of penile tumorigenesis.9
Bowenoid papulosis
Patients with bowenoid papulosis are younger (mean age 30 years) than those
with penile cancer and present with multiple papules affecting the skin of
the shaft, glans, sulcus or foreskin. Some lesions regress spontaneously.16–21
Histologically, at low-power magnification there is acanthosis and either a
spiky or flat appearance. High power shows a proliferation of small ­basophilic
cells with a spotty distribution of atypical forms. Hyperkeratosis, ­parakeratosis
and melanin pigmentation may be present. Human ­papillomavirus types
16 and 18 have been associated with bowenoid papulosis; hence, sexual
­transmission is suspected. The histological appearance of bowenoid papulosis
is similar to that of basaloid or mixed warty–basaloid PeIN and the diagno-
sis should be suggested only when there is a clinical presentation of multiple
papular lesions in younger patients.
Flat ‘acetowhite’ penile lesions
Peniscopic studies of male sex partners of women with HPV-associated
squamous intraepithelial lesion (SIL/CIN) have revealed a clinical lesion
described by Bleeker et al. as ‘flat penile lesion’.22 It was identified in 60%
of 230 cases and affected the inner foreskin surface, frenulum and coro-
nal ­sulcus. HPV was identified in the majority of the lesions by in situ
­hybridization. Grossly (only evident after acetic acid reaction), 2–4 or more
well-demarcated 1–2-cm white flat lesions with a mosaic vascular pattern
were seen. Microscopically, there was squamous hyperplasia or low grade
PeIN. In a minority of cases high-grade PeIN was present. Follow-up of 118
men with flat lesions showed a benign clinical course and regression in 90%
of the cases in 5 years, usually within 12 months.
Invasive squamous cell carcinoma
Squamous cell carcinoma arises on the mucosal surface of the penis ­extending
from the preputial orifice to the urethral meatus, comprising the inner
­surface of the foreskin, coronal sulcus and glans.23 Squamous cell carcinoma
­presenting on the outer skin of the penis is very unusual. Distal urethral
tumors, ­morphologically similar to some penile tumors, are not discussed in
this text.
Penile cancer incidence rates in the West are in the range of 0.3–1.0/100 000
of the population although there is considerable variation amongst the
­different countries. The incidence of penile SCC varies from a high incidence
in Uganda, Kenya and some regions of South America, to a lower incidence
in Northern Europe and the United States, Japan and Israel.2 Comparing
cases from the United States and Paraguay, we have found no geographi-
cal ­differences in the morphology, relative incidence of histologic subtypes
or in the presence or absence of HPV according to histologic subtype.9,24
Differences in geographical distribution of penile cancer are attributed to
environmental factors. Several epidemiological studies have indicated the
­following risk factors: 25–28
• socioeconomic deprivation,
• poor hygiene,
• lack of access to running water,
• phimosis,
• smegma retention,
• lack of circumcision,
• chronic inflammation,
• history of tear or injury to the penis,
• physical inactivity,
• history of warts,
• ultraviolet irradiation,
• partner with cervical cancer,
• immunosuppression,
• smoking,
• HPV,
• lichen sclerosus.
Early circumcision appears to be associated with a lower incidence of penile
cancer when compared to later circumcision. Penile carcinoma in ­circumcised
men is very rare; it has been reported in association with irregular scarring
in patients undergoing ritual circumcision. Postcircumcision penile cancer
appears to be biologically aggressive.29
High incidences of both penile and cervical cancers are seen in some areas
of the world. However, pathologically, penile cancers are similar to vulval
cancers. The overall prevalence of HPV DNA in penile carcinoma (42%)
is lower than that seen in cervical carcinoma (near 100%) and is similar to
­vulval carcinoma.7 Subtypes of penile cancer such as basaloid and condyloma-
tous are consistently associated with HPV, whereas the virus is infrequent in
the usual, verrucous, papillary and sarcomatoid squamous cell carcinoma.9,24
These two groups of tumors appear to develop along different pathogenetic
pathways. HPV-16 is the most common type of HPV associated with penile
cancer. HPV-related anogenital cancers, including penile ­carcinoma, are
­significantly more frequent in HIV-infected patients when compared with the
general population.30,31
Clinical features
The mean age of patients with penile SCC is around 60 years. HPV-related
tumors such as condylomatous and basaloid cancers affect younger patients
(45–55 years) while verrucous and pseudohyperplastic carcinomas occur at
an older age (70–80 years).32 An exophytic or non-ulcerated lesion is the
usual presenting sign. In non-Western countries, up to 40% of patients pres-
ent with inguinal lymph node metastasis and 10% with disseminated disease.
This high figure contrasts with a significantly lower incidence of regional and
systemic metastasis in North American patients (13 and 2.3% respectively).33
The frequency of in situ and invasive carcinoma varies according to geo-
graphical region. In areas of high frequency, the majority of tumors are ini-
tially dignosed as invasive tumors whereas in regions of low incidence, most
cases are diagnosed as in situ lesions. In a series of 500 invasive carcinomas
diagnosed in Paraguay, we found only 20 cases of carcinoma in situ (4%),
whereas in 1605 cases from the SEER database in USA the figure was 37%.33
Geographical differences may reflect the incidence of invasive cancers.
Usual squamous cell carcinoma
Grossly, SCC of the usual type displays wide morphologic appearances vary-
ing from white–gray exophytic to flat or reddish, ulcerated endophytic masses.
The cut surface shows white–gray neoplastic tissues invading variable penile
anatomical levels (lamina propria, corpus spongiosum or corpus cavernosum
in the glans and dartos or skin in the foreskin). In the fresh state or after fixa-
tion there may be a contrast between the white color of the tumor and the
reddish, darker penile tissue. The boundaries between tumor and stroma are
usually jagged and irregular. Adjacent associated squamous hyperplasia or
PeIN can be visualized as a deeply white line measuring 1–2 mm in thickness
in the adjacent epithelium.
Histological features
Microscopically, tumors vary from well-differentiated keratinizing to solid
anaplastic carcinomas with scant keratinization (Figs  12.209–12.211).
Most tumors are highly keratinized and of moderate differentiation. Poorly
­differentiated carcinomas may have variable and usually focal amounts
of spindled cell, giant cell, solid, acantholytic, clear cell, small cell, warty,
basaloid or glandular components. When these features predominate, there
is a morphological justification for separation of the neoplasm as a special
­subtype of squamous cell carcinoma.
 Genital intraepithelial neoplasia and squamous carcinoma 499

Subtypes of squamous cell carcinoma

Table 12.2 TS2
Subtypes of squamous cell carcinoma

Papillae Koilocytosis Interphase HPV

Warty Condylomatous Present Jagged + High
pleom risk
Verrucous Noncondy­ Absent Broad Absent
lomatous
Papillary Complex Absent Jagged Absent
Giant Condylomatous Superficial Broad + Low risk
condyloma

Fig. 12.209
Usual squamous cell carcinoma: well-differentiated (grade 1) usual SCC with
keratinizing tumor nests composed of neoplastic cells showing minimal atypia
limited to the basal/parabasal layers.

A B

C D

(A) Verrucous carcinoma: tight papillae separated by keratin (in red ). Broadly
based boundaries between tumor and stroma. (B) Papillary carcinoma: irregular
papillae without koilocytosis. Jagged tumor–stroma limits. (C) Giant condyloma:
condylomatous papillae, surface koilocytosis (white dots) and broad non invasive
base. (D) Warty (condylomatous) carcinoma: irregular condylomatous papillae,
diffuse koilocytosis and jagged boundary between tumor and stroma.

Fig. 12.210
Usual squamous cell carcinoma: moderately differentiated (grade 2) usual SCC with
more evident atypia (upper right field ) but retained squamous maturation.
Fig. 12.211
Usual squamous cell carcinoma: poorly differentiated (grade 3) usual SCC with
prominent atypia but evidence of squamous differentiation.
Clinical features
Verrucous carcinoma
Verrucous carcinoma (VC) is a slowly growing, well-differentiated tumor,
with a papillomatous appearance and a broad bulbous invasive border
­contrasting with the irregular infiltrating margin of usual squamous cell
­carcinoma. Described by Dr. Lauren Ackerman in 1948 in the buccal mucosa,
verrucous carcinoma continues to pose diagnostic problems with other verru-
ciform tumors sharing some of its characteristics.34 Condyloma, papillary and
condylomatous carcinoma have all been published under the designation of
verrucous carcinoma or Buscke-Löwenstein tumor. We have proposed a clas-
sification of verruciform neoplasms that helps to differentiate verrucous car-
cinoma from other similar lesions.35 It is important to follow strict diagnostic
criteria since classic penile verrucous carcinoma is associated with virtually no
metastatic potential.36,37 There is a spectrum of combined tumors with focal
or significant verrucous features, which need to be distinguished from typical
verrucous carcinoma. The most frequent combination is that of a verrucous
carcinoma with usual invasive SCC. These mixed or hybrid ­verrucous carci-
nomas have a metastatic rate of about 25%.38–40 Verrucous carcinoma may
also be associated with sarcomatoid carcinoma sporadically or after radiation
therapy.41 HPV has been consistently rare or absent in ­various studies.9,24,42
Verrucous carcinoma is rare, accounting for 7% of all penile SCC.2 It
presents during the sixth to seventh decades and the average duration of the
­disease is 56 months, the longest amongst all penile malignant tumors. Any
penile epithelial compartment may be affected and it is equally frequent in
500 Diseases of the anogenital skin

the foreskin or glans penis. Most tumors are unicentric but multicentric cases
or association with other subtypes such as the pseudohyperplastic variant has
been observed.
Grossly, it is an exophytic papillomatous tumor with some variation in
the configuration of the papillae, from multinodular with cobblestone mor-
phology to filiform with a spiky appearance. The cut surface reveals a white
serrated tumor and a broad demarcation between the lesion and stroma.
Verrucous carcinoma is superficial, rarely penetrating beyond lamina propria
or superficial dartos or corpus spongiosum.

Histological features
Microscopically, the tumor is diffusely well differentiated, resembling nomal
squamous epithelium except for the presence of occasional atypical nuclei
in the basal or parabasal layers. Features include papillomatosis, hyper- to
orthokeratosis, acanthosis and a broad-based interface between the tumor
and stroma, the latter considered pathognomonic for this tumor. Koilocytosis
is not present. Although some papillae may harbor fibrovascular cores, this
is not a characteristic feature. The space between papillae is occupied by a
keratin-filled crater that on a tangential cut appears as keratin-filled pseudo-
Fig. 12.213
cysts. The stroma may show a dense lymphocytic infiltrate, sometimes blur- Verrucous carcinoma: showing acanthosis, parakeratosis, papillomatosis, and a
ring the interface between the tumor and the underlying connective tissue broad-based tumor–stroma interface.
(Figs 12.212–12.216). Microscopic small nests of well-differentiated inva-
sive keratinized SCC in the lamina propria (1–3 mm in depth) may rarely be
observed. We have not observed metastasis in these cases. A designation for
such a lesion could be microinvasive verrucous carcinoma. This entity dif-
fers from hybrid verrucous carcinoma where large areas of the tumor show
features of a moderately to poorly differentiated invasive typical squamous
cell carcinoma (Figs 12.217–12.219). Associated lesions which may be seen
in the adjacent epithelium include squamous hyperplasia and differentiated
PeIN. The hyperplasia often adopts the features of verrucous hyperplasia.
Lichen sclerosus is a further frequently found associated condition and may
be pathogenetically related to verrucous carcinoma.43 Verrucous carcinoma,
if insufficiently resected, is prone to local recurrence. Regional metastases are
not seen in typical (pure) lesions.

Condylomatous (warty) carcinoma

Clinical features
Condylomatous carcinoma is a slowly growing, verruciform low- to interme-
diate-grade HPV-related tumor, grossly similar to giant condyloma but with
malignant histology and potential for nodal metastasis.35 It accounts for 7%
of all penile SCC affecting patients younger than those with the usual SCC. Fig. 12.214
A history of previous viral warts is frequently obtained. The foreskin, coronal Verrucous carcinoma: neoplastic cells are extremely well-differentiated with minimal
sulcus and glans are usually involved. Macroscopically, the cut surface shows atypia limited to the basal/parabasal layers.

Fig. 12.212 Fig. 12.215
Verrucous carcinoma: exophytic, verruciform proliferation with papillae showing Verrucous carcinoma: with epithelial thickening, minimal atypia, parakeratosis, and a
inconspicuous fibrovascular cores. well-defined, rounded tumor front.
 Genital intraepithelial neoplasia and squamous carcinoma 501

Fig. 12.216 Fig. 12.219
Verrucous carcinoma: with slightly irregular tumor front and foci suspicious for Hybrid verrucous carcinoma: usual SCC component composed of poorly differentiated
microinvasive verrucous carcinoma (upper right field). neoplastic cells.

a papillomatous growth generally penetrating into the corpora spongiosa and

cavernosa. The interface of tumor and stroma varies from broadly based to
jagged and irregular.

Histological features
Microscopically, the tumor papillae are condylomatous and of various shapes
(round, ovoid or spiky, long or short) but always with a prominent central
fibrovascular core and koilocytotic changes (Figs  12.220–12.224). Unlike
benign condyloma, koilocytosis is not restricted to the surface epithelial cells
but is also present in deep invasive portions of the tumor (Fig.  12.225).
Hyper- and parakeratosis, cellular pleomorphism and clear cell change may
be prominent. The biological behavior of condylomatous carcinoma is inter-
mediate between that of other types of low-grade verruciform tumors (verrucous
and papillary) and squamous cell carcinoma of the usual type. Deeply inva-
sive, high-grade condylomatous carcinoma may be associated with inguinal
nodal metastasis.
The differential diagnosis is with other verruciform tumors, verrucous and
papillary carcinoma and giant condyloma. The histologic evaluation of type
Fig. 12.217 of papillae, presence of koilocytosis, interface of tumor and stroma and pres-
Hybrid verrucous carcinoma: composed of a typical verrucous carcinoma (left field) ence of HPV helps in the differentiation of these neoplasms (see Tables 12.1
and a usual SCC (right field). and 12.2).

Fig. 12.218 Fig. 12.220
Hybrid verrucous carcinoma: verrucous component with pushing tumor borders and Condylomatous carcinoma: exhibiting an exophytic, papillomatous pattern of growth
well-differentiated neoplastic cells; note the underlying stromal reaction. with conspicuous fibrovascular cores.
502 Diseases of the anogenital skin

Fig. 12.221 Fig. 12.224
Condylomatous carcinoma: showing an irregular, jagged infiltrative tumor front Condylomatous carcinoma: showing abundant koilocytes, more prominent at the
(right field). upper layers, and marked parakeratosis.

Fig. 12.222 Fig. 12.225
Condylomatous carcinoma: with papillomatosis, evident fibrovascular cores, and Condylomatous carcinoma: deep infiltrative nests with koilocytes and surrounding
irregular tumor–stroma interface. stromal reaction.

Koilocytosis, condylomatous papillae and jagged irregular boundaries

between tumor and stroma are present in warty but not in verrucous carcino-
mas. In papillary carcinomas, papillae are complex and show no koilocytosis.
Giant condylomas are broadly based noninvasive tumors with surface koilo-
cytosis (see Table 12.2).35,44 Associated precursor lesions of condylomatous
carcinoma include PeIN of the warty or basaloid types.

Papillary carcinoma, NOS

Clinical features
Papillary carcinoma, NOS is the third type of penile low-grade verruciform
carcinoma.2,3,45 Patients are on average around 60 years old. The tumor is
grossly exophytic, large and irregular and involves the glans, coronal sulcus
and foreskin. The cut surface shows a papillary neoplasm involving corpus
spongiosum or dartos. Papillary carcinoma is a slowly growing tumor with a
low but definite incidence of inguinal nodal metastasis.

Histological features
Fig. 12.223 Microscopically, the appearance is that of a well-differentiated papillary
Condylomatous carcinoma: papillae with conspicuous koilocytosis, slight squamous neoplasm. There is hyperkeratosis and papillomatosis. Papillae are
parakeratosis, and underlying chronic stromal reaction. variable and complex, short or long, with or without a fibrovascular core
 Genital intraepithelial neoplasia and squamous carcinoma 503

(Figs 12.226–12.228). The tips may be straight, undulated, spiky or blunt.

Hyperkeratosis and acanthosis are prominent. Keratin cysts or intraepithelial
abscesses are sometimes present. The base of the lesion is irregular and infil-
trative. The interface between tumor and stroma is characteristically jagged
(Fig.  12.229). Koilocytotic-like changes are usually absent. Differentiating
features from verrucous and condylomatous carcinoma are based on the het-
erogeneity of the papillae, the lack of koilocytosis and the jagged irregular
interface between tumor and stroma. The latter feature is crucial to distin-
guish papillary from verrucous carcinoma. HPV studies may be necessary to
differentiate papillary neoplasms, usually negative for HPV, from low-grade
condylomatous carcinoma. Another tumor to be distinguished from papil-
lary carcinoma NOS is the infrequent papillary basaloid SCC.2 In this tumor,
papillae harbor a thin fibrovascular core and the cells are small and ana-
plastic, resembling basaloid or transitional carcinoma. This unusual penile
neoplasm is often deeply invasive. Low-grade squamous intraepithelial lesion
and lichen sclerosus are frequently associated with papillary carcinoma.

Fig. 12.228
Papillary carcinoma, NOS:
showing an irregular,
jagged tumor front of
invasion and prominent
stromal reaction.

Fig. 12.226
Papillary carcinoma, NOS: showing papillomatosis with complex papillae and
irregular fibrovascular cores.

Fig. 12.229
Papillary carcinoma, NOS: irregular tumor nests at the tumor base surrounded by
intense chronic inflammation.

Fig. 12.227
Papillary carcinoma, NOS:
with rounded and tipped
papillae, hyperkeratosis,
and irregular fibrovascular
cores.
Basaloid carcinoma
Clinical features
Basaloid carcinoma is an aggressive, HPV-related variant of SCC occurring in
the fifth decade and preferentially affecting the glans.46 It has been proposed
that it originates within the squamous–transitional junction of the meatal
region. Rarely, basaloid carcinoma may develop in the foreskin. It accounts
for 4% to 10% of penile SCCs. The median age is 53 years. More than half
of patients show inguinal metastasis at clinical diagnosis. Grossly, there is an
ulcerated irregular mass. The cut surface reveals a tan, solid tumor, deeply
invasive into the corpus spongiosum or cavernosum.
Histological features
Microscopically, there are separate or confluent solid nests composed of
small basaloid cells, usually with central necrosis (comedonecrosis) or
­central abrupt keratinization (Figs  12.230–12.233). Nuclei are anaplastic
504 Diseases of the anogenital skin

Fig. 12.230 Fig. 12.233
Basaloid carcinoma: at low-power view showing deeply infiltrative tumor nests. Basaloid carcinoma: composed of neoplastic cells with indistinctive cellular borders,
high mitotic/apoptotic rate, and central (comedo-like) necrosis.

and ­nucleoli inconspicuous. There are numerous mitotic figures. Occasional

­palisading at the nest periphery may be noted but it is usually not as promi-
nent as is seen in basal cell carcinoma of the skin. Basophilic intermediate or
large cell nuclei may be noted in some cases. Pseudoglandular features are
sometimes present (Figs  12.234, 12.235) (adenoid–basaloid carcinomas).
PeIN of the warty–basaloid type is often found in the epithelium adjacent to
the invasive cancer.

Unusual morphological features of basaloid carcinomas

In accordance with their common HPV etiology, some tumors show mixed
basaloid–condylomatous features. The condylomatous component is super-
ficial and papillary and the deep counterpart a typical basaloid carcinoma.
There are deeply invasive nests with central keratinization or comedonecro-
sis surrounded by clear cells with koilocytotic-like changes and peripheral
small basaloid cells. These mixed tumors behave as basaloid carcinomas,
with ­frequent nodal metastasis. Another unusual morphological presenta-
tion is that of a papillary lesion composed entirely of small basaloid cells
(transitional-like papillary basaloid carcinoma). Deep portions of the tumor
Fig. 12.231 show the classic features of a basaloid carcinoma. Unlike other penile
Basaloid carcinoma: with tumor nests showing central, abrupt parakeratosis, and ­papillary tumors, the papillae are entirely composed of small cells simulating
retraction artifact. a ­transitional urothelial carcinoma.

Fig. 12.232 Fig. 12.234
Basaloid carcinoma: tumor nest composed of a monomorphic population of cells Basaloid carcinoma: with tumor nests exhibiting open central areas due to central
with evident atypia and central parakeratotic debris. necrosis, simulating a glandular space.
 Genital intraepithelial neoplasia and squamous carcinoma 505

Fig. 12.235 Fig. 12.237
Basaloid carcinoma: with central, necrotic debris and a pseudoglandular appearance. Sarcomatoid carcinoma: high-grade pleomorphic cells intermingled with spindled cells.

Sarcomatoid carcinoma (carcinoma with heterologous

differentiation, metaplastic carcinoma)
Clinical Features
Sarcomatoid carcinoma is an aggressive penile neoplasm composed predomi-
nantly of spindled cells. It may arise de novo, follow a recurrence of usual
squamous cell carcinoma or develop after irradiation therapy of a verrucous
carcinoma. It accounts for about 1–4% of all penile carcinomas and prefer-
entially involves the glans penis although the foreskin may also be affected.47
As with usual SCC, the mean age is around 60. Grossly, it presents as a bulky
5–10-cm ulcerated or rounded polypoid mass, which on sectioning shows
almost invariably deep invasion into the corpus cavernosum. Regional metas-
tases occur in 85% of sarcomatoid carcinomas and mortality is high.

Histological features
Microscopically, there are variable proportions of squamous and spindled
cell carcinoma but the latter usually predominates. The sarcomatoid com-
ponent includes leiomyosarcoma, fibrosarcoma, myxosarcoma, epithelioid
angiosarcoma, classic angiosarcoma and so-called pleomorphic malig-
nant fibrous ­histiocytoma (Figs  12.236–12.240). Heterologous bone and Fig. 12.238
­cartilage formation is sometimes focally present. Rarely, the tumor shows Sarcomatoid carcinoma: pleomorphic and spindled malignant cells in a myxoid
pseudoglandular and/or pseudovascular differentiation (Figs 12.241, 12.242). background.

Fig. 12.236
Sarcomatoid carcinoma: composed of neoplastic spindle cells simulating a high-grade Fig. 12.239
sarcoma. Sarcomatoid carcinoma: differentiated PeIN with underlying sarcomatoid carcinoma.
506 Diseases of the anogenital skin

The squamous component typically shows the morphology of usual SCC but
areas of ­verrucous, papillary or basaloid carcinoma may also be observed,
indicating that sarcomatoid transformation may occur in practically any
tumor type. HPV is usually absent. Differential diagnosis includes sar-
coma and melanoma. Immunohistochemistry is essential for tumors with
little or no epithelial component and for small biopsy specimens. The spin-
dled cells are usually positive for vimentin, various cytokeratins and p63.
In our ­experience, cytokeratin 34betaE12 and p63 appear to be the more
specific and sensitive markers to categorize these tumors as epithelial. AE1/
AE3 and Cam 5.2 tend to be more variable and often only focally posi-
tive, sometimes highlighting scattered single cells. Smooth muscle actin
can be focally positive; ­however, desmin, muscle-specific actin, myogenin
and S-100 are negative. Tumors which display specific sarcomatous com-
ponents such as ­leiomyosarcoma or angiosarcoma display the expected
immunohistochemistry.

Fig. 12.240
Sarcomatoid carcinoma: neoplastic cells in sarcomatoid carcinomas showing
nuclear positivity for p63 immunohistochemistry.
Pseudohyperplastic carcinoma
Clinical features
Pseudohyperplastic carcinoma is a clinicopathologic entity characterized by a
low-grade ordinary squamous carcinoma preferentially affecting the foreskin
of older patients (eighth decade) in association with lichen sclerosus.48 The
tumor is well differentiated (resembling normal squamous epithelium) and in
small biopsy specimens it may mimic pseudoepitheliomatous hyperplasia. It
is often multicentric and the second or third independent lesion is sometimes
verrucous. We have observed similar cutaneous tumors in association with
severe solar elastosis or in scars after burns. Grossly, it is a flat or slightly
elevated lesion measuring about 2 cm.
In a series of 10 cases, recurrence was noted in the glans of one patient
who was circumcised for a multicentric carcinoma of the foreskin 2 years
after diagnosis. No metastases developed in any of these cases.

Histological features
Characteristic microscopic features are keratinizing nests of squamous cells
with minimal atypia surrounded by a reactive stroma (Fig.  12.243). The
­consistent association with lichen sclerosus suggests that this inflammatory
condition may play a pathogenetic role.

Carcinoma cuniculatum
Clinical features
This tumor was originally documented on the sole of the foot. It is a deeply
Fig. 12.241 penetrating, albeit low-grade squamous cell carcinoma which, because of its
Sarcomatoid carcinoma: low-power view of a sarcomatoid carcinoma with irregular burrowing growth pattern, was designated epithelioma cuniculatum by Ayrd
spaces simulating vascular lumina. in 1954.49 Seven cases of this unusual variant of SCC have been reported in

Fig. 12.242 Fig. 12.243
Sarcomatoid carcinoma: high-grade pleomorphic cells mimicking the pattern of Pseudohyperplastic carcinoma: showing a downward proliferation of irregular tumor
growth of angiosarcomas (‘pseudoangiosarcomatoid carcinoma’). nests composed of extremely well-differentiated neoplastic cells.
 Genital intraepithelial neoplasia and squamous carcinoma 507

the penis.50 The mean age of presentation was 77 years. Grossly, the tumor is
white–gray, exo–endophytic and papillomatous with a cobblestone or spiky
appearance. It affects the glans and often extends to the coronal sulcus and
foreskin (average size 6 cm). The hallmark of the lesion is visible on the cut
surface where deep invaginations of the tumor form irregular, narrow and
elongated neoplastic sinus tracts that connect the surface of the tumor to deep
anatomical structures.
Despite the deep penetration, none of the reported cases of carcinoma
cuniculatum has shown nodal or systemic disease at time of diagnosis.

Histological features
Microscopically, the tumor partially resembles verrucous carcinoma with a
bulbous front of invasion. There may, however, be irregular foci of invasive
squamous cell carcinoma of the usual type (Figs 12.244–12.246). Carcinoma
cuniculatum should be distinguished from classical verrucous carcinoma,
which is also well differentiated, but rarely invades beyond the lamina pro-
pria and has a sharply delineated front.

Clear cell carcinoma

Clear cell features may be noted in squamous cell carcinoma. We have
observed some examples of solid, poorly differentiated SCC composed largely
of PAS-positive clear cells and have attributed the appearance to cytoplasmic
Fig. 12.246
Carcinoma cuniculatum: with its characteristic verruciform pattern of growth (left
field ) associated with an invasive usual SCC (right field).

hyperglycogenation, similar to cervical lesions.2,3 Clear cells may also be con-

spicuous in some condylomatous carcinomas.
A purported different penile tumor composed exclusively of clear cells, and
designated clear cell carcinoma, has recently been reported from Austria.51
The tumors were large, exophytic, partially ulcerated and widely invasive, all
located in the foreskin inner surface.

Histological features
Microscopically, clear cell carcinoma is composed of large neoplastic cells
with clear, PAS-positive cytoplasm (Fig.  12.247). HPV-16 is consistently
present. Follow-up information in the Austrian series showed that all five
patients had groin cystic clear cell metastases. Two patients were reported as
alive and the others either dead or with evidence of disease at last follow-up.

Fig. 12.244
Carcinoma cuniculatum: at low-power view showing its verruciform pattern of
growth extending deep into penile erectile tissues.
Adenosquamous carcinoma
Clinical features
Adenosquamous carcinoma is an exceedingly rare variant thought to arise
within misplaced glandular cells within the perimeatal region of the penis. It
consists of squamous cell carcinoma with foci of mucinous glandular differ-
entiation. It is believed to arise from the epithelial surface of the glans, where

Fig. 12.245 Fig. 12.247
Carcinoma cuniculatum: with a broad-based tumor front, intense stromal reaction, Clear cell carcinoma: composed of polygonal cells with evident atypia and a clear,
neoplastic cells with minimal atypia, and prominent parakeratosis. faintly eosinophilic cytoplasm.
508 Diseases of the anogenital skin
foci of squamous cell carcinoma in situ may be noted. Clinicopathologic
­features and outcome are similar to usual SCC. Grossly, a large firm granular
neoplasm deeply invading penile corpora is present. The few reported cases of
adenosquamous carcinomas have behaved aggressively with frequent nodal
metastasis.
Histological features
Microscopically, there is an admixture of squamous cell carcinoma and
mucin secreting adenocarcinoma (Figs  12.248, 12.249). The squamous
component generally predominates.52 The glandular epithelium expresses
carcinoembryonic antigen (CEA). Differentiated PeIN is usually present in
the adjacent glans mucosa. Adenosquamous carcinomas should be distin-
guished from mucoepidermoid, adeno-basaloid and pseudoglandular SCCs.
In ­mucoepidermoid ­carcinomas, there are isolated cells or group of squamous
cells containing mucin without forming glandular structures.53 In adeno-
basaloid tumors, there are well-formed mucin secreting glands but the solid
component is a basaloid carcinoma. Pseudoglandular (adenoid or acantho-
lytic) SCC most frequently represents SCC of the usual type in which there
is considerable ­dyskeratosis and acantholysis with secondary pseudolumen
­formation ­simulating ­glandular structures. The lack of mucin production
Fig. 12.248
Adenosquamous carcinoma: showing neoplastic nests composed of cells with
glandular and squamous differentiation.
Fig. 12.249
Adenosquamous carcinoma: tumor nest with a high-grade squamous component
associated with areas of glandular differentiation.
aids in their distinction. Another important differential diagnosis is adeno-
carcinoma arising in Littre glands. This tumor is ventrally located around the
penile urethra.
Acantholytic (adenoid, pseudoglandular) carcinoma
Clinical Features
This unusual variant of SCC is characterized by prominent acantholysis and
the formation of pseudoglandular spaces.54 The median age of the patient is
54 years. Tumors are generally large, involve multiple penile anatomical com-
partments and deeply invade into erectile corpora.
Histological features
The pseudoglandular spaces contain keratin, acantholytic cells and necrotic
debris (Figs 12.250, 12.251). CEA and mucin stains are negative. Compared
with usual SCC, pseudoglandular SCC shows higher-grade foci, invades deeper
anatomical structures and is associated with a higher incidence of regional
metastasis and mortality. The differential diagnosis includes gland-forming
penile tumors (surface adenosquamous, mucoepidermoid and urethral adeno-
carcinomas) and the angiosarcomatous variant of sarcomatoid carcinoma.
Fig. 12.250
Acantholytic carcinoma: deeply infiltrative tumor nests with extensive areas of
central acantholysis, giving the lesion a glandular appearance.
Fig. 12.251
Acantholytic carcinoma: tumor nest with central acantholysis showing an admixture
of neutrophils, necrotic debris, and desquamated cells.
 Cloacogenic carcinoma 509

Giant condyloma
Described by Buschke and Löwenstein, this is an exophytic tumor which
reaches a very large size after many years of evolution.55 There has been much
confusion in the correct classification of this lesion which has been confused
with verrucous carcinoma. In our opinion, verrucous carcinoma is a different
tumor (see above). In giant condylomas, patients are older than those with
condyloma acuminatum and younger than those with condylomatous (warty)
carcinoma. Grossly, it presents as a cauliflower-like tumor showing a papil-
lomatous growth with a sharp demarcation between the lesion and stroma on
the cut surface. The deep border may affect lamina propria, dartos or corpus
spongiosum. Histologically, it may have an exo- add/or endophytic growth
pattern with morphology identical to condyloma acuminatum. However, in
our recent experience, there is a morphological spectrum:
• entirely benign, composed of differentiated squamous cells and
indistinguishable from condyloma acuminatum,
• focally atypical,
• entirely atypical but without invasion,
• associated with superficial microinvasive squamous cell carcinoma,
• associated with overtly invasive squamous cell carcinoma (see diagram). Fig. 12.254
The condylomatous papillae show a central fibrovascular core and super- Giant condyloma: with a pushing, downward proliferation extending into penile
ficial koilocytotic changes (Figs 12.252–12.255). The differential diagnosis erectile tissues.

Fig. 12.255
Fig. 12.252
Giant condyloma: with koilocytosis, easily recognized in the upper layers, and mild
Giant condyloma: showing a papillomatous, exophytic pattern of growth, conspicuous
atypia at the base of the papillae (‘atypical condyloma’).
fibrovascular cores, and a broad tumor base.

includes condyloma acuminatum and noninvasive condylomatous carcinoma

(see Table 12.1). Condyloma acuminatum affects younger patients, is smaller
and lesions are usually multiple, affecting not only the squamous epithelium
of penile mucosal epithelial compartments but also the outer skin of the fore-
skin and shaft. Giant condyloma affects older patients, is usually bulky and
unicentric. The distinction of giant condyloma from well-differentiated con-
dylomatous carcinoma may be difficult. Identification of low-risk HPV in
giant condyloma and HPV-16 in condylomatous carcinomas may aid in the
differential diagnosis.

Fig. 12.253
Giant condyloma: with overt koilocytosis, slight parakeratosis, and no cellular atypia.
Cloacogenic carcinoma
This rare tumor presents in middle-aged women as a superficial ulcerated
adenocarcinoma composed of colonic-type glands arising in direct continuity
with vulval surface epithelium (Figs 12.256–12.258).1–5 It is independent of
the perivulval glands and, by definition, direct extension or metastasis from
an underlying large intestinal or visceral adenocarcinoma has been excluded.
The clinical features are not distinctive but tumors may present as lesions
simulating Bartholin’s gland infection.6 In a single case, the neoplastic glands
also contained Paneth cells.5 The origin of this tumor is not known but it is
thought most probably to arise from an area of gastrointestinal metaplasia
510 Diseases of the anogenital skin

Fig. 12.256 Fig. 12.258
Cloacogenic vulval adenocarcinoma: scanning view showing vulval squamous Cloacogenic vulval adenocarcinoma: close-up view showing the tumor cells
epithelium on the far right. Colonic epithelium is present on the left. Mucus-secreting distended by intracytoplasmic mucin.
carcinoma extends throughout the underlying connective tissue.

Fig. 12.257 Fig. 12.259
Cloacogenic vulval
Cloacogenic vulval
adenocarcinoma: high-
adenocarcinoma: the
power view of the junction
tumor is associated with
between squamous and
abundant mucin secretion
colonic epithelium.
forming large lakes.

or from heterotopic intestinal tissue (Fig. 12.259).7 Vulval cloacogenic car-
cinoma should not be confused with the similarly named tumor of the anal
canal. Tumor cells are positive for CK7 and CK20 and negative for estrogen
and progesterone receptors.8
Adnexal tumors
Papillary hidradenoma (mammary-like gland
adenoma of the vulva)
Clinical features
Papillary hidradenoma (hidradenoma papilliferum, mammary-like gland ade-
noma of the vulva) occurs almost exclusively in females.1–6 A single example
of a perianal variant has been described in a male.7
Papillary hidradenoma typically presents in middle-aged women as a
small (1–2 cm diameter) solitary asymptomatic nodule in a vulval, perineal or
­perianal location.4,6 Rare lesions attain a large size.8,9 Ulceration is ­exceptional.
Most often it affects the labium majus, but on occasion it arises on the lateral
aspect of the labium minus, fourchette or clitoris (Fig. 12.260).6,10 Perianal
lesions are very uncommon.11 It is often associated with the anogenital glands
(see below).6,12 Lesions may present with bleeding or pruritus and some are
ulcerated.6 Exceptionally, tumors are multiple and such cases tend to be
located on the same side of the vulva.1,2,13 Very rarely lesions may have been
described on the nipple, eyelid and external auditory canal.3,4
Pathogenesis and histological features
This tumor is now believed to be derived from anogenital mammary-like glands
and the name mammary-like gland adenoma of the vulva has been proposed.6
The epidermis may be normal, acanthotic or ulcerated. The tumor forms a
fairly well-demarcated nodule in the dermis or lamina propria and ­sometimes
 Cloacogenic carcinoma 511

Fig. 12.260
Papillary hidradenoma: the
lesion presents as a warty Fig. 12.262
nodule. By courtesy of the Papillary hidradenoma:
Institute of Dermatology, the papillae have a
London, UK. fibrovascular core.

shows foci of continuity with the overlying epithelium.5 The growth pat-
tern consists of a mixture of tubular, papillary and solid areas.6 It is com-
posed of epithelium-covered papillary processes projecting into cystic spaces
(Fig.  12.261). The epithelial lining is typically double layered, comprising
outer small myoepithelial cells with oval hyperchromatic nuclei and inner tall
columnar cells with eosinophilic cytoplasm, sometimes manifesting decapi-
tation secretion (Figs  12.262, 12.263). Squamous cells can be identified.
Oxyphilic metaplasia of tumor cells is common.14 Tumor cells are epithelial
and myoepithelial, and the latter can display clear cell change.6 Occasionally,
the lining is only one cell thick (columnar). Diastase-resistant, PAS-positive
intracytoplasmic granules are usually present. The occasional finding of
a normal mitotic figure has no sinister implication. The larger villi have a
fibrous core in which occasional ductal structures may be identified. Often,
the fibrous tissue surrounding the tumor is compressed to form a pseudo-
capsule. Some tumors have a pattern identical to those of breast tumors
including syringocystadenoma papilliferum, erosive adenomatosis, sclerosing
adenoma and ductal adenoma.6 An inflammatory cell component is not a
significant feature but foamy histiocytes can be seen.6 Exceptionally rarely,

Fig. 12.263
Papillary hidradenoma: the papillae are covered by a double layer of epithelial cells,
the inner showing typical decapitation secretion.

a malignant variant may be encountered.15,16 The malignant component is

­usually an apocrine carcinoma but an adenosquamous carcinoma has also
been documented.15
HPV has only occasionally been detected in this tumor.14

Benign tumors of Bartholin’s gland

Clinical features
Benign tumors of the Bartholin gland are very rare and the vast majority are
nodular hyperplasias.1 They occur mainly in young women. Occurrence in
postmenopausal women is exceptional.2 Adenomas are exceptionally rare,
as are adenomyomas.1,3,4 They all present as a small asymptomatic mass on
Fig. 12.261 the ­posterolateral aspect of the vulva and are usually diagnosed clinically as a
Papillary hidradenoma: whole mount preparation showing sharply circumscribed cyst. Bilateral lesions are very rare.5 Both hyperplasia and adenomas may be
papillary tumor. ­associated with pain.5,6 Nodular hyperplasia often presents in younger patients.
512 Diseases of the anogenital skin

Histological features
Nodular hyperplasia is well circumscribed and lobular with preserva-
tion of the normal duct–acinar relationship.1 Focal inflammation and
squamous metaplasia of the ducts is commonly seen. Dilated ducts
and sometimes ruptured ducts with extravasated mucin can be noted.7
Adenomas are well circumscribed and composed of small- to medium-
sized glands with focal papillary projections and lined by columnar,
mucin-producing cells with no cytological atypia and very rare mitotic
figures. Tubules and acini proliferate in a haphazard way in contrast to
the hyperplasias, where the normal architecture is preserved.1 A single
case of a papilloma arising from the duct of a Bartholin’s cyst has been
reported.8
In one case of hyperplasia, clonality was demonstrated, suggesting that the
process may be neoplastic rather than reactive.7
Basal cell carcinoma
Clinical features
Basal cell carcinoma can arise on the anogenital skin (Figs 12.264, 12.265).
Prior genital irradiation for cancer or ringworm is a theoretical risk fac-
tor that appertains to basal cell carcinoma at other sites. Vulval and penile
tumors are seen mainly in elderly patients.1 They usually present as an eroded
plaque, which may be pigmented. Less commonly, the tumor forms a nodule
or an ulcer. Symptoms vary from discomfort to pruritus.2,3 Neoplasms occur
most frequently on the labia majora, and sometimes can be multiple.4 Tumors

Adenoma of minor vestibular glands

Clinical features
Adenoma of minor vestibular glands (paravestibular tumor) is exceedingly
rare and occurs in the vulvar vestibule.1–3 It is likely that it represents a
­hyperplasia rather than a true neoplasm. The lesion is very small and usually
­represents an incidental finding in a biopsy taken for another reason.4

Histological features
Histologically, it consists of a small nodular aggregate of mucin-secreting
glands lined by columnar cells.

Bartholin’s gland carcinoma

Clinical features
This rare tumor accounts for only between 2% and 7% of vulval ­neoplasms.1–8
It presents as a painless hard deep subcutaneous nodule, which, as it expands, Fig. 12.264
becomes fixed and painful. The lesion measures from 1 cm to several centime- Vulval basal cell
ters and is located in the posterior aspect of the labium majus. It often invades carcinoma: erythematous,
keratotic plaque on
deeply into fat, muscle or bone and may be associated with a Bartholin’s
left labium majus. By
gland abscess. The diagnosis is often delayed because of the latter association.
courtesy of the Institute of
Adult and elderly women are usually affected. Exceptional cases have been Dermatology, London, UK.
described during pregnancy.4
It is often difficult to decide when a tumor has originated from Bartholin’s
gland and particular attention should be paid to exclude a metastasis from
elsewhere. Distinction from a sweat gland carcinoma can also be a ­diagnostic
problem. Rarely, the tumor is associated with extramammary Paget’s
­disease.9,10 In recent years, a consistent association has been found between
these tumors and HPV-16.11,12 Recurrence rates vary and have been reported
to be as high as 54%.13 Up to 40% of patients present with inguinofemoral
metastases. In these the 5-year survival is less than 50% but this decreases
to around 18% when two or more lymph nodes are involved.5,7,8 Adenoid
cystic carcinoma of Bartholin’s gland has a high local recurrence rate and
­occasionally presents with metastatic disease.14–17

Histological features
About 40% of Bartholin’s gland carcinomas are adenocarcinomas.4,7 A ­further
40% are squamous cell carcinomas and 15% are adenoid ­cystic ­carcinomas.18–21
The remainder are transitional, adenosquamous or ­anaplastic carcinomas.5,8
A case of lymphoepithelioma-like carcinoma and two ­low-grade epithelial–
myoepithelial carcinoma of the Bartholin gland have been documented.22,23
A case of high-grade squamous intraepithelial neoplasia in a Bartholin’s cyst
has also been reported.24
Exceptional cases of neuroendocrine carcinoma have also been Fig. 12.265
Perianal basal cell
described.2,25 Malignant mixed tumor very rarely originates from Bartholin’s
carcinoma: ulcerated
gland.26 A neoplasm can only be accepted as originating from the gland if perianal nodule with a
there is continuity with it. Adenocarcinomas may be mucinous or papil- pearly white rolled border.
lary.5 Cytogenetic analysis of a single case of adenoid cystic carcinoma of By courtesy of the
Bartholin’s gland revealed complex chromosomal abnormalities involving Institute of Dermatology,
chromosomes 1, 4, 6, 11, 14 and 22.27 London, UK.
 Soft tissue tumors 513

can rarely occur in the context of Gorlin’s syndrome.5 Inadequate excision

accounts for a high recurrence rate and exceptional metastases to regional
lymph nodes.6,7 Mohs surgery is often recommended to ensure adequate local
­excision and acceptable cosmetic results.

Histological features
Histologically, the appearances are identical to basal cell carcinomas occur-
ring elsewhere. There has been one case report of the variant fibroepithelioma
of Pinkus affecting the base of the penis.8

Metastatic tumors
The anogenital skin is a rare site for metastatic tumors.1–4 Those that are Fig. 12.266
Juvenile xanthogranuloma:
described are usually from a nearby primary site; for example, vulval metas-
lesions are present
tases may be derived from vaginal, cervical, endometrial, ovarian, renal cell on the lateral shaft of
carcinoma and choriocarcinoma. A large study of metastatic vulvar tumors the penis. Courtesy
found that about 46.9% arise from gynecological primaries and 43.9% from of R. Haufmann, Ulm,
nongynecological primary tumors. The rest of the tumors were metastases Germany. Reproduced
from an unknown primary.4 Vulval metastases usually present as a mass or, with permission from
less commonly, with pain or ulceration.4 Penile metastases most often arise Haufmann RE, Bachor, R.
from the prostate, colon, bladder and kidney. Rarely, they derive from else- Juvenile xanthogranuloma
where including pulmonary carcinoma, squamous cell carcinoma of the of the penis. J Urol.
tongue and cutaneous melanoma.5 The metastases are most commonly sited 1993: 150: 456–457. From
Bunker C: Male Genital
on the labia majora or periclitorally and in the corpus cavernosum of the
Skin Disease. Saunders
penis. Tumor thrombi are often found in the erectile tissue of the penis, pre- Ltd./Elsevier 2004.
dominantly in the corpora cavernosa.5 Penile metastasis may result in pria-
pism.6 They usually represent an ominous sign.5 Metastases may also arise in
an episiotomy scar. An exceptional metastasis to a Bartholin gland has been
reported.7,8 Langerhans cell histiocytosis
This condition is regarded as an abnormality of immune function. It usually
Lymphoma and leukemia affects the genital area as part of disseminated disease but can rarely appear
at this site alone.1–5 Females are affected much more often than males and
Although lymphoma is the most frequent secondary tumor of the testis, it
presentation can occur at any age from infancy to old age. Anogenital lesions
is rare in other parts of the urogenital tract and few case reports exist.1,2
may present as ulcers, erosions, papules, nodules or plaques. Involvement of
Primary anal lymphomas are also extremely rare and the cases described
the penis is very rare.6 Presentation as a fleshy papule on the dorsal penis7 and
have been anorectal, mainly of the plasmablastic variant, associated with
primary penile ulceration8 have been reported.
EBV and AIDS.3
In infants, the diaper area may be affected, typically with a seborrheic-like
Dehner and Smith included two cases of primary lymphoma in their series
dermatitis or purpuric papules.
of soft tissue tumors of the penis, both presenting as painless subcutaneous
nodules without evidence of systemic lymphoma.4 One case presented with
painless priapism and erythematous nodular ulceration of the shaft of the Soft tissue tumors
penis, another case with progressive swelling of the glans penis and another
with chronic penile ulceration.5,6
Doll and Diaz-Arias described a fungating nodular tumor of the scrotum
Keloid
in an HIV-negative homosexual that was shown to be immunoblastic T-cell It has been asserted that the skin of the penis never forms keloid,1,2 but
lymphoma.7 it has been reported after circumcision3 and other forms of trauma4,5 and
Ulceration of the penis due to leukemic infiltration secondary to chronic may be commoner than suspected.6 Keloid has been simulated on the
lymphocytic leukemia has been reported.8,9 Scrotal ulceration due to leukemia ­dorsum of the penis (Fig. 12.267) by chronic edema caused by a condom
cutis in acute myelogenous leukemia has also occurred.10,11 Lymphoma may catheter.7
present with perianal ulceration abscess and suppuration.12 Perianal infiltra-
tion, ulceration or abscess occurs in 5% of hematological malignancies.13 Fibroepithelial stromal polyp
The histopathology of genital lymphomas is identical to that occurring
elsewhere in the skin. The most commonly reported anogenital B-cell lym- Clinical features
phoma is of the diffuse large cell type.
Fibroepithelial stromal polyp (mesodermal stromal polyp, pseudosarcoma
botryoides), which presents in women of reproductive age, predominantly
Juvenile xanthogranuloma affects the vagina and, less commonly, the vulva.1–9 Involvement of the
­cervix is rare.2 In the vagina, the lower third is the most frequent location.
This lesion usually affects the head and trunk but can involve the genitalia Presentation in the very young (including a congenital lesion) or the elderly is
(Fig. 12.266).1 Multifocal penile presentation has been documented,2 also a uncommon.10,11 Interestingly, about one-third of patients are pregnant, sug-
solitary perineal papule,3 and a scrotal swelling.4 Clinicopathologically ­identical gesting that hormonal influences play a significant role in the pathogenesis
solitary lesions may be seen in adults. The histology is of lipid-laden histiocytes of these tumors.5 Lesions can be single or, more rarely, multiple and bilat-
and giant cells, negative for CD1 and S-100 which are found in Langerhans eral,12 the latter occurrence being most frequently seen in pregnancy. Tumors
cell histiocytosis. Juvenile xanthogranuloma is not associated with abnormal are usually less than 2 cm in diameter and are often pedunculated. Giant
lipids but there may be a relationship with urticaria pigmentosa, diabetes mel- lesions are exceptional.13,14 Local recurrence may occur following incomplete
litus, neurofibromatosis, cytomegalovirus infection and leukemia. ­excision but the behavior is benign.
514 Diseases of the anogenital skin

Fig. 12.267 Fig. 12.269
Chronic edema simulating edema: note the dorsal proximal swelling and ventral
Fibroepithelial stromal polyp: in this field, there is striking nuclear atypia. By courtesy
urethral fistula. Courtesy of Dr. Rameshwar Bang, Safat, Kuwait. Reproduced
of M. Nucci, MD, Brigham and Women’s Hospital and Harvard Medical School,
from Bang RL. Penile oedema induced by continuous condom catheter use and
Boston, USA.
mimicking keloid scar. Scand J Urol Nephrol 1994;28:333–5. From Bunker C: Male
Genital Skin Disease. Saunders Ltd./Elsevier 2004.

Histological features
Low-power examination reveals a polypoid and often pedunculated lesion
with fibrovascular stroma and showing variable cellularity. Small to
medium-sized blood vessels with thick walls are conspicuous (Fig. 12.268).
Hypocellular tumors contain abundant collagen and only scattered spindle-
shaped or stellate cells displaying mild focal or no cytological atypia and
occasional to frequent multinucleated cells. With increasingly cellular tumors,
there is more prominent cytological atypia and mitotic figures may be con-
spicuous (Figs 12.269, 12.270).8,9,15
Occasional atypical forms may be seen. Such variants are more frequent in
pregnant patients. Multinucleated tumor cells become more prominent with
a tendency to concentrate in the stroma adjacent to the epithelium. The cel-
lularity is more prominent towards the center of the lesion.8 Small collections
of mononuclear inflammatory cells are also commonly present.
Tumor cells are positive for desmin, vimentin and estrogen and progester-
one receptors.9,16,17 Positivity for actin is rare and macrophage markers are
negative.12
Fig. 12.270
Fibroepithelial stromal polyp: the presence of multiple mitoses as shown in this
field can be a source of concern to the unwary. By courtesy of M. Nucci, MD,
Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.

Ultrastructural studies show cells with features of fibroblasts and

myofibroblasts.17,18

Differential diagnosis
The main differential diagnosis, particularly for lesions presenting in the
vagina, is sarcoma botryoides. The latter lesion, in contrast, tends to occur at a
much younger age, lacks a cambium layer, displays invasion of the epithelium
by tumor cells, and is composed of small, undifferentiated tumor cells.19

Lymphedematous fibroepithelial polyp of

Fig. 12.268
Fibroepithelial stromal polyp: there are thick-walled vessels associated with a
variably cellular loose connective tissue stroma. By courtesy of M. Nucci, MD,
Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
the glans penis and prepuce
Clinical features
Only a handful of cases of this distinctive entity have been reported.1 Patients
developed polypoid or cauliflower-like, usually long-standing, lesions on the
glans penis or prepuce associated with chronic catheter use and phimosis.
All reported cases are in adults with a median age of 40 years. There may be
local recurrences.
 Soft tissue tumors 515

Histological features
Lesions are polypoid with a hyperplastic epidermis and an edematous stroma
with telangiectasia and sometimes focal proliferation of vascular channels. In
the background there are mono- or multinucleated stromal cells and scattered
mononuclear inflammatory cells, mainly lymphocytes. The stromal cells are
focally positive for actin and desmin.

Prepubertal vulval fibroma

Clinical features
This distinctive vulval lesion has been also described under the rubric child-
hood asymmetric labium majus enlargement.1,2 Lesions involve the labium
majus and present as a unilateral and exceptionally bilateral swelling. Patients
are girls between the ages of 3 and 13. A similar case in a postmenopausal
patient has been documented.3

Histological features
The lesion is poorly circumscribed, lies within the dermis and subcutis and
consist of a poorly cellular mass with abundant collagen, edema and focal
myxoid change. The cells within the tumor are positive for CD34.
Angiomyofibroblastoma
Fig. 12.271
Angiomyofibroblastoma: low-power view showing a richly vascular tumor. In this
example, there is a strikingly myxoid stroma. By courtesy of M. Nucci, MD, and
C.D.M. Fletcher, MD, Brigham and Women’s Hospital and Harvard Medical School,
Boston, USA.

Clinical features
This is a distinctive benign soft tissue tumor of the external genitalia and
perineum that must be distinguished from aggressive angiomyxoma (see
below).1–5 Rare cases have been documented in the vagina, fallopian tube,
urethra and retroperitoneum.6–9 It most commonly affects females of repro-
ductive age but has also been described in the elderly.4 Cases in males are
exceptional.10 A tumor sharing many clinical and histological features with
angiomyofibroblastoma has been reported in the male genital tract as angio-
myofibroblastoma-like tumor. These are described in the scrotum and groin
and histologically show hybrid features between angiomyofibroblastoma and
spindle cell lipoma.11,12
Angiomyofibroblastoma presents as a slowly growing, small (usually less
than 5 cm diameter), asymptomatic subcutaneous mass in the vulva or, less
commonly, in the vagina. Polypoid morphology is exceptional.13 They are
frequently confused with a Bartholin’s gland cyst. In males, tumors occur
on the scrotum and rarely in the perineum, groin and spermatic cord.14–16
Behavior is generally benign with little or no tendency for recurrence
although a single malignant case has been reported.17,18 This tumor con-
sisted of typical areas of angiomyofibroblastoma with areas of high-grade
myxoid sarcoma. Fig. 12.272
Angiomyofibroblastoma: the tumor cells have eosinophilic cytoplasm and small
nuclei. Nucleoli are not apparent. By courtesy of M. Nucci, MD, and C.D.M. Fletcher,
Histological features MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
Angiomyofibroblastoma is well circumscribed and surrounded by a fibrous
pseudocapsule. Scanning magnification reveals a tumor with hypo- and
hypercellular areas and a prominent vascular network composed of thin-
walled dilated vascular channels (Figs  12.271, 12.272). The hypocellular Differential diagnosis
areas display prominent myxoid change. Tumor cells are plump, epithelioid or Distinction from aggressive angiomyxoma is not usually difficult as the lat-
­spindle-shaped with imperceptible to abundant pink cytoplasm, finely ­dispersed ter is larger (usually more than 5 cm), infiltrative, less cellular and vascu-
chromatin and inconspicuous nucleoli. They tend to concentrate around the lar and contains vessels with thicker walls. However, tumors with hybrid
vascular channels. Multinucleated forms are frequent. Epithelioid cells with features of angiomyofibroblastoma and aggressive angiomyxoma have been
hyaline cytoplasm often have a plasmacytoid appearance. Cytological atypia reported.21 Despite this, it is controversial whether both entities are related.
is absent and mitotic figures are usually rare or exceptionally more promi- Aggressive angiomyxoma has rearrangements of HMGA2, a member of the
nent.19 Scattered lymphocytes and mast cells are often present. Intratumoral high-mobility-group protein family involved in alteration of chromatin struc-
mature adipocytes are present in a number of cases and may represent most ture and in the transcription of many genes. The latter feature has not been
of the tumor (lipomatous variant of angiomyofibroblastoma).5,20 Degenerative found in angiomyofibroblastoma.22 The rare cases of hybrid tumors are best
nuclear hyperchromatism may sometimes be present. classified and treated as aggressive angiomyxoma, and, if possible, cytoge-
The tumor cells are diffusely and strongly positive for desmin but in only netic analysis or immunohistochemistry for HMGA2 should be performed.
occasional cases are they positive for either smooth-muscle actin or pan- By immunohistochemistry, nuclear staining for this protein is seen in the
muscle actin. Estrogen and progesterone receptor can be positive.5 CD34 majority of (but not all) aggressive angiomyxomas and it tends to be neg-
is only exceptionally positive. Epithelial markers, S-100 and myoglobin are ative in angiomyofibroblastoma.23,24 However, it is important to take into
negative. consideration that there is not always correlation between the translocation
Ultrastructural studies suggest myofibroblastic differentiation.1,3,4 and protein expression.
516 Diseases of the anogenital skin

Aggressive angiomyxoma
Clinical features
This tumor presents as a slowly growing asymptomatic mass involving the
pelvis and perineum.1–6 Exceptionally, the lesion can present in the retroperi-
toneum.7 It mainly affects females in the third or fourth decade of life. Only a
single case has been reported in a child.8 Less than 5% of cases occur in males,
with predilection for the scrotum, perineum or groin.9–11 In males, lesions may
mimic a hydrocele or an inguinal hernia.12,13 Tumors are often 10 cm or more
in diameter and can sometimes attain a very large size. Genitourinary and
anorectal symptoms usually ensue due to external compression by the tumor.
In females, lesions present mainly in the vulva or perineum followed by the
vagina and the pelvis. Because of its extensive infiltrative growth, complete
surgical excision is often difficult; local recurrences are therefore frequent and
occur in up to 30% of cases. Metastasis are exceptional.14,15
Rare case reports have been published of tumors displaying prominent
reduction in size after treatment with gonadotrophin releasing hormone
agonists.16,17
Fig. 12.274
Histological features Aggressive angiomyxoma: in this view, a smooth muscle bundle is evident in the
upper field. By courtesy of M. Nucci, MD, Brigham and Women’s Hospital and
Macroscopic examination reveals a soft, ill-defined, lobulated tumor with Harvard Medical School, Boston, USA.
myxoid change. Microscopically, the lesion is infiltrative, with numerous
small- and medium-sized blood vessels and a small number of tumor cells in
a myxoid stroma (Figs 12.273–12.275). The blood vessels have thick walls,
which are often hyalinized. Tumor cells are small, spindle-shaped or stel-
late with ill-defined pale pink cytoplasm and vesicular nuclei. Cytological
atypia is absent and mitotic figures are rare. Bundles of smooth muscle are
frequently seen adjacent to blood vessels, a finding that can be highlighted
by a desmin stain.9 Residual normal structures including glands and smooth
muscle are often entrapped by the tumor. Scattered mast cells are often pres-
ent. Multinucleated giant cells similar to those found in stromal polyps are
occasionally found. Some cases overlap histologically with angiomyofibro-
blastoma (see above).
Immunohistochemically, tumor cells are positive for smooth-muscle actin
and desmin. Positivity for estrogen and progesterone receptors is also seen and
in men androgen receptors are positive.5,7,18 Cytogenetic analysis of a num-
ber of aggressive angiomyxomas has often shown rearrangements of chro-
mosome 12q13–15. The latter results in an aberrant expression of HMGA2
(a member of the high-mobility-group protein family previously known as
HMGIC).19–23 Interestingly, the area involved (12q14–15) is the same as that
reported in a number of other tumors including leiomyoma and lipomatous
neoplasms. Staining for HMGA2 may be useful to distinguish aggressive
Fig. 12.275
Aggressive angiomyxoma: high-power view showing a uniform cellular population.
There is no pleomorphism. By courtesy of M. Nucci, MD, Brigham and Women’s
Hospital and Harvard Medical School, Boston, USA.

angiomyxoma from potential mimics, mainly angiomyofibroblastoma (see

under the latter), but this marker, although sensitive, is not very specific.24,25
Electron microscopy shows cells with features of fibroblasts and
myofibroblasts.5

Differential diagnosis
See angiomyofibroblastoma.
Chronic lymphedema of the vulva may give rise to a lymphedematous
pseudotumor that can mimic aggressive angiomyxoma.26 In the former, how-
ever, there is massive edema rather than myxoid change, and telangiectatic
lymphatics focally surrounded by lymphocytes. Identical changes may be seen
in massive localized lymphedema secondary to morbid obesity.

Fig. 12.273
Aggressive angiomyxoma: there are conspicuous blood vessels dispersed in a
myxoid stroma. By courtesy of M. Nucci, MD, Brigham and Women’s Hospital and
Harvard Medical School, Boston, USA.
Cellular angiofibroma
Clinical features
Cellular angiofibroma is a distinctive tumor that occurs mainly on the vulva
of middle-aged women.1–7 Very rare cases occur in the vagina.6,7 Presentation

in males is less common, with lesions occurring in the inguinoscrotal region or
rarely in the perianal region.1,2,6,7 Exceptional cases have been reported in the
retroperitoneum and in the subcutaneous tissue of the chest, abdomen, knee,
retroperitoneum, urethra, anus, upper eyelid and oral mucosa.2,7–10 Tumors
tend to be small and behavior is benign, with almost no tendency for local
recurrence except very rarely.1,7,11 Sarcomatous change has been reported but
so far this has not been associated with aggressive behavior.7,12,13
Pathogenesis and histological features
Cytogenetic analysis of cellular angiofibroma has shown loss of chromosome
13q14, a feature also seen in spindle cell lipoma and mammary-type myofi-
broblastoma.7,14,15 In conjunction with histological similarities, this gives fur-
ther support to a link between these neoplasms.
Tumors are well circumscribed but unencapsulated, with only occasional
extension into the surrounding soft tissues (Figs 12.276–12.278).1 An infil-
trative pattern is rare.7 Most lesions are fairly cellular and composed of short,
bland, spindle-shaped cells with poorly defined pale eosinophilic cytoplasm
and vesicular nuclei. Nuclear grooves and intranuclear inclusions are com-
mon. The number of mitotic figures varies but sometimes they may be promi-
nent. Thick-walled, medium-sized hyalinized blood vessels are frequent in
Fig. 12.276
Cellular angiofibroma: the tumor is characterized by thick-walled, hyalinized blood
vessels associated with a densely cellular stroma. By courtesy of M. Nucci, MD,
Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
Fig. 12.277
Cellular angiofibroma: note the associated collagen fibers. By courtesy of M. Nucci,
MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
Soft tissue tumors 517
Fig. 12.278
Cellular angiofibroma: the tumor cells are small, uniform and have round to oval
vesicular nuclei. By courtesy of M. Nucci, MD, Brigham and Women’s Hospital and
Harvard Medical School, Boston, USA.
addition to slender collagen bundles and mast cells. Pseudovascular spaces
are sometimes seen. Mature adipocytes are frequently present (in up to 30%
of cases). Focal cytological atypia resembling symplastic changes seen in other
tumors are described and sarcomatous transformation can be ­identified.7,12,13,16
Malignant areas usually show high cellularity, cytologic ­atypia and multinu-
cleated cells.7 Tumors may rarely show features of a pleomorphic liposar-
coma or of an atypical lipomatous tumor.6,13
Tumor cells are positive for vimentin and are positive for CD34 in up
to 50% of cases. Staining for actin, desmin, caldesmon, S-100 protein and
­epithelial markers is negative.1, 2
Differential diagnosis
Distinction is mainly with angiomyofibroblastoma. The latter consists of
more epithelioid desmin-positive cells with a nested pattern and a tendency
for perivascular distribution. Cellular angiofibroma is negative for desmin
and is often positive for CD34.
Genital leiomyoma
Clinical features
Genital leiomyoma comprises those lesions arising from the vulva, scrotum
and nipple. Tumors arising in the vulva and scrotum are distinctive from
other cutaneous leiomyomas including pilar leiomyoma and angioleiomy-
oma.1 Leiomyomas arising in the nipple are similar to pilar leiomyoma.
Vulval leiomyomas are relatively rare and present mainly in women of
reproductive age or slightly older as an asymptomatic swelling.1–5 Clinical
features are not distinctive. Tumors are subcutaneous, well circumscribed and
are often clinically diagnosed as a cyst. The majority of benign lesions are
less than 5 cm in diameter and present in the labia. Rare cases arise in the
­clitoris.6 Tumors may increase in size during pregnancy and also in ­association
with estrogen/progesterone replacement therapy.7 Benign tumors are typi-
cally ­circumscribed and small, but only histological examination allows for
­distinction between benign, low-grade malignant and malignant tumors.
In the male8 it presents as a painless, slow-growing, palpable mass (pap-
ule or nodule), and/or difficulty with micturition9 if it affects the penis; or
swelling of the scrotum where it arises from the tunica dartos scroti.1,10–12
Scrotal tumors are less common and tend to be larger than their vulval
­counterparts.13,14 They present as an asymptomatic mass that may occasion-
ally be polypoid.14 Rare cases are associated with prominent warty epidermal
hyperplasia and resemble condyloma acuminatum.15 Other benign smooth
muscle lesions of the scrotum such as hamartoma of the dartos muscle are
­exceedingly rare.16
518 Diseases of the anogenital skin

Histological features
Tumors are well circumscribed and noninfiltrative with variable cellularity.1–3
They are composed of admixed spindled and epithelioid cells, often with a single
cell type predominating.4,17,18 Lesions with a spindled cell component are very
similar to those found in the uterus and consist of bundles of cells with well-
defined eosinophilic cytoplasm, vesicular cigar-shaped nuclei and an inconspicu-
ous nucleolus. Focal myxoid change and hyalinization are commonly seen and
sometimes this results in a plexiform appearance. Epithelioid tumor cells have
abundant eosinophilic or pale-staining cytoplasm.
Because of the rarity of vulval smooth muscle tumors, it is often difficult
to separate benign lesions from those with potential for local recurrence or
metastasis (see below). It has been suggested that a tumor with any evidence
of mitotic activity, nuclear pleomorphism or an infiltrative margin should be
regarded as having at least the potential for local recurrence.4 In such cases,
excision with a margin of at least 1 cm should be recommended.4
Because of their rarity, there is even less information relating to histo-
logical evaluation of scrotal leiomyoma. Degenerative cytological atypia
is accepted in these tumors but these changes occur in noncellular, well-
­circumscribed lesions that lack mitotic activity.19 Fig. 12.279
Vulval leiomyosarcoma: this low-power view shows fascicles of tumor cells with
Leiomyosarcoma eosinophilic cytoplasm. By courtesy of C. Crum, MD, Brigham and Women’s
Hospital and Harvard Medical School, Boston, USA.

Clinical features
Vulval leiomyosarcoma is rare and presents in middle-aged to elderly patients
as an asymptomatic mass mainly affecting the labia.1–6 Malignancy is not usu-
ally suspected on clinical examination unless the mass is large and poorly cir-
cumscribed. Lesions may be confused with a Bartholin’s gland cyst.6,7
Scrotal leiomyosarcomas are exceptional and present as an asymptomatic,
rapidly growing mass in elderly patients.8,9
Wide local excision is the treatment of choice. It is difficult to predict the
outcome because of their rarity and the lack of large studies with adequate
follow-up information.

Histological features
Accepted criteria for the histological diagnosis of leiomyosarcoma include
(Figs 12.279–12.281):1,2,10
• size larger than 5 cm in diameter,
• infiltrative margins,
• more than 5 mitoses/10 high-power fields (HPF),
• moderate to severe cytological atypia.
More recently, it has been suggested that tumor necrosis should also be
Fig. 12.280
regarded as evidence of malignancy.10 Vulval leiomyosarcoma: note the nuclear pleomorphism. By courtesy of C. Crum,
MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
Vulvar leiomyomatosis
Clinical features
This rare condition is characterized by multiple leiomyomas in the vulva associated
with esophageal leiomyomas.1–8 The vulval tumors may appear before, concomi-
tantly or after the development of esophageal lesions. Involvement of the clitoris is
sometimes noted. Patients can also present with Alport’s syndrome, characterized
by inherited glomerulonephritis, ocular abnormalities and deafness.5

Pathogenesis and histological features

The pathogenesis of the disease is unknown but deletions and mutations in
the COL4A6 and COL4A5 genes have been described.5,7 These genetic altera-
tions are associated with defects in type IV collagen in Alport’s syndrome.
Vulval and esophageal leiomyomas are identical to those occurring
sporadically.

Myointimoma
Clinical features
This is a rare, recently described tumor involving the corpus spongiosum of
the glans penis.1 The original series consisted of adult patients, but a recent
small series in children and adolescents has been reported.1,2 Few single case
Fig. 12.281
Vulval leiomyosarcoma: high-power view showing a mitotic figure in the center of
the field. By courtesy of C. Crum, MD, Brigham and Women’s Hospital and Harvard
Medical School, Boston, USA.
 Soft tissue tumors 519

reports have been presented.3–5 Lesions are small (usually less than 1 cm) and
asymptomatic. It does not seem to be related to trauma. The behavior is
benign with no tendency for local recurrence.1,2

Histological features
Low-power examination reveals a diffuse myointimal proliferation of the blood
vessels of the corpus spongiosum of the glans penis in a plexiform growth pattern
(Figs 12.282–12.284). The proliferating cells are bland and spindled with abun-
dant pink cytoplasm and vesicular nuclei. A minority of the cells display features
more reminiscent of fibroblasts. The background stroma is sclerotic and myxoid.
Focal degenerative changes may be seen and mitotic figures are absent.
The spindled cells are positive for smooth-muscle actin, muscle-specific
actin and calponin but negative for desmin.

Differential diagnosis
This tumor must be distinguished from myofibroma, intravascular nodular
fasciitis and vascular leiomyoma.

Postoperative spindle-cell nodule Fig. 12.283

Myointimoma: the vascular lumina are compressed by the proliferation of spindle-
Clinical features shaped cells.

This rare reactive lesion presents as a small nodule at the site of a previous
surgical procedure on the genitourinary tract including the bladder, vulva
and the vagina.1–4 It grows rapidly and is usually asymptomatic.1–3 Local
­recurrence is usually not seen.

Fig. 12.284
Myointimoma: areas of hyalinization may be seen.

Pathogenesis and histological features

Fig. 12.282
Myointimoma: note the
multinodular and plexiform
growth pattern.
The lesion is regarded as a non-neoplastic reparative phenomenon,
Interestingly, trisomy 7 has been reported in two cases.5 The nodule is poorly
circumscribed and resembles nodular fasciitis.1–3 It is composed of bundles
of plump myofibroblast-like cells dispersed in a myxoid or edematous back-
ground. Nuclei may be bland or hyperchromatic. Small blood vessels, foci of
hemorrhage, lymphocytes and neutrophils are additional features. Mitotic
figures are common.
 Degenerative and metabolic
13
Chapter

diseases
See
www.expertconsult.com
for references and
additional material
Nooshin Brinster and Eduardo Calonje

The hyperlipidemias  520 Porphyria  549 Lichen myxedematosus/scleromyxedema  574

Eruptive xanthomata  522 Congenital erythropoietic porphyria  550 Acral persistent papular mucinosis  578
Tendinous xanthomata  523 Erythropoietic protoporphyria  551 Cutaneous mucinosis of infancy  579
Tuberous xanthomata  525 Hereditary coproporphyria  553 Self-healing juvenile cutaneous mucinosis  579
Planar xanthomata  527 Porphyria cutanea tarda  553 Reticular erythematous mucinosis  580
Verruciform xanthoma  528 Hepatoerythropoietic porphyria  555 Scleredema  580
Variegate porphyria  555 Papular and nodular cutaneous mucinosis of
Angiokeratoma corporis diffusum  530 systemic lupus erythematosus  581
Pseudoporphyria  559 Myxoid cyst  582
The amyloidoses  532
Primary and myeloma-associated systemic Gout  562 Cutaneous focal mucinosis  582
amyloidosis  534 Mucinous nevus  583
Ochronosis  564 Neuropathia mucinosa cutanea  583
Secondary amyloidosis  536
Alkaptonuria  564 Self-healing infantile familial cutaneous
Hemodialysis-associated amyloidosis  536
Exogenous ochronosis  564 mucinosis  583
Heredofamilial amyloidoses  537
Amyloid elastosis  537 Hartnup disease  565 Localized mucinosis secondary to venous
Primary localized cutaneous amyloidosis, lichen insufficiency  583
and macular types  537
Pellagra  565 Secondary cutaneous mucinosis  583
Secondary localized cutaneous amyloidosis  541 Scurvy  566 Acanthosis nigricans  583
Familial primary cutaneous amyloidosis  541
Nodular amyloidosis  541 Calcinosis cutis  566 Acrodermatitis enteropathica  586
Dystrophic calcinosis cutis  566
Colloid milium  543 Metastatic calcinosis cutis  568 Necrolytic migratory erythema  587
Juvenile colloid milium  543 Idiopathic calcinosis cutis  568 Bullosis diabeticorum  589
Adult colloid milium  544
The mucinoses  571
Hyalinosis cutis et mucosae  546 Generalized myxedema  572
Localized (pretibial) myxedema  573
Cutaneous macroglobulinosis  548

The presence of xanthomata commonly represents a cutaneous manifesta-

The hyperlipidemias
The hyperlipidemias may present as cutaneous xanthomata, which are local-
ized aggregates of histiocytes containing accumulated lipid (primarily free
and esterified cholesterol), in the form of five main clinical types:
• eruptive,
• tendinous,
• tuberous,
• planar,
• disseminated.1
The last, xanthoma disseminatum, in which serum lipid levels are normal,
is discussed in Chapter 29 (see xanthogranuloma). Xanthoma cells express
CD4, CD11c, CD14b, and CD68 in addition to human leukocyte antigen
(HLA) class II antigens.2
Hyperlipidemias may be primary, or secondary to conditions such as dia-
betes mellitus, obesity, pancreatitis, renal disease (the nephrotic syndrome or
chronic renal failure), hypothyroidism, alcohol consumption, pregnancy,
cholestatic liver disease (e.g. primary biliary cirrhosis) and paraproteinemias.
Drug-induced hyperlipidemia also occurs as a result of administration of
estrogens, corticosteroids or 13-cis-retinoic acid. It is often associated with
serious, potentially life-threatening disorders such as atherosclerosis (low
density lipoproteins) and pancreatitis (hypertriglyceridemia).3
tion of systemic disease, and their recognition should therefore be followed
by an intensive investigation to exclude the latter (Table 13.1).2,4 Although
not a hard and fast rule, xanthoma morphology and distribution can
­sometimes point towards specific hyperlipidemia variants.
The plasma lipids are composed of triglycerides and cholesterol; these are
insoluble and their transport is facilitated by their aggregation into lipopro-
teins. The latter are macromolecular complexes composed of an outer shell of
hydrophilic phospholipids, nonesterified cholesterol and apo(lipo)proteins,
which emulsify the associated hydrophobic core of triglycerides and choles-
terol ester.5 There are a large number of apoproteins, with variable structure
and function (e.g. ApoB-48, which is required for the secretion of chylomi-
crons into the thoracic duct).3 In addition to giving structure to the lipopro-
tein, apoproteins also represent ligands for specific receptors (e.g. ApoE is a
ligand for liver chylomicron receptors). They also act as cofactors for a
­number of lipid-modifying enzymes (e.g. ApoCII activates lipoprotein lipase).5
Lipoprotein metabolism, which is summarized in Figure 13.1, involves both
exogenous (dietary) and endogenous pathways.6 For more detailed informa-
tion the reader is particularly referred to references 1 and 6.
The classification of hyperlipidemias is based upon the electrophoretic
separation, on paper or agarose gel, of abnormal quantities of lipoprotein in
the plasma (Fig. 13.2). There are seven main classes of lipoprotein, with
­differing electrophoretic mobilities:
 The hyperlipidemias 521

Table 13.1
Classification of xanthomatous disorders

Hyperlipidemic xanthomatoses: disorders characterized by elevated Normolipidemic xanthomatoses: disorders characterized by normal plasma
plasma triglycerides or cholesterol triglycerides and cholesterol
Primary Elevated plasma triglycerides Disorders characterized by Accumulation of unusual sterols in LDL
hyperlipoproteinemias lipoprotein lipase deficiency altered lipoprotein content cerebrotendinous xanthomatosis(cholestanol)
familial hyperlipoproteinemia, type V or structure sitosterolemia (sitosterol, campesterol,
familial hypertriglyceridemia stigmasterol, etc.)
Elevated plasma triglycerides and Deficiency of HDL
cholesterol plantar and buccal mucosal xanthomas
familial dysbetalipoproteinemia, type III diffuse plane xanthomas
Elevated plasma cholesterol Normocholesterolemic dysbetalipoproteinemia
familial hypercholesterolemia tuberous
xanthelasmas
Hyperapobetalipoproteinemia
tendon xanthomas
xanthelasmas
Secondary Elevated plasma triglycerides Disorders associated with Multiple myeloma
hyperlipoproteinemias diabetes mellitus antibodies directed against Other paraproteinemias
drug-induced chylomicronemia lipoprotein components
alcohol
States with no demonstrated Underlying lymphoproliferative disease
estrogens
lipoprotein abnormalities multiple myeloma
retinoids
cryoglobulinemia
hypothyroidism
Waldenström’s macroglobulinemia
nephrotic syndrome
leukemia
type I glycogen storage disease (von
lymphoma
Gierke’s disease)
other
Elevated plasma cholesterol
Xanthomatosis antedated by local tissue alterations
hepatic cholestasis
normolipemic eruptive xanthomas (after erythema)
primary biliary cirrhosis
xanthelasmas and planar xanthomas (after
biliary atresia
erythroderma)
hypothyroidism
fiverruciform xanthomas (in areas of dystrophic
dysglobulinemias or
epidermolysis bullosa)
paraproteinemias
Other
multiple myeloma
hereditary tendinous and tuberous
xanthomas
normolipemic tendon and tuberous
xanthomas
normolipemic subcutaneous xanthomatosis

HDL, high density lipoprotein; LDL, low density lipoprotein.

Reprinted from Cruz, P.D., East, C., Bergstresser, P.R. (1988) Journal of the American Academy of Dermatology, 19, 95–111 with permission from the American Academy of
Dermatology, Inc.

• chylomicrons, which are composed predominantly of exogenous
triglycerides produced by small intestinal mucosal epithelium in response
to dietary lipid,
• very low density (pre-beta) lipoproteins (VLDL) of hepatic derivation,
which are particularly involved in the transportation of endogenous
triglyceride,
• intermediate density lipoproteins (IDL), which are thought to be VLDL
remnants,
• low density (beta) lipoproteins (LDL), which are mainly involved in
cholesterol transport and derived from IDL or else produced by the liver,
• high density (alpha) lipoproteins (HDL) composed predominantly of
lipoprotein and equal quantities of cholesterol and phospholipid,
• high density lipoprotein variant HDL2,1,5
• high density lipoprotein variant HDL3.1,5
The hyperlipidemias are classified into six types according to the lipopro-
tein anomaly present (Table 13.2). However, it should be noted that each of
these six types may result from a variety of pathogeneses, including those of
a known or presumed genetic basis and others that complicate a diverse group
of disease processes (secondary hyperlipidemia).7–9 High density lipoproteins
are not atherogenic.3 Indeed, their function is to remove cholesterol from the
tissues and high levels serve to protect against vascular disease.5 Conversely,
HDL deficiency (e.g. Tangier disease) is associated with cholesterol
accumulation.10
The lipid content of xanthomata is probably mostly derived from the plasma,
presumably by lipoprotein (particularly LDL and VLDL) permeation of blood
vessel walls with the release of lipid and its subsequent phagocytosis by histio-
cytes, although localized lipogenesis may also be of importance.10–13 The sub-
groups and proportions of lipid deposited within xanthomata are similar to those
found in atheromatous plaques, raising the possibility of a shared pathogenesis.1
Xanthomata are, however, not always associated with hypercholester-
olemia or hyperlipoproteinemia.14 Under such circumstances, they may evolve
as a consequence of altered lipoprotein content or structure, represent local
tissue changes or develop as a consequence of systemic disease including lym-
phoma, multiple myeloma, and Waldenström's macroglobulinemia.15
Normocholesterolemic xanthomata can therefore arise as a consequence of
the accumulation of cholesterol-like substances within histiocytes (e.g.
­cerebrotendinous xanthomatosis and β-sitosterolemia).
Cerebrotendinous xanthomatosis represents an abnormality of bile acid
metabolism inherited in an autosomal recessive pattern.16–18 As a ­consequence of
mitochondrial enzyme sterol 27-hydroxylase deficiency and resultant impaired
oxidation of the cholesterol side chain during the production of cholic acid,
cholestanol (and cholesterol) accumulates in the tissues, ­especially the tendons,
lungs, and brain. The xanthomata particularly affect the Achilles tendons and
the tendons of the knees, elbows, and the interphalangeal joints.19 In addition to
tendinous xanthomata, patients develop j­uvenile cataracts and progressive neu-
rological dysfunction including mental ­retardation, dementia, pyramidal signs,
522 Degenerative and metabolic diseases
Fig. 13.2
Hyperlipidemia: electrophoretic separation of serum lipids. (Chylo, chylomicron;
HDL, high density lipoprotein; LDL, low density lipoprotein; VLDL, very low density
lipoprotein.) By courtesy of B. Lewis, MD, St Thomas’ Hospital, London, UK.
cerebellar ataxia, spinal cord paresis, and sensory changes due to dysmyelina-
tion.18,20,21 Coronary ­atherosclerosis, endocrine ­abnormalities, and diarrhea may
also be present. In addition to cholestanol accumulation, cerebrotendinous xan-
thomatosis has been shown to be ­characterized by abnormal high density
­lipoproteins, which result in impaired cholesterol (and cholestanol) transport
and contribute to the ­consequent xanthomatization.16 The mortality is high,
patients usually dying in the fourth to sixth decades, most often from progres-
sive neurological ­dysfunction, pseudobulbar paralysis or myocardial
infarction.21
Tendinous and tuberous xanthomata may also represent a manifestation
of β-sitosterolemia. This is an autosomal recessive condition in which
increased intestinal absorption of the plant sterols β-sitosterol, campesterol,
and stigmasterol results in tissue deposition along with cholesterol and subse-
quent xanthoma formation.22–24 Normally these sterols are almost completely
unabsorbed from the gastrointestinal tract. β-Sitosterolemia is associated
with an increased risk of atherosclerosis.3
Xanthomata may occur in extracutaneous locations mimicking tumors
in patients with hyperlipidemia. Sites include deep soft tissues and
mediastinum.25
Fig. 13.1
Lipoprotein metabolism. (LDL, low density lipoprotein;
VLDL, very low density lipoprotein.) Reproduced with
permission from Cruz, P.D., East, C., Bergstresser,
P.R. (1988) Journal of the American Academy of
Dermatology, 19, 95–111.
Eruptive xanthomata
Clinical features
Eruptive xanthomata are small (1–4 mm) yellowish papules with a red halo
that have a predilection for the buttocks, shoulders, and extensor surfaces of
the limbs (Fig. 13.3).1 They may also present in the antecubital and popliteal
fossae, axillae, lips, eyelids, and ears.2 They often appear in crops and may
wax and wane with plasma lipoprotein levels.3 Lesions usually resolve spon-
taneously over a period of weeks. Pruritus is frequently present and the pap-
ules are sometimes tender.2 Eruptive xanthomata may rarely display a Koebner
phenomenon.4,5 Healing is occasionally associated with the development of
hyperpigmented scars.2 Cutaneous lesions of Langerhans cell histiocytosis
may mimic eruptive xanthoma.6
Eruptive xanthomata are associated with hypertriglyceridemia and most
often occur in hyperchylomicronemic states. Sometimes their presence
­correlates with increased levels of very low density lipoproteins. The most
­common cause, however, is secondary hyperlipoproteinemia, especially in
those cases associated with diabetes mellitus and alcohol ingestion, or in
those that are drug induced (e.g. due to exogenous estrogens, corticoster-
oids or retinoids).2,7 They may also develop as a consequence of decreased
lipoprotein lipase activity, ApoCII deficiency or increased synthesis of
VLDL, which effectively blocks chylomicron access to lipoprotein lipase.2,8
Eruptive xanthomata are therefore often accompanied by other features of
hyperlipidemia, ­including lipemia retinalis, hepatosplenomegaly, abdomi-
nal pain, and pancreatitis. They may also rarely develop as a manifestation
of primary hyperlipoproteinemia (HPL), particularly autosomal recessive
lipoprotein lipase deficiency (HLP type I) in children and familial HPL type
V in adults.9,10 An exceptional association with β-sitosterolemia, a condi-
tion usually presenting with tuberous or tendinous xanthomata, has been
documented.11 Much rarer ­associations include familial hypertriglyceri-
demia, the nephrotic syndrome, chronic pancreatitis, von Gierke's disease,
and hypothyroidism.7,12,13 An association with acanthosis nigricans has also
been reported.14
Histological features
The histological features are seen predominantly within the superficial reticu-
lar dermis. In early lesions histiocytes are numerous and the fully developed
 The hyperlipidemias 523

Table 13.2
Classification of hyperlipidemias

Type Anomaly Primary cause Secondary cause Atherogenesis Xanthoma Associations

I Raised chylomicrons Familial lipoprotein lipase deficiency − − Eruptive Hepatomegaly
Apoprotein Cll deficiency Pancreatitis
Lipemia retinalis
Abdominal pain
IIA Raised LDL Familial hypercholesterolemia Hepatoma + Tendinous −
Familial multiple type hyper Porphyria Xanthelasma
lipoproteinemia Myxoedema Arcus
Common hypercholesterolemia Anorexia nervosa Tuberous (rare)
Nephrotic syndrome
Cushing’s syndrome
IIB Raised LDL and VLDL Familial hypercholesterolemia Nephrotic syndrome + Tendinous −
Familial multiple type hyperlipidemia Cushing’s syndrome Xanthelasma
Arcus
Tuberous
III Raised IDL Familial dysbetalipoproteinemia Paraproteinemia + Palmar Diabetes
Tendinous Gout
Tuberous Obesity
IV Raised VLDL Familial multiple type hyperlipidemia Diabetes + Eruptive −
Familial hypertriglyceridemia Uremia Tendinous
Sporadic hypertriglyceridemia Paraproteinemia Tuberous
Alcoholism
Lipodystrophy
Obesity
V Raised chylomicrons Familial multiple type Diabetes + Eruptive Hepatomegaly
and VLDL hyperlipoproteinemia Obesity Pancreatitis
Familial lipoprotein lipase deficiency Pancreatitis Lipemia retinalis
Apoprotein Cll deficiency
Familial hypertriglyceridemia
Famial type V hyperlipoproteinemia

IDL, intermediate density lipoprotein; LDL, low density lipoprotein; VLDL, very low density lipoprotein.

Eruptive xanthomata often develop rapidly over the course of several days
and occasionally are associated with spontaneous resolution. The quantity of
­intracytoplasmic lipid (predominantly triglyceride in contrast to other xan-
thomata, which contain mostly cholesterol) is in a state of flux and may be
associated with extracellular deposition, a phenomenon that is rare or absent
in the other types of xanthomata. In all xanthomata the lipid within the mac-
rophage stains positively with fat stains such as oil red O, scarlet or Sudan red
(Fig. 13.7).

Fig. 13.3
Eruptive xanthoma: numerous small yellow papules are present on the buttocks.
By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.
‘foam cells’, which characterize xanthomata, are sometimes few in number.
The infiltrate may also contain an admixture of lymphocytes and
­neutrophils.15,16 In an established papule, xanthoma cells with characteristic
clear or foamy cytoplasm form the predominant cell type (Figs 13.4–13.6).
Differential diagnosis
There can be confusion with granuloma annulare histologically as both con-
ditions have certain features in common, namely a dermal interstitial
­histiocytic infiltrate with variably increased mucin.12,17 Although extracellular
lipid may disrupt dermal collagen, necrobiosis is not characteristic of ­eruptive
­xanthoma. Additionally, it contains few giant cells and the ­perivascular infil-
trate is ­lymphocytic, in contrast to the histiocytes seen in granuloma
annulare.12
Tendinous xanthomata
Clinical features
Tendinous xanthomata, which are associated with raised low density lipo-
protein levels, are slowly enlarging subcutaneous tumors that occur in ten-
dons (especially those of the hands, knees, elbows, and the Achilles tendon),
ligaments, fascia, and periosteum (Figs 13.8, 13.9).1 The overlying skin,
524 Degenerative and metabolic diseases

Fig. 13.6
Eruptive xanthoma: the histiocytes express CD68.
Fig. 13.4
Eruptive xanthoma: biopsy
of an established lesion.
The histiocytes have
abundant vacuolated
cytoplasm.

Fig. 13.7
Eruptive xanthoma: the lipid within the macrophages stains positively with oil red O.

Fig. 13.5
Eruptive xanthoma: high-power view showing an admixture of vacuolated xanthoma
cells and nonlipidized variants with abundant eosinophilic cytoplasm.

which appears normal, is freely moveable over the surface and small tendon
xanthomata may be difficult to palpate.1 The lesions characteristically
‘move with the tendons’ and are thought to be trauma related.2 The ­presence
of these xanthomata is most frequently a feature of heterozygous familial
(LDL receptor deficiency) hypercholesterolemia.2–4 There is a high risk of
associated coronary atherosclerosis. A recent meta-analysis demonstrated a
threefold increased risk of cardiovascular disease in patients with familial
hypercholesterolemia and tendinous xanthomata compared to those with-
out cutaneous lesions.5 Tendinous xanthomata are also seen in familial
combined hyperlipidemia, normocholesterolemic states such as cerebroten-
dinous xanthomatosis (cholestanolosis) and β-sitosterolemia, and the neph-
rotic syndrome.2,6–10 Fig. 13.8
Clinically, the lesions, which may be mistaken for gouty tophi and rheu- Tendinous xanthoma: typical nodules on the heels. These lesions are often related
matoid nodules, are sometimes found in association with tuberous xan- to trauma; the Achilles tendon is a classical site. By courtesy of A.F. Lant, MD,
thomata and xanthelasmata. and J. Dequeker, MD, London, UK.
 The hyperlipidemias 525

Four other conditions may also be characterized by tuberous

xanthomatosis:
• homozygous familial hypercholesterolemia,
• cerebrotendinous xanthomatosis,
• β-sitosterolemia,1
• type IV hyperlipoproteinemia.4
Tuberous xanthomata also occur in secondary hyperlipidemia (e.g. due to
the nephrotic syndrome or hypothyroidism). Protease inhibitors may cause
hyperlipidemia, and ritonavir has been reported to induce tuberous and tendi-
nous xanthoma lesions.5 Clinically, tuberous xanthomata occasionally resem-
ble the lesions of erythema elevatum diutinum. Tuberous and tendinous
normolipemic xanthomata have been described but it seems that, with ade-
quate follow-up, patients usually develop some form of hyperlipidemia.6

Fig. 13.9
Tendinous xanthoma: xanthomata are present overlying the knuckles. By courtesy
of the Institute of Dermatology, London, UK.

Histological features
Tendinous xanthomata are composed of multiple nodules containing
­ anthoma cells, accompanied in early lesions by an admixture of inflam-
x
matory cells including histiocytes, lymphocytes, and neutrophil poly-
morphs. The deposits in tendinous xanthoma are doubly refractile to
polarized light (Fig. 13.10). Older lesions are characteristically ­associated
with fibrosis.

Tuberous xanthomata
Clinical features Fig. 13.11
Tuberous xanthoma: firm
Tuberous xanthomata are firm yellow–red papules and nodules, which are erythematous nodules
found most frequently on the extensor aspect of the knees, elbows, and but- over the elbow. By
tocks (Figs 13.11–13.13).1 Lesions sometimes also occur on the hands and courtesy of R.A. Marsden,
palms.2 They are most characteristically seen in familial dysbetalipoproteine- MD, St George’s Hospital,
mia type III, and there is a particular risk of peripheral ­vascular disease.3 London, UK.

Fig. 13.12
Fig. 13.10 Tuberous xanthoma: erythematous nodule on the back of the arm. By courtesy of
Tendinous xanthoma: intense birefringence of deposits in polarized light (oil red O). the Institute of Dermatology, London, UK.
526 Degenerative and metabolic diseases

Fig. 13.13
Tuberous xanthoma: in this example, eruptive lesions are present on the elbows.
By courtesy of the Institute of Dermatology, London, UK.

Cholesterotic fibrous histiocytomas may be associated with hyperlipidemia and

often simulate a tuberous xanthoma clinically and histologically.7 A rare case of
malignant fibrous histiocytoma clinically presenting as a tuberous xanthoma in
a patient with type IIA hyperlipoproteinemia has been documented.8

Histological features
Tuberous xanthomata consist of multiple nodules in the reticular dermis and
sometimes the subcutaneous fat (Fig. 13.14). Their appearance varies,
depending upon their stage of evolution (Fig. 13.15). Xanthoma cells pre-
dominate in early lesions, but with maturity fibrosis supervenes (Fig. 13.16).
On occasion, foreign body giant cell granulomata containing cholesterol
clefts are seen and a ­perivascular chronic inflammatory cell infiltrate is
B
­sometimes evident (Fig. 13.17).
Fig. 13.15
Differential diagnosis Tuberous xanthoma: (A) the infiltrate is composed of uniform xanthoma cells
Heavily lipidized fibrous histiocytomas that tend to occur mainly around the characterized by pale, foamy cytoplasm and small central vesicular nuclei;
ankle may histologically mimic tuberous xanthoma.9 (B) occasional normal mitoses are commonly present.

Fig. 13.14 Fig. 13.16

Tuberous xanthoma: several nodules are present in the reticular dermis. Tuberous xanthoma: there is marked scarring.
 The hyperlipidemias 527

A B

Fig. 13.17
(A, B) Tuberous xanthoma: in addition to xanthoma cells, occasionally there are foreign body giant cells containing cholesterol clefts. The lipid has been dissolved out during
processing.

Planar xanthomata
Clinical features
Planar xanthomata are typically soft yellow dermal macules or plaques that
occur most frequently around the eyes, where they are known as xanthelas-
mata (Fig. 13.18).1,2 About 50% of patients with xanthelasmata have associ-
ated hyperlipidemia (hypercholesterolemia or hyperlipoproteinemia type III)
which is often accompanied by a cholesterol corneal arcus.3–5 Many of those
who appear biochemically normal on routine testing, however, are shown to
have subtle abnormalities of lipid metabolism on more detailed analysis.6
There is a particularly increased risk of coronary artery atherosclerosis in
younger patients.1 When very extensive (diffuse or generalized plane xan-
thomatosis) and associated with orange–yellow planar xanthomata around
the head and neck, and occasionally the upper trunk and arms, there may be
an associated systemic disorder such as multiple myeloma with paraproteine-
mia, cryoglobulinemia, benign paraproteinemia or, less commonly, leukemia
and rheumatoid arthritis (necrobiotic xanthogranuloma) (Fig. 13.19).1,3,7–13 A
More exceptional associations include idiopathic Bence Jones proteinuria,

Fig. 13.18
Xanthelasmata: note the yellow, periorbital plaques. These are a common manifestation
of hypercholesterolemia. By courtesy of the Institute of Dermatology, London, UK.
Fig. 13.19
Planar xanthoma: (A) widely distributed lesions over the forehead, eyelids, and
cheeks; (B) extensive yellow plaques on the scalp. This appearance should prompt
a search for an associated paraproteinemia. By courtesy of R.A. Marsden, MD,
St George’s Hospital, London, UK.
528 Degenerative and metabolic diseases

Sézary's syndrome, Castleman's disease, relapsing polychondritis, acquired Histological features

palmoplantar keratoderma, adult T-cell leukemia/lymphoma, and Takayasu's
In planar xanthomata, the characteristic lipid-laden foam cells are ­situated
disease.14–20 A patient with monoclonal gammopathy and cutaneous lesions
within the superficial dermis (Figs 13.21–13.23). There is minimal fibrosis.
with features of both plane xanthoma and amyloidosis has been ­documented.21
In rare cases, the histology may overlap with that of necrobiotic
The latter case was also associated with myeloma.
xanthogranuloma.33
In cases of myeloma and plane xanthoma, it has been demonstrated that
complexes form between serum lipoproteins and paraprotein, suggesting
that this interaction may induce a hyperlipidemia and xanthoma forma- Verruciform xanthoma
tion.22,23 The serum lipid levels of patients with diffuse plane xanthomata
are normal or raised. Plane xanthomata may present in the gingiva and, in Clinical features
this location, are usually associated with hyperlipidemia.24 An exceptional The verruciform xanthoma is an uncommon, asymptomatic lesion, which
case has been described in an infant presenting with normolipemic papular occurs predominantly in the oral cavity of adults in their fifth or sixth decade
and nodular lesions progressing to plane xanthomata and resulting in spon- and shows a male predilection (1.7:1).1–5 It is most often found on the
taneous resolution.25 Diffuse plane normolipemic xanthomata with mucosal ­premolar gingiva of the mandible or maxilla.1 At this site it usually ­produces
and conjunctival involvement and aortic valve xanthomatosis may occur a ­solitary, well-circumscribed, asymptomatic, erythematous or yellow–tan
exceptionally.26 Lesions have been reported that clinically resembled plane lesion, 3–20 mm in diameter, which may be papillomatous or ulcerated. The
xanthomata in a patient with systemic lupus erythematosus but histologi- patients are normolipidemic. The clinical differential diagnosis includes viral
cally showed degeneration of collagen bundles with secondary fat warts, leukoplakia, and squamous cell carcinoma.
deposition.27 Verruciform xanthomata of the skin, which are extremely rare, have been
Intertriginous xanthomata seen in patients with raised low density lipo- described at a variety of sites including the ear, nose, and digits.6–9 Most cases
proteins and pathognomonic of homozygous familial hypercholesterolemia described, however, have arisen on anogenital skin (Fig. 13.24).10–16 It may
present as yellow papules and plaques, often with a cobblestone appearance. also develop as a reactive phenomenon within epidermolytic acanthoma,
These occur in the finger webspaces and to a lesser extent in the axillae and
antecubital and popliteal fossae.2,28 They have a particularly high association
with early and severe atherosclerosis. Intertriginous xanthomata may also
rarely be seen in heterozygous familial hypercholesterolemia.29
Planar xanthomata presenting as yellow–orange macules in the skin creases
of the palm and fingers (xanthoma striatum palmare) are diagnostic of famil-
ial dysbetalipoproteinemia (HLP type III, broad beta disease) (Fig. 13.20),
which is due to an abnormality of the apoprotein ApoE (homozygous ApoE2/
E2).1,2,30 This results in impaired uptake of lipoprotein remnant particles by
the liver and macrophages with resultant hyperlipoproteinemia and increased
atherogenesis.29 Interestingly, the tendency to familial dysbetalipoproteinemia
is present in 1% of the population, but a second lipid abnormality appears to
be necessary to induce symptoms.29
Plane xanthomata of cholestasis, for example due to primary biliary cirrho-
sis and biliary atresia, present as well-demarcated, beige–orange plaques that
are particularly found on the hands and feet, but may occur elsewhere.2 They
can also develop in patients with diabetes mellitus and have been described in
the setting of cholestasis resulting from chronic graft-versus-host disease.31
Planar xanthomata have also been described as a feature of HDL
deficiency.32

Fig. 13.21
Planar xanthoma: a dense infiltrate is present in the upper dermis.

Fig. 13.20
Planar xanthoma: palmar lesions presenting as discrete macules with accentuation
in the skin creases. By courtesy of R.A. Marsden, MD, St George’s Hospital, Fig. 13.22
London, UK. Planar xanthoma: there is an admixture on nonlipidized and lipidized histiocytes.
 The hyperlipidemias 529

Although most studies have not demonstrated definitive evidence to support

this hypothesis, there are isolated reports demonstrating HPV DNA by poly-
merase chain reaction (PCR) in the lesions.32–35 Additionally, it has been sug-
gested that keratinocyte necrosis may lead to the release of intracellular lipids,
with resultant macrophage influx and xanthomatization.3,34,36 The inciting
event leading to keratinocyte necrosis has not been identified.
Immunohistochemical and electron microscopic studies tend to give support
to this latter hypothesis (see below).
Verruciform xanthoma is an exophytic lesion characterized by massive
but regular epidermal proliferation, parakeratosis, and hyperkeratosis (Fig.
13.25).32 Neutrophils, neutrophilic debris, and bacterial colonies may be
­evident in the parakeratotic stratum corneum. The acanthosis is associated
with uniform, bulbous epidermal ridges, all of which penetrate to the same
depth, giving a characteristically level lower border. The expanded ridges
are associated with marked central keratinocyte necrosis and a heavy
­neutrophil polymorph inflammatory cell infiltrate (Fig. 13.26). There is no

Fig. 13.23
Planar xanthoma: in addition to xanthoma cells, there are scattered lymphocytes.

Fig. 13.25
Verruciform xanthoma: there is marked acanthosis, hyperkeratosis, and a level
lower border.

Fig. 13.24
Verruciform xanthoma: in this unusual gross example, there are numerous warty
and polypoid lesions showing extensive involvement of the vulva, perineum, and
thighs. A viral etiology was initially suspected clinically.

­seborrheic keratoses, and epidermal nevi (including patients with inflamma-

tory linear verrucous epidermal nevus or with the epidermal nevus syndrome)
and has been recorded as a complication of lymphedema.9,17–22 It has been
described in association with longstanding discoid lupus erythematosus, com-
plicating ulceration in epidermolysis bullosa, and in association with squamous
cell carcinoma of the penis.23–27 Occasionally, verruciform xanthomata are
multifocal.6 Such a case has been described as multiple lesions in the upper
aerodigestive tract of a child with a systemic lipid storage disease.28 Multiple
verruciform xanthomata have also been reported in the anogenital region sev-
eral years following necrotizing fasciitis of the perineum and in the oral mucosa
in a patient with chronic graft-versus-host disease.29,30 A rare case of dissemi-
nated lesions has been described on the hands, feet, and anogenital region.31
In the skin, verruciform xanthoma usually presents as a gray or pink nod-
ule or as a plaque with a variably warty surface. Untreated, the lesions have
a long duration and behave in a benign fashion, recurrence being very uncom-
mon after local excision. Fig. 13.26
Verruciform xanthoma:
there is extensive
Pathogenesis and histological features keratinocyte necrosis
The etiology and pathogenesis of the verruciform xanthoma are unknown. associated with a
Originally, a viral infection by human papillomavirus (HPV) was suspected. polymorph infiltrate.
530 Degenerative and metabolic diseases
epithelial atypia and viral inclusions are invariably absent. The ­accentuated
papillary dermis between the elongated epidermal ridges contains large
numbers of eosinophilic foamy to granular xanthoma cells, which stain pos-
itively with lipid stains, but not usually with the diastase–periodic acid-
Schiff (PAS) technique (Fig. 13.27). No foreign body or Touton giant cells
are present. At the base of the lesion the epidermis may show focal basal cell
hydropic degeneration associated with patchy loss of basement membrane.
The reticular dermis deep to the lesion often contains a moderately dense
lymphocyte–plasma cell infiltrate, which at the edge of the lesion sometimes
adopts a lichenoid distribution. Typically,vascular ectasia is seen beneath
the lesion.
By immunohistochemistry, fully formed foamy cells are negative for histio-
cytic markers including factor XIIIa, Mac 387, Ham-56, and KP1.34,37 Cells
with incompletely lipidized cytoplasm show diffuse positivity for KP1 and
weak positivity for FXIIIa and keratin. Cells with little cytoplasmic lipid are
diffusely positive for FXIIIa and weakly positive for keratin. Nonlipidized
cells located in the periphery of the infiltrate are diffusely positive for FXIIIa
only. This staining pattern has led to the suggestion that FXIIIa-positive der-
mal dendritic cells play an active role in the formation of the lipid cells seen
in this condition.34 It also tends to give further support to the role of damaged
keratinocytes in the pathogenesis of verruciform xanthoma.34 The mechanism
of keratinocyte damage is not fully elucidated. One theory proposes that the
macrophages play an active role in keratinocyte cleavage and keratinolysis
with secondary release of epithelial lipid. Macrophage recruitment is postu-
lated to occur as a consequence of CD8-positive T cells present in the
submucosa.38,39
Ultrastructural studies have revealed histiocytes containing numerous
nonmembrane-bound lipid droplets, lysosomes, and myelin figures.11,40
Smaller numbers of these lipid inclusions may be found in the overlying kera-
tinocytes and in the intercellular space. In one report, basal melanocytes were
found to contain conspicuous lipid droplets.41 This was accompanied by evi-
dence that the latter had been released into the basal intercellular space in
association with disruption of the basal lamina, thereby providing a source
for the lipid within the dermal macrophages.
Differential diagnosis
Verruciform xanthoma must be distinguished from viral warts, granular cell
tumor, and verrucous carcinoma:
Fig. 13.27
Verruciform xanthoma: in
the papillary dermis there
is an infiltrate of uniform
xanthoma cells.
• Viral warts: verruciform xanthoma lacks the vacuolation, clumped
keratohyalin granules and tiers of parakeratosis seen in a viral wart.
Inclusions are not a feature.
• In granular cell tumor the hyperplastic overlying squamous epithelium
often shows an infiltrative growth pattern, in contrast to the exophytic
nature of verruciform xanthoma. The granular cells are larger, often have
a syncytial appearance, and typically stain positively with the PAS
reaction.
• Verrucous carcinoma has both exophytic and endophytic components,
the latter appearing as deeply penetrating bulbous epithelial processes.
The epithelium often has a ‘watery’ appearance and xanthoma cells are
not a feature.
Angiokeratoma corporis diffusum
Clinical features
Angiokeratoma corporis diffusum (Anderson-Fabry's disease) is a sex-linked
recessive disorder of glycosphingolipid metabolism with a high mortality. It is
very rare with an approximate incidence of 1 in 200 000.1 Deficiency of the
lysosomal enzyme α-galactosidase A leads to the widespread accumulation of
neutral glycolipids, mainly globotriaosylceramide (GB3, ceramidetrihexo-
side), and elevated urinary trihexoxylceramide levels.1–6
Globotriaosylceramide is normally broken down by α-galactosidase A to
produce galactose and lactosylceramide. The full-blown syndrome is nor-
mally seen only in men, since female carriers have 15–40% greater enzyme
activity than their male siblings or offspring. Heterozygotes, however, usually
­display abnormal ophthalmological and ultrastructural features.7 Occasionally,
heterozygous females may manifest signs and symptoms due to extreme X
inactivation (lyonization) of the healthy X chromosome.7,8 Cutaneous lesions
are believed to occur in about 20% of heterozygous females.9
In males, the disease normally presents in childhood as episodes of excru-
ciating intermittent pain, frequently in the fingers and toes.10 The attacks may
be accompanied by fever, edema, and malaise. Patients may also have hypo-
hidrosis, acroparesthesiae, and peripheral vasomotor disturbance affecting
the heart, kidney, and central nervous system. Heat intolerance and telangi-
ectases of the ears are often present early in the course of the disease.11
The characteristic angiokeratomata develop after puberty and present as
tiny red–black bilaterally symmetrical papules, 0.5–2 mm in diameter, with
slight hyperkeratosis.10 Lesions are typically seen in the bathing trunk
­distribution including the thighs, buttocks, lower back, penis, and ­scrotum,
although occasional lesions may also be seen on the trunk or buccal mucosa
(Figs. 13.28, 13.29). The number of angiokeratomata is highly variable.
Atypical cases can present with an oligosymptomatic phenotype which
includes only very few cutaneous angiokeratomata and asymptomatic involve-
ment of organs such as the kidney and the heart.12 A female heterozygote with
multiple nonkeratotic cutaneous angiomas has also been described.13
Nonvascular proliferations have been reported in patients with Fabry's
­disease, ­including polyarteritis nodosa and leg ulcers.14,15 Telangiectasias
develop in up to ­one-fourth of affected males.16,17 A recent study correlated
the presence of angiokeratomas and telangiectasias with disease severity.16
In a patient in whom the diagnosis is suspected, confirmation can usually
be obtained by an ophthalmic examination. The conjunctival vessels may be
tortuous or aneurysmal, as may the retinal vessels, and slit-lamp examination
of the eyes reveals characteristic whorled, corneal linear opacities (verticillate
cornea) (Fig. 13.30). Enzyme assay of α-galactosidase A can be performed
using peripheral leukocytes or cutaneous fibroblasts. Hair root analysis has
been recommended for the detection of heterozygotes.18
Affected males can develop transient cerebrovascular accidents, but one of
the most common causes of death is renal failure.19,20 In the early stages, pro-
teinuria is seen and microscopy of the urinary sediment sometimes reveals
characteristic lipid-laden cells even before proteinuria develops (Fig. 13.31).
Electron microscopy may reveal the typical inclusions (Fig. 13.32).
Cardiac involvement is found in approximately 20% of patients.21
Glycosphingolipid deposits in the conducting system, myocardium, endocar-
dium, and valves may give rise to angina, electrocardiographic ­abnormalities,
hypertrophic cardiomyopathy, hypertension, mitral valve incompetence, and
 Angiokeratoma corporis diffusum 531

Fig. 13.28
Angiokeratoma corporis
diffusum: tiny grouped red
papules are present on the
buttocks, a characteristic
site. By courtesy of the
Institute of Dermatology,
London, UK.

Fig. 13.30
Angiokeratoma corporis diffusum: (A) tortuous conjunctival vessels; (B) tortuous
retinal vessels. By courtesy of S. Parker, MD, St Thomas’ Hospital, London, UK.

Fig. 13.29
Angiokeratoma corporis
diffusum: conspicuous
angiokeratomata on
the penis, a commonly
affected site. By courtesy
of R.A. Marsden, MD,
St George’s Hospital,
London, UK.

aortic medial degeneration.22–25 Cardiovascular disease was found to be the most

common cause of death in patients in a recent study of the Fabry registry.26
Oral and dental abnormalities are more common than previously realized
and include the presence of cysts/pseudocysts of the maxillary sinuses and
maxillary prognathism.27

Pathogenesis and histological features

A variety of genetic defects has been identified including point mutations, Fig. 13.31
gene rearrangements, and deletions.28–31 A symptomatic heterozygous female Angiokeratoma corporis diffusum: urinary sediment stained with toluidine blue.
Fabry's disease patient without detectable mutation in the α-galactosidase The metachromasia (purple coloration) is due to the presence of intracytoplasmic
gene has recently been described.32 sulfatides.
532 Degenerative and metabolic diseases
Fig. 13.32
Angiokeratoma corporis diffusum: electron micrograph of urine sediment, showing
typical concentrically lamellated inclusions.
Fig. 13.33
Angiokeratoma corporis diffusum: ectatic blood-filled vascular channels expand the
papillary dermis. Note the hyperkeratosis.
The skin lesions are composed of ectatic blood-filled vessels in the papillary
dermis, associated with slight hyperkeratosis (Figs. 13.33, 13.34). A characteris-
tic feature is vacuolation of endothelial cells due to lipid deposits. The latter are
doubly refractile and can usually be demonstrated in frozen material tissue ­sections.
They may also be identified in toluidine blue-stained material. On electron micros-
copy, lamellar electron-dense inclusion bodies are present within endothelial cells,
pericytes, smooth muscle cells, fibroblasts, sweat gland epithelium, and
­macrophages. It is believed that these are due to lipid deposition within lysosomes
(Fig. 13.35). Lamellar bodies have also been identified in the endothelial cells of
affected vessels with polyarteritis nodosa in a patient with Fabry's disease.14
Differential diagnosis
Other forms of angiokeratomata, for example those of Mibelli or Fordyce,
should be clinically distinguishable by their site and distribution although their
histopathological appearances are identical. It should be noted, however, that
diffuse angiokeratomata may also be seen in fucosidosis, α-galactosidosis,
sialidosis, aspartylglycosaminuria, α-N- acetylgalactosaminidase deficiency
(Kanzaki disease), human beta-mannosidosis, adult-onset GM1 gangliosido-
sis, and indeed, diffuse angiokeratomata of a benign type may occur in patients
with normal enzyme activities.33–38 Widespread angiokeratomata have also
been described as an exceptional finding in tuberous sclerosis.39
Fig. 13.34
Angiokeratoma corporis
diffusum: close-up view.
Fig. 13.35
Angiokeratoma corporis diffusum: the endothelial cells of this small blood vessel
contain typical inclusions (L, lumen; E, endothelial cell).
The amyloidoses
Amyloidosis is characterized by the extracellular deposition of a protein
­associated with particular tinctorial and ultrastructural properties. The amy-
loidoses are classified according to whether the amyloid deposition is ­systemic
or localized (Table 13.3).
The most characteristic staining patterns of amyloid are seen with Congo
red or Dylon (cotton dye pagoda red No. 9), which show apple-green
­birefringence under polarized light (Fig. 13.36).1 Unfortunately, this is not
­specific, and green birefringence may also be seen with collagen and in ­colloid
milium, porphyria, and lipoid proteinosis. Amyloid deposits, which are PAS
positive, may also be identified by the cotton dye Sirius red, or ­metachromatically
using methyl or cresyl violet.2 Further confirmatory evidence can be obtained
by staining with thioflavine-T and examination using fluorescence ­microscopy
or by immunocytochemistry (see below) (Fig. 13.37).
 The amyloidoses 533

Table 13.3
Classification of the amyloidoses

Systemic amyloidosis Localized amyloidosis

Primary (due to an occult plasma Organs other than the skin*
cell dyscrasia)
Myeloma associated Primary cutaneous
Secondary Lichen, macular and biphasic
Hemodialysis associated Secondary cutaneous
Heredofamilial † Associated with neoplasms,
porokeratosis and PUVA therapy
Amyloid elastosis Familial cutaneous Nodular

*Not discussed further in this chapter.

†Including familial Mediterranean fever, Muckle–Wells syndrome, familial amyloidotic

polyneuropathy.

Fig. 13.37
Cutaneous amyloidosis: positive immunofluorescence just beneath the epidermis
in a case of macular amyloid (thioflavine-T).

Fig. 13.38
Cutaneous amyloidosis:
(A) electron micrograph
of macular amyloidosis
showing nodular deposits
in the superficial dermis;
(B) the characteristic
randomly orientated,
straight, nonbranching
A appearance of amyloid
filaments.

Fig. 13.36
Cutaneous amyloidosis: (A) positive staining with Congo red; (B) there is intense
apple-green birefringence when viewed with polarized light.

Amyloid shows characteristic and specific electron microscopic features of

rigid, straight, nonbranching amyloid filaments with a diameter of 6–10 nm
showing a hollow core on cross-section (Fig. 13.38).3 They are haphazardly
distributed, lack the cross-banding of collagen, and are embedded in an
­electron-dense amorphous ground substance, which is probably composed of
B
polysaccharides.
534 Degenerative and metabolic diseases

X-ray diffraction and infrared spectroscopy reveal a beta-pleated

a­ ntiparallel configuration.4,5 Fibrils with a beta-pleated configuration are
insoluble and highly resistant to proteolysis. This, combined with a lack of
immunogenicity, results in their persistence at the site of deposition and
­subsequent tissue-damaging effects.
All forms of amyloid contain up to 14% by dry weight of a nonfibrillary
protein, the serum amyloid P (SAP) component.2,6 The function of SAP is
unknown, but it has been suggested that it may be primarily involved in the
deposition and maintenance of the fibrillary components.2 Its presence, iden-
tified immunohistochemically, is a useful adjunct to the diagnosis of amyloi-
dosis.7 However, it should be appreciated that the antibody also labels
degenerate elastic fibers. The fibrillary component, however, may be derived
in very different ways in each of the recognized types of amyloidosis: 8
• In primary and myeloma-associated amyloidoses it consists of
immunoglobulin light chains (most often of lambda type, or a part
thereof).
• In the secondary form the fibrillary component is composed of amyloid
A protein, which is derived from a normal serum constituent known as
serum amyloid A protein. This serum protein, which is an HDL3-associated
apolipoprotein, is an acute phase reactant.2,8 Fig. 13.39
• Primary cutaneous amyloidosis is derived from filamentous degeneration Primary systemic
of keratin filaments (amyloid-K) (see below).9,10 amyloidosis: a waxy
nodule is present behind
The capacity to form amyloid in the primary and myeloma-associated
the ear. Note the purpura.
variants appears to be dependent upon the inherent ability of a segment of the
By courtesy of R.A.
variable region of the light chain to adopt a beta-pleated configuration.3 This Marsden, MD, St George’s
capability is only evident in a proportion of (so-called amyloidogenic) Bence Hospital, London, UK.
Jones proteins, which explains why not all patients with multiple myeloma
develop amyloidosis. Primary and myeloma-associated amyloidoses can be
distinguished histochemically from secondary amyloidosis using the potas-
sium permanganate reaction.11 The former are potassium permanganate resis-
tant whereas the latter is sensitive and loses its affinity for Congo red following
exposure. ‘Endocrine’ amyloid is also resistant to the effects of potassium per-
manganate solution, as is senile cardiac amyloid. Therefore, although the
amyloidoses all include, by definition, amyloid deposition, they in fact
­represent a very diverse group of conditions.

Primary and myeloma-associated systemic

amyloidoses
Cutaneous disease occurs in up to 40% of patients with primary (due to occult
plasma cell dyscrasia) and myeloma-associated systemic amyloidosis.1–5

Clinical features
Primary and myeloma-associated systemic amyloidoses predominantly affect
the elderly (mean onset at 65 years of age) and show a slight predilection for
males.2 Up to 15% of patients with myeloma have coexisting primary amy-
loidosis. Occasional patients present with primary systemic amyloidosis and
only develop multiple myeloma later.6
The early clinical changes, which are often mild, non-specific, and very dif-
ficult to diagnose, include weight loss, hoarseness, dyspnea, fatigue, paresthesia,
and lightheadedness.7 Subsequently, the most frequent features are development
of the carpal tunnel syndrome and edema due to renal and cardiac involvement.
Bilateral carpal tunnel syndrome may be the first symptom of the disease.8
The commonest cutaneous manifestation is hemorrhage (purpura,
­petechiae, and frank ecchymoses) due to deposition of amyloid within blood
vessel walls, with resultant fragility (Figs 13.39–13.42). It occurs most typi-
cally on the hands (often posttraumatic) and around the eyes, when the pur-
pura may follow proctoscopy or vomiting (Fig. 13.43). Lesions are sometimes
also evident in the nasolabial folds, the neck, axillae, umbilicus, ­anogenital
region, and within the oral cavity.4,9–11 Prominent hemorrhagic bullae may be
present.11 Rarely, systemic amyloidosis presents with solitary vulval lesions
which may mimic a condyloma acuminatum.12,13
Blistering is sometimes an additional feature, which occurs due to ­cleavage
developing within the amyloid deposits as a consequence of ­shearing
stresses.14–23 The blisters are often hemorrhagic, and occur most often on the
tongue, buccal or labial mucosa although they may be more widespread and
thus mimic those of bullous pemphigoid.14 Blisters can sometimes arise on the
Fig. 13.40
Primary systemic
amyloidosis: hemorrhagic
bullous lesion on wrist.
By courtesy of the
Institute of Dermatology,
London, UK.
dorsal surfaces of the hands and fingers and the extensor aspect of the fore-
arms and epidermolysis bullosa acquisita then enters the differential diagno-
sis (Fig. 13.44). Healed lesions are sometimes associated with the development
of milia.19 Bullous amyloidosis most often develops in patients with systemic
disease, particularly myeloma associated.16 Rarely, however, it may compli-
cate primary cutaneous amyloidosis.14 Rare cases present an elastolytic
appearance and development of cordlike indurations associated with inter-
mittent claudication. Prominent perivascular deposition of amyloid has been
documented in these patients.24,25
In more advanced cases, waxy, smooth, shiny papules, plaques, and even
nodules develop. Cystic nodular lesions have also been reported.26 The pap-
ules are skin-colored or yellow and have a dome-shaped appearance.9,27 They

Fig. 13.41
Primary systemic amyloidosis: papular mucosal lesions with hemorrhage on the
inner aspect of the lower lip. By courtesy of R.A. Marsden, MD, St George’s
Hospital, London, UK.
Fig. 13.42
Primary systemic amyloidosis: erythematous and purpuric lesions on the face of an
elderly male. By courtesy of the Institute of Dermatology, London, UK.
Fig. 13.43
Primary systemic amyloidosis: small macular purpuric lesions at a classical site.
By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.
The amyloidoses 535
Fig. 13.44
Primary systemic amyloidosis: blood-filled blisters on the dorsal aspect of the
fingers. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.
Fig. 13.45
Primary systemic amyloidosis: nail dystrophy as seen in this example is a very
rare manifestation. By courtesy of R.A. Marsden, MD, St George’s Hospital,
London, UK.
are found predominantly on the face (especially the eyelids), head and neck,
axillae, umbilicus, inguinal region, and the perineum.4,9 In severely affected
patients the clinical appearances with taut skin, particularly affecting the
face, hands, and digits, may mimic scleroderma.9,27 Alopecia and nail dystro-
phy are sometimes evident (Fig. 13.45). Chronic paronychia, palmodigital
erythematous swelling, and induration of the hands have been described.28
The presence of these features in conjunction with macroglossia and the car-
pal tunnel syndrome is highly suggestive of primary or myeloma-associated
systemic amyloidosis (Fig. 13.46). In addition to macroglossia, the tongue
may be covered with waxy papules, nodules, and plaques and occasionally it
is ulcerated or fissured.4 As a consequence, speaking and swallowing diffi-
culties are not infrequently encountered. The sicca syndrome may also be a
manifestation of primary systemic amyloidosis.29 Exceptionally, association
with normolipemic xanthoma has also been documented.30
Hepatomegaly is found in about 50% of cases and there may also be evi-
dence of cardiomyopathy with arrhythmia or heart failure, peripheral neuropa-
thy, and renal failure or the nephrotic syndrome. Splenomegaly is a feature in
less than 10% of cases.5 Intestinal involvement can lead to malabsorption or an
ulcerative colitis-like picture, sometimes with hemorrhage.4 ­Pseudo-obstruction,
536 Degenerative and metabolic diseases
Fig. 13.46
Primary systemic
amyloidosis: macroglossia.
By courtesy of R.A.
Marsden, MD, St George’s
Hospital, London, UK.
diarrhea, and constipation can also occur.7 There is no effective treatment for
systemic primary amyloidosis and the prognosis is therefore grave. Mortality
relates primarily to cardiac and renal involvement.2,3
Histological features
Masses of eosinophilic, amorphous, fissured material are present in the
­ ermis and subcutaneous tissues.9,31 The overlying epidermis is often
d in up to 50% of patients.27
stretched and flattened, but – in contrast to the macular and lichenoid vari-
ants – shows no evidence of amyloid deposition. In mild cases the changes
may be ­limited to the perivascular tissues, but in more extensive disease large
aggregates are usually evident. Involvement of blood vessel walls, arrector
pili muscles, skin adnexa, and subcutaneous fat (amyloid rings) is frequently
present (Figs. 13.47, 13.48).4,9,27 Amyloid deposits around the piloseba-
ceous units may be accompanied by follicular atrophy with resultant hair
loss.9 There is usually little secondary inflammatory cell infiltration.
Fig. 13.47
Primary systemic amyloidosis: the superficial blood vessels are thickened due to
amyloid deposition.
Fig. 13.48
Primary systemic
amyloidosis: high-power
view of Figure 13.47. Note
the red cell extravasation.
In those cases associated with blistering, the vesicle appears in an
i­ntradermal or less commonly subepidermal location. The dermis, in addition
to showing amyloid deposits, often in association with blood vessel walls,
also shows a fragmented appearance due to the presence of cleftlike spaces.13
Purpura is frequently marked.
Clinically normal skin shows histological evidence of amyloid deposition
Secondary amyloidosis
Secondary amyloidosis develops as a consequence of chronic inflammatory
conditions or infections. Cutaneous involvement has not been recognized as
a clinical feature of secondary systemic amyloidosis. Yet in one publication it
was described in eight out of nine patients with amyloidosis complicating
rheumatoid arthritis.1 It is of interest to note that a considerable number of
chronic dermatoses may be associated with the development of secondary
amyloidosis including psoriasis, lepromatous leprosy, hidradenitis suppura-
tiva, chronically infected burns, and dystrophic epidermolysis bullosa.2–4 In
patients with no cutaneous lesions and symptoms suggestive of systemic amy-
loidosis, the diagnosis can be confirmed by Congo red staining of abdominal
fat aspirates.5
Although frank clinical lesions are not commonly a feature of secondary
amyloidosis, sometimes small deposits are found in specimens of ­normal
skin.1,6 Usually these are present in a perivascular location, but may
­occasionally be present elsewhere in the dermis or even in subcutaneous
fat.7 Deposition of amyloid around sweat glands may also be seen. Deposits
are said to be focal and abdominal subcutaneous fat has been recommended
as the site that is most likely to be positive.1,5,8 Hemodialysis-associated
amyloidosis is a distinctive form of secondary amyloidosis and is described
below.
Hemodialysis-associated amyloidosis
Clinical features
This variant of amyloidosis, induced by beta-2-microglobulin, occurs in
patients on long-term hemodialysis.1–5 Exceptionally, cases may present after
short-term hemodialysis.6 The most commonly involved organs are the heart,
gastrointestinal tract, and lungs.1 Interestingly, the disease does not seem to

involve the spleen.1 Carpal tunnel syndrome, polyarthralgia, and ­destructive
spondyloarthropathy have also been documented.4,7 The walls of blood
­vessels are often involved whereas bone lesions are relatively rare, although
pathological fractures may occur.7,8 Cutaneous involvement, which is very
uncommon, has been reported to present as subcutaneous masses in the but-
tocks and shoulder, lichenoid papules and a wrinkled appearance of the skin
of the palmar aspect of the fingers. 6–11
Histological features
In cases with skin involvement, the amyloid deposits have been found either
in the subcutaneous tissue or in the papillary and reticular dermis, around
sweat glands and hair follicles.6–11 Occasionally, special stains are unhelpful in
demonstrating amyloid and confirmation of the diagnosis by electron micros-
copy is necessary.
Heredofamilial amyloidoses
Familial Mediterranean fever
Clinical features
This is a rare variant of autosomal recessive inherited systemic amyloidosis. It
is characterized by episodes of fever associated with pleuritis, peritonitis, and
synovitis.1–4 Cutaneous lesions are rare and consist of Henoch-Schönlein pur-
pura and erythema of the lower limbs mimicking erysipelas.1,5 Panniculitis and
recurrent urticaria may also occur.6,7 Nail fold capillary abnormalities consist-
ing of increased tortuosity and enlargement of capillary loops have also been
documented.8 Cutaneous amyloid deposition has not been described.
Pathogenesis and histological features
A serum precursor protein forms the amyloid in this condition. This precur-
sor is a high density lipoprotein known as serum amyloid A.
The erysipelas-like lesions are characterized by a perivascular mixed infil-
trate of lymphocytes, histiocytes, and neutrophils with leukocytoclasia.5
Vasculitis is not seen, although on direct immunofluorescence perivascular
C3 and, less consistently IgM and fibrinogen, have been reported.5
Muckle-Wells syndrome and familial cold
autoinflammatory syndrome
Muckle-Wells syndrome is an autosomal inherited disease with variable pen-
etrance. It is characterized by urticaria, deafness, conjunctivitis, and systemic
amyloidosis.1,2 The disease has been mapped to chromosome 1q44. The gene
is called CIAS1 and encodes a pyrin-like protein that appears to play a role in
regulation of inflammation and apoptosis.3,4 Familial cold autoinflammatory
syndrome (familial cold urticaria) is very similar to Muckle-Wells syndrome
but, in the former, there is no deafness and the episodes of urticaria are pre-
cipitated by cold. The same serum precursor protein (serum amyloid A) pro-
duces the amyloid in both conditions. Cutaneous amyloidosis is not typically
seen in Muckle-Wells syndrome. Recently, six patients with this syndrome
were described as having sclerotic, hyperpigmented plaques with hypertricho-
sis on the extremities and abdomen.5
Cold-induced urticarial lesions are characterized by an upper to mid-der-
mal infiltrate of neutrophils with a few eosinophils and dermal edema.6
Neutrophils are seen intravascularly and in vessel walls. Although ­vasculitis
has not been described, some vessels may contain fibrinoid deposits.
Histological features of the sclerotic lesions include dermal thickening with
sclerosis of collagen bundles, fragmentation and thickening of elastic fibers,
focal calcification of degenerated elastic fibers, superficial and deep perivas-
cular and interstitial infiltrate of lymphocytes and histiocytes, numerous
plasma cells and admixed eosinophils and mast cells.
Familial amyloidotic polyneuropathy
Clinical features
Familial amyloidotic polyneuropathy is an autosomal dominant disease in
which the deposition of amyloid occurs predominantly in peripheral nerves.
The amyloid deposits in this disease consist in most cases of variant transthy-
retin with single amino acid substitutions.1–3 Clinical manifestations include
The amyloidoses 537
sensory then motor peripheral neuropathy predominantly affecting the limbs
and autonomic dysfunction manifesting as alternating diarrhea and constipa-
tion, urinary incontinence, orthostatic hypotension, and sexual dysfunction.3
The cutaneous manifestations comprise nonhealing ulcers, multiple atrophic
scars, and anhidrosis of the lower limbs.4,5 In some patients petechiae can be
induced by gentle stroking of the skin.
Histological features
Histologically, biopsies from clinically normal skin reveal the presence of
amyloid in blood vessel walls, sweat glands, and arrector pili muscle.4
Amyloid elastosis
Clinical features
Amyloid elastosis is a very rare disease, characterized by systemic and cutane-
ous deposits of amyloid. Only three cases have been reported to date. Two
patients presented with papular and nodular lesions, a sclerodermatous facial
appearance, a pseudoxanthoma-like appearance of the neck, cordlike thick-
ening of superficial blood vessels, livedo reticularis-like changes on trunk,
Raynaud's phenomenon, venous and arterial thrombosis, and the nephrotic
syndrome.1,2 One of the patients had a lambda light chain paraprotein.2 The
third patient developed xanthomatous, yellow macules and patches in the
intertriginous areas of the axilla, neck, submammary, and abdomen. She was
subsequently diagnosed with systemic AL amyloidosis.3
Histological features
Amyloid is seen in the dermis, around adnexal structures, surrounding elastic
fibers, sometimes forming small globules, and in blood vessel walls, together
with striking deposits in the dermal, subcutaneous, and serosal ­elastic
tissue.1–3
Primary localized cutaneous amyloidosis,
lichen and macular types
Clinical features
Lichen and macular amyloidoses (skin-limited amyloidoses) represent differ-
ent manifestations of the same process and both entities may coexist (biphasic
amyloidosis) or one may transform into the other.1–4 A recent large study of
primary localized cutaneous amyloidosis found that 67% of cases represented
lichen amyloidosis, 8% macular amyloidosis, and 25% biphasic variants.5
Although most cases are sporadic, up to 10% of patients demonstrate an
autosomal dominant inheritance pattern (see familial primary cutaneous
amyloidosis).6,7
Macular primary cutaneous amyloidosis
This is most commonly seen in patients from the Middle East, Asia, and
Central and South America.1,8 It affects females more often than males (3:1),
is seen in younger age groups, and is usually a chronic condition.9,10 Patients
present with a macular, dark brown or grayish, symmetrical pigmentation,
which occurs most frequently on the upper chest and back, although the
extremities and face may also be affected (Fig. 13.49).1,9 The lesions some-
times have a very characteristic reticulated or rippled appearance, which can
be quite subtle, and they are usually moderately pruritic (Fig. 13.50). More
commonly, however, macular amyloid appears as small, 2–3 mm diameter
lesions or else as confluent macular foci, which sometimes have superimposed
micropapules.8 Lesions sometimes follow Blaschko's lines, resembling incon-
tinentia pigmenti.11,12 Exceptionally, widespread diffuse pigmentation occurs.13
Predominantly hypopigmented macules have been described, mimicking gut-
tate morphea and vitiligo.14
Papular or lichen amyloidosis
In papular or lichen amyloidosis, discrete papules and/or plaques occur, which
are often scaly, persistent, and pigmented. They are usually severely pruritic
(Fig. 13.51). Excoriations, lichenification, and nodular prurigo-like lesions
due to chronic scratching are sometimes evident.10 Lesions are ­especially
538 Degenerative and metabolic diseases

c­ ommon on the front of the shins and extensor aspect of the ­forearms
(Figs 13.52, 13.53).15,16 The calves, ankles, dorsa of the feet, thighs and
trunk may also be affected.17–19 Presentation is most often in young adults.
The sex incidence is equal.1,20 Lichen amyloidosis shows a predilection for the
Chinese race and familial cases have been recorded.18,19 An association with
Epstein-Barr virus infection has been reported in a single case but this was not
confirmed in a larger study.21
Association with systemic disease is probably coincidental but there have
been a number of cases described with progressive systemic sclerosis.22,23
Other primary cutaneous amyloidoses
These include anosacral and poikilodermatous variants:
• Anosacral amyloidosis presents as scaly hyperpigmented macules and
lichenoid papules spreading out from the perianal skin.24,25 It is seen in
patients from Japan and China and is very rare. The disease may present
early in life and its cause has not been established, although a
relationship to keratinocyte apoptosis has been suggested.25 Clinically,
lesions can be confused with lichen simplex chronicus, a dermatophyte
infection or even postinflammatory hyperpigmentation.
Fig. 13.49
Macular amyloid: hyperpigmented lesion in a characteristic site. By courtesy of R.A.
Marsden, MD, St George’s Hospital, London, UK.

Fig. 13.50
Macular amyloid: close-up view of a lesion showing the typically rippled
appearance. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK. Fig. 13.52
Lichen amyloidosis: scaly
lichenoid papules on the
shin. By courtesy of R.A.
Marsden, MD, St George’s
Hospital, London, UK.

Fig. 13.53
Fig. 13.51 Lichen amyloidosis: grouped, erythematoviolaceous papules, with a lichenoid
Lichen amyloidosis: pigmented papules on the chest. By courtesy of R.A. Marsden, surface and showing excoriations in some areas. By courtesy of R.A. Marsden, MD,
MD, St George’s Hospital, London, UK. St George’s Hospital, London, UK.
 The amyloidoses 539

• Poikiloderma-like cutaneous amyloidosis is an extremely rare

manifestation of localized cutaneous amyloidosis.26,27 Patients present
with poikilodermatous skin lesions and lichenoid papules. It may be
associated with photosensitivity, short stature, and palmoplantar
keratoderma.27 Blisters are rarely seen. The condition presents early in
life or in young adults. Confusion with other conditions associated with
poikiloderma including poikiloderma atrophicans vasculare is possible.

Pathogenesis and histological features

Chronic irritation to the skin has been proposed as the cause of amyloid
deposition in the macular and lichenoid variants although this has never
been proven.28,29 The documentation, however, of friction amyloidosis due to
nylon brush skin massage and towels does offer some support to this hypoth-
esis.30–33 It may be that chronic trauma in a susceptible or ‘primed’ individual
may be associated with an increased risk of developing cutaneous amyloido-
sis. It has been suggested that amyloid deposition in lichen amyloidosis is a
consequence of scratching, as pruritus tends to be the presenting symptom
even before amyloid is detected in skin biopsies.34 The chronic damage to the
Fig. 13.55
epidermis induces apoptosis of keratinocytes and this leads to amyloid depo- Macular amyloidosis: close-up view of faceted deposits.
sition in the papillary dermis. A similar mechanism has been proposed in
notalgia paresthetica. This is a condition characterized by pruritus, a burn-
ing sensation, and paresthesia or hyperesthesia in an area of the back between
dermatomes D2 and D6.35,36 The resultant irritation and scratching induce
cutaneous hyperpigmentation and amyloid deposition. It has even been sug-
gested that the cutaneous amyloidosis observed in patients with multiple
endocrine neoplasia type 2A is secondary to notalgia paresthetica (see
below).37
In both variants the amyloid is deposited high in the papillary dermis,
often immediately adjacent to the epidermis.8,9,17,38,39
In the macular type, the amount of amyloid present is often very small
and focally distributed. It frequently has a faceted appearance (Figs
13.54–13.56).2,9 Special stains and/or immunocytochemistry are some-
times necessary as the deposits can easily be missed. Intraepidermal cytoid
bodies are present in about 33% of cases.8 Typically, there is associated
pigmentary incontinence, but only minor epidermal changes of hyperkera-
tosis and acanthosis are generally evident. Melanin pigment may be pres-
ent in the stratum corneum. A slight perivascular chronic inflammatory
cell infiltrate is often found in the superficial dermis.9 Mild vacuolar inter-
face alteration can be present.14

Fig. 13.56
Macular amyloidosis:
pigmentary incontinence
is typically present.

In papular or lichen amyloidosis, the histopathological changes are similar

and cannot be reliably distinguished from those of the macular variant, except
that the quantities deposited are greater and there is often more marked epi-
dermal acanthosis, hypergranulosis, and hyperkeratosis. Basal cell hydropic
degeneration may be evident and colloid bodies are usually visible (Figs
13.57, 13.58).1 Satellite cell necrosis is sometimes a feature.1 A superficial
perivascular chronic inflammatory cell infiltrate is typically present.
When special stains fail to demonstrate the presence of amyloid, ultrastruc-
tural studies are usually successful in detecting the presence of the protein.40
In contrast to skin involvement in systemic disease, blood vessel deposits
are not a feature of primary cutaneous localized lesions.
In earlier literature it was postulated that the amyloid might have been
derived from mast cells or fibroblasts. The application of newer technology,
Fig. 13.54 however, has shown that it is indisputably of keratinocyte derivation, and
Macular amyloidosis: typical eosinophilic faceted deposits are present in the amyloid deposits have been shown to contain disulfide bonds and bullous
papillary dermis. pemphigoid antigen.8 Numerous recent publications confirm the presence of
540 Degenerative and metabolic diseases
Fig. 13.57
Lichen amyloidosis: there is hyperkeratosis, acanthosis, and basal cell hydropic
degeneration; small eosinophilic globules are present in the papillary dermis. A mild
chronic inflammatory cell infiltrate is present. Note the pigmentary incontinence.
Fig. 13.58
Lichen amyloidosis: in this view, there is interface change and a lymphocytic infiltrate.
epidermal keratin in the deposits in both macular and lichenoid forms using
monoclonal immunocytochemistry.3,41–49 The amyloid of the skin-limited
­variants, so-called amyloid-K, has been shown to contain 50 and 67 kD kera-
tin filaments.28,48 Apolipoprotein E, one of the proteins found in the amyloid
plaque of Alzheimer's disease and in systemic amyloidosis, has also been
demonstrated in the amyloid present in localized cutaneous amyloidosis.50,51
Electron microscopic studies have provided further evidence that amyloid-K
is of keratinocyte origin by showing tonofilament filamentous (apoptotic)
degeneration into amyloid filaments both within the epidermis and in the
immediately adjacent dermis.52 Under normal circumstances apoptotic kera-
tinocytes (cytoid bodies) are either shed as a consequence of epidermal
upward migration or are released into the dermis where they are removed by
an inflammatory response as is seen, for example, in lichen planus. In macu-
lar and lichenoid cutaneous amyloidosis it appears that the above disposal
mechanism is either overwhelmed or nonfunctioning.
Early ultrastructural changes consist of loss of tonofilament electron den-
sity and development of a wavy morphology accompanied by internalization
of desmosomes, thickening of the keratinocyte cell membrane, and the acqui-
sition of hemidesmosome-like attachments to neighboring cells.28 Cytoplasmic
and nuclear remnants are frequently present in the more superficial deposits.
Fig. 13.59
Lichen amyloidosis:
(A) early filamentous
degeneration is seen in
this basal keratinocyte
(K), lamina densa is
arrowed; (B) compare the
organized appearance of
the tonofilaments with
the haphazardly orientated
amyloid immediately
A adjacent to the lamina
densa.
B
It is thought that on entering the dermis, fibroblasts and macrophages ­convert
the degenerate keratin into amyloid filaments (Fig. 13.59).52 The ­precise
mechanism is unknown, but it must involve the conversion of the normal
alpha tertiary structure of tonofilaments into the beta-pleated ­configuration
of amyloid. The filaments of amyloid and cytoid bodies show ultrastructural
differences. Amyloid fibrils are irregularly distributed whereas the filaments
in cytoid bodies are arranged in bundles or whorls.53
It is postulated that the development of localized cutaneous amyloidosis is
dependent upon mild chronic trauma resulting in excessive production of
cytoid bodies and their subsequent conversion into amyloid deposits. It would
seem that despite a normal humoral response as shown by the presence of
IgM and IgG in association with complement fixation, the normal cellular
response whereby apoptotic keratinocytes are removed is lacking.28,54–56
Amyloid deposits are frequently found in intimate association with dermal
elastic fibers and the deposits in macular amyloidosis have been shown to
contain fibrillin.57 Whether this is of pathogenetic significance or is merely a
secondary phenomenon is uncertain.
The apoptotic theory of amyloidogenesis in the cutaneous variants has, how-
ever, been challenged. On the basis of finding amyloid deposits ­immediately
below the basal keratinocyte, separating its cell membrane from the lamina

densa in the absence of any evidence of filamentous degeneration, it has been
suggested that cutaneous amyloid deposits may also be a direct secretory ­product
of keratinocytes.58,59 It could be that both mechanisms are in operation.
Secondary localized cutaneous amyloidosis
Microscopic foci of amyloid have been described in a number of cutaneous
neoplasms including basal cell carcinoma, sweat gland tumors, syringocysta-
denoma papilliferum, pilomatrixoma, trichoepithelioma, trichoblastoma, intra-
dermal nevus, dermatofibroma, seborrheic keratosis, solar keratosis, and
Bowen's disease (Fig. 13.60).1–7 The amyloid in most cases appears to be
derived from tumor cells. Porokeratosis has also been reported in association
with dermal amyloid deposition as a result of apoptosis of keratinocytes.8,9
Mycosis fungoides and discoid lupus erythematosus may exceptionally be
seen associated with localized cutaneous amyloidosis.10,11
Cutaneous amyloid deposition may also rarely be seen as a consequence of
chronic epidermal damage following PUVA therapy.12,13 So-called concha amy-
loidosis due to chronic actinic damage to the ear has also been
documented.14,15
Repeated insulin injections at the same site have been reported as inducing
amyloid in the skin.16
Familial primary cutaneous amyloidosis
Familial primary cutaneous amyloidosis is a very rare autosomal dominant
variant of amyloidosis that presents with manifestations of either macular
and/or lichenoid amyloidosis.1–5 Lichen amyloidosis is also seen in patients
with multiple endocrine neoplasia type 2A (Sipple's syndrome).6–8 Germline
mutations of the RET proto-oncogene on chromosome 10 involving cysteine
residues have been consistently described in Sipple's ­syndrome. However,
familial primary cutaneous amyloidosis without Sipple's ­syndrome does not
show RET mutations, clearly indicating that they are different conditions.6,9
Recent genetic studies in a small subset of patients with familial primary
cutaneous amyloidosis have isolated a mutation in the OSMR gene on chro-
mosome 5.10,11 This encodes the oncostatin M receptor beta which is expressed
in various tissues including keratinocytes, cutaneous nerves, and in the dorsal
root ganglion. This is a cytokine receptor complex, and it is speculated that
mutations in it lead to dysfunctional cell signaling resulting in apoptosis of
keratinocytes, amyloid deposition, and reduction of nerve fibers, which
causes pruritus.10,12 Not all patients with familial primary cutaneous
­amyloidosis have been shown to have the same mutation in chromosome 5,
indicating genetic heterogeneity in this disease.13
The histopathological findings are identical to those described in the
­primary nonfamilial variants of localized cutaneous amyloidosis.
Fig. 13.60
Tumor-associated amyloid: amyloid deposits in a basal cell carcinoma.
The amyloidoses 541
Amyloidosis cutis dyschromica (vitiliginous) is another familial ­variant
of primary cutaneous amyloidosis characterized by reticulate ­hyper- and
hypopigmentation of the trunk and limbs, with onset typically in
­childhood.14–19 Papules, atrophy, and telangiectasia are usually not ­present.
One patient with concomitant morphea has been described.18 It has been
suggested that the disease is caused by hypersensitivity to ultraviolet B
light with possible DNA repair defects.16 Histologically, the amyloid is
present in the papillary dermis. Amyloidosis cutis dyschromica may repre-
sent the same disease described as X-linked reticulate pigmentary disorder
in which cutaneous amyloidosis occurs as a secondary phenomenon in
patients with a disease characterized by failure to thrive, chronic respira-
tory disease, photophobia with corneal dystrophy, and gastrointestinal
disease.20,21
Nodular amyloidosis
Clinical features
In this rare variant, which is more common in females, pink–brown single
or multiple nodules develop on the trunk, extremities, genitalia, face or
scalp (Fig. 13.61).1–7 Bilateral nodular amyloidosis of the eyelids in the
absence of systemic amyloidosis has rarely been documented.8 The lesions
often have a waxy appearance and the surface may be atrophic or ulcer-
ated. Most cases of nodular amyloidosis are limited to skin and only 7%
show progression to systemic amyloidosis.7,9 Occasional reports have doc-
umented monoclonal paraproteinemia, lymphoplasmacytoid lymphoma,
Sjögren's syndrome, proteinuria, bone marrow abnormalities, and a posi-
tive rectal biopsy.10–15 Nodular cutaneous amyloidosis has also been
described in association with carpal tunnel syndrome induced by the amy-
loidogenic transthyretin His 114 variant.16 An unusual variant of nodular
­amyloidosis with bilateral plantar involvement is very occasionally
encountered.17
Histological features
The histological appearances cannot be distinguished from those of systemic
amyloidosis and, indeed, as in primary amyloidosis, the amyloid consists of
light chain-derived AL protein.18–21 It is thought likely that this nodular vari-
ant results from local production of light chains by a localized group of
plasma cells.1 PCR studies have demonstrated that the infiltrating plasma
Fig. 13.61
Nodular amyloidosis: an
irregular infiltrated plaque
limited to the nose.
542 Degenerative and metabolic diseases

cells in cases of nodular amyloidosis are usually monoclonal.22,23 Polyclonality,

­however, has also been reported.11 In all patients with nodular amyloidosis, it
is important to exclude systemic disease.2,7
The deposits of amyloid are present in both the papillary and ­reticular
dermis and may involve the subcutaneous fat (Figs 13.62–13.64). Sometimes
the vasculature and nerve sheaths are affected ­(Figs 13.65–13.67).2

Fig. 13.64
Nodular amyloid: the
A amyloid deposits fill the
papillary dermis.

Fig. 13.62
Nodular amyloidosis: (A) massive deposits of amyloid are present in the dermis; Fig. 13.65
(B) there is a heavy associated plasma cell infiltrate. Nodular amyloidosis: amyloid deposits have thickened the blood vessel walls.

Fig. 13.63 Fig. 13.66

Nodular amyloidosis: in this example there is a broad bandlike deposit in the upper dermis. Nodular amyloid: the deposits are strongly Congo red positive.
 Colloid milium 543

Fig. 13.69
Juvenile colloid milium:
Fig. 13.67 there is papular thickening
Nodular amyloid: in this example, vessels in the subcutaneous fat showing striking of the skin, particularly
involvement. involving the cheeks,
nose, and forehead.
By courtesy of
S. Hendfield-Jones, MD,
Institute of Dermatology,
London, UK.

Fig. 13.70
Juvenile colloid milium:
Fig. 13.68 this less severely affected
Nodular amyloidosis: there is a conspicuous plasma cell infiltrate. child shows typical
yellow–brown translucent
papules on the nose and
upper lip. By courtesy of
Characteristically, plasma cells are seen around blood ­vessels and at the S. Hendfield-Jones, MD,
­margin of the amyloid deposits (Fig. 13.68).4,24 Rarely, an ­associated for- Institute of Dermatology,
eign body giant cell reaction and/or calcification are evident.4,6 London, UK.

Colloid milium
Colloid milium, which is characterized by the deposition of amorphous,
eosinophilic granular deposits in the superficial dermis, has a number of sub-
types including the juvenile and adult variants. It may also develop as a
­manifestation of ochronosis due to use of the skin bleaching agent hydroqui-
none.1 Two other variants – nodular colloid degeneration and paracolloid of
the skin – are probably variants of nodular amyloidosis.2–4 An alternative
name proposed for adult colloid milium is that of papular elastosis.5
Juvenile colloid milium
Clinical features
The juvenile variant, which is exceedingly rare, develops in children before
puberty and sometimes has a familial incidence.6 Patients present with
­discrete, or sometimes confluent, papules measuring 0.2–1.5 cm in diame-
ter.7 Lesions, which are yellow–brown in color, appear translucent and when
­ unctured characteristically express gelatinous material. The underlying
p
tissues often feel indurated. Juvenile colloid milium predominantly affects
the face, in particular the cheeks, nose, and around the mouth (Figs 13.69–
13,71). Induction of purpura after stroking has been described in both
­juvenile and adult colloid milium.8 This phenomenon has been attributed to
vascular fragility due to infiltration of the blood vessel walls by colloid mate-
rial. Exceptionally, ­juvenile colloid milia may present with gingival ­deposits
and ligneous conjunctivitis as a result of infiltration of these tissues by
­colloid-like material.9–11
Pathogenesis and histological features
Although the etiology remains unknown, in some cases at least, sunlight plays
an important role. The pathogenesis, however, shows considerable overlap with
macular and lichenoid amyloidosis. Juvenile colloid milium represents a primary
degenerative disorder of epidermal keratinocytes, which through the process of
apoptosis are transformed into colloid bodies within the superficial dermis.
544 Degenerative and metabolic diseases
Fig. 13.71
Juvenile colloid milium: close-up view from the brother of the patient shown in
Figure 13.70. By courtesy of S. Hendfield-Jones, MD, Institute of Dermatology,
London, UK.
Fig. 13.72
Juvenile colloid milium: this shows an apoptotic keratinocyte, the cytoplasm of
which is filled with fascicles of pale-staining filaments that contrast strikingly with
adjacent tonofilaments.
The initial change is one of filamentous transformation whereby the
­relatively straight electron-dense keratin filaments are converted into short-
ened, curved 8–10 nm filaments arranged in weaved or whorled fascicles (Fig.
13.72).7 Occasionally, both types of filament may be identified simultane-
ously within the cytoplasm of basal keratinocytes. With progression, filamen-
tous transformation comes to affect the entire cell, and nuclear, cytoplasmic,
and desmosomal remnants may be identified within the filamentous mass
(Fig. 13.73). Residual desmosomes are sometimes present around the border
of the colloid deposit. Finally, the apoptotic cell is extruded into the adjacent
dermis. In addition to the transformed filaments characteristic of all cytoid
bodies, amyloid filaments have also been identified in juvenile colloid milium,
thereby prompting the authors to classify this entity along with other amy-
loid-K dermatoses.2 Positive labeling of the deposits for epidermal keratin
gives support to this hypothesis.2,12
Juvenile colloid milium has also been shown by direct immunofluores-
cence to be accompanied by immunoglobulin, complement, and fibrin
­deposits.7 Whether this represents an autoimmune-mediated reaction as is
seen in ­macular-lichenoid amyloidosis or a secondary non-specific reactive
phenomenon has yet to be determined.
Fig. 13.73
Juvenile colloid milium: internalized desmosomes are evident within this degenerate
keratinocyte.
Fig. 13.74
Juvenile colloid milium: the papule consists of an intradermal deposit of eosinophilic
material. There is no inflammatory response.
Histologically, the deposits are present in the superficial dermis where they
impinge on the overlying and often somewhat frayed epidermis (Figs 13.74–
13.77). The colloid is composed of eosinophilic amorphous aggregates, often
showing a fractured appearance. The overlying epithelium shows prominent
cytoid bodies, while laterally, acanthosis associated with downward and
inward growth results in cuffing or even encirclement of the colloid islands by
an epidermal collarette.2 An admixture of fibroblasts and mast cells may be
evident and pigmentary incontinence is sometimes present. Juvenile colloid
milium is histochemically indistinguishable from amyloid: it is diastase-­
resistant, PAS positive, thioflavine-T positive and shows positive staining
with Congo red with apple-green birefringence.
Adult colloid milium
Clinical features
This variant, which is much commoner than the childhood form, affects middle-
aged patients and shows a predilection for males. Outdoor workers are most
often affected and lesions seen on sun-exposed skin are often ­accompanied by
the features of solar elastosis, giving rise to the synonym of papular elastosis.

Fig. 13.75
Juvenile colloid milium:
this high-power view
shows the faceted nature
of the deposit.
Fig. 13.76
Juvenile colloid milium:
the adjacent epidermis
shows massive apoptosis.
Adult colloid milium presents as dome-shaped yellowish translucent
­ apules measuring 0.1–0.5 cm in diameter and, in common with juvenile
p more recent studies suggest that it derives from actinic elastoid.14,20–22
­colloid milium, they contain gelatinous material. Lesions are most often
seen on the face, ears, neck, and the dorsum of the hands (Fig. 13.78) and
may be skin colored to brown.2,13 Adult colloid milium affects fair-skinned
patients and follows excessive sun exposure. This has been dramatically
illustrated in patients whose lesions are limited to sun-exposed areas of the
body.14,15 Adult colloid milium has also been reported following the exces-
sive use of cosmetic ultraviolet A (UVA) sunbed exposure.16 A rare associa-
tion with multiple myeloma has been described.17 A further report described
a patient who developed lesions of adult colloid milia in areas exposed to
Colloid milium 545
Fig. 13.77
Juvenile colloid milium: the amorphous material that characterizes this condition
is of epidermal derivation. Tonofilaments undergo filamentous degeneration
(apoptosis). Note the keratin positivity of the colloid aggregates (pankeratin).
Fig. 13.78
Adult colloid milium: predominantly unilateral, streaked, orange plaque involving the
forehead and nose. By courtesy of the Institute of Dermatology, London, UK.
mineral oils.18 A single case has also been described in a patient with beta
thalassemia major.19 Rare cases of pigmented colloid milium have been doc-
umented as a consequence of exogenous ochronosis due to ­bleaching creams
and fertilizers.1,13
Pathogenesis and histological features
In contrast to the keratinocyte changes seen in the juvenile variant, adult col-
loid milium represents an extreme degree of actinic damage centered upon the
upper dermal elastic fibers. Although earlier studies suggested that the colloid
might have represented abnormal collagen or a fibroblast secretory product,
Ultrastructural studies have shown that there is direct continuity between
actinic elastoid and the colloid deposits and that, within the electron-dense
colloid, remnants of both normal and elastotic fibers may sometimes be
­identified.21,23 Amyloid filaments are not present. Further support for this
hypothesis is given by the identification of serum amyloid P component within
the colloid deposits.21 Although this protein is characteristically present within
amyloid, it is also a constant component of normal elastic tissue and has also
been identified in actinic elastoid.24,25 Adult colloid milium does not label with
antikeratin antibodies, and immunoglobulins and complement are absent.
546 Degenerative and metabolic diseases

The gene for lipoid proteinosis has been mapped to chromosome 1q21
and the disease is caused by mutations in the extracellular matrix protein 1
gene (ECM1) which lead to partial or complete loss of function of the pro-
tein.12 ECM1 is thought to play a critical role in dermal structure and orga-
nization by binding to dermal ground susbstance (molecules such as perlecan
and matrix metalloproteinases), in the formation and maintenance of the
basement membrane, and in stromal signaling.13 It has been called ‘­biological
super-glue’.13,14 It is also overexpressed in cancers, influencing tumor growth
and metastasis.13 Over 40 different mutations in this gene have been reported
in association with lipoid proteinosis, and studies thus far have not demon-
strated a relationship between the specific type of mutation and ­clinical
­phenotype.13,14 Interestingly, patients with lichen sclerosus have auto­
antibodies to ECM1.15
The initial symptom, a hoarse cry, develops in infancy and results from
incomplete closure of the vocal cords, which are thickened and irregular due
to the hyaline deposits. Induration of the oral mucosa (including the inner
aspect of the lips, the gingivae, uvula, palate, and floor of the mouth) begins
in childhood and is progressive, so that adults have extensive yellow infiltra-
tion (Fig. 13.81).4,16 The lower lip often assumes a cobblestone appearance.
Fig. 13.79 The tongue also tends to be thick and immobile with sublingual frenulum
Adult colloid milium: deposits of eosinophilic material are present in the superficial
thickening and ankyloglossia. Recurrent ulcers on the tongue have been
dermis. There is adjacent solar elastosis.
described.5 Nail growth is frequently abnormal and the upper incisors, pre-
molars or molars can be hypoplastic or aplastic.6
Early inflammatory skin lesions (bullae, pustules, and crusts) are followed
by acneiform infiltrated scars on the face and limbs (Fig. 13.82).10
Papulonodular lesions develop on the face, fingers, and around the eyelashes,
where they produce the pathognomonic ‘string of beads’ appearance (monili-
form blepharosis) (Fig. 13.83). Thicker xanthoma-like plaques, which some-
times become verrucous, later develop on the areas of trauma including the
knees, elbows, feet, and hands.17 With chronicity in severely affected patients
the entire skin becomes yellow, waxy and thickened, particularly the flex-
ures.18 Similar lesions in the scalp may produce alopecia, which can be patchy
or diffuse.6,8
Intracranial disease sometimes occurs, associated with calcification, which
is thought to complicate deposition of hyaline material around cerebral blood
vessels and basal ganglia.4 Epilepsy is a not uncommon result.17,19,20 Other
neurological manifestations include memory loss, rage attacks, and mild
mental retardation.21
Involvement of the small bowel by the disease may lead to intestinal
bleeding.22
The disease is usually associated with normal life expectancy although
there might be some increase in the mortality rate during childhood due to
Fig. 13.80 respiratory insufficiency.2
Adult colloid milium: the typical faceted appearance.

Histologically, the eosinophilic amorphous, autofluorescent clefted depos-

its are typically separated from the epidermis by a grenz zone containing nor-
mal collagen (Figs 13.79, 13.80).21 Fibroblasts often occupy the fissures
between the fragmented deposits.21
Histochemically, adult colloid milium is diastase-resistant, PAS positive,
thioflavine-T positive and demonstrates apple-green birefringence with
Congo red.14 It is also Dylon positive.2 Colloid milium can be ­difficult to
­distinguish from amyloidosis, and electron microscopy may be
necessary.26,27

Hyalinosis cutis et mucosae

Clinical features
Hyalinosis cutis et mucosae (Urbach-Wiethe disease, lipoid proteinosis), is a
very rare, autosomal recessive condition first described in 1929 in which hya-
line material is deposited in virtually any organ in the body, but particularly
the skin, the pharyngeal mucosa, and the larynx.1–7 It has been reported most
frequently in South Africa (descendants of German and Dutch immigrants) Fig. 13.81
and Sweden, and it has been suggested that up to 35% of documented cases Lipoid proteinosis: small pale papules are present on the mucosal aspect of the
have had South African lineage.8–11 lower lip. By courtesy of the Institute of Dermatology, London, UK.

Fig. 13.82
Lipoid proteinosis: marked thickening of the skin is present with conspicuous
scarring. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.
Fig. 13.83
Lipoid proteinosis: note the waxy nodules on the lower eyelid, producing the
typical ‘string of beads’ appearance. By courtesy of the Institute of Dermatology,
London, UK.
Pathogenesis and histological features
The epidermis is acanthotic and occasionally papillomatous, with overlying
hyperkeratosis. Homogeneous eosinophilic material is distributed in a very
characteristic pattern in the dermis.8 Initially, it is found around capillaries
and concentrically around sweat coils (Figs 13.84, 13.85); later, more exten-
sive deposits are seen, which tend to be vertically orientated within the der-
mis. The hair follicles and arrector pili muscles are often surrounded by a
hyaline mantle.23 In advanced cases, the perineurium of nerves can also be
affected.24 This material stains very strongly with PAS (diastase-resistant) and
only very weakly with Congo red and thioflavine-T (Fig. 13.86). The name
lipoid is used because the hyaline material usually has a lipid component.25
Ultrastructurally, the deposit is amorphous, electron dense, and may con-
tain ill-defined, anastomosing amyloid-like (5–10 nm) filaments and delicate
collagen fibers (Figs 13.87, 13.88).23 Reduplication of basal lamina is evi-
dent around blood vessels, hair follicles, and sweat glands, and excess type IV
collagen has been demonstrated immunohistochemically.8,17,18,26 The
­fibroblasts contain abundant rough endoplasmic reticulum and numerous
mitochondria. Intracytoplasmic inclusions, probably lysosomal in nature,
have also been described.
Hyalinosis cutis et mucosae 547
Fig. 13.84
Lipid proteinosis: the
blood vessel walls are
thickened by pale-staining,
eosinophilic homogeneous
material.
Fig. 13.85
Lipoid proteinosis: in this advanced example, there is considerable involvement of
eccrine sweat glands which, as a result, are atrophic.
The etiology of bullous lesions in lipoid proteinosis is unclear. A recent
report sheds light on a possible pathogenesis. It describes subcorneal and
intraepidermal acantholysis without dyskeratosis in a child with lipoid
­proteinosis.27 Subepidermal clefting was also noted but thought to be artifac-
tual. Direct immunofluorescence studies were negative.
Despite considerable research, the precise pathogenesis of lipoid proteinosis
remains an enigma. Quantitative abnormalities of dermal collagen have been clearly
demonstrated, but little is known about the nature of the hyaline deposits other than
that they are probably composed of an admixture of ­glycoproteins, glycosaminogly-
cans, and lipids, as may be determined by s­ pecial staining techniques.8
Numerous mechanisms have been hypothesized, but none has satisfactorily
unraveled the nature of the primary disturbance in this disease. The identifica-
tion of lipid droplets within the hyaline deposits therefore led to the suggestion
that lipoid proteinosis might represent a systemic lipoidosis.8 However, the
lipid deposition is very variable and lesional chemical analyses have not dem-
onstrated any consistent abnormalities. Fibroblast tissue culture experiments
548 Degenerative and metabolic diseases

Fig. 13.86
Lipoid proteinosis: the
deposit is strongly periodic
acid–Schiff positive
(diastase-resistant).
A in collagen types III and V compared with collagen type I.32 Immunofluorescence
Fig. 13.88
Lipoid proteinosis: high-power view of amorphous electron-dense material
containing occasional collagen fibers.
have not supported this concept.25 It probably denotes a secondary phenome-
non. The ultrastructural finding of intracytoplasmic inclusions – including
myelin figures and lysosomes accompanied by an increased fibroblast
hexuronic acid content – has raised the possibility of a lysosomal storage dis-
order.28 This has recently been given further support by the demonstration of
abnormal lysosomes in eccrine cells and histiocytes in two patients with this
disease.29 These lysosomes were found to contain amorphous granular mate-
rial, zebra bodies, and curved tubular profiles. The curved tubular profiles are
similar to those found in Farber's disease and it has been suggested that lipoid
proteinosis represents a disease with not only impaired production of collagen
but also with alterations in ceramide metabolism.
A number of recent publications have described a variety of changes in the
dermal collagen content.30 The reduplicated basement membrane laminae
noted ultrastructurally have been shown to be composed of laminin accom-
panied by collagen types III and IV.31 This feature, however, is of doubtful
significance as similar appearances have been described in a wide variety of
conditions including psoriasis, systemic lupus erythematosus, and diabetes
mellitus.8 Basement membrane replication most likely represents a non-spe-
cific secondary response to a range of stimuli.
Dry weight studies of lipoid proteinosis dermis have shown an apparent
decrease in collagen content although there appears to be a relative increase
data, however, suggest that there are reduced absolute levels of both type I
and type III collagen.8 In vitro studies of fibroblast collagen synthesis as deter-
mined by radioactive hydroxyproline synthesis have revealed no significant
abnormality.17 Fibroblasts, however, have reduced replicative capacity. Recent
investigations have disclosed reduced fibroblast type I procollagen mRNA
and a diminished type I:III procollagen mRNA ratio.17 Type IV procollagen
mRNA levels have been shown to be raised.33 No DNA abnormalities or
chromosomal alternations have yet been identified in lipoid proteinosis.
It is likely that the collagen changes are not directly responsible for the
accumulation of the granular hyaline material so characteristic of this ­disorder.
It is, however, most probably of fibroblast derivation.34

Cutaneous macroglobulinosis
Clinical features
Cutaneous macroglobulinosis (IgM storage papules) is a rarely documented
B manifestation of Waldenström's macroglobulinemia.1–7 The latter is a chronic
lymphoproliferative condition that typically presents in the fifth and sixth decades
Fig. 13.87 and shows a slight predilection for males.5 It is characterized by ­proliferation of
(A, B) Lipoid proteinosis: transverse section through blood vessel showing lymphoplasmacytoid cells in the bone marrow, lymph node, and spleen and IgM
reduplication of the basement membrane. paraproteinemia.5 Patients present with weakness, fatigue, weight loss, anemia,
 Porphyria 549

mucous membrane bleeding, retinal hemorrhages, lymphadenopathy, hepatos-
plenomegaly, peripheral neuropathy, and the hyperviscosity syndrome.7,8 Skin
involvement is very uncommon and includes tumors, plaques, and macroglobu-
linosis cutis. Additional features that sometimes encountered include purpura,
xanthomata, cryoglobulinemia, and Raynaud's phenomenon.7
Clinically, macroglobulinosis presents as sometimes pruritic, skin-colored, ery-
thematous or translucent papules measuring up to 1.0 cm in diameter distributed
predominantly on extensor sites including knees, elbows, buttocks, and the arms
and legs..7 Umbilication, erosion, and crusting and hyperkeratosis are commonly
seen.5,9,10 Cutaneous tumor deposits present as violaceous nodules and plaques.
Histological features
The papules are characterized by homogeneous eosinophilic material in the
papillary and reticular dermis (Fig. 13.89).2 Hair follicles may be encased.2
The deposits are PAS positive but are Congo red negative (Fig. 13.90).
A ­lymphoplasmacytoid infiltrate is variably present.7 The plasma cells may
contain intracytoplasmic IgM-rich vacuoles.4
Direct immunofluorescence shows that the deposits stain strongly for
IgM.2,5,7
Ultrastructurally, the deposits are composed of amorphous or granular and
sometimes filamentous material which by immunoelectron microscopy consists
of IgM.1–3,7 The periodicity of amyloid is absent in the filamentous
component.7
The plaques and tumor nodules are composed of lymphoplasmacytoid
infiltrates.
Porphyria
The porphyrias constitute a heterogeneous group of conditions characterized
by the excessive production of porphyrins or their precursors resulting from
defects in the activity of the enzymes regulating heme synthesis (Fig. 13.91).1–12
Porphyrin synthesis occurs mainly in the erythropoietic system and the liver.

Fig. 13.89
Macroglobulinosis
cutis: these are nodular
deposits of eosinophilic
material in the superficial
dermis. By courtesy of
A. Wang, MD, Brigham
and Women’s Hospital,
Boston, USA.

Fig. 13.90 Fig. 13.91

Macroglobulinosis cutis: the material is strongly periodic acid–Schiff positive. Biochemistry of porphyria. Reproduced with permission from Young, J.W., and
By courtesy of A. Wang, MD, Brigham and Women’s Hospital, Boston, USA. Conte, E.T. (1991) International Journal of Dermatology, 30, 399–406.
550 Degenerative and metabolic diseases

Deficiency of a specific enzyme results in an accumulation of heme ­precursors
due to stimulation of the rate-limiting enzyme aminolevulinic acid synthetase as
a consequence of diminished heme concentration.10,13
Genetic mutations account for the enzyme deficiencies seen in the various
types of porphyria. These mutations have all been delineated at a molecular
level, are very heterogeneous, and often result in enzyme deficiencies that may
remain silent throughout life.13 If a patient is homozygous for a specific muta-
tion, however, symptoms usually develop even in early life.
Patients may present with acute porphyria (abdominal pain with neurologi-
cal and/or psychiatric symptoms) often induced by drugs, fasting, alcohol or
sex hormones.14–17 The enzyme defect leads to the accumulation in the skin of a
photosensitizing porphyrin, which absorbs light predominantly in the
400–410 nm range. The energy absorbed may then be released to adjacent
nucleic acids or proteins, either directly or indirectly by involving acceptor mol-
ecules such as oxygen, and toxic changes causing damage to lysosomal and cel-
lular membranes result.16,17 There is also some evidence to suggest that activation
of the complement cascade may be involved in the phototoxic reaction mecha-
nism.16,17 The cutaneous manifestations in acute attacks consist of prominent
erythema in sun-exposed areas with a burning sensation. Subacute or chronic
skin involvement consists of skin fragility, blister formation, and progressive
scarring. Exceptional cases of a photosensitive bullous eruption associated with
transient elevation of porphyrin levels have been described in neonates during
phototherapy for ­treatment of hyperbilirubinemia due to hemolytic
disease.18,19
Porphyria is primarily classified into erythropoietic and hepatic types
depending upon which tissue is predominantly affected. The erythropoietic
porphyrias (congenital erythropoietic porphyria and erythropoietic protopor-
phyria) are characterized by altered heme synthesis mainly in the bone
­ arrow. In the hepatic porphyrias the altered synthesis mainly occurs in the
m
liver (porphyria cutanea tarda, hepatoerythropoeitic porphyria, acute inter-
mittent porphyria, aminolevulinic acid (ALA) dehydratase deficiency, varie-
gate porphyria, and hereditary coproporphyria). Of the eight major types of
porphyria, six are associated with cutaneous disease (Table 13.4). The clini-
cal and biochemical findings are very different in these six types of ­porphyria,
although the cutaneous histology is similar in all.20–23 Type II porphyria
­cutanea tarda, hereditary coproporphyria, variegate porphyria, and erythr­
opoietic protoporphyria are all inherited as autosomal dominants with incom-
plete penetrance. Fewer than 20% of affected individuals display ­symptoms
and patients often deny a family history.2
Congenital erythropoietic porphyria
Clinical features
Congenital erythropoietic porphyria (Gunther's disease) is the most severe
and mutilating of the erythropoietic porphyrias. It is inherited as an auto-
somal recessive and develops as a consequence of deficiency of the fourth
enzyme of the heme pathway (uroporphyrinogen III synthase) resulting in
excessive production of uroporphyrin I and coproporphyrin I, which give the
urine a pink–burgundy color.1–3 Patients with the more severe form of the dis-
ease may present with fetal hydrops.4 The diapers of affected children usually
show a characteristic pink stain. Uroporphyrin I accumulates in the bone
marrow, peripheral blood, and other organs. It has been demonstrated that
there is a clear correlation between the degree of porphyrin excess and disease
severity.5 There is increased production of uroporphyrins and ­coproporphyrins
in the urine and coproporphyrins in the feces.

Table 13.4
Classification of porphyria

Site of metabolic
Condition Mode of inheritance Enzyme defect expression Laboratory abnormality
Non-acute porphyrias producing cutaneous lesions
Congenital erythropoietic Autosomal recessive URO-S Erythroid cells Elevated uroporphyrin
porphyria Coproporphyrin in urine and feces
Porphyria cutanea tarda Hepatocytes Urinary uroporphyrin:coproporphyrin = 3:1
inherited Autosomal dominant URO-D Elevated urinary uroporphyrin
sporadic Acquired/sporadic URO-D Urinary and stool isocoporphyrins
toxic Acquired
Erythropoietic protoporphyria Autosomal dominant Ferrochetalase Erythroid cells and Normal urine
hepatocyte Elevated plasma, RBC and stool
protoporphyrin
Elevated fecal and RBC coproporphyrin
Hepatoerythropoietic porphyria Autosomal recessive URO-D (severe) Erythroid cells and Increased urine and stool URO
hepatocyte Elevated stool coproporphyrin and
isocoproporphyrin
Elevated RBC protoporphyrin
Acute porphyrias (porphyrias producing abdominal, neurological and psychiatric symptoms)
Acute intermittnt porphyria Autosomal dominant Porphobilinogen Hepatocyte Stool and blood usually normal
deaminase Elevated urinary ALA and PBG
ALA dehydratase deficiency Autosomal recessive ALA dehydratase ? ALA alone elevated
(porphobilinogen
synthase)
Porphyrias producing abdominal, neurological, psychiatric and cutaneous manifestations
Variegate porphyria Autosomal dominant Protoporphyrinogen Hepatocyte Urine normal between attacks
oxidase Increased stool protoporphyrins and
coproporphyrin
Increased urinary ALA and PBG during
attacks
Hereditary coproporphyria Autosomal dominant Coproporphyrinogen Hepatocyte Increased stool and urine coproporphyrins
oxidase

ALA, aminolevulinic acid; PBG, porphobilinogen; RBC, red blood cell; URO, uroporphyrinogen.
Reproduced with permission from Young, J.W., Conte, E.T. (1991) International Journal of Dermatology, 30, 399–406.
 Porphyria 551

Affected patients develop intense photosensitivity to sunlight as well as to

fluorescent light, typically in infancy (Fig. 13.92). Symptoms include painful
and pruritic erythema and swelling which occurs within minutes of sun expo-
sure. Vesicles and bullae are supervened by a mutilating scarring process on
the face and hands, where autoamputation may occur (Figs 13.93, 13.94). A
rare case of metastatic squamous cell carcinoma has been reported in an
amputation stump.6 Sclerodermoid change is sometimes seen.7 Coarse hair
may be found on the face, and lanugo hair develops on the limbs. Pigmentary
changes are sometimes evident. In addition, patients develop cicatricial alope-
cia of the scalp, nail changes, conjunctivitis, ectropion, keratoconjunctivitis,
symblepharon, blepharitis, or brown staining of the teeth (erythrodontia).8,9
The teeth characteristically fluoresce intense orange–red with Wood's light
(400 nm). The sclera also demonstrates pink fluorescence under Wood's
light.10

Fig. 13.94
Congenital erythropoietic
porphyria (Gunther’s
disease): adult patient
showing very severe
photodamage. By
courtesy of the Institute of
Dermatology, London, UK.

Hemolytic anemia and splenomegaly occur in a large proportion of the

Fig. 13.92
Congenital erythropoietic porphyria (Gunther’s disease): this variant is associated
with severe photosensitivity. There is marked erythema and edema of the backs of
the hands and fingers. Scarring frequently supervenes. By courtesy of G. Murphy,
MD, Beaumont Hospital, Dublin, Eire.
patients and hypersplenism is sometimes a feature. Patients with congenital
erythropoietic porphyria have an increased risk of bone fragility with ­resultant
fractures and developmental defects.2 Acro-osteolysis, soft ­tissue calcifica-
tions, and widening of the diploic space have also been documented.11 Early
death may result, often in the third decade. Rare cases are associated with the
nephrotic syndrome, probably secondary to renal siderosis.12 A delayed
­late-onset variant has rarely been described.13–15 Some of these patients ­present
with thrombocytopenia and others with myelodysplasia.14–17
The URO-synthase gene has been mapped to chromosome 10q25.3-
q26.3,15 The molecular defects in this disease are very heterogeneous and up
to 38 mutations in the URO-synthase gene have already been described.18–23
These include single base substitutions, insertions and deletions, and splic-
ing defects. By far the most common mutation is C73R, which has been
found in up to 40% of patients with the disease. Two other relatively com-
mon mutations include L4F and T228M, seen in 8% and 7% of patients,
respectively.19 Prenatal diagnosis of the disease is possible not only by
­measurement of uroporphyrin I levels in amniotic fluid but also by DNA
mutation analysis.24

Erythropoietic protoporphyria
Clinical features
Although this condition was not recognized until 1961, it is now known to
be the second commonest type of porphyria. It results from increased pro-
Fig. 13.93 duction of protoporphyrin due to diminished ferrochelatase (heme synthase)
Congenital erythropoietic activity.1–3 Ferrochelatase is the enzyme responsible for the combination
porphyria (Gunther’s between protoporphyrin IX and iron to form heme. Urinary porphyrins are
disease): in this severely normal because protoporphyrins are insoluble in water. Protoporphyrin is
affected patient, there is elevated in plasma, erythrocytes, and occasionally in the feces.1
marked hyperpigmented Coproporphyrins may be found in erythrocytes and feces. The mode of
scarring on the cheeks, inheritance is predominantly autosomal dominant with incomplete pene-
nose, and around the
trance although an autosomal recessive inheritance has also rarely been
mouth. The brownish
discoloration of the teeth
reported.4,5 The gene for ferrochelatase has been mapped to the long arm of
is characteristic. By chromosome 18 (18q21.3).6
courtesy of G. Murphy, The variable clinical manifestations of this disease are probably the
MD, Beaumont Hospital, result of heterogeneity of the ferrochelatase gene defects.7 Acute photosen-
Dublin, Eire. sitivity usually presents in early childhood.8 A painful burning erythema
552 Degenerative and metabolic diseases

with edema occurs immediately after exposure to sunlight.9 Petechiae can
occur, ­particularly with prolonged exposure. Vesicles are uncommon, but a
scaly, erythematous reaction may be seen, leading to circular or linear
depressed scars on the face (particularly on the bridge of the nose and
around the mouth) and over the knuckles (Figs 13.95–13.99).1 Purpura
and urticaria are sometimes seen. There may also be a waxlike thickening
of the skin, particularly of the dorsum of the hands and, more rarely, the
face (Fig. 13.100).1 Bullae and milia have been documented exceptionally.3
A further case presented with pseudoainhum.10 An association with lupus
erythematosus is very rare.11 Hypertrichosis and hyperpigmentation are
not typically seen.2
In the majority of cases the disease is limited to the skin, but some affected
patients develop protoporphyrin-rich gallstones, and 5–10% of patients
develop liver disease, which may progress to liver failure in fewer than 5% of
patients and rarely to cirrhosis.6,12–14 Patients who develop liver failure have a
different form of the disease with an autosomal recessive form of transmis-
sion.15 Neurological manifestations are not common. Anemia is rare and if
present is very mild.
Recently, a late-onset variant has been described, which is more commonly
associated with hematological malignancy, where the disease occurs second-
ary to an acquired somatic mutation in the malignant clone within the bone
marrow.16–19 Exacerbation of the disease by blood transfusion and by iron
ingestion has been described.20,21

Fig. 13.97
Erythropoietic
protoporphyria: there
are characteristic,
depressed, small linear
scars on the bridge and
Fig. 13.95 sides of this patient’s
Erythropoietic nose. By courtesy of the
protoporphyria: crusted Institute of Dermatology,
lesions are present London, UK.
on the cheeks, nose,
and around the mouth.
By courtesy of G. Murphy,
MD, Beaumont Hospital,
Dublin, Eire.

Fig. 13.98
Erythropoietic
protoporphyria: there
is very severe actinic
damage.
Fig. 13.96 By courtesy of the
Erythropoietic protoporphyria: there is marked scarring. Note the depressed linear Institute of Dermatology,
lesions. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire. London, UK.

Fig. 13.99
Erythropoietic protoporphyria: note the characteristic scaly scars over the knuckles.
By courtesy of the Institute of Dermatology, London, UK.
Fig. 13.100
Erythropoietic protoporphyria: there is characteristic waxy thickening of the skin of
the hands. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire.
Hereditary coproporphyria
Clinical features
This very rare autosomal dominant form of porphyria develops as a result of
a deficiency of coproporphyrinogen oxidase.1,2 This enzyme catalyzes the
sixth step in the heme biosynthetic pathway. It has been mapped to the long
arm of chromosome 3 (3q11.2).3 A number of different mutations have been
documented.4,5 Heterozygous patients often do not manifest symptoms of the
disease.6 In those who develop symptoms, these usually appear after puberty.
Affected patients develop intermittent attacks of abdominal pain in associa-
tion with neurological and psychiatric manifestations. About 30% of cases
develop photosensitivity, usually at the time of the acute attacks. The cutane-
ous changes are similar to those described for porphyria cutanea tarda. The
disease may be precipitated by pregnancy, the contraceptive pill, fasting,
infections, and the anabolic steroid methandrostenolone.3,7–9 Diagnosis is
confirmed by the presence of increased excretion of coproporphyrinogen III
in urine and feces. Porphobilinogen and aminolevulinic acid are increased
during the episodic attacks.
Harderoporphyria is regarded as a variant form of hereditary copropor-
phyria in which hematological alterations predominate.2,10 Patients ­present
Porphyria 553
with jaundice, severe chronic hemolytic anemia starting in the neonatal period,
hepatosplenomegaly, and photosensitivity. Neuropsychiatric ­symptoms or
abdominal pain are not seen. These patients usually have a specific mutation
(K404E) on one or both alleles of the coproporphyrinogen gene.11
Porphyria cutanea tarda
Clinical features
This is the commonest type of porphyria and usually manifests in middle
age.1–3 It shows a marked male predominance.4 The highest incidence is found
in the South African Bantu.4 Cases are also often seen in Europe and North
America.
There are two main forms of porphyria cutanea tarda: familial and spo-
radic.1 Both variants have in common a reduced activity of uroporphyrinogen
decarboxylase (URO-D), which catalyzes the decarboxylation of uroporphy-
rinogen to coproporphyrinogen. In the familial variant there is decreased
URO-D activity in erythrocytes and most other tissues while in the ­sporadic
form there is decreased URO-D activity restricted to the liver.5,6 In rare ­familial
cases, normal URO-D activity has been reported in erythrocytes.7
The rare familial form exhibits an autosomal dominant inheritance. The
onset tends to be earlier than that of the sporadic form and the exceptional
cases occurring in childhood are usually familial. The disease is related to
many different mutations in the URO-D gene.8,9 There is no clear correlation
between disease severity and the type of mutation.10 Porphyria cutanea tarda
may be precipitated by many exogenous factors including alcohol abuse, iron
overload, childbirth, and sun exposure.11 Pregnancy may exacerbate the
symptoms of the disease during the first trimester.12 Multiple factors often
contribute to precipitate the disease in a given patient.13 Rare cases of familial
porphyria cutanea tarda present with constrictive pericarditis.14
The second much more common form is sporadic or acquired. Up to 80%
of patients with porphyria cutanea tarda have the sporadic form of the dis-
ease. It has been demonstrated that sporadic porphyria cutanea tarda is a
multifactorial disorder involving a combination of genetic and environmen-
tal factors. Recent studies have demonstrated that the hemochromatosis
gene mutations C282Y and H63D represent a susceptibility factor in Western
European and Australian patients affected by this form of the disease.15–19
These mutations probably induce the disease through iron overload. It has
also been suggested that the IVS4+198 T allele in the human transferrin
receptor-1 may play an independent role in the development of the disease.15
However, this has not been substantiated in other studies.18 Coinheritance of
mutations in the uroporphyrinogen decarboxylase and in the hemochroma-
tosis genes appears to accelerate the onset of porphyria cutanea tarda.20
Sporadic cases mainly occur in patients exposed to a variety of hepatotoxic
chemicals, such as ethanol, estrogens, griseofulvin, vitamin B12, sulfon-
amides, tamoxifen, pravastatin, barbiturates, hydantoins, and chlorinated
hydrocarbons: for example, an epidemic form occurred in Turkey due to
exposure to the fungicide hexachlorobenzene.21–25 Rare associations include
diabetes ­mellitus, Wilson's disease, myelofibrosis, the CREST syndrome,
and hepatocellular carcinoma.26–29
Increased hepatic iron stores are a major predisposing factor.6,30 The mech-
anism by which this happens is not well understood. Iron catalyzes the forma-
tion of reactive oxygen species and this may enhance uroporphyrin formation
by increasing the rate at which uroporphyrinogen is oxidized to uroporphy-
rin, leading to the manifestations of the disease. A second possible proposed
mechanism considers the indirect inhibition of uroporphyrinogen decarboxy-
lase by iron. Whatever the mechanism, the iron overload has important
­therapeutic implications as venesection can induce a remission.
Hepatitis C virus infection is often associated with porphyria cutanea
tarda.31–33 A frequent association is also the acquired immunodeficiency syn-
drome (AIDS).34–39 AIDS patients with porphyria cutanea tarda are often hep-
atitis C virus-positive.40 Patients who have had both acquired and familial
variants have developed the typical features of increased skin fragility, blister-
ing, hyperpigmentation, and hypertrichosis, but scarring and milia have
rarely been evident.41 Often, the development of porphyria has preceded the
­diagnosis of HIV infection.41 In many instances this has been related to
­excessive alcohol consumption and/or infectious hepatitis, particularly
554 Degenerative and metabolic diseases
­ epatitis C.38,42 The association has been reported too often to be merely
h cheeks and temples, the eyebrows, ears, and arms (Fig. 13.105).4 The
­fortuitous and liver damage seems to be the common denominator. The causal
agent (be it hepatitis C virus or HIV) seems to have a direct effect upon hepa-
tocyte porphyrin metabolism. It has been demonstrated that elevated serum
porphyrin levels occur in early-stage HIV infection and hepatitis C infec-
tion.43 Porphyria cutanea tarda has also been described in association with
nonalcoholic liver disease, chronic hemodialysis, noninsulin dependent diabe-
tes mellitus and lupus erythematosus.1,44,45 An autoantibody study in a large
series of patients with lupus erythematosus suggests that the association is
fortuitous.46 The association with hematological malignancies including leu-
kemia and lymphoma is usually related to the treatment, particularly repeated
blood transfusions.47,48
Typically, blisters occur on light-exposed skin and are traumatic or actini-
cally induced (Figs 13.101–13.103).4 Cutaneous fragility is usually marked.
The blisters are slow to heal and leave superficial atrophic scars with milia.
Although they are most often seen on the backs of the hands, they may also
be found on the palms, face, scalp, forearms, trunk, and under the finger
nails.4 Hypertrichosis and premature aging with chronic actinic damage are
usual and sclerodermatous changes may be marked (Fig. 13.104). The hyper-
trichosis is characterized by long dark lanugo hair developing about the
Fig. 13.101
Porphyria cutanea tarda: in addition to a blood-filled vesicle there are numerous
milia. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire.
Fig. 13.102
Porphyria cutanea tarda: there are numerous ruptured blisters. Milia are also
evident. By courtesy of the Institute of Dermatology, London, UK.
­sclerodermatous features, which are more common in females, are found on
both light-exposed and unexposed skin. Sites that are particularly affected
include the face, neck, scalp, chest, and backs of hands, and often there is
hyper- or hypopigmentation or both.4,49 Hyperpigmentation, if present, may
be diffuse, reticulate or spotty. Preauricular calcification is a common
­complication. The dermal fibrosis appears to be related particularly to high
uroporphyrin ­levels.49 Uroporphyrin has been shown to stimulate fibroblast
collagen synthesis independent of ultraviolet light.50
Uncommon cutaneous manifestations of porphyria cutanea tarda include
alopecia affecting the frontoparietal, temporal, and occipital regions of the
scalp, and centrofacial papular lymphangiectasis.51,52 Hair darkening has also
been reported.53 Very rare cases have been documented presenting with
plaques or simulating solar urticaria.54,55
Fig. 13.103
Porphyria cutanea tarda: note the scarring and milia. By courtesy of the Institute of
Dermatology, London, UK.
Fig. 13.104
Porphyria cutanea
tarda: there is marked
facial scarring with
sclerodermiform features.
By courtesy of G. Murphy,
MD, Beaumont Hospital,
Dublin, Eire.
 Porphyria 555

Fig. 13.106
Fig. 13.105 Variegate porphyria:
Porphyria cutanea numerous ruptured
tarda: hypertrichosis as vesicles are present on
seen in this patient is the back of the hand
a very typical feature. and fingers. By courtesy
By courtesy of the of G. Murphy, MD,
Institute of Dermatology, Beaumont Hospital,
London, UK. Dublin, Eire.

Acute attacks are not a feature of this variant. Biochemical evidence of

liver involvement is common, but clinical manifestations are unusual.1 Urinary
porphyrin levels are increased and result in pink–red fluorescence with a
Wood's lamp.56
The diagnosis is confirmed by the presence of uroporphyrin and hepta­
carboxylic porphyrins in urine and plasma and by the presence of
­isocoproporphyrin in feces.

Hepatoerythropoietic porphyria
Clinical features
Hepatoerythropoietic porphyria is very rare and, in fact, represents the
homozygous form of familial porphyria cutanea tarda.1 Both diseases share
some of the mutations that have been described.2 This form of porphyria is
also heterogeneous and different mutations in the URO-D gene may occur.3,4
The activity of uroporphyrinogen decarboxylase is much lower than in
­porphyria cutanea tarda. As a consequence, disease manifestations are
­typically severe. Recently, mild variants have been reported in association
with certain genetic mutations.5,6 Extreme immediate photosensitivity occurs Fig. 13.107
in infancy.7–9 Erythema, edema, and vesicles lead to severe scarring, with Variegate porphyria: there are ruptured blisters with scarring and milia. By courtesy
hypertrichosis and sclerodermatous changes in exposed areas.10 Ocular fea- of the Institute of Dermatology, London, UK.
tures include photophobia, conjunctivitis, and scleromalacia perforans.11
Hepatitis, cirrhosis, and normochromic anemia may also occur.
chromosome 1q22-23.5,6 The genotype is not a significant determinant of the
clinical manifestations.7–9 Usually, there is approximately a 50% reduction in
Variegate porphyria the activity of the enzyme.9
Acute attacks may be precipitated by a wide range of drugs that induce
Clinical features hepatic microsomal activity including barbiturates, alcohol, oral contracep-
This familial type of porphyria manifests the cutaneous features of porphyria tives, pregnancy, anticonvulsants, and sulfonamides.10–13 Acute variegate por-
cutanea tarda and the acute abdominal and neurological attacks of acute phyria has also presented during an episode of viral hepatitis.10 The cutaneous
intermittent porphyria, both of which usually become apparent in the second manifestations are sometimes mild or absent during the acute attack and the
or third decade (Figs 13.106–13.109).1,2 It is particularly common in South condition may therefore be misdiagnosed as acute intermittent porphyria.2
Africa where it can be traced to the descendants of a single Dutch family.2,3 It
is an autosomal dominantly inherited condition and more severely affected Histological features of the porphyrias
homozygotes have been recognized (Figs 13.110, 13.111). Variegate por- Direct immunofluorescence reveals immunoglobulin (particularly IgG and
phyria is associated with diminished activity of protoporphyrinogen oxidase, to a lesser extent IgM), fibrinogen, and C3 outlining characteristic donut-
the penultimate enzyme in the heme biosynthetic pathway.4 Several different shaped blood vessels in the papillary dermis (Fig. 13.112). Although this is
mutations have been demonstrated in the protoporphyrin oxidase gene on particularly evident in erythropoietic protoporphyria, it is also a feature of
556 Degenerative and metabolic diseases
Fig. 13.108
Variegate porphyria: note the blistering over the toes and dorsum of the foot.
By courtesy of the Institute of Dermatology, London, UK.
Fig. 13.109
Variegate porphyria: an intact blister is present on the left little finger. Elsewhere,
there is marked scarring and milia are present. By courtesy of the Institute of
Dermatology, London, UK.
the other ‘cutaneous’ variants.1,2 Immunoreactants are also frequently pres-
ent at the dermoepidermal junction and have been identified within the
basement membrane region of eccrine sweat glands and ducts.1–4 This find-
ing is believed to be due to the non-specific binding of serum components
rather than an immunologically mediated reaction.3 In addition, both type
IV collagen and laminin are present in increased amounts, thereby contrib-
uting to the vessel wall thickening.5 Cytoid bodies are also commonly evi-
dent.3 Recently, direct immunofluorescence studies have demonstrated
granular and homogenous deposition of the membrane attack complex
C5b-9 in vessel walls of the superficial and mid dermis in patients with por-
phyria cutanea tarda. It is proposed that UV light activated uroporphyrins
in turn activate complement, possibly playing a pathological role.6 Indirect
immunofluorescence is invariably negative for basement membrane zone
autoantibodies.
The histological changes for all types of porphyria are very similar. The
characteristic feature is the presence of a PAS-positive, diastase-resistant, hya-
line material around the blood vessels of affected skin (Figs 13.113, 13.114).
In mild disease the deposits are delicate and are usually limited to the papil-
lary dermal capillaries, but in more severe cases the deposits are widespread,
occur more deeply in the dermis, and give the vessel walls a characteristic
Fig. 13.110
Homozygous variegate
porphyria: there is
marked scarring of the
dorsal surface of the
forearms, hands, and
fingers. By courtesy of the
Institute of Dermatology,
London, UK.
Fig. 13.111
Homozygous variegate porphyria: note the perioral erosions and scarring. By courtesy
of the Institute of Dermatology, London, UK.
lamellated appearance. These appearances are particularly conspicuous in
erythropoietic protoporphyria.1,7 Alcian blue-positive mucin is sometimes
evident around the blood vessels and to a lesser extent at the dermoepidermal
junction in both porphyria cutanea tarda and erythropoietic protoporphyria.1
Lipid droplets are sometimes also demonstrable. A false-positive Congo red
stain for amyloid may be evident in the lower dermis.1
Electron microscopic observations include considerable basement mem-
brane reduplication around the dermal vasculature and to a lesser extent at
the dermoepidermal junction (Fig. 13.115).1,7 This is consistent with the
effects of repetitive endothelial cell injury and regeneration with subsequent
new basement membrane formation. In addition, finely fibrillar material is
typically present both around the vessels and at the epidermal basement mem-
brane region. Irregular electron-dense amorphous deposits may also be
evident.1

There may be subepidermal blisters, characteristically associated with slight
mononuclear inflammatory cell infiltration (Figs 13.116, 13.117). Neutrophil
polymorphs showing leukocytoclasis have been described in acute lesions of
erythropoietic protoporphyria and red cell extravasation is ­sometimes evident.8
Festooning of the dermal papillae is often, though not invariably, present.
Fig. 13.112
Porphyria cutanea tarda: the superficial blood vessels show striking IgG circumferential
deposition.
B
Fig. 13.113
(A, B) Porphyria cutanea tarda: the superficial vessels are thickened and appear hyalinized.
Porphyria 557
The plane of cleavage appears to be variable.9 Some blisters arise beneath the
lamina densa in the superficial dermis similar to ­epidermolysis bullosa acquisita.
In others, they develop within the reduplicated basement membrane constitu-
ents. Most often, however, as shown by antigen mapping experiments, blister-
ing commences in the lamina lucida.9,10 Type IV collagen and laminin are
therefore usually present along the floor of the blister while bullous pemphig-
oid antigen is evident in the roof. Linear segmented structures composed of
type IV collagen and laminin have been identified in the roof of blisters from
patients with porphyria cutanea tarda.11 These so-called caterpillar bodies may
also be seen in specimens from patients with erythropoietic protoporphyria and
drug-induced pseudoporphyria (Fig. 13.117b).12 They are PAS positive and
appear as globules arranged in a linear fashion in the epidermis overlying the
subepidermal blisters. Ultrastructural studies suggest that these bodies ­represent
a combination of degenerating keratinocytes, colloid bodies, and basement
membrane fragments formed by repeated blistering and re-epithelialization.13
A recent study of caterpillar bodies demonstrated their presence in 43% of
Fig. 13.114
Erythropoietic
protoporphyria: the
appearances are much
more dramatic in this
periodic acid–Schiff-
stained section.
Fig. 13.115
Porphyria cutanea tarda: there is striking basement membrane reduplication
surrounding this small dermal vessel.
558 Degenerative and metabolic diseases
­ orphyria cutanea tarda specimens.14 ‘Caterpillar body-like clusters’ have also
p Rarely, a lichenoid tissue reaction has been documented in porphyria
been identified in patients with porphyria cutanea tarda, erythropoietic proto-
porphyria, bullous ­pemphigoid, and junctional and dystrophic epidermolysis
bullosa. These clusters were histologically identical to classical caterpillar bod-
ies but did not stain for type IV collagen or PAS stains.14
Fig. 13.116
Porphyria cutanea tarda: a bland subepidermal blister is present.
Fig. 13.117
Porphyria cutanea tarda: (A) the blister is cell free; (B) the superficial vessels are
thickened (periodic acid–Schiff). Note the caterpillar bodies in the overlying epidermis.
­cutanea tarda.15
The histological features of the blisters seen in variegate porphyria are
identical to those described for porphyria cutanea tarda.16
A secondary sclerodermatous change is frequently present in more
chronic lesions, characterized by thickened collagen bundles and reduced
numbers of cutaneous adnexae (Fig. 13.118).3,7,17 Diastase-resistant,
­PAS-positive material may be identified throughout the involved dermis.1
This is particularly marked in porphyria cutanea tarda. Its distinction from
the dermal changes of scleroderma may be very difficult, but it has been
said that the texture of the collagen bundles is somewhat looser in
­porphyria.1 Basement membrane thickening due to diastase-resistant, PAS-
positive material is usually present, particularly in porphyria cutanea
tarda.1,7 Solar elastosis is often evident in the latter condition, but this is
probably largely a consequence of the age of the patient and is unlikely to
be a fundamental process (Fig. 13.119). It is not a feature of ­erythropoietic
protoporphyria.1,7
In the alopecia associated with porphyria cutanea tarda, the initial changes
are those of swelling and homogenization of the perifollicular connective ­tissue
Fig. 13.118
Porphyria cutanea tarda: there is intense scarring of the entire dermis. The fat
entrapment is reminiscent of scleroderma.
Fig. 13.119
Porphyria cutanea tarda: there is colloid milium-like solar elastosis deep to this
blister.
 Pseudoporphyria 559

sheath.18 Later, the features of sclerodermatous transformation of the ­reticular

dermis supervene. Centrofacial papular lymphangiectasis is ­characterized by
the presence of dilated lymphatics in the superficial dermis.19
The hepatic changes of porphyria cutanea tarda are variable and
include needle-shaped uroporphyrin crystals, hepatitis, liver cell degenera-
tion and regeneration, fatty change, hemosiderosis, and scarring, some-
times amounting to cirrhosis (Fig. 13.120).18,20,21 There is an increased
risk of hepatocellular carcinoma.21 Hepatic changes of erythropoietic pro-
toporphyria include birefringent, dark brown, protoporphyrin crystal
deposition in the hepatocytes and Kupffer cells, hepatocyte necrosis, por-
tal and periportal fibrosis, cholestasis and, less commonly, cirrhosis (Fig.
13.121).22
Differential diagnosis
The major differential diagnosis histologically is between porphyria, pseudo-
porphyria, epidermolysis bullosa acquisita and congenita, and bullous amy-
loidosis. All produce cell-poor or cell-free subepidermal blisters. Their
distinction is readily made in the majority of cases with clinical information,
immunofluorescence studies, and Congo red staining.
Pseudoporphyria
Clinical features
Pseudoporphyria (drug-induced pseudoporphyria, drug-induced pseudopor-
phyria cutanea tarda, pseudoporphyria cutanea tarda, bullous dermatosis in
end-stage renal failure, bullous dermatosis of hemodialysis) refers to a photo-
distributed blistering dermatosis resembling porphyria cutanea tarda but in
the absence of any serum, urine or stool porphyrin abnormality (Figs 13.122–
13.125).1 It is now recognized as having many causes including drugs, exces-
sive UVA (including the use of sunbeds), and sunlight exposure and may
develop in patients undergoing hemodialysis for chronic renal failure.1–20
Pseudoporphyria occurs in up to 6% of patients receiving hemodialysis.21
Small tense blisters develop on the backs of the hands and fingers, and
occasionally involve the face, upper chest, and legs.1,2 Milia, skin fragility,

Fig. 13.122
Pseudoporphyria: there
is extensive purpura with
freckling and conspicuous
excoriations. The patient
had used a sunbed for a
number of years.
Fig. 13.120 By courtesy of G.M.
Porphyria cutanea tarda: in addition to fatty change and mild chronic inflammation, Murphy, MD, Beaumont
brown uroporphyrin crystals are evident. Hospital, Dublin, Eire.

Fig. 13.121 Fig. 13.123

Erythropoietic protoporphyria: the Kupffer cells contain abundant brown pigment. Pseudoporphyria: small tense grouped vesicles are present on the arm. By courtesy
By courtesy of D.R. Davies, MD, St Thomas’ Hospital, London, UK. of G.M. Murphy, MD, Beaumont Hospital, Dublin, Eire.
560 Degenerative and metabolic diseases
photosensitivity, and scarring are often present. Hypertrichosis, hyperpig-
mentation, sclerodermoid changes, and dystrophic calcification as seen in
porphyria cutanea tarda are not features of pseudoporphyria.1 In children
affected with this condition (usually receiving naproxen for juvenile arthritis),
facial scarring reminiscent of erythropoietic protoporphyria has been
­documented.7,22 In general, hepatic abnormalities appear to be absent.1
Pathogenesis and histological features
Pseudoporphyria is a UVA-related phototoxic dermatosis.1 It may develop fol-
lowing both hemodialysis and peritoneal dialysis and also in patients with
chronic renal failure in the absence of dialysis. Suggested risk factors in such
patients include iron overload, aluminum intoxication, PVC-induced photo-
sensitivity, drugs, and ethanol.1,2 The condition has also been documented
­following use of non-steroidal anti-inflammatory medications including
naproxen and cyclooxygenase inhibitors.7–10 A wide variety of other drugs
Fig. 13.124
Pseudoporphyria: note the hemorrhagic blister overlying the knuckle. By courtesy of
G.M. Murphy, MD, Beaumont Hospital, Dublin, Eire.
Fig. 13.125
Pseudoporphyria: there
are multiple erosions and
milia. By courtesy of the
Institute of Dermatology,
London, UK.
including ­various antibiotics (e.g. nalidixic acid, tetracyclines, and cipro­
floxacin), antifungals (e.g. voriconazole) and diuretics (e.g. furosemide
(frusemide), torsemide) have also been incriminated (for details see references
1 and 2).13–18,23–25 Recent case reports also implicate the tyrosine kinase inhibi-
tor imatinib, ciclosporin, and oral contraceptive pills.27 The use of UVA sun-
tanning beds is also a well-recognized cause of pseudoporphyria.12,27 Young
females are almost exclusively affected and PUVA therapy has also rarely been
incriminated.1 A rare case of narrow-band UVB-induced ­pseudoporphyria has
been reported in a patient being treated for psoriasis. 20
The blisters are subepidermal and rather bland, containing perhaps a little
fibrin and, occasionally, red blood cells (Fig. 13.126).7,11,27,28 The floor of the
blister is typically lined by well-preserved dermal papillae (festooning). There
is usually no significant inflammatory component although occasionally, a
light perivascular lymphocytic infiltrate may be seen in the superficial dermis.
Thickening of the superficial vessels (highlighted by a PAS stain) and dermal
sclerosis with elastosis may be apparent.
Direct immunofluorescence reveals Ig (usually IgG, IgM, and sometimes
IgA) with C3 around the superficial vasculature in a donut distribution and
as a fine granular deposit at the epidermal basement membrane region (Fig.
13.127).2,7,22,23,26–29 Indirect immunofluorescence is invariably negative.2
Fig. 13.126
Pseudoporphyria: (A) there
is a subepidermal blister;
(B) the superficial dermal
vessels are thickened
with a hyaline deposit.
(B) By courtesy of G.M.
A Murphy, MD, Beaumont
Hospital, Dublin, Eire.
B
 Pseudoporphyria 561

Fig. 13.127
Pseudoporphyria: the
vessel wall thickening is in
part due to excess type IV
collagen, as shown in this
field. By courtesy of G.M.
Murphy, MD, Beaumont
Hospital, Dublin, Eire.

On electron microscopic examination, the plane of cleavage is variable: in

some it has been shown to be within the lamina lucida, whereas in others it
has been deep to the lamina densa (Fig. 13.128).7,30,31 As in porphyria ­cutanea
tarda, basement membrane reduplication is typically present both at the der-
moepidermal junction and also around the superficial vasculature (Fig.
13.129).7

Differential diagnosis B
The invariably negative indirect immunofluorescence and absence of
­porphyrin abnormalities distinguish this disease from autoimmune bullous Fig. 13.129
­dermatoses and porphyria cutanea tarda.32,33 (A, B) Pseudoporphyria: note the striking basement membrane duplication.

A B

Fig. 13.128
(A, B) Pseudoporphyria: in this example, the blister is located in the superficial papillary dermis deep to the lamina densa (arrowed).
562 Degenerative and metabolic diseases

Gout
Clinical features
Gout represents a group of disorders of purine metabolism in which ele-
vated levels of uric acid occur.1–4 The majority of affected patients have
reduced excretion of purines which may be caused by diuretic therapy or
renal disease. Hyperuricemia may also complicate diabetic ketoacidosis
and starvation, and can develop in patients with sarcoidosis and psoria-
sis.5,6 Some have increased purine synthesis and this type of disturbance
can occur dramatically in the myeloproliferative diseases, particularly fol-
lowing therapy with cytotoxic drugs. Less commonly, gout represents a
primary inherited disorder of purine metabolism. A number of enzymatic
defects are recognized including hypoxanthine guanine phosphoribosyl-
transferase activity (X-linked recessive), abnormal phosphoribosylpyro-
phosphate synthetase variants (X-linked dominant) and
glucose-6-phosphatase deficiency.4 These defects represent a small propor-
tion of patients with gout. More recent genome-wide association studies
have rapidly expanded the knowledge of other genetic defects responsible
Fig. 13.130
for the disease.7–9 Many of the implicated genes are believed to function as
Gout: massive deposit on the dorsal aspect of the hand.
urate transporters in the renal tubules.8,9
Males are affected more often than females and presentation is usually in
the fourth to sixth decades. However, the incidence in females is rising, par-
ticularly in those on diuretics and those with altered renal function.10 The The diagnosis of gout rests primarily on the identification of uric acid
prevalence of the disease is higher in black patients.11 c­ rystals within joint fluid or tophi rather than on serum uric acid levels, which
Gout produces recurrent, acute, exceedingly painful monoarticular can be unreliable. Acute attacks of gout can be associated with normal uric
arthritis, classically of the great toe, but also of the large joints of the legs. acid levels.12
Many patients present initially with acute inflammation of the first metatar-
sophalangeal joint (podagra).12 The affected joint is characteristically
exceedingly tender, hot, and erythematous, and cellulitis may therefore Histological features
enter the differential diagnosis. Precipitating factors include trauma, exces-
The demonstration of uric acid crystals in tophi requires alcohol fixation
sive alcohol consumption, dietary excess (particularly red meat consump-
and anhidrous processing because monosodium urate is water ­soluble (Fig.
tion), lead exposure, hypertension, renal insufficiency, surgery, and
13.131).36 In formalin-fixed sections, uric acid crystals appear as amorphous
infections.4,12–14 Alcohol and obesity are associated with increased nucle-
material in the dermis or subcutaneous tissues, surrounded by a marked
otide catabolism and decreased urate excretion.15–17 Not surprisingly, more
­granulomatous response in which many giant cells are usually ­evident (Figs
recent studies indicate a close relationship with the metabolic syndrome,
13.132, 13.133). Calcification may be a late complication. In secondarily
and as a consequence patients with gout also have an increased risk of dia-
infected lesions, a neutrophil polymorph infiltrate is sometimes present.37 In
betes, myocardial infarction, and premature death.8,18 Certain medications,
alcohol-fixed sections, the deposits are seen to be composed of ­needle-shaped
including diuretics (loop and thiazide), low-dose aspirin, and ciclosporin
brown crystals, which lie in bundles and show negative ­birefringence with
increase the risk of gout.14,19 With chronicity, a disabling and often crippling
polarized light and a first-order red compensator filter (Figs 13.134,
arthritis may develop, particularly affecting the hands and feet.3 Subsequently,
13.135).38
uric acid crystal deposition in skin and soft tissues produces gouty tophi;
these nodules are seen most commonly on the external ear, but also over the
elbows and on the digits (Fig. 13.130). When large, they often discharge a
chalky material. Rare clinical presentations include bullous lesions, a fun-
gating mass, and sparing of hemiplegic limbs by the tophi.20–22 Nowadays,
only a minority of patients present with tophi because of ­improvement in
the ­diagnosis and treatment of the disease.23 Tophi are rarely the first mani-
festation of the ­disease.24,25 They have exceptionally been described in the
mitral valve, breast, nose, ­cervical spine, sacroiliac joint, larynx, and eyes.26–32
Bone involvement gives rise to characteristic lytic lesions in the distal sub-
chondral region of the digits.4 Fracture due to bone erosion has been
reported.33
Renal disease, which is an important complication, presents as urate
nephropathy and/or uric acid nephrolithiasis.18,34,35 In secondary types asso-
ciated with increased cell turnover, including myeloproliferative disease and
multiple myeloma, acute precipitation of uric acid crystals sometimes occurs
in the collecting ducts of the kidney during chemotherapy. Uric acid neph-
ropathy may also develop in patients with the inherited variants. Patients
present with acute renal failure. More commonly, in primary gout, renal
stones are a feature, and chronic urate nephropathy (due to deposition of
monosodium urate monohydrate salt crystals in the interstitial tissues of the
kidney), presenting as mild proteinuria and hypertension, occasionally
develops.4 Uric acid stones develop in about 40% of patients with gout sec- Fig. 13.131
ondary to myeloproliferative diseases and in 10–25% of patients with the Gout: characteristic needle-shaped crystals. By courtesy of G.T. McKee, MD,
primary variants.4 Massachusetts General Hospital, Boston, USA.
 Gout 563

A A

B B

Fig. 13.132 Fig. 13.134

Gout: (A) circumscribed deposits of uric acid are scattered within the dermis, note (A, B) Gout: characteristic needle-shaped uric acid crystals are seen in alcohol-fixed
the accompanying fibrosis; (B) formalin fixation has destroyed the uric acid crystals and anhydrous processed material.
to leave amorphous eosinophilic material.

Fig. 13.135
Fig. 13.133 Gout: the crystals display striking birefringence when viewed with polarized
Gout: multinucleate giant cells are present. light.
564 Degenerative and metabolic diseases
Ochronosis
The term ‘ochronosis’ was first used by Virchow in 1866 to describe a
clinical condition in which blue–black cutaneous pigmentation in the
skin was associated with the microscopic deposition of an ochre-colored
pigment. There are two main types: alkaptonuria and exogenous
ochronosis.
Alkaptonuria
Clinical features
This is an autosomal recessively inherited condition (with an approximate
incidence of 1:106) in which deficiency of homogentisate 1,2-dioxygenase
(HGD) in the liver and kidneys (necessary for the catabolism of phenyla-
lanine and tyrosine) leads to the accumulation of homogentisic acid
(2,5-hydroquinone acetic acid) in cartilage, tendon, skin, and fibrous tis-
sue.1–4 The condition is particularly seen in patients of Eastern European
origin, mainly those from Slovakia where the incidence is as high as
1:19 000.5 Clinical features relate particularly to joint and cardiovascular
involvement, renal and prostatic stones, and ocular and cutaneous lesions.
Alkaptonuria, or blackening of the urine after standing or alkalinization
due to oxidation of homogentisic acid, usually becomes obvious in child-
hood. Most patients present with either dark urine or early-onset arthritis.
The blue–black discoloration of the tissues (known as ochronosis) is due
in part to the Tyndall effect.
The cutaneous changes develop later, at about 30–40 years of age. They
are seen particularly on sun-exposed skin and areas with maximum numbers
of sweat glands.1–4 Deposition of polymerized oxidase pigment in the ear car-
tilage produces painful thickening and blue–black speckled discoloration.
Involvement of the eardrum and ossicles may result in tinnitus and deafness.4
Subsequently, discoloration of the sclera, conjunctiva, tendons, and skin of
the face, hands, and flexures occurs.6 A rare case of vaginal hyperpigmenta-
tion has been reported.7 The skin pigmentation may be more prominent on
the palms and soles.8 Finally, a characteristic arthritis, which is often severe,
develops in almost all patients.9 Low back pain is followed by involvement of
the large joints of the limbs. Spinal involvement leads to disc herniation,
spondylosis, and osteophytosis with resultant limitation of movement and
loss of height.1,10 Musculoskeletal disease caused by alkaptonuria can be
severe and result in significant disability.12 Despite widespread morbidity,
alkaptonuria is not associated with significant mortality, and life expectancy
is typically normal.1
Osteoarticular involvement – which is particularly evident in the
knees, shoulders, and hips, and in advanced cases the vertebral column –
is characterized by pigmentation of the articular cartilage, synovium,
and capsule associated with fibrillation, fragmentation, calcification,
and erosion. 11,12 Osteoarthritis may also be evident and chronic
­n on-specific synovitis is commonly present. Cardiovascular involvement
occurs in up to 50% of patients and mainly consists of pigmentation and
calcification of the aortic valve, which may lead to stenosis. 13–15
Cardiovascular pigmentation, which is especially seen on the endocar-
dium and valves (aortic and mitral), also affects the intima and media of
arteries. Surprisingly, even with heavy pigment deposition and smooth
muscle cell degeneration, aneurysm formation is not a feature of ­vascular
involvement.16
In up to 60% of patients the kidneys typically show very marked pigmenta-
tion, especially involving the pyramids and calculi.17 Ochronotic prostatic stones
are a nearly invariable feature, but bladder calculi are much less frequent.4,16
Asymptomatic ocular involvement is seen in up to 70% of patients.18
Pigmentation particularly affects the sclera and to a lesser extent the conjunc-
tiva and cornea.6,16 The lesions are typically noninflammatory.
Ochronotic pigmentation is frequently seen in the hyaline cartilage of the
larynx, trachea, and bronchi.16,19 Involvement of endocrine organs, central
nervous system, and teeth is rare.20–22
Exogenous ochronosis
Clinical features
Deposition in the skin of an identical pigment to that seen in alkaptonuria
may occur as a result of the application of phenol (carbolic acid) to leg
ulcers, therapy with resorcinol and picric acid, the oral and intramuscular
­administration of antimalarials such as chloroquine, and the application to
dark skin of bleaching creams containing hydroquinone, most often in
black women.23–32 Antimalarials result in slate-gray pigmentation affecting
the knees, face, palate, and subungual regions.33 In hydroquinone-induced
ochronosis, lesions occur particularly over bony prominences such as the
forehead, temples, nose, and lower jaws and also on the sides of the neck
(Fig. 13.136).34 Time to onset of lesions is approximately 6 months. The
first stage is characterized by erythema and mild hyperpigmentation.24
Subsequently, the hyperpigmentation intensifies and patients develop wide-
spread ‘­caviar-like’ black papules; cutaneous atrophy and colloid milia
may also occur.34 In longstanding disease, nodules develop.24,35–37
Hydroquinone-induced ochronosis is a major problem in the black popula-
tion of South Africa. In one series the prevalence among users of skin light-
eners was almost 70%.28 The reason for the high incidence of ochronosis
in this population is not entirely clear but is thought to be due in part to
high concentrations of hydroquinone used in their products and the syner-
gistic effect of multiple compounds used in combination with hydroqui-
none such as mercury and resorcinol, which can also cause ochronosis.24
Exogenous ochronosis due to hydroquinone is thought to be photoacti-
vated. Exogenous ochronosis tends to chronicity. In addition to causing
ochronosis, hydroquinones containing bleaching creams have been shown
to be carcinogenic in rodents. As a result, in 2006, the US Food and Drug
Administration proposed a ban on all over-the-counter bleaching creams
containing hydroquinone.29
Pathogenesis and histological features
In alkaptonuria, as a result of the deficiency of homogentisate 1,2-dioxy-
genase, homogentisic acid is oxidized and polymerized by polyphenol
­oxidase to form benzoquinone acetic acid. This results in a black pigment
that binds irreversibly to collagen. Polyphenol oxidase is particularly com-
mon in cartilage and skin and this reflects in their preferential ­involvement.
Fig. 13.136
Exogenous ochronosis:
hyperpigmented plaque
with numerous colloid
milia in a Bantu female.
The lesions developed
as a consequence
of the application of
hydroquinone bleaching
cream.
 Pellagra 565

The pigment formed has not been characterized but there are some simi-
larities to ­melanin.38 It appears that the pigment deposition occurs both in
previously damaged ­collagen and in normal collagen. The gene responsi-
ble for alkaptonuria has been localized to chromosome 3q.23-21.39–41 The
human homogentisate 1,2-dioxygenase gene has been cloned and it has
been shown that patients with alkaptonuria carry two copies of a loss-of-
function homogentisate 1,2-dioxygenase allele.42 Over 91 different genetic
mutations have been identified thus far in the HGD gene.41 A study of
patients with ­alkaptonuria has demonstrated that they have a significantly
higher prevalence of HLA-DR7 than those without the disease.43
The exact pathogenesis of exogenous ochronosis is not known. Proposed
mechanisms include:
• the inhibition in the skin of homogentisate 1,2-dioxygenase by
hydroquinone with formation of pigment, 44
• increased tyrosinase activity induced by hydroquinone.23
Ochronosis presents as yellow–brown, sharply defined, irregularly shaped
and frequently fragmented fibers in the superficial dermis (Fig. 13.137).1,26
The ochronotic pigment is autofluorescent, appears black with methylene
blue, but does not stain with van Gieson, Perl's stains or the Masson-Fontana
reaction.1 Pigment granules are often present in the epithelium and basement
membrane of sweat glands, in endothelial cells, and within dermal
macrophages.16,19
In ochronosis due to hydroquinones the skin may, in addition, show Fig. 13.138
Exogenous ochronosis:
­melanophages in the upper dermis associated with depigmentation of the
early lesion showing
­epidermal melanocytes.35 markedly swollen collagen
In early lesions the collagen fibers appear basophilic and swollen before fibers.
developing the characteristic yellow ochronotic morphology (Fig. 13.138).
With chronicity, large amorphous eosinophilic granules may develop, resem-
bling colloid milium.35 Solar elastosis and foreign body granulomata (some- Hartnup disease
times indistinguishable from sarcoidosis) are less common features.26,27,37,45
An actinic granuloma-like variant has been described.36 Transepidermal and Clinical features
transfollicular elimination of ochronotic fibers has occasionally been
Hartnup disease is an autosomal recessive disorder characterized by defective
documented.37,46
gastrointestinal absorption and renal reabsorption of monoamine and mono-
Antimalarial pigmentation is due to melanin and hemosiderin deposition
carboxylic amino acids due to a defect in the neutral brush border system.1
in addition to the classical ochronotic fibers.1
One of the effects is tryptophan deficiency.2 The disease typically presents in
Electron microscopic studies have shown that initially electron-dense
childhood. In addition to a pellagra eruption (see below), patients also have a
ochronotic pigment is deposited around swollen collagen fibrils that charac-
characteristic aminoaciduria and cerebellar ataxia.3,4 An uncommon cutane-
teristically lose their banding pattern.35 These fibrils subsequently degenerate
ous manifestation is an acrodermatitis-like eruption involving the perioral
until the whole collagen fiber is replaced by amorphous ochronotic pigment.
region, perineum and acral skin.5 The disease may, however, sometimes be so
Rupture of the fibrils also occurs, so that the pigment comes to lie scattered
mild as to remain asymptomatic.6 Additional symptoms include diarrhea and
free in the dermis. Phagocytosis of the latter by macrophages and giant cells
central nervous system dysfunction ranging from mild apathy to psychosis
may be seen.16,26 The colloid milium-like deposits in hydroquinone-associated
and frank dementia.7 An exceptional case of a patient with identical symp-
ochronosis consist of electron-dense granular material lacking a significant
toms and signs of Hartnup disease in the absence of a recognized metabolic
fibrillar component.35
abnormality or aminoaciduria has been described.8 The disease has been
mapped to chromosome 5p15 and the defective gene is SLC6A19, a sodium
dependent neutral amino acid transporter.9–11

Histological features
The cutaneous histology is identical to that of pellagra (see below).

Fig. 13.137
Ochronosis: typical
swollen, irregular, golden-
brown fibers are seen
(bottom left).
Pellagra
Clinical features
Pellagra develops as a consequence of deficiency of nicotinic acid (niacin,
vitamin B3) or its precursor tryptophan.1–3 The cause may be dietary. It has
traditionally been associated with high consumption of corn.3 In developed
countries it is most frequently observed in alcoholics, in those living in condi-
tions of socioeconomic deprivation, and in patients with anorexia nervosa or
malabsorption due to extensive gastrointestinal disease (e.g. partial gastrec-
tomy, gastroenterostomy, and Crohn's disease).1,4 A severe case of cytomega-
lovirus colitis in an immunocompetent patient has also been associated with
pellagra.5 It is sometimes also a feature of the carcinoid syndrome because the
tumor cells consume available tryptophan to produce serotonin.5,6 Pellagra
occasionally develops after therapy with a number of drugs ­including
566 Degenerative and metabolic diseases
i­soniazid, 6-mercaptopurine, and 5-fluorouracil.6–10 Finally, it can occur in
Hartnup disease and in association with defects in the metabolism of trypto-
phan.11 Pellagra is particularly prominent in parts of Africa and Asia where
nutritional deficiencies are prevalent.1 A rare case has been described in asso-
ciation with the intake of alternative medicines.12 A further report describes
an association with amyloidosis secondary to multiple myeloma.13
The classic triad of pellagra is ‘dermatitis, diarrhea, and dementia’. The
skin eruption of pellagra is photosensitive in nature. An initial painful sun-
burn-like erythema subsides to leave a dusky brownish discoloration with a
dry scaly appearance (Figs 13.139, 13.140). Blisters may sometimes be
­evident. The eruption is typically sharply demarcated, symmetrical, and
occurs on the backs of the hands (most commonly), the forearms, the knees,
­central chest, neck, and face.7 The thickened skin around the photoexposed
skin of the neck typically resembles a necklace (Casal's necklace). Other
­features sometimes present include cheilosis, glossitis, angular stomatitis, and
oral or perianal sores.3,7
Gastrointestinal disease in pellagra manifests as nausea, vomiting, abdom-
inal pain, gastritis, and diarrhea. Neurological involvement evolves, with
headache, depression, and ataxia initially and more severe symptoms of
­disorientation, delirium, and coma and eventually death.3
Fig. 13.139
Pellagra: scaling and hyperpigmentation are present on the dorsal aspect of the
knuckles and fingers. By courtesy of the Institute of Dermatology, London, UK.
Fig. 13.140
Pellagra: close-up view of hyperpigmentation and scaling. By courtesy of the Institute
of Dermatology, London, UK.
Histological features
The appearances in pellagra are usually non-specific. There is ­hyperkeratosis,
parakeratosis, and acanthosis associated with increased melanin pigmenta-
tion and, in early lesions, keratinocyte vacuolation in the upper reaches of the
epidermis.7,8 Telangiectasia and a perivascular chronic inflammatory cell infil-
trate in the upper dermis may also be evident. Older lesions sometimes show
epidermal psoriasiform hyperplasia.14 In some instances the histology can
resemble that of necrolytic migratory erythema and acrodermatitis
enteropathica.
Differential diagnosis
The diagnosis is very much dependent upon clinicopathological correlation,
particularly in those cases that resemble necrolytic migratory erythema and
acrodermatitis enteropathica.
Scurvy
Clinical features
Scurvy, due to vitamin C deficiency, results from a diet inadequate in fresh
fruit and vegetables and is nowadays most often encountered following inap-
propriate dieting, food fads, and in alcoholics and socially isolated individu-
als.1 Scurvy is rare in children but does occur in those with developmental and
psychiatric disorders. It may also be secondary to drinking boiled or evapo-
rated milk which is deficient in vitamin C.2
Cutaneous manifestations include dry skin, follicular hyperkeratoses par-
ticularly affecting the forearms, legs and abdomen, perifollicular hemorrhages
especially affecting the legs, petechiae and subungual splinter hemorrhages,
leg edema, alopecia, erythematous, swollen and bleeding gums with tooth
loss, and clinical evidence of poor wound healing.1–4 Painful subperiosteal
hemorrhage, ‘Barlow's disease’, is characteristically seen in infants.2 Less spe-
cific manifestations which may cause a delay in diagnosis include fatigue,
arthralgia, and myalgias.3
Pathogenesis and histological features
Vitamin C is necessary for hydroxylation of proline and lysine residues dur-
ing the conversion of procollagen into collagen fibers. As a result of impaired
collagen synthesis, basement membrane synthesis is defective, with conse-
quent loss of blood vessel wall integrity. This, combined with impaired der-
mal connective tissue constituents, results in a bleeding tendency.
The cutaneous features include follicular dilatation and keratin plugging,
perifollicular hemorrhages with chronic inflammation, and hemosiderin
deposition.4–7 The alopecia is characterized by hair shaft fracture and
­corkscrew hairs within a dilated and plugged follicle (Fig. 13.141).1,4,8
Calcinosis cutis
Calcinosis cutis may occur when connective tissue is abnormal (dystro-
phic) or where calcium or phosphate levels in the blood are high
­(metastatic); alternatively, there may be no obvious underlying cause (idio-
pathic) (Table 13.5).1–3
Dystrophic calcinosis cutis
Clinical features
In this, the most common variant of calcinosis, the changes are limited to the
dermis and subcutaneous tissues and there is no involvement of internal
organs. This form of calcinosis always occurs in tissue that has been previ-
ously damaged either by external agents or as the result of a disease. Under
this variant, iatrogenic calcinosis cutis induced by local application of
­chemicals or medications is also included. In the localized form of dystrophic
­calcinosis cutis, the underlying anomaly may be inflammatory or traumatic in
nature, for example acne scars, burns, fat necrosis or subcutaneous and
­intramuscular injections.4,5 Calcification and necrosis have been reported
­following electroencephalography and electromyography.6,7 Calcification is a
 Calcinosis cutis 567

Fig. 13.141
Scurvy: the hair follicle
is dilated and there is a
typical corkscrew hair cut
in multiple planes. Note Fig. 13.142
the surrounding chronic Dystrophic calcinosis cutis: calcification has developed in this ruptured cyst.
inflammation and red cell
extravasation. By courtesy
of S. Tahan, MD, Beth
Israel and Deaconess
Medical Center, Boston,
USA.

Table 13.5
Classification of calcinosis cutis

Type Distribution Clinical features

Dystrophyic Localized Acne scars; fat cell necrosis;
Widespread epidermoid cysts; pilomatrixoma;
infantile calcinosis of the heel
Dermatomyositis; systemic lupus
erythematosus; Ehlers-Danlos
syndrome; pseudoxanthoma
elasticum
Metastatic Hypercalcemic Hyperparathyroidism; sarcoidosis;
vitamin D excess; milk alkali
syndrome; destructive bone disease
Normocalcemic Chronic renal failure; Fig. 13.143
pseudohypoparathyroidism Iatrogenic calcinosis cutis: this widespread dermal calcification followed calcium
Idiopathic Generalized Calcinosis universalis gluconate infusion.
Localized Subepidermal calcified nodule;
localized idiopathic dermal
calcinosis; tumoral; scrotal
nodules which can ulcerate. They usually develop within a few weeks of expo-
sure.18 Deep soft tissue calcification has been described in association with
pentazocine and pitressin.19,20 Similar reactions following calcium-containing
characteristic feature of pancreatic disease-associated panniculitis and in heparin in patients with renal insufficiency have also been reported.21,22
older lesions of subcutaneous fat necrosis of the newborn. Auricular calcifica- Widespread dystrophic calcification occurs most commonly as a sequel to
tion (also known as ‘petrified ear’) may occur as a result of chondritis, trauma connective tissue disease (Figs 13.144, 13.145). Localized dystrophic calcifi-
or frostbite.1,8,9 Less commonly, it is associated with hypercalcemia associated cation with bone formation has also been described in mixed connective tis-
with systemic disorders and endocrinopathies.8,9 A distinct example of dys- sue disease.23 Dermatomyositis, especially in children, may be complicated by
trophic calcification is infantile calcinosis cutis of the heel, in which calcific extensive deposits of calcium in the skin and subcutaneous tissues, as well as
dermal nodules develop approximately 1 year after birth in infants who have in muscles and tendons. Scleroderma, especially the CREST variant, tends to
had multiple heel punctures for venesection.10,11 show localized deposition of calcium, particularly on the digits and over bony
Localized dystrophic calcinosis may also complicate epithelial cysts or prominences. Fingertip lesions are a common presentation in patients with
neoplasms (Fig. 13.142).12 It is particularly seen within the keratin of trichil- Raynaud's phenomenon (with or without underlying connective tissue dis-
emmal cysts. Calcification may occur in many adnexal tumors, for ­example ease) and have also been reported in a patient with Sjögren's syndrome who
pilomatrixoma and trichoepithelioma. It is much more common in basal cell did not have Raynaud's.24,25 Systemic lupus erythematosus is infrequently
carcinoma than in squamous cell carcinoma.13,14 Subungual epidermoid associated with calcinosis.26,27 It is usually an incidental radiological observa-
­inclusions are rare tumors of the nail bed in which calcification may occur.15 tion, most commonly seen in the buttocks and extremities and unassociated
Calcinosis cutis has also been documented following the intravenous with panniculitis. Mostly it develops in patients with severe acute disease
administration of calcium chloride, phosphate, and gluconate (iatrogenic cal- including cardiac, renal or central nervous system (CNS) manifestations.2 It
cinosis cutis) (Fig. 13.143).16–18 Lesions consist of multiple, erythematous also appears to correlate with high doses of corticosteroids and myositis.28,29
568 Degenerative and metabolic diseases
Fig. 13.144
Dystrophic calcinosis cutis: this large deposit is associated with focal ulceration
and transepidermal elimination. By courtesy of the Institute of Dermatology,
London, UK.
Fig. 13.145
Dystrophic calcinosis cutis: multiple digital deposits are present. By courtesy of the
Institute of Dermatology, London, UK.
Calcification complicating discoid lupus erythematosus and subacute lupus
erythematosus is limited to a few case reports.30,31 Lupus panniculitis and
other types of panniculitis (including pancreatic fat necrosis) may also be
associated with calcification.32 Patients with porphyria cutanea tarda rarely
develop calcinosis cutis. Lesions are most common on the scalp, neck, preau-
ricular area, and hands, and are more likely to develop in patients with scle-
rodermoid disease.33 Calcium is also deposited in inherited connective tissue
disorders, especially Werner's syndrome, pseudoxanthoma elasticum (PXE),
and Ehlers- Danlos syndrome, in which small calcific nodules typically
develop within atrophic scars over bony prominences. Alternatively, dystro-
phic calcification in PXE may occur as large, painful, pruritic nodules in areas
involved by the underlying disease.34
Calcification has recently been described in patients with nephrogenic sys-
temic fibrosis, associated with the cutaneous lesions as well as in fascia and
muscle.35,36 The etiology of calcification in this disease is debated. Some
believe it occurs secondarily as part of a dystrophic process while others con-
tend that calcification is intrinsic to the pathological process, particularly as
it is also seen in vessels, in patterns resembling calciphylaxis.37
Fig. 13.146
Metastatic calcinosis cutis: there are gross deposits, many ulcerated. By courtesy
of R.A. Marsden, MD, St George’s Hospital, London, UK.
Metastatic calcinosis cutis
Clinical features
Metastatic calcification occurs as a result of hypercalcemia or hyperphos-
phatemia as may be seen in chronic renal failure, hyperparathyroidism, and
sarcoidosis.38–41 Calcium deposits occur in the skin, subcutaneous tissues,
muscle, tendon, and internal organs. In the skin, the clinical appearances are
of hard nodules and plaques, which may ulcerate to liberate chalky material
and ultimately leave a scar (Fig. 13.146). This may be particularly frequently
seen over large joints, the iliac crest or in the flexures. Fingertip lesions are
usually very painful. A case report describes a patient with vulvar cystic nod-
ules and hyperphosphatemia.42
Albright's hereditary osteodystrophy is a genetic disorder associated with
end-organ resistance to parathyroid hormone. Patients present in infancy or
childhood with obesity, short stature, mild mental retardation, shortened
fourth and fifth metacarpals, and cutaneous calcification.43,44 The skin lesions
are typically multiple erythematous to purpuric papules, plaques, and nod-
ules on the trunk and extremities.
Vascular calcification with thrombosis may lead to livedo reticularis, ulcer-
ation, and gangrene, particularly affecting the hands, fingers, toes, and lower
legs (so-called clinical calciphylaxis).41,45,46 A frequent complication is sepsis
and this often results in death. Patients usually have chronic renal failure in
association with hyperphosphatemia and hyperparathyroidism.47–49 Other
conditions associated with calciphylaxis include hypervitaminosis D and A,
hypercalcemia, primary or secondary hyperparathyroidism, AIDS, and pro-
tein C deficiency.50,51 The exact mechanism of calciphylaxis is not clear but it
seems to be related to an imbalance in calcium and/or phosphorus metabo-
lism.52 Rarely, the condition occurs in patients with normal levels of calcium
and phosphorus.52
Idiopathic calcinosis cutis
Clinical features
There are six main clinical types of calcinosis in which there is no known pre-
disposing condition:
• In calcinosis universalis, there is progressive deposition of calcium in the
skin and subcutaneous tissue, producing discharging hard nodules and
plaques very similar clinically to those seen in metastatic calcification.
Some cases may represent dermatomyositis in which the acute phase was
not diagnosed.
• In contrast, idiopathic calcinosis may occur as a solitary nodule on the
extremities and face, particularly the eyelids (subepidermal calcified

Fig. 13.147
Tumoral calcinosis: bilateral nodules over the elbows, with perforation on the
patient’s left. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.
Fig. 13.148
Tumoral calcinosis: these small deposits are undergoing transepidermal elimination.
By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.
nodule, cutaneous calculus).53,54 It usually presents in early childhood and
is more common in males; the majority of the nodules are hyperkeratotic
and tender on palpation. Rarely, it may be present at birth and
occasionally multiple lesions are present.55
• Localized idiopathic dermal calcinosis may also occur as a solitary
nodule on the limbs.56,57 The fingers and elbows are particularly affected.1
An equivalent lesion, designated oral mucosal calcified nodule, which
affects the gingiva and tongue, has recently been documented.58
• In tumoral calcinosis, large deposits of calcium are present in the skin
and subcutaneous tissues, typically over bony prominences (hip, elbow,
and scapula) (Figs 13.147, 13.148). It is rare in Europe and North
America, but is not uncommon in South, Central and East Africa and
Papua New Guinea, where it is known as hip stone. It shows a female
preponderance (2:1) and affects younger age groups. These deep deposits
may be visualized radiologically (Fig. 13.149).
• Scrotal calcinosis may occur spontaneously. Patients present in childhood
or early adulthood with multiple, asymptomatic, flesh-colored or yellow
nodules of varying sizes, which often release granular chalky material.59 A
similar finding on the penis has also been reported in young men with no
prior history of trauma and without a known underlying adnexal lesion.60
Calcinosis cutis 569
Fig. 13.149
Tumoral calcinosis: subcutaneous deposits are present overlying the thigh and
lateral border of the knee. By courtesy of R.A. Marsden, MD, St George’s Hospital,
London, UK.
• Finally, milia-like idiopathic calcinosis cutis is a rare condition seen in
children (usually under the age of 21 years).61,62 Lesions are multiple, skin
colored to whitish papules with a generalized distribution. Perforation
may occur. Two-thirds of cases have been associated with Down's
syndrome and up to one-third of patients have coexisting syringomata.
Lesions resolve spontaneously without scarring.
Pathogenesis and histological features
Calcium stains blue with hematoxylin and eosin. In calcinosis cutis a rather
homogeneous deep blue material is seen, either as small superficial deposits
or as deeper globular ones (Fig. 13.150). Owing to the concomitant presence
of phosphate and carbonate, the deposit stains black with the Von Kossa
stain (Fig. 13.151).
The presence of calcium in the skin variably excites a foreign body reac-
tion, so giant cells are sometimes seen at the edge of the deposit. On other
occasions a chronic inflammatory cell infiltrate is present. Transepidermal
elimination of calcified debris is sometimes a feature.4
Dystrophic calcification due to extravasation of intravenous solutions
containing calcium is characterized by dermal calcium surrounding degener-
ated collagen bundles.18 Lesions caused by calcium-containing heparin also
demonstrate calcium in fat lobules, surrounding adipocytes, in septae as well
as within the media of small vessels in the subcutaneous fat and dermis.22
There may be fibrosis of vessel walls; however, thrombosis is not a usual
feature.20,22
In calciphylaxis, there is prominent calcification of walls of dermal and
subcutaneous small blood vessels (Fig. 13.152).52 Often, the findings also
include some degree of intimal proliferation and thrombosis. These changes
result in prominent ischemic necrosis. Calcification of the subcutaneous fat
accompanied by lipophagic necrosis may also be seen.
The pathogenesis of calciphylaxis is not completely understood. Recent
studies point to osteopontin as a possible factor.63 Osteopontin is a phospho-
protein adhesion molecule with a high affinity for calcium. It is normally
expressed by various cell types, including osteoblasts, osteocytes, fibroblasts,
macrophages, and smooth muscle cells. It plays an important role in bone
remodeling. Previous studies have suggested a role for osteopontin in calcifi-
cation of heart valves and pilomatrixoma.64,65 A recent study examined its
presence in calciphylaxis and demonstrated expression in the media and, less
often, the intima of vessel walls and surrounding adipocytes in the subcutane-
ous fat in areas involved by calcification.63 The authors speculate that calci-
phylaxis may be caused by osteogenic differentiation of vascular smooth
muscle cells.
570 Degenerative and metabolic diseases
A B
Fig. 13.151
Calcinosis cutis: the calcified deposit stains positively with the Von Kossa reaction.
Calcification deposits in nephrogenic systemic fibrosis occur in the dermis,
associated with CD34-positive spindled cells and in the media of small arteries
in the deep dermis and subcutaneous fat, similar to that seen in
calciphylaxis.37
A report of an exceptional case of metastatic calcification showed calcifi-
cation only of sweat ducts.66
There may be histological evidence of the underlying disease process.
In localized dystrophic calcinosis, for example, there is sometimes evidence of
a preceding epidermoid cyst. In widespread dystrophic calcinosis cutis
­secondary to connective tissue disease, there is occasionally evidence of
­preceding collagen degeneration.
In a subepidermal calcified nodule, there is sometimes pseudoepithelioma-
tous hyperplasia, associated with transepidermal elimination of calcium.
In tumoral calcinosis the histological features depend upon the stage of evo-
lution of the lesion (Figs 13.153–13.155).67 In early examples, multiple cystic
spaces lined by epithelioid and giant cells are seen. The cyst lumina contain
Fig. 13.150
Calcinosis cutis: (A) small deposits of intensely basophilic
material are present in the superficial dermis; (B) these
calcium deposits are associated with scarring.
Fig. 13.152
Calciphylaxis: note the subendothelial calcification and thrombosis.
eosinophilic debris undergoing calcification. In advanced lesions, densely calci-
fied material is seen embedded in hyalinized connective tissue. The occasional
finding of necrobiosis and vasculitis may have pathogenetic significance.
The pathogenesis of the scrotal variant is most probably calcification of
the contents of pre-existent dermal cysts, mostly epidermoid, but occasionally
pilar.62,68–72 Some authors have failed to detect an epithelial component;43
however, this may be a reflection of the age of the lesion. A recent study of 20
cases identified residual epidermal cysts in 14.71 In many examples, typical
epidermoid lining epithelium surrounds the calcified deposit and sometimes
residual keratinous contents are visible. A foreign body giant cell reaction is
not uncommon.
The etiology of milia-like calcinosis cutis is unclear. Theories include
increased calcium content of excreted sweat and calcification of a pre-existing
cyst.61 Histologically, there is a focus of calcium in the papillary dermis sur-
rounded by a lymphocytic infiltrate and giant cells. Perforation may be
­present.61,62 Cyst epithelium is not present.
 The mucinoses 571

Fig. 13.153
Tumoral calcinosis: this low-power view shows a dense hyalinized stroma with
numerous cystic cavities containing necrotic and calcified debris.
The mucinoses
The mucinoses are a group of conditions in which accumulation of acid gly-
cosaminoglycans (mucin), particularly hyaluronic acid and to a lesser extent
chondroitin (-4 and -6) sulfate and heparin, occurs either diffusely or focally
in the dermis (Table 13.6).1–6 Mucinosis also may occur as a secondary phe-
nomenon in dermatoses such as lupus erythematosus, scleroderma, dermato-
myositis, Degos' disease, granuloma annulare, and chronic graft-versus-host
disease.5,7 In this chapter, however, only primary cutaneous mucinoses are
discussed.
The glycosaminoglycans, which are secreted by fibroblasts, are constitu-
ents of normal cell membranes and connective tissue. This substance is usu-
ally secreted in only small amounts by fibroblasts. It is not clear why mucin
production is increased in pathological states. Although the cause is probably
multifactorial, it has been suggested that cytokines and/or immunoglobulins
and unidentified factors in the serum of affected patients can induce synthesis
of glycosaminoglycans.5,8–10 Cytokines that play an important role in this pro-
cess include tumor necrosis factor, interleukin-1, and transforming growth
factor beta (TGF-β).5,11,12 Actively secreting fibroblasts have a characteristic
stellate shape and contain intracytoplasmic secretory vesicles; their presence
in sections should therefore prompt a careful search for mucin deposition
(Figs 13.156–13.158).

Table 13.6
Classification of the dermal mucinoses

Diffuse
lichen myxedematosus – generalized form (scleromyxedema)
scleredema
reticular erythematous mucinosis
generalized myxedema
pretibial myxedema
Focal
lichen myxedematosus – discrete papular form
acral persistent papular mucinosis
papular and nodular mucinosis associated with lupus erythematosus
self-healing juvenile cutaneous mucinosis
cutaneous mucinosis of infancy
cutaneous focal mucinosis
myxoid cyst
Follicular
follicular mucinosis
Fig. 13.154
Tumoral calcinosis: early lesions characteristically show a histiocytic and giant cell
palisade around eosinophilic, degenerate connective tissue.

Fig. 13.155 Fig. 13.156

Tumoral calcinosis: in older lesions, calcified deposits lie within lacunae. Myxoma: Note abundant stromal mucin.
572 Degenerative and metabolic diseases

Hyaluronic acid stains with colloidal iron (blue–green), Alcian blue at pH

Fig. 13.157
Mucinosis: this electron micrograph from a patient with acral persistent papular
mucinosis shows collagen bundles widely separated by a faintly electron-dense
granular deposit.
2.5 (blue) (but not at pH 0.4), and mucicarmine (red) but it is negative for
PAS. It also stains metachromatically with toluidine blue, methylene blue,
and thionine.13 Sulfated acid mucins stain with Alcian blue at pH 0.5 and
aldehyde-fuschin.2 Hyaluronic acid absorbs enormous amounts of water,
which accounts for the induration and thickening common to this group of
conditions.14
Routine fixation and processing results in an anhydrous state so that
mucin presents as basophilic strands and granules in hematoxylin and eosin
stained sections.3 In normal skin it is found particularly around appendages
and the vasculature (Fig. 13.159). In the cutaneous mucinoses the deposits
are hyaluronidase sensitive because most of the mucin present is hyaluronic
acid. The excessive mucin disrupts the collagen fibers, giving them a frayed
appearance. In general, with the exception of scleromyxedema, there is con-
siderable histological overlap within this group of conditions. Diagnosis
depends considerably upon clinical features and the results of biochemical
investigations.14
There are five major mucinoses:
• generalized myxedema,
• pretibial myxedema,
• lichen myxedematosus,
• reticular erythematous mucinosis,
• scleredema.
Follicular mucinosis is considered in Chapter 29.

Generalized myxedema
Clinical features
Generalized myxedema occurs as a consequence of severe hypothyroidism.
Patients with myxedema may appear pale yellow due to the combined effects
of edema, anemia, and carotenemia.1,2 The last, which is due to defective con-
version of betacarotene to vitamin A in the liver, is seen particularly on the
palms, soles, and in the nasolabial folds.3 Rarely, the color change is general-
ized.4 The skin is cool, dry, coarse, waxy, and puffy, especially around the eyes
and cheeks, and the hands and feet may show nonpitting edema (Fig.
13.160).3,5–7 The face is often expressionless. Eccrine and sebaceous gland
secretions are reduced and this may result in xerosis, an ichthyotic appear-
ance or asteatotic eczema.4 Hyperkeratosis over bony prominences resem-
bling avitaminosis A is also sometimes evident.8 Alopecia is a common finding
and the outer third of the eyebrows is typically affected. There is usually thin-
ning of the beard and sexual hair in addition to loss of the scalp hair.
Myxedema is associated with a greatly increased percentage of hair follicles
A in the telogen phase.9 The rate of hair growth is also diminished. Residual

Fig. 13.158
Mucinosis: (A) actively secreting fibroblasts contain abundant rough endoplasmic Fig. 13.159
reticulum; (B) numerous intracytoplasmic vesicles containing amorphous material Eccrine sweat gland: this section of normal skin from the sole of the foot shows
are commonly present. abundant dermal mucin when stained with Ehrlich’s hematoxylin.

Fig. 13.160
Generalized myxedema:
note the waxy infiltrated
plaques on the eyelid.
By courtesy of R.A.
Marsden, MD, St George’s
Hospital, London, UK.
hair is dry, coarse, and brittle.3 The nails often become thin, brittle, and stri-
ated.1 Additional cutaneous manifestations have included pruritic papular
lesions, purpura and ecchymoses, impaired healing, generalized follicular
mucinosis, and multiple focal cutaneous mucinoses.1,5,9–11 Oropharyngeal and
laryngeal involvement is common and many patients are hoarse. Patients
with myxedema have an increased risk of developing hyperlipidemia with
resultant eruptive and tuberous xanthomata (Fig. 13.161).
Histological features
The epidermis may show mild hyperkeratosis with occasional follicular
plugging.3 Most frequently, the dermal changes are subtle and nondiagnos-
tic. However, in cases of greater severity, there is slight swelling and separa-
tion of the collagen bundles with edema, and special stains show that small
quantities of mucin are present within the dermis and occasionally in the
subcutaneous fat.12 Fibroblastic proliferation is not a feature of generalized
myxedema.13
Localized (pretibial) myxedema
Clinical features
Localized (pretibial) myxedema is most often associated with hyperthyroid-
ism.1 It occurs in 3–5% of cases.2 It is one of three processes classically seen
in autoimmune thyroid (Graves') disease, the other two being exophthal-
mos and thyroid acropachy (clubbing of the digits associated with
­subperiosteal new bone formation). Pretibial myxedema, also known as
‘Graves’ or thyroid dermopathy', is usually a late manifestation of Graves'
disease and follows the development of Graves' ophthalmopathy.3 It has
only been reported exceptionally preceding the diagnosis of Graves' disease
and in the absence of ophthalmopathy.4 In 10% of cases of Graves' disease,
patients are not clinically hyperthyroid.5 They may be hypothyroid or euthy-
roid.5 Pink or yellow waxy plaques, nodules, and sometimes ‘tumors’
develop, most frequently first on the anterolateral aspects of the lower legs
(Fig. 13.162). Lesions are classically nonpitting. In some patients there is
induration with prominence of the follicles, giving rise to a peau d'orange
appearance, and secondary hypertrichosis is occasionally marked. Localized
hyperhidrosis at the site of the myxedema may also rarely occur.6 The dis-
ease may progress to involve much of the lower leg, which rarely becomes
grossly elephantiasiform (Fig. 13.163).2,7–9 The feet and toes sometimes can
The mucinoses 573
Fig. 13.161
(A, B) Generalized
myxedema: this
patient has widespread
xanthomata.
By courtesy of the
A Institute of Dermatology,
London, UK.
B
be involved.9 Small lesions are usually asymptomatic or mildly p ­ ruritic; the
larger plaques are often painful.10 Infrequently, localized myxedema occurs
on other sites such as the arms, shoulders, abdomen, neck, face, and even
the ears (Fig. 13.164).11 Nodular lesions rarely occur on the hands.12
Deposition on the forearm has been described as ‘preradial myxedema’.12
Occurrence at atypical sites is most likely related to trauma.13 For example,
it has been described localized to scar tissue.14–16 The latter includes the site
of a smallpox vaccination scar.17 Presentation at the site of a thigh donor
graft site has also been reported.18
Rare patients with pretibial myxedema have no evidence of thyroid dis-
ease. Biopsies from these patients tend to show changes associated with sta-
sis and this feature is useful in the histological differential diagnosis.19 One
such variant has been described in morbidly obese patients with
­lymphedema.20,21 Lesions occur as papules, vesicles, and nodules on the
pretibial surfaces.
Pretibial myxedema is sometimes self-limiting, involution occurring after a
number of years. Complete remission occurs in up to 26% of cases but this
depends on the severity of the disease.5,22
An exceptional form of pretibial mucin deposition that may be confused
with pretibial myxedema associated with Graves' disease has been documented
574 Degenerative and metabolic diseases
Fig. 13.162
Pretibial myxedema:
(A) erythematous,
somewhat translucent
plaques are present over
the shin; (B) close-up view.
By courtesy of R.A.
A Marsden, MD, St George’s
Hospital, London, UK.
B its of IgM have been identified within the superficial papillary dermis.10
in association with Sjögren's syndrome under the name acral ichthyosiform
mucinosis.23 In the cases described, the patients had normal thyroid function
tests and the mucin deposition was predominantly in the papillary dermis.
Pathogenesis and histological features
The etiology is uncertain; the presence of pretibial myxedema is usually asso-
ciated with detection of long-acting thyroid stimulator (LATS) in the serum,
but LATS is not believed to be causal.24 It was suggested in 1978 that a fibro-
blast stimulating factor associated with mucigenic properties isolated from
the serum of patients with pretibial myxedema might play a role in the patho-
genesis of the disease.25 More recent studies have shown that fibroblasts in
pretibial skin and in the orbit of affected patients contain sequences identical
to those of the thyroid stimulating hormone receptor.26,27 It has also been pro-
posed that the fibroblasts might contain a cross-reacting protein rather than
the true receptor, which binds with the autoantibodies against thyroid stimu-
lating factor receptor.28,29 Based on these observations, it has been proposed
that autoantibodies against thyroid-stimulating hormone receptor react with
fibroblasts containing these sequences, resulting in production of cytokines
and induction of increased glycosaminoglycan secretion.28,29
Fig. 13.163
Pretibial myxedema: in
this extreme example,
the features resemble
elephantiasis. By courtesy
of R.A. Marsden, MD,
St George’s Hospital,
London, UK.
Localization to the legs most typically is thought to be due to dependency
and mechanical factors.3 Additionally, tobacco is a known risk factor for the
development of pretibial myxedema and Graves' ophthalmopathy; however,
the precise mechanism for this is presently unknown.3
The epidermis is often hyperkeratotic, with follicular plugging; in
gross cases it may be papillomatous and acanthotic. The reticular dermis
shows separation of collagen bundles by large quantities of mucin (Figs
13.165, 13.166).1 Fragmentation of collagen fibers can be seen.3 Stellate
­fibroblasts are evident, but there is usually no increase in their number
except ­perhaps in the more elephantiasiform examples. Lesions seen in
the setting of ­lymphedema and obesity are also characterized by small
vessel angiogenesis, vessel wall thickening, edema, and hemosiderin
deposition.20,21
Immunofluorescent studies are usually negative, although granular depos-
Electron microscopic studies show amorphous granular material both
within fibroblast endoplasmic reticulum, coating the surface of the fibroblast,
and in the interstitium surrounding the widely separated collagen and elastic
fibers.8 Tubuloreticular structures have been identified in the cytoplasm of
endothelial cells in one case and in the dermis of another.10,14
Lichen myxedematosus/scleromyxedema
Clinical features
As originally classified, there were four variants of this rare disease of adults.1
These were:
• generalized lichenoid papular eruption (Figs 13.167, 13.168).
• discrete papular variant presenting as much smaller numbers of flesh-colored
papules on the trunk and extremities (Fig. 13.169),
• localized and generalized lichenoid plaques mimicking lichen planus,
• urticarial or nodular lesions, which often evolved into the generalized
papular form.2,3
With the subsequent delineation of new entities, the validity of this classi-
fication was called into question.4 Lichen myxedematosus is now divided into
three forms:5–8
• a localized form, which includes several variants: discrete papular lesions
occurring at any site, acral persistent papular mucinosis (see below), ­
 The mucinoses 575

Fig. 13.164
(A, B) Localized
myxedema: these pictures
came from same patient
shown in Figure 13.162.
Following a road traffic
accident, the patient
developed additional
mucinous deposits on
her arm close to the site Fig. 13.165
of a fracture. By courtesy Pretibial myxedema: there
of P.G. Goodwin, MD, is loss of collagen fibers
A The Royal Bournemouth associated with mucin
Hospital, UK. deposition.

self-healing papular mucinosis (see below), papular mucinosis of infancy

(see below) and nodular mucinosis,
• a generalized form (scleromyxedema) characterized by lichenoid papules,
indurated and thickened skin and a monoclonal gammopathy; by
definition, thyroid function is invariably normal.
• an atypical or intermediate form where patients may have generalized
lesions without systemic symptoms/gammopathy, localized lesions with
systemic symptoms/gammopathy or other manifestations that do not
strictly fulfill criteria for either the localized or generalized variants.
The generalized form of lichen myxedematosus (scleromyxedema) occurs
equally in males and females and is seen most often in the fourth and fifth
decades.3 It often presents on the hands and wrists, but soon becomes gener-
alized although lesions are particularly seen on the hands, elbows, neck, face,
and upper trunk.9,10 Prominent linear papules may be evident on the fore-
head, neck, axillae, and behind the ears.11 The papules are small, 2–3 mm in
diameter, white or erythematous, and often have a waxy consistency. They
tend to coalesce to form infiltrated plaques and, when associated with
­hardening and thickening of the underlying skin (scleromyxedema), result in
­tethering and limitation of movement, so that sclerodactyly, microstomia,
Fig. 13.166
Pretibial myxedema: the
mucin (hyaluronic acid)
stains positively with
Alcian blue.
and a ­mask-like facies may result (Fig. 13.170).4 Gross involvement of the
glabellar skin sometimes causes a leonine appearance.12 A rare patient with
leonine facies and tumor-like nodules mimicking lymphoma has been
reported.13 The lack of acral calcification and absence of Raynaud's phenom-
enon help to ­distinguish this condition from scleroderma. The mucous mem-
branes are not usually affected.3 The lesions are variably pruritic.
There are occasional reports of systemic symptoms. Esophageal aperistal-
sis, peripheral neuropathy, proximal myopathy, and cardiac and cerebrovas-
cular diseases have all been described.4,14 There has been little postmortem
confirmation of visceral involvement and therefore it is likely that many of
576 Degenerative and metabolic diseases
Fig. 13.167
Lichen myxedematosus:
erythematous papules are
widely distributed over the
forearms. A more diffuse
plaque is present over the
dorsum of the left hand.
Fig. 13.168
Lichen myxedematosus: numerous papules are present in the antecubital fossa.
By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.
these associations are no more than coincidental. Neurological ­manifestations
have, however, been reported most often and are probably of significance.
They have included acute psychoses, encephalopathy and coma, epileptiform
seizures, aphasia, memory loss, depression, and motor dysfunction.9,14–16
Dermatoneuro syndrome describes a rare manifestation of central nervous
system disease where patients develop high fever, flulike symptoms followed
by seizures, and coma.17,18 Carpal tunnel syndrome has also been reported
fairly frequently.19–21 Pulmonary involvement is not uncommon and consists
of restrictive or obstructive disease and pulmonary hypertension.22 Renal dis-
ease similar to that seen in scleroderma is rare.23 There is usually no
­relationship between lichen myxedematosus and neoplasia. An exceptional
case of lichen myxedematosus and hepatocellular carcinoma has been
reported.24 Rare cases associated with HIV infection have also been
­documented.25,26 Further associations include chronic hepatitis C and
­dermatomyositis.27–29 The latter finding is interesting because in the past
Fig. 13.169
Lichen myxedematosus:
this is an example of the
discrete papular form
showing small numbers
of papules on the anterior
wrist. By courtesy of R.A.
Marsden, MD, St George’s
Hospital, London, UK.
inflammatory myopathy not dermatomyositis has been described in associa-
tion with sclerom­yxedema.30 It has been suggested that the development of
myopathy is associated with a poor prognosis.30
Scleromyxedema is usually (but not invariably) associated with a parapro-
teinemia; most often this is IgG with lambda light chains.15,31–34 Occasionally
it has been of the IgM or IgA class.3 An occasional association with multiple
myeloma has also been noted but occurs in less than 10% of patients.5,9
Pathogenesis and histological features
The pathogenesis of lichen myxedematosus is unknown. There is no evidence
to suggest that the paraprotein is responsible for the fibroblastic prolifera-
tion. However, serum from scleromyxedema patients has been shown to con-
tain a nonparaprotein-associated fibroblast growth factor. This requires
further characterization.8,35 There is some evidence to suggest that the para-
protein may, however, have mucinogenic properties.36,37 Fibroblasts grown in
tissue culture produce greater quantities of hyaluronic acid and sulfated gly-
cosaminoglycans than normal controls.38 Collagen synthesis, as determined
by H3-hydroxyproline estimations, is diminished.
Immunofluorescent studies have revealed immunoglobulin (IgG and to a
lesser extent IgM) in the reticular dermis or just below the epidermis in 35%
of cases.12 Indirect immunofluorescence is invariably negative.
The epidermis may be normal, acanthotic or atrophic, and sometimes
hyperkeratosis with parakeratosis is evident. In early lesions stellate
­fibroblasts are seen between disorganized collagen fibers in the reticular
­dermis (Figs 13.171, 13.172).3,7 The papillary dermis is not affected.
Increased numbers of mast cells are sometimes present.29 Focal deposits of
mucin are readily identifiable (Fig. 13.173).2 A slight perivascular chronic
­inflammatory cell infiltrate is often seen in the superficial dermis.
In the more severe scleromyxedema variant, fibroblasts are numerous and
there is consequent fibrosis and thickening of the dermis (Figs 13.174–
13.176).4 Mucin deposits may be less evident or even absent.12 Decreased
elastic fibers have occasionally been reported.3 A chronic inflammatory cell
infiltrate is frequently present surrounding the superficial vasculature.
Recently, a less common granulomatous variant of scleromyxedema has
been described in which there is an interstitial histiocytic infiltrate with giant
cells, similar to granuloma annulare or interstitial granulomatous dermati-
tis.39,40 Although there is increased mucin, prominent stellate fibroblasts and
dense bundles of collagen are not a feature.
 The mucinoses 577

Fig. 13.170
(A, B) Scleromyxedema: this
severely affected patient
shows sclerosis and linear
papules on the forehead. Note
the pinched, mask-like facies.
By courtesy of R.A. Marsden,
A B MD, St George’s Hospital,
London, UK.

Ultrastructural studies show active fibroblasts characterized by abundant
rough endoplasmic reticulum and Golgi apparatus, increased numbers of
mitochondria, and cytoplasmic inclusions accompanied by collagen
deposition.41
Systemic involvement has only rarely been documented. Mucin deposi-
tion has been described in the adventitia of visceral blood vessels and in the
renal papillae in single case reports.9,41 It has also been described within­
r­ ectal mucosa and in muscle in one patient with scleromyxedema. Whether
this ­represents true primary involvement or a secondary unrelated phenom-
enon is uncertain. In a particularly unusual case the features of systemic scle-
rosis were found in the kidney.9 In the absence of any autopsy evidence of
further sclerodermatous lesions, it may be that the renal vascular and glom-
erular changes reflected unrecognized scleromyxedematous pathology.
Demyelination and focal gliosis have also been reported.12,42 Nevertheless,

A B

Fig. 13.171 Fig. 13.172

Lichen myxedematosus: increased mucin is evident (A, B) Lichen myxedematosus: the collagen fibers are widely separated by mucin deposits. Fibroblasts are
in the superficial dermis. increased in number.
578 Degenerative and metabolic diseases
Fig. 13.173
Lichen myxedematosus: staining with colloidal iron emphasizes the mucin deposits.
Fig. 13.174
Scleromyxedema: the
dermis is markedly
thickened. There is fibrosis
and increased numbers of
fibroblasts are evident.
autopsy studies have usually shown no evidence of widespread mucinosis
and it is likely that in the great majority of cases the pathological changes are
limited to the skin.
Differential diagnosis
It may be impossible to distinguish scleromyxedema from nephrogenic
­systemic fibrosis based solely on histopathological features.43 Both conditions
demonstrate an intradermal proliferation of spindled cells associated with
increased mucin. The spindled cells stain for CD34, factor 13a, and procol-
lagen I in both disorders. Although correlation with clinical parameters is
critical for ultimate distinction between the two disorders, a recent study sug-
gests that the depth of the infiltrate may be a helpful differentiating feature.44
In scleromyxedema the infiltrate is confined to the mid to deep dermis,
whereas in nephrogenic systemic fibrosis the process begins in the dermis but
also extends into the septa of the subcutaneous fat.
Fig. 13.175
Scleromyxedema: delicate strands of mucin separate the collagen fibers.
Fig. 13.176
Scleromyxedema: Alcian blue.
Acral persistent papular mucinosis
Clinical features
This rare condition, which predominantly affects females, is characterized by
the development of persistent multiple discrete and often symmetrical smooth-
surfaced small papules (2–7 mm) on the dorsal aspects of the hands and
wrists, sometimes extending on to the forearms (Fig. 13.177).1–4 The condi-
tion is generally regarded as a localized variant of lichen myxedematosus.5–11
The papules are ivory or flesh-colored and translucent, and on puncture char-
acteristically contain clear viscous fluid.2 Lesions do not occur on the face or
trunk and there is no thickening or induration of the skin.12 Pruritus is excep-
tional.13 Occurrence in two sisters has been reported, raising the possibility of
a familial form of the disease.14 Acral persistent papular mucinosis is not usu-
ally known to be associated with any systemic abnormalities such as thyroid
disease or paraproteinemia.15,16 An exceptional case associated with IgA
monoclonal gammopathy has been reported.17
Histological features
The papules show extensive mucin deposition in the upper reticular ­dermis
separated by a grenz zone from the overlying epidermis (Figs 13.178,
13.179).10,12,18 Increased numbers of spindled or stellate-shaped fibroblasts
 The mucinoses 579

Fig. 13.177
Acral persistent papular Fig. 13.179
mucinosis: discrete papule Acral persistent papular mucinosis: close-up view showing mucin deposits.
on the dorsal surface of
a forefinger. This patient
had similar lesions on the
The eruption consists of densely grouped, firm, 1–2 mm papules on the
arms. By courtesy of R.A.
elbows and smaller numbers of more dispersed lesions about the forearms
Marsden, MD, St George’s
Hospital, London, UK. and dorsa of the hands.1 Congenital linear papules on the backs of two ­fingers
have been reported in one infant and another was born with clustered ­papules
on the lower back.2,3 More recently, a patient with multiple congenital pap-
ules on the fingers and toes has been described.6 Owing to the paucity of
cases, the natural history and prognosis of this condition are unknown.

Histological features
Excessive mucin (hyaluronic acid) is present in the papillary dermis under an
acanthotic epidermis. Sectioning artifact may make the deposits appear to
have an intraepidermal location. Biopsies from late lesions show features
identical to those of lichen myxedematosus with fibrosis and proliferation of
dermal fibroblasts.4 A perivascular chronic inflammatory cell infiltrate is
­evident in the superficial dermis.

Self-healing juvenile cutaneous mucinosis

Fig. 13.178
Acral persistent papular mucinosis: note the presence of a discrete superficial
papule with a well-developed collarette.
may occasionally be evident.19 Fibrosis, however, as seen in lichen myxedema-
tosus, is not a ­feature of this condition. Direct immunofluorescence has revealed
granular IgM at the dermoepidermal junction and linear IgG around the eccrine
glands in one case.2 Ultrastructural studies reveal active fibroblasts with promi-
nent dilated rough endoplasmic reticulum. The collagen bundles are widely
separated and focal deposits of electron-dense amorphous material are evi-
dent.5 Conspicuous lamellated electron-dense lysosomes have been described in
one case.19 This probably represents a non-specific secondary change.
Cutaneous mucinosis of infancy
Clinical features
This variant of papular mucinosis is very rare.1–3 It has recently been sug-
gested that the condition might represent a pediatric localized form of lichen
myxedematosus.4,5 Familial cases have been documented.4
Clinical features
This is an extremely rare condition, only a handful of cases having been docu-
mented.1–17 It most commonly presents in children, with a rapid onset of
asymptomatic erythematous papules and plaques, which show a predilection
for the face, neck, scalp, abdomen, and extremities, accompanied by deep nod-
ules on the face and periarticular regions.1 The plaques have a characteristic
appearance as linear groups of papules, giving the skin a corrugated appear-
ance.3 The deep nodules can mimic fasciitis.11 The eruption resolves within a
period of weeks to months. Mild arthritis involving the elbows, knees, and
interphalangeal joints has been documented as has possible polychondritis.1,3
These latter manifestations may be persistent.1 In one patient bilateral carpal
tunnel syndrome was present. Non-specific features of fatigue, weight loss,
and myalgia may also be evident. The age of those who are typically affected
ranges from infancy to teenagers. Exceptionally, the disease presents in
adults.14–17 There is no evidence of thyroid dysfunction or paraproteinemia.
Pathogenesis and histological features
The etiology is unknown although it has been suggested that the fibroblast
activity may have been stimulated by a preceding viral infection.3
Histologically, the epidermis is normal or may show mild hyperkeratosis.
Mucin deposition is seen in the papillary and upper reticular dermis separat-
ing and splitting the collagen bundles. In one case the mucin was PAS positive
and identified as a sialomucin, whereas in others it was found to consist of
hyaluronic acid.1,3,9,10,12,14,16 Fibroblasts are slightly increased in number and a
mild chronic inflammatory cell infiltrate surrounds the superficial ­vasculature.
580 Degenerative and metabolic diseases

Deeper nodules demonstrate similar involvement of the septa and lobules of

the subcutaneous fat which can also extend into the fascia. Epithelioid,
­ganglion-like histiocytes can be seen and may cause confusion with prolifera-
tive or nodular fasciitis.11,12

Reticular erythematous mucinosis

This condition is described in Chapter 8.

Scleredema
Clinical features
Scleredema (Buschke) is a rare primary mucinosis that presents with nonpit-
ting indurated edema and associated dermal hardening in the absence of any
significant clinical abnormality of the overlying skin.1,2 Three distinct ­subtypes
are recognized:2–5
• Most commonly seen is an acute variant predominantly affecting children
and characterized by a rapid onset arising a few weeks after an infection,
most often of the upper respiratory tract. Streptococcal infections are
Fig. 13.180
particularly implicated, but cases have followed a variety of viral illnesses
Scleredema: a diffuse, firm thickening of the tissues is present over the neck
including measles, mumps, influenza, cytomegalovirus infection, and and shoulders. By courtesy of G. Murphy, MD, Institute of Dermatology,
chickenpox.6–8 Scleredema has also occurred in the setting of chronic London, UK.
scabies and secondary streptococcal infection.9 Although many of these
cases resolve spontaneously within a period of months and years, a
significant number are persistent and exacerbations are not uncommon.10
Females are affected more often than males and the disease is more
common in the winter months.11 Sometimes there is a prodromal illness
of malaise, myalgia, generalized myasthenia, and arthralgia.10 Some
patients develop a variety of cutaneous manifestations including transient
erythema, urticarial or annular eruptions and dermographism before the
onset of the more typical features.4 Scleredema in children may
exceptionally present overlapping features with eosinophilic fasciitis.12
• Secondly, scleredema may have an insidious onset unaccompanied by any
previous acute illness.2
• Lastly, scleredema sometimes develops in association with late-onset
diabetes mellitus. Patients, more often males, are often obese and there
are usually other manifestations of diabetes including nephropathy,
hypertension, coronary and peripheral vascular insufficiency, retinopathy
and peripheral neuropathy.2,13,14 The diabetes commonly precedes the
development of scleredema, which is usually widespread and associated
with a chronic course.1,15,16 This variant of scleredema does not tend to
resolve spontaneously or with treatment.
Scleredema is occasionally associated with a paraproteinemia (usually IgG,
but sometimes IgA) and rarely multiple myeloma.17–19 There is no evidence
that the paraprotein results in the skin lesions; hence it is probably a second- A
ary phenomenon. Evolution to systemic amyloidosis has been reported in one
patient.20
It should be noted that despite the original nomenclature of scleredema
adultorum, many of the patients are in fact children.10,11,21 Only very rarely
are childhood cases associated with diabetes.21 An exceptional case of con-
genital scleredema has been reported.22
Rare cases have had associated primary and secondary hyperparathyroid-
ism, rheumatoid arthritis, Sjögren's syndrome, and sarcoidosis.23–26 Scleredema
has also been described in HIV infection, in association with a nuchal fibroma,
following exposure to organic solvent, in the setting of a malignant insuli-
noma and carcinoid, with acanthosis nigricans, with generalized hyperpig-
mentation, and as an adverse consequence of infliximab.13,18,27–32 The
cutaneous manifestations are similar for all three subtypes, differences being
merely a matter of degree.
Patients present with symmetrical nonpitting edema and dermal hardening,
which particularly affects the posterior and lateral aspects of the neck
(Fig. 13.180).2 The face, anterior neck, upper trunk, and upper limbs are also
frequently affected.1 Rarely, the disease may spread to the lower abdomen and B
legs. Confinement of the changes to the thighs has been described.33 The palms
and soles are rarely affected and genital involvement is ­uncommon.10 Lesional Fig. 13.181
skin is shiny and feels hard, and wrinkling is impossible due to involvement of (A, B) Scleredema: there is marked thickening and induration of the skin of the
the papillary dermis (Fig. 13.181). In severely affected patients reduced ­mobility upper back. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire.
 The mucinoses 581

is often a problem. The face may be expressionless, the lines of ­cleavage lost,
and smiling and mouth opening may be difficult.1 The overlying skin may
demonstrate erythema, hyperpigmentation and/or a peau d' orange ­appearance.
An unusual case with hyperkeratosis has been described.8
In some patients systemic disease may be evident, including pericardial,
pleural, and peritoneal effusions, dysarthria and dysphagia due to tongue and
pharyngeal lesions, hepatosplenomegaly, cardiac and skeletal muscle mani-
festations, parotid gland involvement and ocular changes presenting as indu-
ration of the eyelids and conjunctivae.10,11,34 Periorbital edema can be the sole
presentation.35 In cases with systemic involvement, mucin deposition has been
demonstrated in the bone marrow, liver, nerve, salivary gland, and heart.36,37
Cardiac and pulmonary disease may exceptionally lead to death.38

Pathogenesis and histological features

The pathogenesis of scleredema is unknown. The serum from one patient
with scleredema and a paraprotein markedly stimulated collagen production
in normal skin fibroblast cultures, suggesting that a circulating factor(s) prob-
ably related to the paraprotein might induce the dermal fibrosis.39 The
involved skin shows increased synthesis of type I collagen, which appears to
Fig. 13.183
be responsible, at least in part, for the dermal fibrosis.40,41 The fibroblasts in Scleredema: the collagen fibers appear swollen. There is excess mucin.
involved skin from individuals with scleredema show increased protein pro-
duction, collagen synthesis, and glucosamine incorporation. This correlation
is associated with increased levels of type I and type III collagen.42 Biochemical
analysis of involved skin in scleredema has confirmed an increase in gly-
cosaminoglycans, the main component being hyaluronic acid.43
The histological features are often subtle and the diagnosis is difficult. The
epidermis may be slightly thinned or appear normal. The reticular dermis is
greatly thickened, often at the expense of the subcutaneous fat, and the eccrine
glands therefore become abnormally situated within the upper third or mid
dermis (Figs 13.182, 13.183).1 The collagen fibers are broadened and,
­particularly in the earlier stages, are abnormally separated by clear spaces
­(dermal fenestration).2 The latter may contain small quantities of mucin, but
often special stains (Alcian blue, colloidal iron) and multiple biopsies are
­necessary for their demonstration (Fig. 13.184).16,44 Up to one-third of cases
may not demonstrate mucin even with the aid of special stains.45 Fibroblasts
are present in normal numbers. A mild chronic inflammatory cell infiltrate is
sometimes evident in the superficial dermis and mast cells may be increased in
number (Fig. 13.185).1 Direct immunofluorescence studies are negative.2,17

Fig. 13.184
Scleredema: the abundant mucin is highlighted by Alcian blue/chromotrophe 2R
staining.

Differential diagnosis
Scleredema may be distinguished clinically from scleroderma by the absence
of Raynaud's phenomenon, acral sclerosis with calcification, pigmentary
changes, and telangiectasia.2 Histologically, the appendages are atrophic and
compressed or absent in scleroderma and there is diffuse dermal sclerosis
rather than the fenestrated appearance seen in scleredema.

Papular and nodular cutaneous mucinosis

Fig. 13.182
Scleredema: early lesion
showing collagen bundle
separation.
of systemic lupus erythematosus
Clinical features
Mucin deposition as a specific clinical manifestation of lupus erythematosus
has been recorded only rarely in the literature yet is said to occur in up to
1.5% of dermatological patients with this disease.1–3 The condition presents as
asymptomatic, flesh-colored, occasionally umbilicated papules and nodules
on the neck, trunk, and upper limbs.4–12 Presentation with massive cutaneous
mucinosis has also rarely been reported.13 The papules may rarely be hyperpig-
mented.14 Lesions are best appreciated using tangential light, which gives the
skin a lumpy appearance.5 Mucin deposition occurs most often in patients
582 Degenerative and metabolic diseases

Fig. 13.186
Myxoid cyst: the translucency is typical. By courtesy of R.A. Marsden, MD, St George’s
Hospital, London, UK.

Fig. 13.185
Scleredema: superficial
dermal lymphohistiocytic
infiltrate.

with the systemic variant, usually with diffuse antinuclear ­factor and anti-
DNA antibodies, and is particularly associated with joint and kidney
lesions.4,11,15 There are, however, occasional reports of its occurrence in patients
with discoid and subacute cutaneous lupus erythematosus 4,7–9 An inconstant
relationship to sunlight has been recorded.4,16 Exceptionally, systemic sclerosis
may present with similar papular and nodular mucinous lesions.17

Histological features
The epidermis shows no significant features; in particular, the changes of
lupus erythematosus are usually absent. However, an interface change has
been described in a single case.18 The mucin is present in the papillary and
upper reticular dermis associated with a slight perivascular chronic inflam-
matory cell infiltrate.4,19 Fragmentation of collagen bundles has been noted in
one case in association with mucin accumulation.11
Direct immunofluorescence may show linear or granular immunoglobulin Fig. 13.187
Myxoid cyst: localization
(IgG, IgM) deposits and complement at the dermoepidermal junction.
over the distal
interphalangeal joint is
Myxoid cyst characteristic. By courtesy
of the Institute of
Clinical features Dermatology, London, UK.

Cutaneous myxoid cyst, sometimes inappropriately referred to as synovial

cyst, presents as a soft or fluctuant cystic nodule on the dorsal aspect of the
distal interphalangeal, the metacarpophalangeal and, less frequently, the meta-
tarsophalangeal joints (Figs 13.186, 13.187).1,2 An exceptional case occur-
ring on the lateral aspect of the knee has been described.3 Occasionally, lesions
are multiple.4 Cutaneous myxoid cysts may present at any age and are more
common in females. The surface is usually smooth, although verrucous vari-
ants are occasionally encountered. The cyst contains yellow, clear viscous
fluid. Lesions are often painful or tender. Myxoid cyst involving the proximal
nail fold can be associated with longitudinal grooving of the nail.5 Although
the precise cause is not well elucidated, underlying osteoarthrosis is sometimes
evident, and repetitive trauma is proposed to be one possible mechanism.1,4
Histological features
The cyst is devoid of any lining and consists of a large pool of mucin con-
taining spindled/stellate fibroblasts with prominent cytoplasmic processes
(Fig. 13.188). The overlying epidermis is often atrophic and ­hyperkeratotic,
and acanthosis may be seen at the edges. Early lesions are sometimes
­indistinguishable from cutaneous focal mucinosis. There is no evidence of any
­connection with an underlying joint.
Cutaneous focal mucinosis
Clinical features
Cutaneous focal mucinosis presents as an asymptomatic, usually solitary,
­dermal papule or nodule most commonly on the face, neck, trunk or extremi-
ties of adults.1–5 It is not seen in relation to the joints of the hands, feet or
wrists. The lesion is usually dome-shaped, white or flesh-colored and
­sometimes has an erythematous halo.2 Occasional verrucous variants have
been documented.1 There is usually no evidence of an associated thyroid
abnormality. Exceptional cases, however, are associated with reticular
­erythematous ­mucinosis or scleromyxedema.6 Multiple lesions are rare.7

A There is only one case report of this condition, which presented in a young
B
Fig. 13.188
(A, B) Myxoid cyst: excessive mucin deposition has resulted in this fluid-filled cyst.
The overlying epithelium may appear attenuated or verrucous and occasionally the
cyst is, in part, intraepidermal in location.
Histological features
The lesion is usually located in the mid and upper dermis, often separated from the
epidermis by a grenz zone of dermal sparing.2 It consists of a localized, but usually
poorly delineated, focus of mucin deposition containing increased numbers of
spindled cells and stellate fibroblasts with elongated cytoplasmic processes.2
Sometimes these contain conspicuous intracytoplasmic vacuoles.3 Collagen fibers
are usually diminished in number.4 A mild perivascular chronic inflammatory cell
infiltrate is often present in the adjacent dermis. There may be an increase in the
number of small-caliber blood vessels. The overlying epidermis is typically
­uninvolved; however, immature follicular germlike induction can occur.8
Ultrastructurally, the fibroblasts contain prominent rough endoplasmic
reticulum and membrane-bound intracytoplasmic vesicles containing abun-
dant granular electron-dense material.3
Differential diagnosis
Cutaneous focal mucinosis must be distinguished from superficial angiomyx-
oma, a benign myxoid cutaneous and subcutaneous lesion with a tendency
for local recurrence, associated with Carney complex.
Mucinous nevus
Clinical features
Mucinous nevus (nevus mucinosis) is a rare lesion that may be congenital or
acquired.1–5 The most common site affected is either the trunk or lower limbs.
Acanthosis nigricans 583
Patients present with papules, nodules and/or plaquelike lesions, usually with
a linear or dermatomal distribution.4 Large pedunculated lesions are rare.6
A familial case has been described in two young brothers.7
Histological features
Histologically, the mucin is located in the superficial dermis where it replaces
the collagen and elastic fibers.5 Some cases are associated with epidermal
hyperplasia and these may represent a combined epidermal and mucinous
nevus.3,8 A recent immunohistochemical evaluation demonstrated that the
stromal cells are CD34 positive, with rare cells staining for factor 13A.9
Differential diagnosis
These lesions must be distinguished from the mucinous eccrine nevus, which
comprises abundant mucin surrounding eccrine glands and ducts.10
Neuropathia mucinosa cutanea
male with hyperesthesia and livedoid lesions on the lower limbs. A biopsy of
these lesions revealed hypertrophic nerves surrounded by mucin.1
Self-healing infantile familial cutaneous
mucinosis
This very rare entity has been reported only once, in two brothers. Multiple
lesions developed during the first few months of life and in one patient
regressed spontaneously over a few years.1
Localized mucinosis secondary to venous
insufficiency
A recent case report describes two elderly patients with violaceous plaques
and coalescing papules on the lower extremities.1 The lesions were painful
and occurred in the setting of venous stasis. There was no history of thyroid
disease, connective tissue disease or antecedent treatment with ultraviolet
light. The histological features consisted of large amounts of mucin deposi-
tion in the papillary and reticular dermis with characteristic extension around
the eccrine glands. There was a slight increase in the number of blood vessels
which demonstrated thickened walls. However, an inflammatory infiltrate
was not present. The pathogenesis of this condition is unknown.
Secondary cutaneous mucinoses
Clinical features
Mucinous lesions on the skin have been described as part of a reactive process
associated with various triggers. A patient recently developed multiple ery-
thematous to skin-colored papules following infection with varicella-zoster
virus.1 The lesions occurred in the same dermatome affected by postherpetic
neuralgia and resolved as the pain improved. Mucinosis complicated by cuta-
neous necrosis can occur following injection with interferon. Recombinant
interferon-beta-1b and interferon alfacon-1 have been implicated in the setting
of treatment for multiple sclerosis and hepatitis C, respectively.2,3 Erythematous
ulcerative plaques develop at injection sites. Additionally, mucinosis papules
and plaques have been described in the vicinity of a recently replaced joint.4
Histological features
These mucinous disorders are characterized by intradermal mucin without a
significant increase in dermal fibroblasts. 1–4 Ulcerative lesions associated
with interferon injections can also demonstrate intravascular thrombi.3
Acanthosis nigricans
Clinical features
Acanthosis nigricans develops under a variety of circumstances.1–3 In addition
to the well-recognized tumor-associated variant, acanthosis nigricans may
present with benign familial forms, endocrinopathy and drug-related ­variants,
584 Degenerative and metabolic diseases

and the condition can be seen in association with a range of congenital condi-
tions including lipoatrophy, leprechaunism and the type A and type B syn-
dromes described below. Genetic conditions associated with acanthosis
nigricans include:
• Alstrom syndrome (retinopathy, progressive sensorineural hearing loss,
truncal obesity),
• Crouzon syndrome (facial palsy, sensorineural hearing loss with skeletal
and mental retardation),
• Seip-Lawrence syndrome (congenital lipodystrophic diabetes),
• Costello syndrome (postnatal growth deficiency, coarse facies, redundant
skin of the neck, palms, soles, and fingers, dark skin, and papillomas),
• Bannayan-Riley-Ruvalcaba syndrome (subcutaneous lipomas, vascular
malformations, lentigines of the penis and vulva, warty lesions,
macrocephaly, mental retardation, intestinal polyposis, skeletal
abnormalities, vascular malformations of the central nervous system, and
thyroid tumors),4–8
• Lelis syndrome (ectodermal dysplasia with hyptrichosis, hypohidrosis,
hypodontia, palmar-plantar hyperkeratosis, perioral furrows).9
Acanthosis nigricans has been described in association with a missense
mutation of the fibroblast growth factor receptor.4 This disease is also associ-
ated with severe neurological impairment and severe achondroplasia.10 Fig. 13.190
Additional rare associations include Wilson's disease (hepatolenticular degen- Acanthosis nigricans:
eration) and primary biliary cirrhosis.11,12 In the latter case, the acanthosis there is velvety thickening
of the axillary skin.
nigricans resolved after liver transplantation. In an exceptional family with
By courtesy of the
several members affected by acanthosis nigricans, absence of the eyebrows Institute of Dermatology,
and eyelashes and sparse hair elsewhere has been reported.13 London, UK.
Development of acanthosis nigricans may also antedate or present con-
comitantly with a variety of connective tissue diseases including systemic
lupus erythematosus, systemic sclerosis, and dermatomyositis.14–16
The condition is characterized by the presence of symmetrical brown vel-
vety or verrucous plaques with a predilection for intertriginous sites such as
the back of the neck, groin, and axillae (Figs 13.189, 13.190). In more
extreme forms the changes may be generalized.17 Involvement of the eyelids
also rarely occurs.18 In addition, there is sometimes brown thickening of the
skin over the dorsum of the fingers or, rarely, the palms of the hands (tripe
palms) (Fig. 13.191). The latter is a distinctive appearance due to broadened
epidermal ridges and deep sulci giving the skin a velvety rugose texture.19
Tripe palms are usually associated with internal malignancy and often (but
not invariably) accompany acanthosis nigricans. However, the lesion may

Fig. 13.191
Acanthosis nigricans: tripe palms. The palmar skin is thickened and the creases are
accentuated. By courtesy of the Institute of Dermatology, London, UK.

also represent a benign reversible phenomenon unassociated with neoplasia.

Less frequently, there are similar changes on mucosal surfaces such as the
mouth (particularly the tongue and upper lip) or genitalia (Fig. 13.192).20,21
The latter changes are more common in cases related to malignancy.
Oral lesions have been reported in 25–50% of all cases of acanthosis nig-
ricans and in at least 35% of patients with associated malignancy.20,22,23 The
tongue lesions consist of hypertrophied filiform papillae producing a deeply
fissured papillomatous surface and the lips develop papillary and verrucous
lesions.20 The palate and buccal mucosa may also be involved.23 Oral lesions
are usually nonpigmented. Involvement of the esophagus is rare and is almost
Fig. 13.189 invariably associated with malignancy, particularly in the gastrointestinal
Acanthosis nigricans:
tract.24
thickening of the skin of
the groin. By courtesy
A drug-induced variant has been documented, and glucocorticoids, nico-
of R.A. Marsden, MD, tinic acid, oral contraceptives, and diethylstilbestrol have been implicated.25
St George’s Hospital, Acanthosis nigricans has also been reported in association with ­somatotrophin
London, UK. therapy.26
 Acanthosis nigricans 585

• In type A, the patients are young (particularly black) women with

acanthosis nigricans, primary amenorrhea with hypertestosteronemia,
virilization, increased somatic growth, hyperglycemia and hyperinsulinemia,
with insulin resistance due to a congenital defect of insulin receptors.
• In type B, the patients are older and have features suggesting other
autoimmune diseases, including raised erythrocyte sedimentation rate (ESR),
proteinuria, and hypocomplementemia with antinuclear and anti-DNA
antibodies. Antibodies directed against the insulin receptor may be detected.
• A third type, type C, has recently been proposed, in which acanthosis
nigricans and insulin resistance are associated with a postinsulin receptor
defect.
Studies have found that the presence of acanthosis nigricans in African-
Americans and Native Americans is a cutaneous marker of hyperinsulinemia
and insulin resistance.44,45
Obesity-associated acanthosis nigricans, previously called pseudoacantho-
sis nigricans, develops in the flexures of obese patients. This is the most com-
mon type of acanthosis nigricans in children and adults and is associated with
insulin resistance.46
Transient acanthosis nigricans-like lesions have been described at the sites
Fig. 13.192
Acanthosis nigricans: the skin of the groins and vulva is thickened and hyperpigmented.
of healing lesions of pemphigus vulgaris and pemphigus foliaceous.47,48
By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK. Acanthosis nigricans-like lesions have been described after local applica-
tion of fusidic acid.49

Pathogenesis and histological features

Rarely, the disease presents as an autosomal dominant nevoid lesion, The pathogenesis is uncertain, although in the diabetes-associated patients
which may present at birth, in childhood or at puberty.27,28 The condition has hyperinsulinemia is likely to be of importance.41 In malignancy-related acan-
also been reported in association with Cohen's syndrome (truncal obesity, thosis nigricans, peptide or hormonal secretion appears to be of significance
­hypotonia, mental retardation, microcephaly, and ocular abnormalities).29 in at least a proportion of cases.32 It has been demonstrated that some malig-
So-called benign familial acanthosis nigricans occurs more commonly in nant tumors secrete transforming growth factor alpha (TGF-α) in large quan-
females. This autosomal dominantly inherited condition usually presents in tities and this stimulates proliferation of keratinocytes.50
early childhood with lesions that particularly affect the face, dorsal surfaces The histopathological findings are subtle, comprising delicate, elongate
of the fingers, and the flexures.30 There are usually no associated endocrinop- papillomatosis, hyperkeratosis and slight acanthosis, sometimes alternating
athies or congenital abnormalities. with foci of atrophy (Fig. 13.193). The occasional presence of keratin-filled
Acanthosis nigricans presents in up to 51% of patients with Down's syn- cysts may result in a seborrheic keratosis-like appearance.20 Despite the clini-
drome and is probably due to insulin resistance.31 It has also been described cally obvious brown appearance of the lesions, there is normally little increase
in up to 5% of patients with severe atopic dermatitis but the pathogenesis in in the amount of melanin present. A non-specific perivascular chronic inflam-
this setting is unknown.31 matory cell infiltrate is sometimes evident in the superficial dermis.
It may occur as a sign of occult malignancy and obesity. The sex incidence Distinguishing this type of benign acanthosis from others such as epidermal
is equal. Malignant acanthosis nigricans is often severe, widely disseminated, nevi may be difficult.
and has a rapid course. Lesions may also be pruritic and are more difficult to Oral lesions show hyperkeratosis and patchy parakeratosis associated
treat. Tumors that are particularly associated include gastric adenocarci- with marked acanthosis and epithelial papillary hyperplasia.20
noma, and, less often, malignancies of the extrahepatic biliary tree, breast, Tripe palms are characterized by hyperkeratosis, acanthosis, and papillary
pancreas, bladder, and colon.24,32,33 Ovarian and uterine tumors, bronchial dermal hypertrophy.19
squamous and adenocarcinoma, and lymphoma have also been implicated.34 Florid cutaneous papillomatosis is also characterized by hyperkeratosis,
Acanthosis nigricans as an indicator of insulin resistance has been reported papillomatosis, and acanthosis.36
in HIV-positive patients receiving treatment with protease inhibitors.35
The malignant form sometimes develops in association with other cutane-
ous markers of internal malignancy including palmoplantar hyperkeratosis,
eruptive seborrheic keratoses (Leser-Trélat sign), and florid cutaneous papil-
lomatosis.36 The last condition presents as numerous viral wartlike itchy pap-
illomata, which show a predilection for the trunk and extremities and
invariably accompany an internal malignancy, most often gastric adenocarci-
noma. The course of malignant acanthosis nigricans usually parallels that of
the underlying neoplasm, which is generally aggressive and associated with a
high mortality. Lesions may sometimes abate following surgical removal of
the tumor, only to return with its recurrence.
Acanthosis nigricans is also associated with a wide range of endocrine dis-
eases, including Cushing's disease, acromegaly, gigantism, Addison's disease,
polycystic ovary syndrome, diabetes mellitus, acromegaly, and thyroid disor-
ders. The association between hyperandrogenism (HA), insulin resistance
(IR), and acanthosis nigricans (AN) is known as HAIR-AN syndrome. There
appears to be an association between acanthosis nigricans, obesity, hyperten-
sion, ischemic heart disease, and type 2 diabetes, the inheritance of which is
autosomal dominant.37 Acanthosis nigricans may also occur in nonobese
patients in association with diabetes mellitus and insulin resistance due to
diminished receptor binding.38–43 Patients with this sporadic syndrome are Fig. 13.193
divided into two groups: Acanthosis nigricans: there is hyperkeratosis, papillomatosis, and slight acanthosis.
586 Degenerative and metabolic diseases
Acrodermatitis enteropathica
Clinical features
Acrodermatitis enteropathica is a rare autosomal recessive inherited disorder
of zinc malabsorption, which predominantly affects infants and responds
dramatically to dietary zinc supplements.1–4 It presents with diarrhea, stoma-
titis, irritability, and failure to thrive, accompanied by erythematous scaly
and crusted lesions with vesicles, pustules, and erosions, predominantly
affecting the extremities, perineal, and periorificial region (Figs 13.194,
13.195). Frankly bullous lesions have been described. 5 Nonscarring alopecia
may also be present. Additional features include nail dystrophy, prolonged
wound healing, impetiginization, short stature, psychiatric symptoms, and
photophobia.1–7 Corneal lesions and decreased visual acuity have also excep-
tionally been reported.8,9 Patients are also prone to developing infections, par-
ticularly by bacteria and fungi, illustrating the importance of normal zinc
levels in maintaining the integrity of the immune system.10–13 The disease can
persist into adulthood or rarely be diagnosed for the first time in adult life.14–16
An acquired variant may complicate artificially fed or, rarely, breast-fed
infants either full term or premature.17–28 This is due to the low concentration
Fig. 13.194
Acrodermatitis enteropathica: extensive crusted erosions in a characteristic
distribution. By courtesy of Z.S. Tannous, MD, Harvard Medical School, Boston, USA.
Fig. 13.195
Acrodermatitis enteropathica: in this infant, there is very extensive involvement
with widespread erosion. By courtesy of Z.S. Tannous, MD, Harvard Medical
School, Boston, USA.
of zinc in breast milk secondary to a defect in zinc uptake from maternal
serum into the breast.28 In premature infants, the problem is aggravated by
the low gastrointestinal absorption of zinc and low body stores of zinc that
were transferred from mother to fetus in the last 10 weeks of pregnancy.28
Many other conditions with acquired zinc deficiency have been associated
with signs and symptoms of acrodermatitis enteropathica including Crohn's
disease, alcoholic cirrhosis, alcoholic pancreatitis, intestinal bypass opera-
tion, chemotherapy for hematological malignancies, anorexia nervosa, lym-
phoma, biotin deficiency, dialysis, cystic fibrosis, Hartnup disease, essential
fatty acid deficiency, citrullinemia, deficiency of ornithine transcarbamylase,
and following total intravenous hyperalimentation.9,29–49 A similar picture has
also been described in a number of aminoacidopathies and organic acidemias.
The latter include methylmalonic acidemia, propionic acidemia, glutaric aci-
duria type I, and nonketotic hyperglycinemia.50–56 The changes are due not
only to zinc deficiency, but also to a deficiency in branched chain amino acids
including isoleucine. This is induced by the low protein diet that these patients
receive. Acrodermatitis enteropathica has also been described in ­relation to
HIV infection.57
Pathogenesis and histological features
The manifestations of acrodermatitis enteropathica result from insufficient
absorption of zinc by the intestine. The mechanism of the disease involves a
defect in a zinc transporting protein. Initial studies of genes that encode for
proteins important in the transport of zinc including SLC30A4 and ZNT4
did not show association with the disease.58–60 More recently, the gene for
acrodermatitis enteropathica has been identified on chromosome 8q24.3.61
This gene, designated SLC39A4, encodes a histidine-rich transmembrane
protein known as hZIP4 which is involved in zinc uptake.62–69 The mutation
in acrodermatitis enteropathica also affects zinc metabolism in fibroblasts
and reduces the activity of 5′-nucleotidase.70,71 Over 30 different mutations in
this gene have been described thus far in association with acrodermatitis
enteropathica.67 The vast majority of patients carry a homozygous or com-
pound heterozygous mutation in SLC39A4. However, there are some without
such an identifiable genetic mutation, indicating that other genetic factors
may possibly play a causative role in the disease.67
The mechanism of infections in acrodermatitis enteropathica is related to
alterations in the immune system due to zinc deficiency.12,13 Zinc is critical to
the development and function of lymphoyctes, neutrophils, macrophages, NK
cells, and cytokine production. It also functions as an antioxidant and ­prevents
cellular damage by free radicals.13 Lymphopenia and thymic atrophy are
­frequent findings in acrodermatitis enteropathica and are due to the loss of­
B- and T-cell precursors in the bone marrow. The zinc deficiency induces apop-
tosis mediated by glucocorticoids with resultant decrease in lymphopoiesis.
The histopathology varies according to the stage of evolution.72 Very early
lesions show subtle changes consisting of focal parakeratosis alternating with
orthokeratosis. As lesions advance, the parakeratosis becomes more promi-
nent and confluent and the stratum granulosum is decreased or absent. The
keratinocytes in the upper layers of the epidermis display marked cytoplasmic
pallor (Figs 13.196, 13.197). In addition there is focal spongiosis.
Dyskeratotic cells are rarely seen.
In late stages there is cytoplasmic vacuolation and necrosis which may
result in intraepidermal vesicles or occasionally progress to blister forma-
tion.73,74 Subcorneal pustules may be seen and usually indicate secondary
infection. An atypical case of bullous acrodermatitis enteropathica with a
lichenoid infiltrate has been reported.75
Differential diagnosis
Histologically, acrodermatitis enteropathica is indistinguishable from necro-
lytic migratory erythema and pellagra. Very similar histological features are
also seen in necrolytic acral erythema, a condition that occurs on the dorsum
of the feet and legs of patients with hepatitis C infection.76–79 Lesions are ery-
thematous and psoriasiform plaques and decreased serum and lesional zinc
levels have been associated with this condition.78,79 Prominent pallor of
­keratinocytes in the upper layers of the epidermis is also seen in deficiency of
the M subunit of lactate dehydrogenase.80,81 The cutaneous manifestation of the
latter condition has been described as annually recurring acroerythema.82
 Necrolytic migratory erythema 587

anemia, nausea, diarrhea, abdominal pain, neurological symptoms (ataxia

and fecal and urinary incontinence), thromboembolic pathology (deep
vein thrombosis and pulmonary thromboembolism), and weight loss in
addition to the cutaneous manifestations.10 About 57% of patients pres-
ent with the ­typical visceral, cutaneous, and laboratory abnormalities.11
Exceptional cases of ­glucagonoma arise from the duodenum, ­kidney, and
lung.12–14
Necrolytic migratory erythema, so-called because of its superficial resem-
blance to toxic epidermal necrolysis and the waxing and waning nature of the
eruption, is seen most frequently on the central face, particularly around the
mouth, on the perineum and other intertriginous sites, the thighs, buttocks,
and distal limbs (Fig. 13.198).3 Patients most often present in their sixth
decade (median 52 years) with intense erythema, which progresses to flaccid
bullae that rupture readily and develop crusting.11,15 Pressure, friction, and
trauma have occasionally been noted to precipitate the eruption.8 Central
healing with active borders gives rise to annular and serpiginous lesions.
Lesions are often painful and pruritic.
Postinflammatory hyperpigmentation follows resolution. Individual
lesions usually last 1–2 weeks and, characteristically, lesions in varying stages
Fig. 13.196 of evolution are evident at any one time.8,15
Acrodermatitis Additional features may include stomatitis, angular cheilitis, blepharitis,
enteropathica: low- conjunctivitis, hair loss, and nail changes.9–11 Laboratory investigations com-
power view showing monly reveal an abnormal glucose tolerance test, normochromic normocytic
hyperkeratosis and
anemia, hypoproteinemia, hypoalbuminemia, and hypoaminoacidemia.9,16
marked epidermal
eosinophilia on the right
Low amino acid levels were detected in 96% of patients in one reported
side. series.17 However, in larger series, the percentage of patients with low amino
acid levels has been lower, ranging between 41% and 78%.10,11
Glucagonoma syndrome may constitute part of the multiple endocrine
neoplasia syndrome.18
Rarely, necrolytic migratory erythema has been described in the absence
of a glucagonoma, so-called ‘pseudo-glucagonoma syndrome’.19–25 Abnormal
liver function tests have usually been present and it has been suggested that
this may have resulted in impaired glucagon catabolism with resultant
hyperglucagonemia or raised levels of one of the glucagon immunofrac-
tions.20 Patients have had associated gastrointestinal malabsorption disor-
ders such as celiac disease, ulcerative colitis, Crohn's disease, short bowel
syndrome, liver diseases including cirrhosis and hepatitis, as well as chronic
pancreatitis, cystic fibrosis, and other malignancies.23,26–30 A study of 24
patients with nonglucagonoma-associated necrolytic migratory erythema
found increased glucagon in 52% of patients and low zinc levels in 37% of
patients.23
Despite its relatively indolent growth characteristics, a large majority of
tumors have metastasized by the time of diagnosis.

Fig. 13.197
Acrodermatitis
enteropathica:
keratinocyte necrosis is
seen in this high-power
view.

Necrolytic migratory erythema

Clinical features
Necrolytic migratory erythema is a distinctive dermatosis that is classi-
cally seen in patients with the glucagonoma syndrome.1–9 The latter, due to
a slowly progressive malignant tumor of the pancreatic islets, consists of
hyperglucagonemia, diabetes mellitus, glossitis, normochromic ­normocytic
Fig. 13.198
Necrolytic migratory erythema: note the intense erythema in a characteristic
distribution. By courtesy of the Institute of Dermatology, London, UK.
588 Degenerative and metabolic diseases

Pathogenesis and histological features

The precise etiology of necrolytic migratory erythema is unknown. Although
it is certainly related to hyperglucagonemia, this is not necessarily causal.
Therefore, although the signs and symptoms rapidly abate following surgery
or the use of glucagon secretion inhibitors such as somatostatin,
­hyperglucagonemia does not readily explain the intermittent nature of the erup-
tion.20 The topical or intradermal application of glucagon does not produce the
dermatoses.8 Similarly, there are alternative causes of hyperglucagonemia
including burns and acute trauma, diabetes mellitus, septicemia, cirrhosis,
renal failure, Cushing's syndrome, and primary hyperglucagonemia, in which
necrolytic migratory erythema is not a feature.16
Hypoaminoacidemia is an extremely common manifestation and it may
have pathogenetic significance for the cutaneous lesions. It has been proposed
that the diminished amino acid availability may result in epidermal protein
depletion and eventual necrosis.15 Certainly, treatment with intravenous
amino acids has been shown to control the eruption, but this, of course, may
have been coincidental, considering the characteristic fluctuating course of
the dermatoses.20 Fatty acid and zinc deficiency and abnormal arachidonic
acid distribution have also been proposed as pathogenetic mechanisms.9,31 It Fig. 13.200
has been suggested that diminished tryptophan levels may be the cause of the Necrolytic migratory erythema: close-up view of Figure 13.199.
dermatoses.9 A further hypothesis points to hepatic dysfunction as having a
role in the pathogenesis of the disease.20,21,23,25,32 This is mainly based on the
fact that patients with necrolytic migratory erythema and absence of gluca-
gonoma often have liver dysfunction. The model of ‘multifactorial malnutri-
tion’ has been suggested as an explanation for the several disorders associated
with this disease.25 It is proposed that deficiencies in zinc, amino acids, fatty
acids, and protein result in a metabolic alteration which affects a final com-
mon pathway that manifests clinically with epidermal inflammation and
necrosis in areas of trauma. The precise pathways involved remain
unknown.
Histological examination reveals parakeratosis accompanied by vacuola-
tion and pallor of the mid and upper keratinocytes (Figs 13.199–13.201).33
Dyskeratosis has been described as a clue to early diagnosis.34 This is accom-
panied by necrosis and separation of the upper layers of the epidermis, giving
rise to intraepidermal clefting or vesiculation.33 A neutrophil polymorph infil-
trate may be evident, particularly in well-established lesions.35 Subcorneal
pustulation has also been described.16 This may develop in a background of
epidermal necrosis or, less often, represents an isolated phenomenon.35
Suprabasal acantholysis has exceptionally been described.36 The dermis shows
a lymphohistiocytic chronic inflammatory cell infiltrate surrounding dilated
blood vessels. In lesions associated with pustulation, neutrophils may also be
Fig. 13.201
Necrolytic migratory erythema: high-power view showing marked overlying
parakeratosis.

present. Older lesions may show parakeratosis, marked acanthosis, and pap-
illary dermal angiogenesis, and psoriasis may therefore enter the ­differential
diagnosis.7,33,35 Pustular folliculitis in association with more typical features
has also been described.35
Immunofluorescence studies are invariably negative.13,15,31,35,37
An ultrastructural study revealed widening of the intercellular space with
reduced numbers of desmosomes in the absence of acantholysis.38 Cytoplasmic
vacuolation with lysed organelles and dyskeratotic cells was also present.
These changes are largely degenerative and non-specific.

Differential diagnosis
Necrolytic migratory erythema shows considerable clinicopathological
overlap with acrodermatitis enteropathica, and niacin and zinc deficiencies,
suggesting a possible shared pathogenesis.9 Pellagra can also show similar
histological features. The histology of necrolytic acral erythema is that of
necrolytic migratory erythema. This condition is, however, associated with
Fig. 13.199 hepatitis C infection and clinically tends to be restricted to the dorsum of
Necrolytic migratory erythema: low-power view showing extensive vacuolation with the feet, with less common involvement of the lower legs and dorsal
vesiculation. hands.39
 Bullosis diabeticorum 589

If subcorneal pustules are evident, impetigo, dermatophyte infection,

­ ustular psoriasis, subcorneal pustular dermatosis, and pemphigus foliaceus
p
enter the differential diagnosis. Multiple biopsies are sometimes necessary
before the correct diagnosis can be established.

Bullosis diabeticorum
Clinical features
There are numerous cutaneous manifestations of diabetes mellitus. These
include vascular complications such as peripheral gangrene, especially
­affecting the foot, and infective lesions including candidiasis and dermato-
phytosis. Other dermatological features include necrobiosis lipoidica
­diabeticorum, ­disseminated granuloma annulare, acanthosis nigricans,
­eruptive ­xanthomata, scleredema, diabetic dermopathy (shin spots), waxy
skin, and bullous lesions.1–4
Bullosis diabeticorum (bullous eruption of diabetes mellitus) is rare, affect-
ing approximately 0.16% of diabetics, and affects men more commonly
(male:female ratio 2:1).5 It usually presents as spontaneous blisters, typically
without underlying inflammation, affecting the periphery. Lesions, which are Fig. 13.202
Bullous eruption of diabetes: this example from the fingertip shows a subepidermal
sometimes mildly painful or associated with a burning sensation, are found
vesicle.
most often on the feet and lower legs although the hands may also be
affected.6–10 Blisters range in size from a few millimeters to a few centimeters
and can evolve rapidly and become hemorrhagic.4 The lesions, which are
often recurrent, commonly heal in a few weeks and are not associated with
scarring. Rarely, secondary ulceration and infection can occur. 5 Osteomyelitis
has been reported recently.11

Pathogenesis and histological features

The cause of blistering in diabetic patients is unknown, but theories implicat-
ing a vascular or neurological mechanism have been favored in the literature.
The occasional finding of epidermal infarction overlying the blister cavity
favors the former in at least some patients.6 The discovery that diabetic patients
have a diminished threshold for suction-induced blisters may have pathoge-
netic significance.12 Others have suggested an abnormality of calcium and
magnesium metabolism as a consequence of diabetic nephropathy.13 Despite
lesions being predominantly acral in distribution, trauma does not seem to be
generally implicated. In all likelihood, the cause is probably multifactorial.
The reported histopathological features have been variable and include
subcorneal, suprabasal, and subepidermal vesiculation, sometimes associated
with spongiosis (Figs 13.202, 13.203).13–15 Some of the discrepancies may be
due at least in part to variable ages of the lesions, biopsies with re-epithelial-
ization resulting in an apparent intraepidermal location. Electron microscopic Fig. 13.203
Bullous eruption of
studies in two cases have shown that the plane of separation is through the
diabetes: in this field,
lamina lucida in the subepidermal lesions.6,13 Absence of hemidesmosomes the epidermis shows the
and anchoring filaments has also been described.13 changes of infarction.
Immunofluorescence studies are almost invariably negative, although one Note the intense
report described IgM and C3 around the superficial vasculature in ­uninvolved cytoplasmic eosinophilia
skin.16 and absence of nuclei.
Chapter

14 Cutaneous adverse reactions

to drugs
Nooshin Brinster
See
www.expertconsult.com
for references and
additional material

Adverse drug reactions – Vasculitic drug reactions  604 Penicillamine  617

introduction  590
Purpuric drug reactions  605
Type A drug reactions  591
Granulomatous drug reactions  605
Type B drug reactions  591
Drug-induced erythema nodosum  606
Type C drug reactions  591
Drug-induced alopecia  606
Adverse drug reactions – clinical Drug-induced lupus erythematosus  607
manifestations  592 Bullous drug reactions  607
Exanthematous reactions  592 Drug-induced linear IgA disease  607
Drug-induced bullous pemphigoid  608
Urticarial reactions, angioedema and Drug-induced epidermolysis bullosa acquisita  609
anaphylaxis  594 Drug-induced pemphigus  609
Drug-induced pseudoporphyria  609
Serum sickness/serum sickness-like drug
reactions  594 Psoriasiform drug reactions  609
Phototoxic and photoallergic reactions  595 Pityriasiform drug reactions  610
Anticonvulsant hypersensitivity Pustular drug reactions  611
syndrome  597
Ichthyosiform drug reactions  612
Lichenoid and interface drug reactions  598
Drug-induced pseudolymphoma  612
Fixed drug eruptions  599
Specific drug reactions  614
Erythema multiforme  601 Arsenic  614
Iododerma  615
Stevens-Johnson syndrome and toxic
epidermal necrolysis  601 Bromoderma  615
Warfarin  616
Drug-induced hyperpigmentation  601 Heparin  617
Gold  618
Silver  619
Mercury  619
Bismuth  620
Voriconazole  620
Lithium  620
Barbiturates and coma blisters  621
Chemotherapeutic agents  621
Chemotherapy-induced acral erythema  623
Chemotherapy-associated eccrine gland
reactions  623
Neutrophil eccrine hidradenitis  623
Eccrine squamous syringometaplasia  624
Adverse reactions to cytokine therapy 625
Cutaneous reaction of lymphocyte
recovery  626
Dental amalgam tattoos  626
Tumor necrosis factor-a inhibitors  626
Esthetic microimplants  627
Alpha-melanocyte stimulating hormone
analogues (melanotan I and II)  629
EMLA cream  630

Adverse drug reactions – Introduction

Adverse drug reactions are unintended and undesired effects of drugs used for
prevention, diagnosis or treatment of disease.1,2 In light of the ever-increasing
number of medications available, it should come as no surprise that such
reactions are extremely common. The incidence statistics vary considerably
depending upon the method by which the data are derived and the nature of
the population under study.3 Estimates, however, range from 2% to 7% of
hospital inpatients.4–8 Although most reactions are mild, they are sometimes
severe and a source of considerable morbidity and occasional mortality.6,7
The diagnosis of an adverse drug reaction is frequently problematical, the
clinical appearances often being similar, if not identical, to a number of pri-
mary dermatoses and infectious conditions (particularly viral exanthems) and,
in the context of transplantation patients, graft-versus-host disease (GVHD).
The histological diagnosis can also be extremely difficult, as drug reactions can
demonstrate several inflammatory histological patterns that mimic other der-
matoses (i.e. spongiotic, psoriasiform, lichenoid, pityriasiform).9 The problem
is exacerbated in the immunologically compromised patient. Frequently, the
diagnostic difficulties are worsened by the multitude of drugs prescribed. The
problem is further compounded by the multiplicity of different eruptions that
any one particular drug may induce. Contrariwise, a given clinical appearance
may be caused by a large number of unrelated drugs.10
The prevalence of agents responsible for adverse drug reactions reflects
the prescribing tendencies for any given population as much as the relative
risks ascribed to any particular drug.11 It should come as no surprise, there-
fore, that – in a hospital environment – antibiotics, nonsteroidal antiinflam-
matory agents (NSAIDs) and psychotropic drugs are commonly reported as
being the most frequently incriminated.8 In a large hospital survey, penicil-
lin and sulfonamides accounted for over 80% of all adverse drug reactions.8
Experience in general practice has been much less often documented. In a
survey from the Netherlands, sulfonamide-trimethoprim combinations, flu-
oroquinolones, and penicillin were the most common antibacterials caus-
ing drug-related eruptions.3 In the series of approximately 150 000 patients,
1% developed a reaction.

Adverse drug reactions are mostly nonimmunologically mediated. They
develop either as a result of an unwanted but known property of the drug
(and hence are entirely predictable) or as a consequence of drug intolerance/
idiosyncrasy (and are completely unpredictable).5,12–15 The former are by far
the more common, accounting for approximately 80% of all adverse drug
reactions. Less often, adverse drug reactions represent a manifestation of an
immunological phenomenon, so-called allergic drug reactions.5,15 Although
in theory the above subdivisions are sharply defined, in many patients the
underlying pathogenetic mechanisms are far from clear.13
Adverse drug reactions are particularly encountered in certain population
groups, for example the elderly, females, patients with Sjögren's syndrome,
and those suffering from the effects of immune deficiency including patients
receiving immunosuppressive therapy and those suffering from the acquired
immunodeficiency syndrome (AIDS).5
Adverse drug reactions can be divided into three categories: type A, type
B, and type C.1,12,16
Type A drug reactions
Type A reactions, which are predictable and are related to the pharmacologi-
cal actions or metabolism of the drug, include:1
• side effects,
• drug toxicity,
• drug interactions.
Side effects
Side effects, which occur with almost all drugs, represent unwanted phar-
macological actions. For example, methotrexate, cyclophosphamide and
nitrosourea commonly result in anagen alopecia by inducing Bax protein-
mediated apoptosis.17–21 Gold may be associated with cutaneous pigmenta-
tion (chrysiasis) and penicillamine can be associated with the development of
skin laxity and fragility.22–25
Drug toxicity
Drug toxicity develops as a consequence of the gradual accumulation of
a drug or its metabolite (e.g., minocycline or amiodarone deposition with
resultant abnormal pigmentation).15,26–29 Delayed toxicity may take months
to many years before expression (e.g., arsenical keratoses).30–33
Drug interactions
Drug interactions develop when one drug alters the pharmacological effi-
cacy of another that is given concurrently.12,13,34,35 The effect may enhance or
diminish the effect of the drug with resultant toxicity or loss of therapeutic
value.13,14 Drug interactions are thought to arise when one drug affects clear-
ance of the other as a consequence of several mechanisms including:3,4
• alteration in the rate of absorption resulting in diminished drug levels,
• alteration in the renal excretion resulting in inappropriately high drug
levels,
• plasma protein or tissue drug binding site competition resulting in
displacement and inappropriately high drug levels,
• alterations in hepatic cytochrome P-450-mediated drug metabolism.
The last is believed to be of particular importance and includes increased
enzyme synthesis with excessive drug degradation and diminished circulating
or tissue levels and inhibition of drug breakdown with increased circulating
and tissue levels.34,36
Drug interactions are of particular importance in the elderly, the immuno-
suppressed, and in those patients receiving multiple medications.3,4
Type B drug reactions
Type B reactions are uncommon and unpredictable. They do not have an
allergic pathogenesis and include: 1
• idiosyncratic drug reactions,
• exacerbation of a pre-existing condition,
• pseudoallergic drug reactions.
Type C drug reactions 591
Idiosyncratic drug reactions
Idiosyncratic reactions (drug intolerance) develop as a result of genetic or
metabolic influences. They may represent the effects of abnormal or altered
hepatic drug metabolism. For example, a lupus erythematosus-like condition
is a rare complication of hydralazine therapy in the average population but
the risk is greatly increased in patients who metabolize the drug slowly.3,7
Drug-induced lupus erythematosus may also be caused by procainamide,
chlorpromazine, isoniazid, methyldopa, penicillamine, minocycline, quini-
dine, and sulfasalazine.36–38 Cefaclor-induced serum sickness-like eruptions
and the antiepileptic hypersensitivity syndrome are also believed to result
from reactive intermediate metabolic products.39,40
Exacerbation of a pre-existing condition
This is a not uncommon problem; for example, lithium, beta-blockers, anti-
malarial drugs, NSAIDs, and tetracycline may precipitate, aggravate or induce
a psoriatic eruption.4,41–45
Pseudoallergic drug reactions
Pseudoallergic reactions result from the nonimmunologically mediated
release of effector substances such as histamine from tissue-bound mast cells
or circulating basophils with resultant urticarial reactions, angioneurotic
edema, and anaphylaxis.1,4 The complement system can also be activated
by similar nonimmune mechanisms, and there is evidence that perturbation
of arachidonic acid metabolism may be involved in some cases.1,3,17 Drugs
which have been incriminated in such pseudoallergic reactions include radio-
contrast media, NSAIDs, acetyl salicylic acid, opium derivatives, codeine,
curare, d-tubocurare, polymyxin B, and angiotensin-converting enzyme
(ACE) inhibitors.46–50
Type C drug reactions
Type C reactions are rare, immunologically mediated, and develop as a conse-
quence of previous exposure to the drug with resultant allergy.1 The majority
of drugs are of low molecular weight (less than 1000 Daltons) and therefore
on their own are incapable of eliciting an immune response. By functioning
as haptens and forming conjugates with carrier plasma proteins or cell mem-
brane constituents they develop immunogenic potential.1,2,17 The ability of
the majority of drugs to cause an immune response is therefore dependent
on whether it is able to bind to circulating or tissue protein.51 A number of
drugs are likely to induce allergic reactions, including antibiotics, anticon-
vulsants, chemotherapeutic agents, heparin, insulin, protamine, and biolog-
ical response modifiers such as interferons and growth factors.1 A variety
of mechanisms may be involved in cutaneous drug-induced hypersensitivity
reactions including:12
• IgE mediated type 1 reactions,
• immune complex-associated type 3 reactions,
• type 4 delayed hypersensitivity reactions.
IgE-mediated type 1 cutaneous reactions
In type 1 reactions, the release of histamine and other chemical mediators
from tissue-fixed mast cells results in increased vascular permeability with
development of edema in the dermis or deeper tissues.5,17 Immediate reac-
tions which develop within an hour or less of drug exposure present as
urticaria, angioedema or anaphylaxis whereas accelerated reactions which
develop from 1 to 72 hours following the administration of the drug are usu-
ally urticarial.17 Urticaria following treatment with penicillin is a typical type
1 reaction. Certain other antibiotics, antisera, and gammaglobulin are also
common offenders.12
The most common cause of anaphylaxis is penicillin.52 Other causes
include foods, stings, anesthetics, muscle relaxants, latex, contrast material,
antibiotics, and allergenic extracts.52–54 In addition to histamine, anaphylaxis
is mediated through a number of substances including prostaglandin D2,
­leukotriene C4, interleukin (IL)-4 and IL-13, and tumor necrosis factor alpha
(TNF-α).51
592 Cutaneous adverse reactions to drugs

Immune complex-associated type 3 reactions
Type 3 reactions are expressed as urticaria, the Arthus reaction, serum sick-
ness, and leukocytoclastic (allergic) vasculitis.12 The disease manifests a week
or more after exposure to the drug, by which time sufficient circulating anti-
body has been generated to result in immune complexes of an appropriate
size to avoid phagocytosis. Their deposition in the tissues or within blood ves-
sel walls is accompanied by complement fixation and resultant acute inflam-
matory reaction.
Delayed hypersensitivity type 4 reactions
Delayed hypersensitivity reactions are T-lymphocyte mediated and exem-
plified in acute allergic contact dermatitis.12,17 Cytotoxic T-cell-mediated
reactions are of importance in many other adverse allergic drug reac-
tions including exanthematous/morbilliform, bullous, and interface vari-
ants.55–58 Although most delayed hypersensitivity reactions are immune
responses to the hapten-carrier complex, recent studies indicate that some
drugs may be capable of directly activating the immune system, inde-
pendent of a covalent drug–peptide complex.59 Certain medications may
directly bind T-cell receptors and MHC molecules and trigger the release
of cytokines which recruit specific leukocytes. The delayed hypersensitiv-
ity reactions may be subclassified based on the cell type recruited: mono-
cytes (type 4a), eosinophils (type 4b), T cells (type 4c), and neutrophils
(type IVd). The resultant clinical phenotype may be determined by which
cells are involved.59

Adverse drug reactions – clinical manifestations

Although the range of drugs that may result in adverse drug reactions is
extensive, the variety of clinical responses encountered is fairly limited. Many
drugs may cause more than one clinical response and any given reaction pat-
tern may result from a wide range of drugs. There are, however, a number of
clinicopathological responses that are fairly unique to a particular drug and
these are dealt with individually, later in this chapter.1–8
Adverse drug reactions may therefore present with a considerable number
of clinical manifestations as outlined in Box 14.1.1,2

Exanthematous reactions
Clinical features
Exanthematous (morbilliform, maculopapular) reactions are the most fre-
quently encountered adverse drug reaction, accounting for 51% to 95% of
skin reactions, and mimic a variety of infective conditions including scarlet
fever, measles, and rubella (Figs 14.1, 14.2).1–5 Patients present with ery-
thematous macules and papules that may become confluent or gyrate/ polycy-
clic. Pruritus, low-grade fever, and eosinophilia are sometimes present.2 The Fig. 14.1
eruption is often symmetrical and usually presents on the trunk and extremi- Exanthematous
ties or sites of pressure and trauma.1 The palms and soles are sometimes drug reaction: typical
affected but the mucous membranes are not usually involved. erythematous
maculopapular eruption
on the lower extremities
due to ampicillin. By
courtesy of the Institute of
Box 14.1
Dermatology, London, UK.
Clinical manifestations of adverse drug reactions

• Exanthematous reactions
• Urticaria, angioedema and anaphylaxis
• Serum sickness
• Phototoxic/photoallergic eruptions
• Hypersensitivity syndrome
• Lichenoid drug reactions
• Fixed drug eruptions
• Erythema multiforme
• Stevens-Johnson syndrome/toxic epidermal necrolysis
• Pigmentary abnormalities
• Vasculitis
• Purpura
• Granulomatous drug reactions
• Erythema nodosum
• Drug-induced alopecia
• Lupus erythematosus-like drug reactions
• Bullous drug reactions
• Psoriasiform drug reactions
• Pityriasis rosea-like eruptions
• Pustular drug reactions
• Ichthyosiform drug reactions
• Pseudolymphomatous drug reactions Fig. 14.2
• Eczematous drug reactions Exanthematous drug reaction: more extensive lesions on the abdomen associated
with amoxicillin therapy. By courtesy of the Institute of Dermatology, London, UK.
 Exanthematous reactions 593

Exanthematous eruptions typically develop within 1–2 weeks of starting

the drug.1 Occasionally, the eruption is delayed and may even present after
the treatment has ceased.1,6 In more seriously affected patients the eruption
can progress to erythroderma (exfoliative dermatitis) in which the erythema
becomes generalized and is often accompanied by scaling.7 Resolution of
exanthematous drug reactions is characterized by exfoliation and sometimes
is followed by postinflammatory hyper- or hypopigmentation.1 Penicillin, sul-
fonamides, ampicillin, amoxicillin, phenylbutazone, isoniazid, barbiturates,
phenytoin, carbamazepine, benzodiazepines, gold, and trimethoprim are
especially incriminated.1,8–10 Patients who suffer from infectious mononucleo-
sis are at risk of developing an exanthematous reaction following therapy
with ampicillin or amoxicillin.11

Pathogenesis and histological features

The pathogenesis of exanthematous drug reactions is not fully understood,
although a cytotoxic T-cell-mediated reaction is likely in most cases (see
Immunohistochemistry).
The histological features are often subtle. Although the epidermis may
appear normal, focal parakeratosis is commonly present. The characteris- Fig. 14.4
tic changes include lymphocytic exocytosis with mild spongiosis, typically Exanthematous drug
reaction: in this example
accompanied by basal cell liquefactive degeneration and a few dyskeratotic
due to carbamazepine
keratinocytes (Figs 14.3–14.7).12,13 The dermis shows a perivascular infil-
therapy, there is
trate of lymphocytes and histiocytes with variable numbers of eosinophils. spongiosis, dyskeratosis,
Eosinophils – although often emphasized in the literature as an important fea- and interface change
ture of drug reactions – can, in our experience, be very scanty or even absent. associated with
Sometimes marked edema is seen, particularly if an urticarial element is clini- lymphocytic exocytosis.
cally evident. Red cell extravasation may also be a feature in those lesions
that include a purpuric component.
By immunohistochemistry, the lymphocytes are largely CD3+ T-cells with
a predominance of CD4+ cells in the superficial perivascular infiltrate.14
Lymphocytes at the dermoepidermal junction and within the epidermis con-
sist of approximately equal numbers of CD4+ and CD8+ forms.14–19 These
latter cells regularly express human leukocyte antigen (HLA)-DR and a sub-
population also expresses CD25.19 There is an admixture of T-helper Th1
and Th2 cells.18 Occasionally, the infiltrate is almost entirely composed of
the CD4+ lymphocytes and, contrariwise in human immunodeficiency virus
(HIV) positive patients, the infiltrate may consist of CD8+ cells alone.14,17
CD1a+ dendritic cells and CD68+ histiocytes are also present.18 CD56+ nat-
ural killer (NK) cells may be identified.17 Cytotoxic pathways mediated by

Fig. 14.5
Exanthematous drug reaction: low power view showing focal parakeratois, mild
acanthosis and a heavy upper dermal inflammatory cell infiltrate.

perforin and granzyme B have been shown to be of particular importance in

exanthematous drug reactions.16,18,19 Fas/Fas-L cytotoxic mechanisms are not
thought to be of relevance.14
The features of drug-induced erythroderma are rather non-specific and
include parakeratosis and psoriasiform hyperplasia, sometimes accompanied
Fig. 14.3 by mild spongiosis. Eosinophils may be identified within the dermal chronic
Exanthematous drug inflammatory cell infiltrate.
reaction: early lesion
due to penicillin Differential diagnosis
showing slight interface
Exanthematous adverse drug reactions are a frequent feature in transplanta-
change, spongiosis, and
lymphocytic exocytosis. tion patients who are usually taking multiple medications and, therefore, must
There is a superficial be distinguished from acute GVHD. In reality, it is difficult, if not impossible,
perivascular lymphocytic to make this distinction histologically. Traditionally, the presence of eosino-
infiltrate, and one or two phils has been thought to support a drug reaction. However, a recent study
plasma cells are present. found tissue eosinophils in both graft-versus-host disease and drug reactions,
594 Cutaneous adverse reactions to drugs

submucosal layers are affected, angioedema results.2–4 Urticaria can also be a

manifestation of serum sickness and anaphylaxis.
Urticarial reactions may be caused by a large number of drugs. Aspirin,
penicillin, ACE inhibitors, and blood products are particularly incriminated.5,6
Drugs which directly stimulate mast cell release of vasoactive substances such
as histamine can cause urticaria, include opiates, curare, vancomycin, and
polymyxin B.3,7,8 Radiocontrast media may have a similar effect.3 Urticarial
reactions due to aspirin and NSAIDs are thought to sometimes be a result of
abnormal arachidonic acid metabolism.3

Pathogenesis and histological features

The pathogenesis of urticarial drug reactions includes IgE-mediated type 1
reactions, immune complex mechanisms, and pseudoallergic phenomena
(non IgE-mediated).5,9,10
Histologically, urticaria is characterized by dermal edema and vascular
dilatation accompanied by a perivascular infiltrate consisting of lymphocytes
Fig. 14.6 and eosinophils (Fig. 14.8). Edema is often difficult to appreciate histologi-
Exanthematous drug cally but may be inferred by separation of collagen bundles. Mast cell degran-
reaction: in this high ulation may be present.3 Vasculitis is not a feature.
power view there Angioedema is characterized by edema extending into the deeper dermis
is parakeratosis, and subcutaneous fat.
focal spongiosis and
lymphocytic exocytosis.
A heavy dermal infiltrate
is present with one or
Serum sickness/serum sickness-like
two eosinophils. drug reactions
Clinical features
Serum sickness develops within 1–3 weeks after taking the serum or vac-
cine.1–8 It presents with an erythematous maculopapular or urticarial
response or with palpable purpura variably accompanied by fever, arthral-
gia, myalgia, arthritis, lymphadenopathy, glomerulonephritis, myocarditis,
and neuritis (Fig. 14.9).1–4 The cutaneous manifestations often commence
on the sides of the fingers, toes, and hands before becoming more gener-
alized.2 A wide range of drugs has been implicated in the development of
serum sickness-like drug reactions including phenytoin, phenylbutazone,
and carbamazepine. Antibiotics are also a common offender, with cefaclor
featured most prominently along with other antibiotics such as cefprozil,
ciprofloxacin, minocycline, penicillin V, amoxicillin, flucloxacillin, and co-
trimoxazole.6,9–19 More recently, therapy with monoclonal antibodies such
as rituximab, infliximab, and natalizumab has been associated with serum
sickness-like reactions.20–22

Fig. 14.7
Exanthematous drug
reaction: note the
interface change and
cytoid bodies.

making histological distinction impossible.20 A viral exanthem also commonly

enters the differential diagnosis – the histological findings are often indistin-
guishable although the presence of eosinophils may favor a drug reaction.

Urticarial reactions, angioedema

and anaphylaxis
Clinical features
Urticaria is the second most common adverse drug reaction.1 It is character-
ized by pruritic, erythematous, and edematous wheals. If accompanied by
marked edema involving the deeper dermis and subcutaneous fat, or if the
Fig. 14.8
Urticarial drug reaction: high-power view showing a predominately perivascular
lymphohistiocytic infiltrate with one or two eosinophils.
 Phototoxic and photoallergic reactions 595

Fig. 14.9
Serum sickness: there is a widespread erythematous and urticarial eruption.
Fig. 14.11
Phototoxic drug reaction:
Pathogenesis and histological features in this example there
Serum sickness is thought to represent an immune complex-mediated type are well-developed
3 reaction although the possibility of direct toxicity against vessel wall, auto- blisters arising on an
immunity, and cell-mediated cytotoxicity have been proposed as alternative erythematous base.
pathogenetic mechanisms.2 Direct immunofluorescence reveals immunoglob-
ulin and C3 in relation to blood vessel walls.6
The histological features are those of leukocytoclastic vasculitis (Fig. 14.10).23

Phototoxic and photoallergic reactions

Clinical features
There are two types of photosensitive drug reactions: phototoxic and photo-
allergic. Phototoxic reactions are more common; however, they are not neces-
sarily mutually exclusive and are not always clinically distinguishable.1–30 The
clinical appearances of acute phototoxic reactions mimic severe sunburn and
include erythema, edema, and blistering with subsequent desquamation and
postinflammatory hyperpigmentation (Figs 14.11, 14.12).6,7 Typically, only
exposed skin is affected and it occurs minutes to hours after sun exposure.
Phototoxicity has also been associated with onycholysis.21,25
Chronic phototoxicity presents with poikilodermatous features including
hyper- and hypopigmentation, epidermal atrophy, and telangiectasia. It is an
important feature of the porphyrias and the inherited ­photodermatoses such

Fig. 14.12
Phototoxic drug reaction: the lesions in this patient followed PUVA therapy.
By courtesy of the Institute of Dermatology, London, UK.

as xeroderma pigmentosum, Rothmund-Thomson syndrome, and Bloom's

syndrome. It rarely results from drug treatment but may follow long-term
therapy with psoralen and UVA (PUVA therapy) where there is also an
increased incidence of actinic keratosis, basal cell carcinoma, squamous cell
carcinoma and, more rarely, melanoma.6,31–34
Drugs that are incriminated in acute phototoxic reactions include thi-
azide diuretics, sulfonamides, tetracycline antibiotics, NSAIDs (including
naproxen, diclofenac, and ketoprofen), phenothiazines (particularly chlo-
rpromazine), amiodarone, tars, and psoralens.6–13,19,20,23,24,29 Phototoxicity has
also been described with use of St. John's wort and following photodynamic
therapy.22,26 Porphyrins are potent phototoxic sensitizers.6 In this instance, the
damage affects the dermal constituents including the vasculature, leaving the
epidermis relatively unaffected.
The clinical appearances of photoallergic drug reactions are variable and
Fig. 14.10 include eczematous and lichenoid dermatitides (Figs 14.13, 14.14).14 The
Serum sickness: there is a florid leukocytoclastic vasculitis. rash usually develops 24 hours or more after sun exposure. Unlike phototoxic
596 Cutaneous adverse reactions to drugs
Fig. 14.13
Photoallergic drug reaction: note the obvious sparing of covered skin. By courtesy
of the Institute of Dermatology, London, UK.
Fig. 14.14
Photoallergic drug
reaction: this example
resulted from treatment
with tetracycline.
By courtesy of the
Institute of Dermatology,
London, UK.
reactions, unexposed skin may also be affected in addition to exposed skin.7
Typically, the dermatitis resolves after withdrawal of the offending agent.
Rarely, a persistent light reaction may occur in which the photodermatitis
persists despite removal of the photosensitizing chemical. This usually occurs
in the setting of photoallergic contact dermatitis.
The majority of photoallergic reactions are induced by the application of
topical medicaments and chemicals (contact photoallergy) including antihista-
mines, local anesthetics, chlorpromazine, hydrocortisone sunscreens contain-
ing p-aminobenzoic acid, and halogenated phenolic compounds in soaps and
fragrances (e.g., 6-methylcoumarin and musk ambrette).2,7,15,17 Photoallergy
can also follow systemic administration of drugs including sulfonamides,
griseofulvin, phenothiazines, tetracyclines, NSAIDs, chloroquine, and thiaz-
ides.8,18 Diagnosis is best confirmed by a photopatch test.
Phytophotodermatitis represents a phototoxic drug reaction due to contact
with plants containing furanocoumarins.35–37 Patients develop erythema fol-
lowed by postinflammatory hyperpigmentation. Rarely, blisters may develop
Fig. 14.15
Phytophotodermatitis:
this variant represents
an allergic reaction to a
plant chemical. Linear
lesions on the limbs are
characteristic and usually
follow gardening.
By courtesy of the
Institute of Dermatology,
London, UK.
(Fig. 14.15).35 Members of the Umbelliferae, Rutaceae and Moraceae fami-
lies are implicated.36,37
Pathogenesis and histological features
Photosensitization has been described as a process whereby 'a reaction to
non-ionizing radiation occurs as a consequence of the introduction of a radi-
ation-absorbing reagent (the sensitizer), which induces another substance
(the substrate) to undergo chemical change'.1–6 There are two basic mecha-
nisms: phototoxic and photoallergic. While an enormous range of drugs has
been implicated in photosensitivity reactions, NSAIDS, phenothiazines, ami-
odarone, antibiotics, and antifungal agents such as griseofulvin appear to be
of particular importance.30
Two types of phototoxic reactions are recognized: photodynamic and non-
photodynamic.6
• Photodynamic reactions are oxygen-dependent and result in singlet
oxygen or superoxide anions which cause injury to cellular constituents
such as cell membranes, cytoplasmic proteins and nucleic acids.
• Nonphotodynamic reactions are oxygen independent and damage DNA
or RNA directly.
Many drug reactions are photodynamic, whereas psoralen represents a
nonphotodynamic reaction. Phototoxic reactions do not depend on prior
exposure to the drug and will affect all patients of the same skin type pro-
vided that sufficient bound drug is available for reaction with the appropri-
ate radiation.1 The action spectrum for phototoxicity is UVA, and less often
UVB and visible light.
Photoallergic drug-induced photosensitivity is immunologically mediated
and represents a delayed papular, vesicular or eczematous response.6 It is a
lymphocyte-mediated delayed hypersensitivity type 4 reaction. It typically
requires previous exposure to the drug or chemical.1,5 Only a proportion of
patients taking the drug will develop a reaction. Photoallergic reactions are
usually induced by UVA.1,2
The histological appearances of acute phototoxic reactions include con-
spicuous apoptotic keratinocytes (sunburn cells) which in severe cases may
affect the entire epidermis, with variable neutrophil exocytosis, dermal
edema, and a perivascular lymphohistiocytic infiltrate with small numbers of
neutrophils and eosinophils (Figs 14.16, 14.17).38
Chronic lesions are characterized by hyperkeratosis, hypergranulosis,
variable acanthosis and epidermal atrophy, increased melanin pigmenta-
tion, melanocyte hyperplasia, and pigmentary incontinence.38 Elastosis and
 Anticonvulsant hypersensitivity syndrome 597

It can also be caused by other medications including allopurinol, azathio-

prine, dapsone, minocycline, sulfonamides, terbinafine, and more recently
efalizumab.12–17 The syndrome has been predominantly described in black
patients. There is no sex predilection.4 Children may be affected.18–22
Symptoms appear 1 to 8 weeks after starting the offending drug. Clinical fea-
tures include pyrexia, a maculopapular or erythrodermatous eruption, facial
or periorbital edema, strawberry tongue, tender lymphadenopathy, myosi-
tis and hepatitis associated with leukocytosis and eosinophilia (Figs 14.18,
14.19).4,5 Less often the cutaneous manifestations include localized or gener-
alized follicular pustules, erythema multiforme, and toxic epidermal necroly-
sis.4,6,22,23 In patients with the pustular variant, lesions present on the scalp
before becoming generalized.8,23,24 Conjunctivitis and/or pharyngitis may also
be present.2 Renal, pulmonary (interstitial pneumonitis), and hematological
(atypical lymphocytosis) involvement sometimes occur.5 The prognosis of this
syndrome is variable.25,26 The majority of patients recover but in those with
hepatitis, the mortality is approximately 20%.5,27

Fig. 14.16
Phototoxic drug reaction: this is a very severe reaction. Dermal edema has resulted
in subepidermal vesiculation.

Fig. 14.18
Anticonvulsant hypersensitivity syndrome: there is striking facial edema with
periorbital accentuation. By courtesy of C.C. Kim, MD, Department of Dermatology,
Harvard Medical School, Boston, USA.

Fig. 14.17
Phototoxic drug reaction: note the multiple necrotic keratinocytes (sunburn cells).
The blister cavity is cell-free and the dermal papillae are preserved (festooning).

t­ elangiectatic vessels may be conspicuous, and in severely affected patients

stellate atypical myofibroblasts can be a feature. Epidermal disorganization
and dyskeratosis may also be present.6
The histological appearances of drug induced photoallergic reactions
includes spongiosis (often with vesiculation, lymphocytic, and eosinophil
exocytosis), accompanied by papillary dermal edema and an upper dermal
lymphohistiocytic infiltrate with variable numbers of eosinophils.38

Anticonvulsant hypersensitivity syndrome

Adverse drug reactions to phenytoin – which include erythematous maculo-
papular lesions, erythroderma, acneiform lesions, hypo- and hyperpigmenta- Fig. 14.19
tion, vasculitis, erythema multiforme, and toxic epidermal necrolysis – affect Anticonvulsant
up to 19% of patients taking this drug.1–7 Pseudolymphomatous drug reac- hypersensitivity
tions may also occur and these are discussed later in the chapter. syndrome: there is a
maculopapular eruption
A potentially fatal hypersensitivity syndrome develops in approximately 1
and pustules are present.
in 3000 patients receiving phenytoin.5,6 This is defined by a triad of pyrexia, By courtesy of C.C.
exanthematous skin rash, and evidence of systemic involvement.6 The acro- Kim, MD, Department
nym DRESS describes drug rash with eosinophilia and systemic symptoms. of Dermatology, Harvard
Administration of other antiepileptics including phenobarbital, carbam- Medical School, Boston,
azepine, primidone, and lamotrigine may result in an identical ­condition.8–11 USA.
598 Cutaneous adverse reactions to drugs

Pathogenesis and histological features

The precise etiology of this syndrome is uncertain. It is thought to result
from an inability to detoxify arene oxide anticonvulsant metabolites due to
absence, possibly genetically determined, of specific hydrolases. The condi-
tion has been associated with reactivation of human herpes virus 6 and 7,
Epstein-Barr virus, and cytomegalovirus.28–33
The histological features vary from spongiotic dermatitis to those of ery-
thema multiforme or toxic epidermal necrolysis. Pustular lesions are char-
acterized by a subcorneal pustule associated with follicular infundibular
dilatation (Figs 14.20, 14.21).8
Lichenoid and interface drug reactions
Clinical features
Lichenoid drug reactions are clinically similar to lichen planus although lesions
are often larger, Wickham's striae are usually not apparent, and mucosal
involvement is commonly absent.1–4 In contrast to lichen planus, where
lesions are characteristically on the flexural surfaces of the forearms, the legs,
and the genitalia, in lichenoid drug reactions the trunk and extremities are
more often affected (Figs 14.22, 14.23 ).4,5 The eruption may sometimes be
photodistributed and predominantly affect the hands and forearms although
other sun-exposed sites can be involved.4,6,7 The latent period between start-
ing the drug and the onset of the eruption is often long, months or even
years.4 Atypical features including eczematous and psoriasiform lesions are
sometimes seen and bullous or ulcerative variants are occasionally encoun-
tered.3,4,8 Postinflammatory hyperpigmentation may be very marked and is

Fig. 14.20
Anticonvulsant
hypersensitivity
syndrome: this example
shows a subcorneal
Fig. 14.22
pustule.
Lichenoid drug reaction:
lichenoid papules are
widely distributed about
the patient’s face and
upper chest.

Fig. 14.21
Anticonvulsant
hypersensitivity
syndrome: the
underlying dermis
shows a superficial
dermal perivascular
lymphohistiocytic Fig. 14.23
infiltrate with scattered Lichenoid drug reaction: lichenoid papules on the back. By courtesy of
eosinophils. B Al-Mahmoud, MD, Doha, Qatar.
 Fixed drug eruptions 599

often persistent. Scarring alopecia is sometimes present and some patients

may develop anhidrosis.4
Although many drugs can cause a lichenoid reaction, those of particularly
importance include gold, antimalarials such as quinine and quinidine, pen-
icillamine, captopril, various beta-blockers (e.g., propranolol), lithium, thi-
azide diuretics, furosemide (frusemide),spironolactone, and ethambutol.4,7–19
More recently, the TNF-alpha inhibitors infliximab, adalimumab, and etan-
ercept have been associated with lichenoid eruptions.20–22
Contact with p-phenylenediamine by workers in the photographic color
developing process and hairdressers may also result in a cutaneous lichenoid
reaction. This is of two types:
• Continuous exposure to small amounts results in the appearance of
typical lichen planus.
• If exposed to a single large dose, the features are those of a lichenoid
contact dermatitis.4
Other causes of a contact lichenoid eruption include dental restorative
materials, musk ambrette, nickel, and gold.4
Captopril and cinnarizine may cause lichen planus pemphigoides-like
eruptions (see bullous drug reactions below).23,24
Fig. 14.25
Lichenoid drug reaction: In this example, the changes of hypertrophic lichen planus-
Histological features like lesions are evident. There is pseudoepitheliomatous hyperplasia and a dense
The histological features are frequently indistinguishable from typical lichen upper dermal lymphohistiocytic infiltrate.
planus although focal parakeratosis and spongiosis are sometimes present and
interface change may be patchy (Figs 14.24–14.26). The epidermis is often thin-
ner and hypergranulosis less marked.15 Cytoid bodies may be found in the upper
granular cell layer or even in the stratum corneum.5,7 Sometimes, eosinophils and
occasionally plasma cells are found in the dermal infiltrate.5 Focal interruption
of the granular cell layer, exocytosis of lymphoid cells into the upper epidermis
and a perivascular infiltrate in the deeper dermis are said to be additional helpful
diagnostic pointers.7 Photodistributed lichenoid drug reactions are said to more
closely resemble idiopathic lichen planus than nonphotodistributed variants.5 The
changes that allow distinction from lichen planus are often seen in hypertrophic
lichen planus. However, in lichenoid drug eruptions, prominent hyperplasia is
hardly ever present. With some drug reactions, interface changes are present in the
absence of a background of epidermal lichenoid features (Figs 14.27, 14.28).

Fixed drug eruptions

Clinical features
Fixed drug eruptions present as one or more circumscribed erythematous
to violaceous or brown plaques that show a predilection for the extremities
including the hands, feet, and external genitalia (Figs 14.29, 14.30).1–8 Fig. 14.26
Lichenoid drug reaction: focal interface change is present. Eosinophils are conspicuous.

Fig. 14.24 Fig. 14.27

Lichenoid drug reaction: there is hyperkeratosis, hypergranulosis with Interface drug reaction: more extensive lesion due to propranolol showing
interface change. Note the superficial bandlike infiltrate. The appearances are hyperkeratosis, widespread apoptosis, upper dermal edema, and a superficial
indistinguishable from idiopathic lichen planus. chronic inflammatory cell infiltrate.
600 Cutaneous adverse reactions to drugs
Fig. 14.28
Interface drug reaction: there are numerous apoptotic keratinocytes and severe
interface change is evident.
The  mucous membranes may be affected, either alone or in association
with cutaneous manifestations.3 Lesions – which may be pruritic or pres-
ent with a burning sensation – typically recur at the same site on rechallenge
with the offending drug. They usually develop within 30 minutes to 8 hours
after ­taking the drug.3 Vesiculation and blistering are common. Resolution
is typically marked by postinflammatory hyperpigmentation varying from
brown to brown-violet or even black.6 In cases with multiple lesions the
multiple pigmented patches result in an appearance described as ‘Dalmatian
dog’. Occasionally, the eruption is generalized and resembles toxic epider-
mal necrolysis.9 Although the number of drugs that are capable of eliciting a
fixed reaction is very large, those that are said to be more commonly incrimi-
nated include barbiturates, phenylbutazone, ibuprofen, acetyl salicylic acid,
sulfonamides, trimethoprim-sulfamethoxazole, tetracyclines, dapsone, phe-
nolphthalein, and quinine.2,3,6
Fig. 14.29
Fixed drug eruption:
typical localized brown
plaque with a small
central blister.
By courtesy of the
Institute of Dermatology,
London, UK.
Fig. 14.30
Fixed drug eruption: early, sharply delineated erythematous lesion.
By courtesy of the Institute of Dermatology, London, UK.
Pathogenesis and histological features
Fixed drug eruption is unique owing to the precise localization of the erup-
tion and its recurrence at the same site on rechallenge. To understand this
process, initial research was directed towards identifying the site of cutaneous
memory. Autotransplantation experiments in which normal skin was grafted
to a previously affected site and vice versa, followed by rechallenge with the
causative drug, produced conflicting results. Some workers found that fol-
lowing challenge, grafted normal skin was unaffected, whereas transplanted
previously affected skin developed erythema and became symptomatic.10
Others experienced quite the opposite results.11
Immunofluorescence studies have been equally conflicting. While some
authors have documented in vivo bound immunoglobulin and complement
in the intercellular region of the epidermis or at its basement membrane, the
majority of investigations have been negative.12,13
It seems unlikely, therefore, that humoral immunity has a significant part
to play in the pathogenesis of fixed drug eruption. Current research is directed
towards understanding the role of cellular immunity. On initial exposure, the
drug appears to bind to the epidermal keratinocytes (thereby functioning as a
hapten) and is presented by Langerhans cells to lymphocytes within the der-
mis or in local lymph nodes. This stimulates an effector CD8+ lymphocyte
population which, on returning to the epidermis, produces various cytokines
including interferon-gamma (IFN-γ) and TNF-α which result in epidermal
necrosis.14,15 Keratinocyte death is believed to be mediated by both cytolytic
pathways (e.g., perforin, granzyme A, and granzyme B) and FAS-mediated
apoptosis.14–16 Resolution of the disease is thought to be due to recruitment of
CD4+ T cells into the epidermis which suppress CD8+ T-cell activation and
limit cell destruction, possibly via production of IL-10.17
Although the precise mechanism by which memory in fixed drug eruption
is achieved is incompletely understood, there is now considerable evidence
to suggest that an intraepidermal effector-memory CD8+ T-cell popula-
tion residing in the epidermis after the initial drug reaction is of particular
importance.13–20 Such cells are defined immunohistochemically by expression
of CD3, CD45RA, TCR-alpha beta, CD11a, and CD11b, and absence of
CD27, CD28, and CD62L.19,21 It has been demonstrated that they remain in a
state of activation (CD69+) in the unchallenged state and, following exposure
to the drug, rapidly up-regulate IFN-γ expression and induce FAS and FAS-
ligand expression, soon followed by epidermal necrosis.16,20
Histologically, the acute fixed drug eruption is characterized by marked
basal cell hydropic degeneration, with lymphocyte tagging along the dermoepi-
dermal junction and individual keratinocyte necrosis (Figs 14.31–14.33).22
Marked pigmentary incontinence is typical. Subepidermal vesiculation may
be a feature of advanced lesions. Lymphocytes, histiocytes, and neutrophils
are evident in the upper dermis. Eosinophils may sometimes be prominent. In
late lesions, pigmentary incontinence may be the sole histological finding.
 Drug-induced hyperpigmentation 601

Erythema multiforme
Although infectious agents (herpes simplex virus, Mycoplasma species) are
the most common cause of erythema multiforme (EM), medications, or a
combination of medications and viral infections, are implicated in a subset
of patients. Drugs with the strongest association include antibiotics, anticon-
vulsants, and nonsteroidal antiinflammatory agents.1 Sulfonamides, specifi-
cally trimethoprim-sulfamethoxazole, carry the highest relative risk. Other
causative antibiotics include aminopenicillins, quinolones, cephalosporins,
and tetracyclines. The anticonvulsants associated with EM most often are
phenobarbital, carbamazepine, phenytoin, and valproic acid. EM due to a
combined viral infections and drug exposure has been described with cyto-
megalovirus and Epstein-Barr virus.2,3

Stevens-Johnson syndrome and toxic

Fig. 14.31
Fixed drug eruption: there is epidermal hyperplasia, interface change, and a
superficial dermal chronic inflammatory cell infiltrate.
epidermal necrolysis
In contrast to erythema multiforme, Stevens-Johnson syndrome (SJS) and toxic
epidermal necrolysis (TEN) are strongly associated with medication use.1 The
profile of implicated drugs is similar to that seen in EM (see above).2 Studies
on newer medications cite strong associations for nevirapine, lamotrigine and
weaker but significant associations for sertraline, pantoprazole and tramadol.3

Drug-induced hyperpigmentation
Clinical features
Cutaneous hyperpigmentation is a frequent complication of drug ther-
apy. It may result from increased melanin synthesis or deposition of the
drug or its metabolite within the skin.1–5 Heavy metals can also result in
skin pigmentation.4 Most often, however, it results from postinflammatory
hyperpigmentation.3
Long-term treatment with minocycline might result in usually reversible
(types I and II) cutaneous pigmentation.6–13 Three clinical variants of cutane-
ous minocycline pigmentation are generally recognized (Figs 14.34–14.36):
• Type I: blue-black macules localized to areas of scarring and
inflammation (e.g., facial acne scars),

Fig. 14.32
Fixed drug eruption: high-power view showing apoptosis and interface change.

Fig. 14.34
Minocycline
pigmentation: extensive
lesions involving the
cheek and periorbital
Fig. 14.33 region. By courtesy of the
Fixed drug eruption: in this example, the infiltrate has a predominantly perivascular Institute of Dermatology,
distribution. London, UK.
602 Cutaneous adverse reactions to drugs

• Type II (most common): blue-black, brown or slate-gray pigmentation on
the shins, ankles and arms,
• Type III: generalized muddy-brown pigmentation which may be
exacerbated on sunlight-exposed regions.
A fourth variant affecting the lips and possibly representing a fixed drug
eruption has been described.14
Nail pigmentation most often presents as a persistent slate-gray coloration
of the proximal nail bed.15 Additional features include longitudinal melanon-
ychia, diffuse nail pigmentation, and photo-onycholysis.15
Minocycline may involve the teeth (causing a green–gray or blue–gray dis-
coloration) predominantly affecting the middle and occasionally the incisal
thirds of the crown.16 Lesions of the oral mucosa are rare although pigmenta-
tion has been described on the buccal mucosa, gingiva, tongue, and lips.17–21
The bones underlying the oral cavity (black bone disease) represent the single
site most commonly affected by minocycline pigmentation.22 This is best visu-
alized by inspecting the maxillary and mandibular anterior alveolar mucosa.14
The hard palate and lingual alveolar bone are also commonly affected.14
The conjunctiva, sclera, thyroid (black thyroid), aorta, endocardium, and ath-
erosclerotic plaques may also be involved in minocycline pigmentation.23–29
Many other tetracyclines including methacycline and tetracycline hydro-
chloride have also been associated with cutaneous pigmentation.30, 31
Amiodarone, which is used primarily in the treatment of cardiac arrhyth-
mias, is associated with a phototoxic/photosensitivity reaction in up to 50% of
patients.32–38 In addition, cutaneous golden-brown to slate-gray or blue/viola-
ceous pigmentation predominantly affecting the exposed surfaces including
the face and the backs of the hands may develop, especially in those receiving
high doses over a protracted period of time (Fig. 14.37).32 Pigmentation is
also sometimes seen in the sclera and cornea.35
Antimalarials also result in abnormal skin pigmentation.39–42 Mepacrine
(quinacrine) typically produces a yellow coloration although local-
ized blue–black mucocutaneous lesions have been described (Figs 14.38,
14.39).42 Chloroquine and hydroxychloroquine cause yellow–brown to gray

Fig. 14.35
Minocycline
pigmentation: these
blue–black lesions
have developed in a
patient with pyoderma
gangrenosum. By
courtesy of the Institute
of Dermatology, London,
UK.

Fig. 14.37
Amiodarone pigmentation: note the slate-gray discoloration on the forehead, a
characteristic site. By courtesy of the Institute of Dermatology, London, UK.

Fig. 14.36
Minocycline
pigmentation; typical
pigmentation affecting
the shin. By courtesy
of the Institute of Fig. 14.38
Dermatology, London, Mepacrine pigmentation: a yellow discoloration is characteristic. By courtesy of the
UK. Institute of Dermatology, London, UK.
 Drug-induced hyperpigmentation 603

Pathogenesis and histological features

The histological features of minocycline pigmentation are variable.7,10,11,14 In
types I and II variants, golden-brown to brown–black granules are found pre-
dominantly within macrophages distributed mainly around the vasculature
and sweat gland coils (Fig. 14.41). The pigment, which fluoresces yellow
under ultraviolet light, stains positively with both Masson-Fontana and Perl’s
Prussian blue reactions in type II variants (Figs 14.42, 14.43).11 The pigment
is periodic acid-Schiff (PAS) negative. In contrast, in type I, the pigment only
stains with Perl's reaction. It is believed to represent minocycline or its break-
down product chelated with hemosiderin, ferritin or iron.7 Calcium, sulfur,
and chlorine are also present but melanin is absent.11 Melanocytes and the
epidermis show no increase in melanin pigmentation in types I and II vari-
ants. Type III hyperpigmentation is characterized by an increase in epidermal
basal cell melanin pigmentation.6 The Perl’s stain is negative. Minocycline
pigmentation of the subcutaneous fat has recently been described in the clini-
cal setting of type II disease.52,53 Histologically, there is pigment within mac-
rophages and giant cells in the subcutaneous fat, with positive staining for
Masson-Fontana and variable staining with Perl’s reaction. One study also
described green–gray nonrefractile globules within macrophages in the fat.53
Fig. 14.39 Histologically, amiodarone pigmentation is characterized by macrophages
Mepacrine pigmentation: containing PAS-positive, yellow–brown lipofuscin-like granules located in a
in this patient the drug perivascular distribution (Figs 14.44, 14.45).32 Melanin pigmentation of the
resulted in black lesions.
By courtesy of the
Institute of Dermatology,
London, UK.

­ igmentation.2,39–41 Sun-exposed skin is predominantly affected, although

p
mucosal pigmentation may also occur.43
In addition to causing photosensitivity and contact dermatitis, chlorpro-
mazine therapy (particularly when protracted and in high doses) can result
in cutaneous pigmentation, especially on sun-exposed skin such as the face,
dorsum of the hands, and the neck.2,44–47 Patients may present with a golden-
brown, tanned appearance while others develop a slate-gray, bluish or purple
appearance. The cornea and lens of the eye can also be involved.2
Long-term treatment with imipramine may result in photodistributed
hyperpigmentation affecting the face, neck, ‘V’ of chest, arms, and hands
(Fig. 14.40).48–50 The coloration varies from golden-brown to blue-gray or
slate-gray. The irises may also darken.
Photodistributed blue-gray pigmentation has been documented following
treatment with desipramine.51
Heavy metals including gold, silver, and mercury can all result in cutane-
ous pigmentation (see below).
Fig. 14.41
Minocycline pigmentation: note the presence of perivascular granular brown pigment.

Fig. 14.40
Imipramine pigmentation: note the intense brown pigment of the hands and
forearms in comparison with the chest. By courtesy of L. Cohen, MD, Cohen Fig. 14.42
Dermatopathology, Massachusetts, USA. Minocycline pigmentation: the pigment stains positively with Masson-Fontana.
604 Cutaneous adverse reactions to drugs

Fig. 14.43 Fig. 14.46

Minocycline pigmentation: the pigment also stains with Prussian blue. Imipramine pigmentation: typical golden-brown granules. Note that the Prussian
blue reaction is negative. By courtesy of L. Cohen, MD, Cohen Dermatopathology,
Massachusetts, USA.

epidermis is not increased; indeed its absence in involved skin has recently
been documented.38 By electron microscopy, the granules are located within
lysosomes.33,37 Lamellar myelin bodies may also be identified.23 Similar
inclusions may be found in the hepatocytes, Kupffer cells, pulmonary mac-
rophages, and neutrophils.
In mepacrine (quinacrine) pigmentation, yellow–brown pigment is
found within the cytoplasm of histiocytes throughout the dermis.42 The
pigment is weakly positive with the Perl’s Prussian blue reaction for iron
and is Masson-Fontana negative.38,43 The histological findings in hydroxy-
chloroquine-related pigmentation have been described as yellow–brown
granular deposits within macrophages and extracellularly.54 These gran-
ules are nonrefractile and stain positively with Masson-Fontana and are
negative for iron.54
Histologically, chlorpromazine hyperpigmentation is characterized by
golden-brown macrophage-bound granules surrounding the superficial vas-
culature. The granules are positive with the Masson-Fontana reaction but
Fig. 14.44 do not stain with Perl’s Prussian blue.47 Ultrastructurally, the pigment is lys-
Amiodarone pigmentation: pigmented macrophages are present in a perivascular osome bound and present in endothelial cells, fibroblasts, Schwann, and
distribution. smooth muscle cells, in addition to macrophages.44,45 Increased melanin also
contributes to the cutaneous pigmentation.44
Histologically, imipramine and desipramine hyperpigmentation contain
Masson-Fontana positive golden-brown granules within the upper dermis,
lying both free and within macrophages (Fig. 14.46).48,49,51 Perl’s Prussian
blue is negative. Ultrastructurally, histiocytes contain melanosomes in addi-
tion to lysosomal-bound electron-dense granules.48

Vasculitic drug reactions

Adverse drug reactions are a common cause of vasculitis.1,2 An immune com-
plex mechanism mostly represents the pathogenesis in the majority of cases.
A wide range of drugs has been implicated, including anti-infective agents,
cancer chemotherapeutic agents and adjuvants, psychoactive and cardiovas-
cular drugs, diuretics, anticoagulants, beta-adrenergic receptor agonists, and
anticonvulsants.2 The more important agents include trimethoprim, peni-
cillin, sulfonamides, NSAIDs, and aspirin.3 Other implicated drugs include
cimetidine, clarithromycin, coumadin, furosemide (frusemide), hydralazine,
ibuprofen, iodides, phenacetin, phenothiazines, procainamide, rifampin, pro-
pythiouracil, and streptokinase (Figs 14.47, 14.48).4–13 More recently, anti-
TNF-alpha therapies have been linked to vasculitic reactions.14,15
Fig. 14.45 Granulomatous vasculitis has been described following treatment with
Amiodarone pigmentation: high-power view. chlorothiazide, allopurinol, phenytoin, and carbamazepine.4,16–18

Fig. 14.47
Vasculitic drug reaction: hemorrhagic papules and plaques with central necrosis
complicating treatment with propylthiouracil. By courtesy of M. Mailberger, MD,
Virginia Commonwealth University, Richmond, Virginia, USA.
Fig. 14.48
Vasculitic drug reaction: there is acute vasculitis with thrombosis.
Purpuric drug reactions
Clinical features
Purpura may be a manifestation of an adverse drug reaction. Causes include
NSAIDs, diuretics, meprobamate, zomepirac sodium, ampicillin, pseu-
doephedrine, linezolid, and lidocine/prilocaine cream.1–4
Histological features
The histological features are those of red cell extravasation in the absence of
changes of vasculitis (Fig. 14.49).
Granulomatous drug reactions
Clinical features
Interstitial granulomatous drug reactions are rare and have been associated
with a number of drugs including calcium channel blockers, ACE inhibitors,
beta-blockers, lipid-lowering agents, diuretics, NSAIDs, antihistamines, anti-
convulsants, and antidepressants.1 More recently, IL-1 inhibitor (anakinra)
and adalimumab have been associated with an interstitial granulomatous
Granulomatous drug reactions 605
Fig. 14.49
Purpuric drug reaction: there is massive subepidermal edema with red cell
extravasation.
reaction.2,3 This reaction pattern may also be related to a variety of systemic
illnesses including rheumatoid arthritis, hepatobiliary disease, diabetes mel-
litus, Crohn’s disease, and chronic infections such as hepatitis C, herpes
simplex/varicella-zoster, Epstein-Barr virus (EBV), and HIV.2 Patients pres-
ent with erythematous to violaceous, nonpruritic, irregular and sometimes
annular papules or plaques predominantly affecting the inner arms, inner
thighs, and the groins (Fig. 14.50).1 Erythroderma in a case of anticonvul-
sant-induced hypersensitivity syndrome has also been described.4
Histological features
Histologically, the eruption is characterized by an interstitial infiltrate of
lymphocytes, histiocytes, eosinophils, plasma cells, and multinucleate giant
cells, sometimes associated with increased dermal mucin and showing more
than a superficial resemblance to interstitial granuloma annulare (Figs 14.51,
14.52). Fragmentation of collagen fibers and elastic tissue is commonly evi-
dent and phagocytosis of connective tissue debris by giant cells is typically
seen (Figs 14.53, 14.54). Discrete granulomata may also be identified and
granulomatous vasculitis has been documented.5 Flame figures and Churg-
Strauss-like granulomata have also been described.6,7 Atypical lympho-
cytes with hyperchromatic, irregular and variably enlarged nuclei showing
Fig. 14.50
Lichenoid and granulomatous dermatitis: note the flat-topped lichenoid papules.
This reaction developed during rituximab therapy. By courtesy of J. Francis, MD,
Virginia Commonwealth University, Richmond, Virginia, USA.
606 Cutaneous adverse reactions to drugs
Fig. 14.51
Granulomatous drug
reaction: there is a
marked infiltrate involving
the full thickness of the
dermis.
Fig. 14.52
Granulomatous drug reaction: in this example there is an obvious interstitial
distribution reminiscent of granuloma annulare.
e­ pidermotropism are present in up to 50% of cases.1 The changes of interface
dermatitis, sometimes with an associated lichenoid infiltrate, are found in the
majority of cases.1,5
Differential diagnosis
Interstitial granulomatous drug reactions must be distinguished from granu-
loma annulare and systemic disease-associated lesions as described above.
Granuloma annulare is not usually associated with interface dermatitis, and
necrobiosis and mucin deposition are not features of granulomatous drug
reactions. Systemic disease-associated granulomatous dermatitis is usually
associated with vasculitic and/or thrombotic phenomena.7 In cases where
significant lymphoid atypia is present, cutaneous T-cell lymphoma enters
the differential diagnosis. When elastophagocytosis is marked, granuloma-
tous slack skin or an elastolytic granuloma may be important diagnostic
considerations.
Fig. 14.53
Granulomatous drug reaction: there is extensive elastophagocytosis (elastic van
Gieson).
Fig. 14.54
Granulomatous drug reaction: phagocytosis of collagen may also be seen (Masson’s
trichrome).
Drug-induced erythema nodosum
This topic is discussed in the chapter on panniculitis.
Drug-induced alopecia
Drug-induced alopecia is usually reversible, predominantly nonscarring, and
affects females more often than males.1–4
Anagen effluvium, in which hair growth stops due to cessation of mitotic
activity, is a common feature of anticancer therapy and often develops days
or a few weeks after starting the drug.1,2 The scalp and beard areas, which
contain a high percentage of anagen follicles, are particularly affected.
It especially complicates combination chemotherapy and is likely to be severe.5
Although all anticancer drugs may be associated with some degree of alope-
cia, particular offenders include bleomycin, cyclophosphamide, dactinomy-
cin, daunorubicin, doxorubicin, 5-fluorouracil, ifosfamide, and vindesine.1,2
There is some variation in drug effect. Some cause alopecia in all individuals
whereas others affect only a minority of patients.5
Telogen effluvium, in which hairs are transformed into the telogen phase,
develops several months after commencing therapy.1 Anticoagulants, including
 Bullous drug reactions 607

heparin and warfarin and dextran sulfate, cause telogen effluvium in up to 50%
of patients.3,5–11 Other causes include antithyroid drugs such as iodine, thiouracil
and carbimazole, oral contraceptives, lithium, interferons and retinoids.5,12,13
Alopecia areata may develop as a consequence of TNF-alpha inhibitors
such as adalimumab and etanercept.14,15

Drug-induced lupus erythematosus

Clinical features
Drug-induced systemic lupus erythematosus was first described as a com-
plication of hydralazine.1–8 It has also been reported in association with
procainamide, quinidine, sulfasalazine, chlorpromazine, penicillamine, meth-
yldopa, carbamazepine, acebutalol, isoniazid, captopril, propylthiouracil,
and minocycline.2,3 Therapy with TNF-alpha inhibitors has been associated
with a lupus-like syndrome.9,10 With the exception of hydralazine and pro-
cainamide (high risk) and quinidine (medium risk), the other associations are
low risk.2 Laboratory investigations reveal anti-Ro, anti-La, and antinuclear
antibodies (ANA) in the majority of cases.1 Subacute cutaneous lupus ery-
thematosus-like features have been described following treatment with ter- Fig. 14.55
binafine.11–13 More recently, localized cutaneous lupus lesions were described Bullous drug reaction: this subepidermal blister arose against a background of an
exanthematous drug reaction.
occurring at the site of IFN injection.14 Cutaneous lesions including malar
erythema, discoid lesions, photosensitivity, oral ulceration, and alopecia are
rare.2 Anti-TNF-alpha therapy-induced lupus may result in a higher incidence described following treatment with trimethoprim- sulfamethoxazole, penicil-
of cutaneous lesions, hypocomplementemia, and positive serology for dou- lin, phenytoin, somatostatin, lithium, amiodarone, captopril, cefamandole,
ble-stranded DNA as compared to other medications.13 Symptoms typically ceftriaxone, cyclosporin, IL-2, IFN-alpha, penicillin, amoxicillin, vigabatrin,
develop months to years after initiating therapy.15 Diagnostic criteria have and diclophenac.2,11–21 Cutaneous manifestations of vancomycin-induced
been defined as follows:2 linear IgA disease include pruritic, erythematous, urticarial, targetoid and
• continuous treatment with the suspected drug for 1 month or longer, bullous lesions with a predilection for the trunk, extremities, palms, and
• common presenting symptoms include arthralgias/arthritis, myositis, soles (Figs 14.56, 14.57).1 Morbilliform lesions have also been described.8
serositis, malaise and fever, Mucosal involvement is present in up to 40% of cases. As such, there can be
• antihistone antibodies frequent, particularly IgG anti-([H2A-H2B]-DNA), considerable clinical overlap with EM and TEN.2,9,10 Laryngeal involvement
• most importantly, clinical improvement within days or weeks after has been documented.20
stopping the suspected drug.
Pathogenesis and histological features
Histological features By definition, linear IgA deposition along the basement membrane region
The histological features of cutaneous lesions are indistinguishable from is present in all cases (Fig. 14.58). C3 is seen in approximately 20% of
those seen in the idiopathic forms.16 cases.7 Linear IgG may also very exceptionally be present, although distinc-
tion from drug-induced bullous pemphigoid can then be problematical.3,17
Such cases may, in fact, represent examples of drug-induced IgA-mediated
Bullous drug reactions bullous pemphigoid.21 Circulating IgA anti-basement membrane zone anti-
bodies are found in 25% of cases.1 Split skin studies predominantly localize
Blisters may develop within the setting of an adverse drug reaction either to the floor of the blister cavity.1,2 By immunoelectron microscopy, the results
as a consequence of severe spongiosis or marked interface change or they
may reflect drug-related autoimmune bullous disorders (Fig. 14.55). In this
section, only the last are discussed. These include drug-induced linear IgA
disease, bullous pemphigoid, epidermolysis bullosa acquisita, pemphigus
variants, and drug-induced pseudoporphyria. Many alleged drug reactions
are single case reports, particularly in patients taking multiple medications.
It is often difficult to determine which associations are therefore coinciden-
tal and which are genuine. In occasional reports, recrudescence following re-
exposure to the offending agent has been documented.
The precise mechanism of drug-induced blistering is unknown, although
multiple factors have been suggested:1
• direct toxicity to basement membrane constituents or intercellular
junctions with resultant autoantibody production,
• the drug may function as a hapten,
• the drug may be antigenically similar to a basement membrane or
intercellular junction constituent,
• perturbation of the immune system with inappropriate production of
anti-basement membrane antibodies,
• drug-induced abnormality of cell membrane calcium metabolism.

Drug-induced linear IgA disease Fig. 14.56

Drug-induced linear IgA disease: these blisters developed following treatment with
Drug-induced linear IgA disease is most often associated with intravenous vancomycin. By courtesy of B.A. Solky, MD, Department of Dermatology, Harvard
therapy with vancomycin.1–7,8–10 Similar eruptions, however, have also been Medical School, Boston, USA.
608 Cutaneous adverse reactions to drugs

Fig. 14.57 Fig. 14.59

Drug-induced linear IgA disease: oral lesions were also present. By courtesy of B.A. Vancomycin-induced linear IgA disease: this case showed a neutrophil-rich
Solky, MD, Department of Dermatology, Harvard Medical School, Boston, USA. subepidermal blister.

Fig. 14.60
Fig. 14.58
Vancomycin-induced linear IgA disease: the adjacent skin showed neutrophil dermal
Vancomycin-induced linear IgA disease: immunofluorescence showed strong
papillary microabscesses.
basement membrane deposition of IgA.

are heterogeneous, IgA having been detected within the lamina lucida, lamina
densa, and in the sublamina densa.18–20 Western immunoblotting has detected
a number of antigens including a 230-kD antigen (bullous pemphigoid anti-
gen 1), a 97-kD antigen (an anchoring filament protein) and also a 250-kD
antigen corresponding to type VII collagen.19,20
Histologically, a neutrophil-rich subepidermal blister is seen in the major-
ity of cases but sometimes eosinophils are conspicuous (Figs 14.59–14.61).2

Drug-induced bullous pemphigoid

Clinical features
A variety of drugs including captopril, ciprofloxacin, chloroquine, furo-
semide (frusemide), ibuprofen, mefenamic acid, nifedipine, penicillamine,
penicillins, phenacetin, sulfasalazine, spironolactone, and enoxaparin have
been incriminated in alleged drug-induced bullous and mucosal pemphi-
goid.1–14 Of these, antirheumatics, cardiovascular drugs, and antimicrobial
drugs are the most important.6 Penicillamine is among the most commonly
incriminated (mucosal more than bullous), usually in rheumatoid arthritis
patients.6,15–17 Furosemide (frusemide) is believed to be an important cause of Fig.14.61
drug-induced bullous pemphigoid although recently this has been challenged, Vancomycin-induced linear IgA disease: conspicuous eosinophils may raise
the author suggesting that diagnoses of pseudoporphyria or epidermolysis suspicion for bullous pemphigoid if the clinical information is unavailable.

bullosa acquisita may be more appropriate.6,18 The ACE inhibitors, capto-
pril and enalapril, have both been associated with immunologically proven
bullous pemphigoid.2,8 The penicillins including amoxicillin and procaine
penicillin G are the most frequently implicated antibiotics.6
Clinically, drug-induced bullous pemphigoid is similar to idiopathic disease
although the lesions are often polymorphic, mimicking other drug-induced
bullous dermatoses such as erythema multiforme, eczematous dermatitis, and
porphyria cutanea tarda.6 In drug-induced disease, mucous membranes are
often involved, thereby blurring the distinction between bullous and mucosal
variants of pemphigoid. In some patients there appears to be overlap between
bullous pemphigoid and pemphigus vulgaris.6
Histological features
Drug-induced variants are characterized by linear IgG and C3 along the base-
ment membrane region on direct immunofluorescence.7,8 By indirect immu-
nofluorescence, the antibodies bind to the epidermal side (roof) of split
skin.2,5,6 Western immunoblotting has demonstrated that the antibodies react
with both the 230 kD and 180 kD bullous pemphigoid antigens.2,3
Histologically, drug-induced variants are similar to typical bullous pem-
phigoid, being characterized by an eosinophil-rich subepidermal blister.
Drug-induced epidermolysis
bullosa acquisita
Drug-induced epidermolysis bullosa acquisita has been described following
treatment with granulocyte–macrophage colony stimulating factor (GM-CSF)
and in a patient receiving vancomycin and gentamicin therapy.1,2 In both
patients, the blisters were subepidermal and eosinophil rich; direct immu-
nofluorescence disclosed linear IgA and IgG deposits at the basement mem-
brane region. Split skin indirect immunofluorescence in the former patient
labeled the floor of the blister cavity and by immunoelectron microscopy the
deposits were localized to the lamina densa and the sublamina densa region.1
In the latter patient, IgG antibodies against type VII collagen were recog-
nized by an enzyme-linked immunosorbent assay (ELISA).2 An epidermol-
ysis bullosa acquisita-like reaction has also been described after treatment
with penicillamine. Histological features included a pauci-inflammatory sub-
epidermal blister. Linear deposition of C3, IgG and IgM are seen on direct
immunofluorescence, and IgG labels to the base of the blister on salt-spilt
direct immunofluorescence.3
A significant number of cases of vancomycin-induced linear IgA disease
are characterized by antibodies which label the floor of split skin on indirect
immunofluorescence. Many of these might represent examples of drug-induced
epidermolysis bullosa acquisita.2 An epidermolysis bullosa acquisita-like blis-
tering dermatosis has been described with penicillamine therapy but this has
not been confirmed with immunofluorescent or molecular data.3
Drug-induced pemphigus
Clinical features
Pemphigus may be related to a wide range of drugs, either directly as a caus-
ative factor or indirectly as a precipitating or triggering factor.1–14 The range of
drugs is quite wide but many belong to the thiol group of compounds (char-
acterized by the presence of an -SH group) including penicillamine, capto-
pril, bucillamine, and thiopronine.1,4 Thiol-induced acantholysis is mediated
by both immune and direct biochemical mechanisms.5 Penicillamine most
often induces pemphigus in the setting of rheumatoid arthritis.6 Although
foliaceus is most commonly encountered, vulgaris, erythematosus, and her-
petiform variants may occur.2,6–8 Other drugs that contain sulfur, which
can also form -SH groups, include gold compounds, penicillins, rifampicin,
and cephalosporins.4 Topical application of imiquimod has been reported
to cause pemphigus foliaceus and vegetans.15–17 Additionally, both pemphi-
gus foliaceus and vulgaris lesions have been described as a consequence of
radiotherapy.18–21 Clinically, drug-induced pemphigus can resemble vulgaris,
foliaceus, erythematosus, and vegetans variants, the first being most often
encountered.4 In the older literature, foliaceus variants were typical but with
Psoriasiform drug reactions 609
a change in prescribing habits to non-thiol related drugs, vulgaris-type cases
are more frequently seen.4 In most cases of imiquimod-induced pemphigus
foliaceus, disease is localized to the sites of application, although there is one
report of both localized and distant lesions.16 In the setting of radiotherapy,
all patients developed pemphigus at the site of radiation.18–21 One patient also
had distant lesions.22
Pathogenesis and histological features
Histologically, drug-induced and idiopathic variants are indistinguishable.23
Intercellular IgG and circulating antibodies are variable in drug-induced pem-
phigus, although in a series of 10 patients all had positive direct immunofluo-
rescence and 80% had circulating antibodies.4 Such antibodies may recognize
desmoglein 3 and/or 1.1,22
Drug-induced pseudoporphyria
Clinical features
Pseudoporphyria is a rare blistering disease which clinically and histologi-
cally mimics porphyria but which develops in the setting of normal porphy-
rin metabolism (Fig. 14.62). There are many causes including drugs, chronic
renal failure usually in the setting of dialysis, excessive sun exposure and
UVA. It has also been described following excessive use of sunbeds.1–15 The
most common medications include diuretics such as furosemide (frusemide)
and NSAIDs, particularly naproxen. Other drugs include isotretinoin and the
oral contraceptive. More recently imatinib (tyrosine kinase inhibitor) and
voriconazole have been implicated.14,15
Pathogenesis and histological features
The pathogenesis of pseudoporphyria is unknown but it may (at least in some
patients) represent a phototoxic photosensitivity reaction.12
Histologically, pseudoporphyria is characterized by a subepidermal cell-
free blister, typically with preservation of the dermal papillae (festooning).
By immunofluorescence, immunoglobulin (most commonly IgG) is pres-
ent at the dermoepidermal junction and also outlining the superficial dermal
vasculature.
Psoriasiform drug reactions
Clinical features
Psoriasis and psoriasiform dermatoses can be caused by a number of drugs
including lithium, beta-blockers, NSAIDs, synthetic antimalarials, and tetracy-
cline.1–5 Drug-induced disease may have variable presentations including:1,2
Fig. 14.62
Pseudoporphyria: trauma-induced blisters on the backs of the hands and fingers are
characteristic. By courtesy of the Institute of Dermatology, London, UK.
610 Cutaneous adverse reactions to drugs

• exacerbation of pre-existing psoriasis,

• induction of new lesions in uninvolved psoriatic skin,
• precipitation of psoriasis de novo,
• resistance to treatment.
Lithium-induced psoriasis varies from exacerbation of pre-existing pso-
riasis to development of new disease.2 Manifestations vary from plaque
disease to generalized pustular psoriasis, palmoplantar pustulosis, scalp pso-
riasis, and psoriatic erythroderma.2,6–8 Latency varies from 1 week to years
or more.2
Beta-blockers (e.g. propranolol, oxprenolol, pindolol, alprenolol, and the
now discontinued practolol), antimalarials (e.g. chloroquine and hydroxy-
chloroquine) and NSAIDs (e.g. indometacin, phenylbutazone, oxyphenylb-
utazone, and ibuprofen) can also induce psoriasiform eruptions or result in
exacerbations and flares.1,2,9–15
The increasing use of TNF-alpha inhibitors is associated with new-onset
or exacerbated psoriasiform eruptions.16–21 Most patients develop palmo-
plantar pustulosis or plaque-type psoriasis.18–20 The average time to onset of
lesions is 6–10 months, although the range is variable.16–21 It is speculated that
inhibition of TNF-alpha increases levels of type 1 interferons which result in
psoriasiform lesions.21
A large number of other drugs have been linked with exacerbation of pso-
riasis or development of new disease. These include the antifungal agent ter-
Fig. 14.64
binafine, antibiotics such as penicillin and tetracycline, digoxin, amiodarone, Psoriasiform drug
IFN-α, recombinant IFN-α, and erlotinib (tyrosine kinase inhibitor).2,22–31 reaction: the capillaries
in the dermal papillae are
Histological features tortuous and dilated.
The histological features overlap lichen simplex chronicus and psoriasis.
Occasionally, they are indistinguishable from psoriasis vulgaris (Figs 14.63–
14.65). Psoriasis secondary to TNF-alpha inhibitors may also demonstrate
lichenoid inflammation and spongiosis.21

Pityriasiform drug reactions

Clinical features
Pityriasiform drug reactions may be particularly caused by ACE-inhibitors
and gold.1–4 Less often, terbinafine, omeprazole, benfluorex, arsenicals, bis-
muth compounds, isotretinoin, naproxen, acetaminophen, barbiturates,
and bacille Calmette-Guérin (BCG) therapy have been implicated.5–11 The
tyrosine kinase inhibitor imatinib has been associated with pityriasiform
dermatitis.12–14 Patients present with small erythematous lesions accompa-
nied by a peripheral scale, which may follow Langer's lines, giving rise to the
typical ‘fir tree’ appearance. The trunk and extremities are predominantly
affected.

Fig. 14.65
Psoriasiform drug
reaction: neutrophils are
present in the stratum
corneum.

Fig. 14.63
Psoriasiform drug eruption: there is confluent parakeratosis with elongated,
broadened, and partially fused rete ridges.
Histological features
Histologically, pityriasiform drug reactions are typically characterized
by patchy parakeratosis, focal spongiosis with lymphocytic exocytosis,
and a superficial perivascular lymphocytic infiltrate, sometimes associ-
ated with red cell extravasation (Fig. 14.66)3,6 On occasions, clinically
typical pityriasiform drug eruptions may demonstrate a more psorias-
iform histology.9

Fig. 14.66
Pityriasiform drug reaction: there is a focal parakeratotic scale associated with
acanthosis and spongiosis. A perivascular chronic inflammatory cell infiltrate
surrounds the superficial vasculature.
Pustular drug reactions
Clinical features
Drug-induced pustules are a manifestation of reactions to corticosteroids,
anabolic steroids, oral contraceptives, isoniazid, haloperidol, and lithium
therapy (Fig. 14.67).1 In addition, they are a feature of the halogenodermas
(see below).
Pustules are also the main feature of acute generalized exanthematous pus-
tulosis (AGEP, toxic pustuloderma) (Fig. 14.68). This rare condition is char-
acterized by the sudden onset of numerous small, nonfollicular pustules arising
against a background of pruritic or burning edematous erythroderma.2–11 The
eruption often starts on the face or in the intertriginous regions but soon
becomes generalized.3 The mucous membranes are affected in a minority of
patients.3 Facial edema, purpura, vesicles, blisters, and erythema multiforme-
like lesions have also been described.3,6 Pyrexia is usually present. Although in
the majority of patients there is no history of significant previous skin disease,
in some there is a background of psoriasis.3 The eruption usually resolves rap-
idly and is followed by widespread desquamation.9 Peripheral leukocytosis
with high neutrophil levels and sometimes eosinophilia can be present.3,9
Fig. 14.67
Pustular drug reaction: numerous pustules are present on an erythematous
background. By courtesy of the Institute of Dermatology, London, UK.
Pustular drug reactions 611
Fig. 14.68
Acute generalized exanthematous pustulosis: tiny pustules are evident. There is
intense erythema. By courtesy of B.A. Solky, MD, Department of Dermatology,
Harvard Medical School, Boston, USA.
While this disorder may occur as a feature of mercury toxicity or follow
a viral infection (particularly enteroviruses) or spider bite, in the majority of
cases it represents an adverse drug reaction.3,12,13 In most patients, the eruption
has followed antibiotic therapy including penicillin, amoxicillin, ampicillin,
metronidazole, trimethoprim, and erythromycin.3,9 Analgesics (e.g. acetamin-
ophen), antiepileptics (e.g. carbamazepine), antidiabetics (e.g. carbutamide),
antifungals (e.g. terbinafine), antimalarials (e.g. hydroxychloroquine), and
many other drugs have also been implicated.3,11–19 The condition often devel-
ops rapidly following the administration of the drug – sometimes in a matter
of hours.3,7
Histological features
The pustules are present in a subcorneal and/or intraepidermal location and
sometimes contain a few acantholytic keratinocytes in addition to large num-
bers of neutrophils (Figs 14.69, 14.70).3,9 A background of spongiosis is
usually evident. The dermal papillae are often edematous and occasionally
subepidermal vesiculation is a feature. A perivascular infiltrate of lympho-
cytes and histiocytes with conspicuous neutrophils and variable numbers of
eosinophils is generally present in the superficial dermis. Leukocytoclastic
vasculitis may be a feature in a significant proportion of cases.3,9,11
Fig. 14.69
Acute generalized exanthematous pustulosis: there is a subcorneal pustule. The
dermis is intensely inflamed.
612 Cutaneous adverse reactions to drugs
Fig. 14.70
Acute generalized exanthematous pustulosis: high-power view of pustule. Note the
acantholysis.
Differential diagnosis
The differential diagnosis includes pustular psoriasis, subcorneal pustular
dermatosis, IgA pemphigus, pustular necrotizing angiitis, and acute general-
ized pustular bacterid.20,21
Ichthyosiform drug reactions
Clinical features
Exceptionally, acquired ichthyosis following lipid-lowering agents (includ-
ing triparanol and diazacholesterol) and kava consumption has been docu-
mented.1–3 The clinical features may resemble ichthyosis vulgaris or lamellar
ichthyosis.
Histological features
In ichthyosis vulgaris-like drug-induced variants, there is mild hyperkeratosis
associated with a diminished to absent granular cell layer. A mild superficial
perivascular lymphohistiocytic infiltrate with occasional eosinophils may be
present.
In the lamellar ichthyosis-like variant, there is marked hyperkeratosis,
mild acanthosis, and a normal or thickened granular cell layer.
Drug-induced pseudolymphoma
Clinical features
Drug-induced pseudolymphoma includes pseudolymphomatous reactions to
systemically administered medications (lymphomatoid drug eruption) and
the much less frequent contact variant associated with locally administered
agents (lymphomatoid contact dermatitis).1–3
Lymphomatoid drug eruptions are commonly a T-cell type, although B-cell
lymphomatoid drug eruptions are also recognized. T-cell variants are divided
into anticonvulsant-related and nonanticonvulsant-related variants.2
Anticonvulsant-related T-cell lymphomatoid drug eruption typically devel-
ops within weeks or months of commencing treatment. Patients present with
pyrexia, lymphadenopathy, and an eruption of single or generalized lesions
comprising erythematous, morbilliform maculopapules, plaques, nodules or
tumors often associated with leukocytosis, circulating Sézary cells, eosino-
philia, hepatosplenomegaly, and variable liver dysfunction (Fig. 14.71).2,4–16
Vesicles and purpuric lesions have also been described.14 Sézary’s syndrome-
like features may rarely be seen.17 A number of anticonvulsants have been
implicated including phenytoin, primidone, mephenytoin, carbamazepine,
Phenobarbital, and trimethadione.2
Fig. 14.71
Drug-induced pseudolymphoma: this patient developed a maculopapular eruption
following treatment with phenytoin.
Nonanticonvulsant-related pseudolymphomatous reactions present simi-
larly with single lesions or multiple papules, plaques, and nodules. Associated
drugs include antihypertensives, antidepressants, tranquilizers, beta-blockers,
calcium channel blockers, diuretics, NSAIDs, and antibiotics.2,18–22 Sézary’s
syndrome-like features have also been documented.23
Lymphomatoid contact dermatitis is much less common and usually repre-
sents a T-cell reaction to a contact allergen that histologically shows features
reminiscent of mycosis fungoides.2,24–31 Patients present with pruritic, local-
ized to generalized scaly papules and plaques.2 A number of antigens have
been incriminated including matchbox striking surface antigens, ethylenedi-
amine dihydrochloride, isopropyl-diphenylenediamine, phosphorus, nickel,
cobalt naphthenate, and para-phenylenediamine.
B-cell lymphomatoid drug reaction is rare but has been described in asso-
ciation with fluoxetine hydrochloride and amitriptyline hydrochloride.2,21,22
Patients present with solitary nodules, multiple infiltrative plaques, or mul-
tiple papules.
B-cell lymphomatoid contact reactions may be seen with gold and nickel
earrings. Patients present with one or more firm, erythematous nodules at the
site of piercing.32–34
B- and, less commonly, T-cell pseudolymphomatous reactions may
develop within tattoos.35–39 Papules and nodules localized to the tattoo occur
months to years after tattoo placement. The most common culprit is red
pigment, although reactions to blue and green dyes have been reported.38,39
Both metals and organic synthetic pigments are implicated as antigens in
such reactions.
Pathogenesis and histological features
The pathogenesis of lymphomatoid drug reactions is not completely under-
stood, but is thought to be secondary to immune dysregulation. Studies show
that medications implicated in drug-induced pseudolymphoma can induce
proliferation of T cells and inhibit suppressor T cells, both in vivo and in
vitro.40,41 This may lead to an increase in helper T cells as well as B cells,
resulting in T-cell and B-cell pseudolymphoma, respectively.
Drug-induced T-cell pseudolymphoma most often presents as a dense
superficial perivascular or bandlike infiltrate composed of lymphocytes, his-
tiocytes, and atypical lymphoid cells with irregular, enlarged, and hyper-
chromatic nuclei (Figs 14.72–14.76).42 Cerebriform variants may be seen
and there is often associated epidermotropism. Pautrier-like microabscesses
reminiscent of mycosis fungoides, however, are only occasionally identified.
Eosinophils are frequently evident and often the epidermis shows significant
spongiosis. Giant cells, collections of histiocytes, and epithelioid granulomata
may also be evident. Dense nodular and tumor-like variants more suggestive
of pleomorphic T-cell lymphoma may also be encountered (Figs 14.77–14.79).
A follicular mucinosis-like variant has rarely been described.22

Fig. 14.72
Drug-induced pseudolymphoma: there is an atypical superficial perivascular
lymphocytic infiltrate. Note the marked epidermotropism. The histological features
are suggestive of mycosis fungoides.
Fig. 14.73
Drug-induced
pseudolymphoma:
the lymphocytes are
surrounded by a well-
developed retraction
artifact and there
is a small Pautrier
microabscess.
By immunohistochemistry, the infiltrate consists of CD3+ T cells. CD4+
cells most often outnumber CD8+ forms, and CD20+ B cells are either
extremely sparse or absent. A CD8+ variant has, however, been recently
described following treatment with gemcitabine.35 CD30 expression with
resultant confusion with an anaplastic large cell lymphoma has exceptionally
been described.11,43–45
Reported T-cell receptor gene rearrangement studies have disclosed a
clonal population in only a small minority of patients.5,6,12,14
Lymphomatoid contact dermatitis most often is reminiscent of mycosis
fungoides and is characterized by a superficial dermal bandlike infiltrate
composed of atypical lymphocytes and histiocytes with variable lymphocyte
epidermotropism. The epidermis is typically acanthotic, and spongiosis may
sometimes be present.
Immunohistochemical analysis has been reported in a small number of
cases. The atypical lymphocytes usually express CD3 and CD4 with no loss
of CD5 and CD7. A CD8 predominant variant has been documented.29
Drug-induced pseudolymphoma 613
Fig. 14.74
Carbamazepine-induced
pseudolymphoma: in this
example, there is a dense
bandlike upper dermal
lymphocytic infiltrate.
Fig. 14.75
Carbamazepine-induced pseudolymphoma: there is marked lymphocytic atypia.
Cerebriform cells are present. The features are very suggestive of plaque stage
mycosis fungoides.
In the limited number of cases in which T-cell receptor (TCR) gene rear-
rangements have been documented, two have disclosed a polyclonal pattern
while one has displayed a weak monoclonal band.26,29,31
B-cell lymphomatoid drug reactions are characterized by a nodular or ­diffuse
pandermal infiltrate, often accompanied by extension into the subcutane-
ous fat. The infiltrate consists of lymphocytes and histiocytes with variable
numbers of plasma cells and eosinophils. Mitoses are sometimes numerous.
Blasts are often present and lymphoid follicles with germinal centers may be
evident.
By immunohistochemistry, the majority of the lymphocytes are CD20+ B
cells although a subpopulation of CD3+ T-cells is also present. Identification
of CD21+ follicular dendritic cells may be helpful in confirming the pres-
ence of poorly developed follicles. Kappa and lambda immunohistochemistry
invariably show no evidence of light chain restriction.
Tattoo-associated pseudolymphomas may be of the B- or T-cell type, with
a B-cell pattern being more common. In addition to the features described
614 Cutaneous adverse reactions to drugs

Fig. 14.78
Drug-induced pseudolymphoma: scattered multinucleated giant cells are evident.
Fig. 14.76
Carbamazepine-induced
pseudolymphoma:
diagnosis depends upon
careful clinicopathological
correlation.

Fig. 14.79
Drug-induced pseudolymphoma: there is marked lymphocytic atypia. The nodules
melted away following withdrawal of drug.

Fig. 14.77 is withdrawal of the suspected drug. It is important that correlation always be
Drug-induced undertaken in any case of an unanticipated lymphoma in order that reactive
pseudolymphoma: this conditions do not receive inappropriate lymphoma treatment.
very dense dermal
infiltrate developed
following treatment Specific drug reactions
with an antidepressant.
Multiple cutaneous
nodules were present. Arsenic
Clinical features
above, there is tattoo pigment extracellularly and within macrophages. Arsenic exposure can be encountered under a variety of circumstances.1–7 It
Rarely, a lichenoid infiltrate is present.39 may be a constituent of proprietary medicines and is an active component
of pesticides and herbicides.3 Fowler's solution – once used in the treatment
Differential diagnosis of psoriasis and other dermatological disorders – contained 1% potassium
Distinction between cutaneous lymphoma and a drug-induced pseudolym- arsenate.1,3 The most common source of arsenic exposure now is through
phoma can be exceedingly difficult. Features that favor a drug-induced contaminated ground water. For many years (as a consequence of its use as an
process over mycosis fungoides include vacuolar alteration, keratinocyte insecticide) it was an ingredient in cigarette tobacco.2,4 High levels of arsenic
necrosis, spongiosis, and papillary dermal edema.40 However, there can be occur in the mining and smelting industries.3
considerable histological overlap and rare instances of a T-cell receptor gene Exposure to arsenic may cause acute arsenical dermatitis, although more
rearrangement necessitate close clinicopathological correlation. If cutaneous commonly patients are seen with long-term sequelae.2–7 The former presents
pseudolymphoma is suspected, the most effective way to make the distinction with a diffuse erythematous papular or pustular/bullous dermatosis that can
 Specific drug reactions 615

progress to exfoliative dermatitis.5 Transverse white nail striations may be a

feature.5 Chronic complications of arsenic exposure include pigmentary dis-
turbances and cutaneous tumors. Patients are also at increased risk of internal
malignancies.1,7 Other systemic manifestations include atherosclerosis, hepatic
fibrosis, peripheral neuropathy, respiratory disease, and diabetes mellitus.7
Characteristic of arsenicism is the ‘rain drops on a dusty road’ appear-
ance in which patients develop hyperpigmented macules containing foci of
hypopigmentation and areas of darker pigmentation.7–10 Lesions are often
seen on the trunk and in heavily pigmented regions such as the areola and
flexural creases.3 The cutaneous pigmentary changes are especially seen in
Asian populations.3
Palmar and plantar keratoses are common and present 2 years or more
after exposure.5 After many years they may be associated with malignant
transformation.7
Skin tumors are a late manifestation, are often multiple, and are particu-
larly found on non-sun-exposed sites. Bowen’s disease, squamous cell carci-
noma, and superficial basal cell carcinoma may develop.1,2
Patients with evidence of arsenic exposure should be investigated for vis-
ceral malignancies, particularly carcinoma of the lung, bladder, and kid-
ney.7,11,12 There are occasional reports documenting an association between Fig. 14.80
Iododerma: ulcerated vegetative plaques are present on the backs of the hands
arsenic and hepatic angiosarcoma.13,14
and fingers. By courtesy of the Institute of Dermatology, London, UK.

Pathogenesis and histological features

The mechanism of arsenic carcinogenesis is multifactorial. Arsenic is meth-
ylated as part of the metabolization process.6 This results in free radicals
which damage DNA, contribute to chromosomal aberrations, and increase
sister chromatid exchange.7 Arsenic also impairs the DNA repair process and
diminishes p53 activity.15 Transcription factors, cytokines, and cell signal-
ing pathways critical to regulation of cellular proliferation and differentia-
tion are also affected by arsenic and lead to uncontrolled cell growth and
de-differentiation.7,15,16
Histologically, cutaneous hyperpigmentation demonstrates increased mel-
anin synthesis, with excess pigment being present at all levels of the epider-
mis.3 There is no evidence of melanocytic proliferation. Skin cancers arising
as a result of arsenic exposure show no distinguishing features histologically
and are described elsewhere.

Iododerma
Clinical features
Potassium iodide is encountered in various settings. It is often included in Fig. 14.81
expectorants/bronchodilators and is used for treatment of thyroid disease and Iododerma: in this patient,
as a radiocontrast medium. nodules are conspicuous.
Superimposed pustules
Adverse reactions are rare.1–9 Acneiform papulo/pustular lesions are most
are evident. By courtesy
common and affect the face, neck, and back.3,4 Erythematous, urticarial,
of the Institute of
vesiculobullous, and pustular psoriasis-like lesions have been described.1,7 Dermatology, London,
Rarely, chemical burnlike changes develop in patients, often post-surgical, UK.
when there is concomitant occlusion and maceration.9 Lesions affecting the
lower limbs may be petechial, hemorrhagic or resemble erythema nodo-
sum.1,2 Nodular and ulcerated vegetative plaques constitute more extreme Differential diagnosis
forms. This latter variant affects the face, shoulders, trunk, and extremities
and presents as 1–7 cm disfiguring, crusted, erythematous lesions, sometimes Histologically, the nodular lesions of iododerma resemble an infective process
with central umbilication (Figs 14.80, 14.81).3 Healing may be complicated such as blastomycosis or an atypical mycobacterial condition. The presence
with scarring. of occasional eosinophils within the infiltrate and epidermal degeneration in
Iododerma is associated with multiple myeloma, polyarteritis nodosa, association with the abscesses may result in confusion with pemphigus veg-
lymphoma, and glomerulonephritis.3,7,10 Renal insufficiency may be a predis- etans. In early lesions, when the epidermis is normal thickness, the features
posing factor. can be mistaken for Sweet’s syndrome and pyoderma gangrenosum.

Pathogenesis and histological features Bromoderma

Although delayed hypersensitivity is believed to represent the underlying
pathogenesis, the precise mechanism is unknown. Acute lesions are char-
acterized by an intense dermal neutrophil-rich infiltrate. With chronicity,
pseudoepitheliomatous hyperplasia and ulceration are common. Neutrophil
microabscesses may be seen in the epidermis and the dermis; in some cases,
there is focal leukocytoclastic vasculitis.3,5
Clinical features
Methyl bromide has been used as a pesticide and disinfectant and in the phar-
maceutical, film, and dye industries.1–5 It may be found in sedative syrups
and expectorants. Although occupational exposure is associated with severe
respiratory effects including pulmonary edema, occasional reports of skin
616 Cutaneous adverse reactions to drugs
contact have also been documented.3,4 Potassium bromide is used as an anti-
convulsant in many parts of the world. Other sources of exposure include
brominated pool disinfectants and brominated vegetable oil, a product used
in citrus-flavored drinks.6 Patients present with sharply circumscribed ery-
thematous lesions containing vesicles and bullae.4 Intertriginous regions and
sites of mechanical pressure are predominantly affected. Ingested bromide
may give rise to hyperpigmentation, urticaria, acneiform/pustular lesions
(acne bromica), vegetative and ulcerated plaques (vegetant bromoderma,
tuberous bromoderma), necrotizing panniculitis, and pyoderma gangreno-
sum-like ulcers (Fig. 14.82).7–12 Lesions may be multiple or solitary. Vegetant
bromoderma most often presents on the face, scalp, and legs and predomi-
nantly affects infants.7 It is commonly mistaken for an infection. A case which
complicated bromine secretion in breast milk has been documented.13
Histological features
Cutaneous lesions that develop following acute exposure to methyl
bromide are characterized by spongiosis, keratinocyte necrosis, papil-
lary dermal edema, and subepidermal blister formation.4 A perivascu-
lar inflammatory cell infiltrate containing neutrophils, eosinophils, and
smaller numbers of lymphocytes and histiocytes is present in the super-
ficial dermis.
In vegetating lesions, there is striking pseudoepitheliomatous hyperpla-
sia with intraepidermal and dermal abscesses accompanied by an intense
neutrophil, eosinophil, and lymphohistiocytic infiltrate in the underlying
dermis.
Urticarial lesions show papillary dermal edema accompanied by a neutro-
phil and eosinophil-rich infiltrate.4
Differential diagnosis
Vegetating lesions may be easily confused with deep fungal and atypical myco-
bacterial infections. Pemphigus vegetans also enters the differential diagno-
sis. The diagnosis may be most easily reached by careful clinicopathological
correlation.11
Warfarin
Warfarin (coumadin) may be associated with a number of adverse reactions
including hemorrhage, alopecia, urticaria, maculopapular eruptions, der-
matitis, purple toe syndrome, and leukocytoclastic vasculitis.1–8 Cutaneous
necrosis develops in 0.01–0.1% of patients and may cause severe morbidity
and significant mortality.5
Fig. 14.82
Bromoderma: vegetant plaques and nodules are seen around the eye. Ulceration
is present. By courtesy of the late M. Beare, MD, Royal Victoria Hospital, Belfast,
N. Ireland.
Clinical features
Warfarin necrosis typically develops 3 to 6 days after starting anticoagu-
lation therapy. Paresthesia is present initially and is followed by a painful,
well-­circumscribed, edematous, and erythematous plaque resembling peau
d’orange with purpura.1,5 Large blood-filled blisters that rapidly break down,
accompanied by progressive necrosis of the underlying dermis and subcuta-
neous fat, are later sequelae. Tissue destruction is often considerable and the
resultant scarring is very disfiguring. Occasionally, the onset of this condition
is delayed for weeks or months although in most instances this reflects an
interrupted therapeutic regimen.9,10
The condition shows a predilection for obese females (85%) and pre-
dominantly affects the breasts, buttocks, and thighs.2 The reason for the
female predominance is unknown. In males, the thighs and buttocks are
also affected and sometimes the penis is involved. Occasionally, lesions
are seen on the hands. Deeper soft tissues and internal viscera are not
affected.
Patients almost invariably have received anticoagulation for thrombophle-
bitis (deep venous thrombosis) and/or pulmonary embolism. Patients who
receive warfarin for treatment of cardiovascular disorders such as atrial fibril-
lation only very exceptionally develop this condition.5
Pathogenesis and histological features
Cutaneous necrosis rarely complicates therapy with warfarin. Although
hypersensitivity reactions and direct toxicity have been postulated as etio-
logical factors, an imbalance in the ratio of procoagulative and anticoag-
ulative factors is currently thought to be most important.5 In addition to
depressing the vitamin K-dependent clotting factors II, VII, IX, and X, war-
farin reduces the levels of naturally occurring anticoagulants including pro-
tein C, protein S, and antithrombin III. It first affects protein C, which has
an extremely short half-life, and until the anticoagulative effect comes into
play with depressed levels of coagulating factors, the patient is paradoxi-
cally at increased risk of thrombosis. Why this should so rarely result in skin
necrosis is uncertain.
Congenital protein C deficiency is an important predisposing factor in
some patients. This is a relatively common autosomal dominant condition
that affects between 1:200 and 1:300 of the population. Protein C is acti-
vated by thrombin under the influence of the cofactor thrombomodulin.5
The activated form inactivates factors VIIIa and Va, which inhibit conver-
sion of factor X to factor Xa and prothrombin to thrombin with resul-
tant inhibition of coagulation.5 Protein C deficiency is, therefore, associated
with a thrombotic tendency.11 Approximately 30% of patients who develop
warfarin necrosis have an underlying protein C deficiency.2 Warfarin ther-
apy, therefore, tips the balance in an already protein C-deficient patient.
The proposed mechanism, however, by no means offers an explanation in
the majority of cases.
Acquired or congenital deficiency of protein S may also be of importance
in a small number of cases.12–15 Protein S is a vitamin K-dependent cofactor
for activated protein C.5 Acquired protein S deficiency may be encountered in
patients with renal failure or antiphospholipid syndrome, or who are under-
going hemodialysis.16,17
An episode of thrombophlebitis and/or pulmonary embolism leading to
the warfarin therapy seems to be of major etiological importance.1,2 It is
proposed that the vascular inflammatory changes play a role in precipitat-
ing the thrombotic tendency by reducing endothelial cell thrombomodulin
levels, inactivating protein S and decreasing fibrinolytic activity.1–4 Protein C
or protein S deficiency (inherited or developing as a consequence of warfarin
therapy) may then represent an additional predisposing factor. Other condi-
tions that predispose to the development of warfarin necrosis include reduced
antithrombin III levels, lupus anticoagulant syndrome, factor V Leiden, and
prothrombin gene mutation.18–20
Histologically, warfarin-associated skin necrosis is characterized by fibrin
thrombi in the small veins and venules of the dermis and subcutaneous fat,
with widespread erythrocyte extravasation (Figs 14.83, 14.84). In advanced
lesions, subepidermal blood-filled blisters are seen. In older lesions, the
changes of infarction are superimposed; however, vasculitis is not a feature.
Arteries are not affected.

Fig. 14.83
Coumadin necrosis: there are thrombosed vessels throughout the superficial
dermis associated with epidermal regeneration.
Fig. 14.84
Coumadin necrosis: high-power view of Figure 14.83.
Differential diagnosis
Identical histological features may be seen in a number of conditions includ-
ing antiphospholipid antibodies, hereditary hypercoagulation disorders (fac-
tor V Leiden mutations, protein C or S, and antithrombin III deficiencies)
in the absence of warfarin therapy, heparin-induced thrombocytopenia syn-
drome and disseminated intravascular coagulation (DIC). Cryoglobulinemia
and cryofibrinogenemia may also have to be excluded. Calciphylaxis can be
excluded by the absence of vascular calcification. The diagnosis ultimately
depends upon adequate clinicopathological correlation.
Heparin
Adverse side effects of heparin include hemorrhage, urticaria, anaphylaxis,
macular erythema, and alopecia.1–3 Of greater significance, patients may
develop thrombocytopenia, paradoxical thrombosis, and skin necrosis –
­heparin-induced thrombocytopenia syndrome (HIT syndrome).1–6
Clinical features
Urticarial reactions are exceptionally rare.7–9 Delayed hypersensitivity reac-
tions are the most common of the adverse cutaneous responses to heparin,
occurring in 7.5% of patients.9,10 Macular erythema and eczematous lesions
Specific drug reactions 617
occur at the injection site. There is a striking female predominance.2,11 Rarely,
blisters may develop, and exceptionally the erythema becomes generalized.10
Hemorrhagic vesicles have also been described in patients given low molec-
ular weight heparin.12,13 Reported patients have been elderly and received the
medication while hospitalized. Lesions develop distant from injection sites
and occur on the extremities.
HIT syndrome – in addition to definitional thrombocytopenia – is char-
acterized by thrombosis (venous more often than arterial) which account for
the high morbidity and potential mortality.4,6 Venous thrombosis results in
deep venous lesions in the lower legs in up to 50% of patients, and of these
25% may develop pulmonary embolism.6 Additional complications include
­warfarin-induced limb gangrene, adrenal hemorrhage, and DIC.6 Arterial
thrombosis is more likely in catheterized or traumatized arteries and may
affect the aorta and ileofemoral arteries, resulting in peripheral gangrene,
myocardial infarction or stroke.4,6
Cutaneous necrosis develops in 10–20% of patients with the HIT syn-
drome.6,14 The injection site is predominantly involved but more distant
areas (thighs, abdomen, and buttocks) may also be affected in a minority of
patients.1,2,15–24 Initial lesions are painful or burning erythematous plaques fol-
lowed by ulceration and tissue necrosis.2 The condition shows a predilection
for middle-aged females and the obese.2,15
Thrombocytopenia and thromboembolism are potentially life-threatening
complications.
Pathogenesis and histological features
The heparin-induced thrombocytopenia syndrome results from platelet acti-
vating HIT/PF4 antibodies induced in response to a platelet factor 4-heparin
complex.1,22,23 The resulting immune complexes bind to platelet Fc receptors
and activate platelets. In addition, the antibody reacts with surface endothe-
lial cell platelet factor 4-inducing endothelial cell injury and thrombosis.4,23
Only a minority of patients with HIT antibodies develops skin necrosis, and
it is postulated that additional prothrombotic factors such as protein C or S
deficiency are necessary for the development of thrombosis and its sequelae.1
Adverse side effects are more common and more severe in patients receiving
unfractionated as opposed to low molecular weight heparin.24
The histological features of the macular erythema are those of spongiotic
dermatitis. Within the superficial dermis is a perivascular lymphohistiocytic
infiltrate with variable numbers of eosinophils. The lymphocytes are predom-
inantly of the T-helper subclass.25
Heparin-induced cutaneous necrosis is characterized by widespread super-
ficial small vessel (capillary and venule) thrombi accompanied by hemorrhage
and necrosis.16,17 The presence of leukocytoclastic vasculitis is variable.2
Bullous hemorrhagic lesions are intraepidermal blisters filled with
extravasated red blood cells.12,13 Perivascular lymphocytes, histiocytes, and
eosinophils are variably present. Leukocytoclastic vasculitis is absent. Direct
immunofluorescence studies are negative.
Penicillamine
Clinical features
Penicillamine therapy is associated with various adverse reactions including
exanthematous eruptions, urticaria, lichenoid reactions, papulosquamous
dermatoses, alopecia, hypertrichosis, nail changes, dermatomyositis, systemic
lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, pemphigus
erythema, and bullous and mucosal pemphigoid.1–12 The autoimmune blister-
ing dermatoses complicating penicillamine therapy are not dose dependent
and are seen particularly in patients with other immunologically mediated
diseases including rheumatoid arthritis and systemic sclerosis.9 Pemphigus is
by far the most common bullous disorder associated with penicillamine, pem-
phigus foliaceus being the most frequent variant encountered.4,9 Herpetiform
pemphigus has also rarely been described as complicating the use of pen-
icillamine.10,11 Additional manifestations – particularly seen in patients tak-
ing high doses in the treatment of Wilson’s disease and cystinuria – include
penicillamine dermopathy, elastosis perforans serpiginosa, skin fragility with
hemorrhages and milia formation on the extensor surfaces, wrinkling and
anetoderma-like changes, cutis laxa, and pseudoxanthoma elasticum-like
618 Cutaneous adverse reactions to drugs

appearances.13–19 Patients on long-term therapy may present with small yel-

low papules resembling a plucked-chicken appearance or disfiguring loose
folds of skin particularly affecting the flexures.16,17

Histological features
Penicillamine acts by impairing cross-linking in newly formed collagen and
elastic fibers.13 The histological features include increased numbers of abnor-
mally formed elastic fibers in the reticular dermis (Fig. 14.85). These are
thickened with irregular serrated appearance on cross-section. When viewed
in a longitudinal plane, the fibers show conspicuous lateral projections
(Figs 14.86, 14.87).
Evidence of similar elastic tissue damage has been documented in the joint
capsules, lungs, intestine, and large elastic arteries.13

Gold
Clinical features
Gold therapy may result in eczematous, lichenoid, pityriasiform, and psorias-
iform dermatoses and stomatitis.
Cutaneous pigmentation which results from parenteral treatment with gold
salts is known as chrysiasis (auriasis, chrysoderma, hautaurosis).1–5 It is a pho-
Fig. 14.87
Penicillamine dermopathy: the changes can be highlighted by an elastic tissue stain.
todependent, irreversible condition most often documented in patients with
rheumatoid arthritis.2,3 Patients are at risk once a threshold of 50 mg/kg of
gold is reached.1 Disease severity correlates with the cumulative dose of gold.6
Coloration varies from mauve/blue to blue to slate-gray.2 The ­sun-exposed
skin of the face is particularly affected. In severe cases lesions may be seen on
the neck, front of chest, and backs of the forearms and hands (Fig. 14.88).2
In bald patients, scalp involvement is sometimes apparent. Pigmentation has
also been described in the sclera and buccal mucosa.2

Pathogenesis and histological features

The pathogenesis of chrysiasis is uncertain. It is probably related to an effect
of UV radiation on tissue-bound gold particles. Support for this hypothesis
is the observation that skin lesions can be induced by UVB irradiation of
­sunlight-protected skin.7 Similarly, typical skin lesions have been described
following Q-switched ruby laser treatment in patients treated with gold.8–10
Chrysiasis is characterized by deposits of small black macrophage-
bound particles surrounding the vessels in the deeper reticular dermis and
around the sweat gland coils (Fig. 14.89).2 Perl’s Prussian blue (hemo-
siderin) and Masson-Fontana staining for melanin are negative. The gold
particles show orange–red birefringence with cross-polarized light.11 There
Fig. 14.85 is no inflammatory response. Epidermal melanin pigmentation usually
Penicillamine dermopathy: there are thickened, intensely eosinophilic elastic fibers appears normal.2
throughout the reticular dermis.

Fig. 14.88
Fig. 14.86 Chrysiasis: multiple foci of blue discoloration are present on the cheek. By courtesy
Penicillamine dermopathy: the serrated appearance is characteristic. of J. Kerner, MD, Department of Dermatology, Harvard Medical School, Boston, USA.
 Specific drug reactions 619

Fig. 14.89 Fig. 14.90

Chrysiasis: there are fine black granules both within macrophages and lying Argyria: there is striking slate-blue pigmentation; the eyes are also affected. By
free around the superficial vasculature. By courtesy of S. Lyle, MD, Beth Israel courtesy of the Institute of Dermatology, London, UK.
Deaconess Medical Center, Boston, USA.

By electron microscopy, the gold appears as granular, particulate, and fila-

mentous material, sometimes showing a starlike morphology within phago-
lysosomes (aurosomes). The diagnosis can be confirmed by electron/X-ray
probe microanalysis.2,4,12–14

Differential diagnosis
Gold pigment must be distinguished from silver deposits (argyria), mercury,
and tattoo pigment.5,10 Silver pigment is predominantly deposited in relation
to basement membranes, particularly of the sweat glands. It does not show
orange–red birefringence with cross-polarized light.10 Mercury particles are
large (up to 340 μm in diameter) and brown-black in color. Tattoo usually
consists of a variety of different pigments of varying colors. Clinical history
should readily establish the diagnosis in the majority of cases.

Silver
Clinical features
Generalized tissue accumulation of silver (argyria) follows dietary, medici-
nal, and industrial exposure to silver compounds.1–9 Occupational exposure
may be encountered in silver mining and smelting, electroplating, and in the
photographic industries.3 Silver deposits are found in the skin and mucous
membranes in addition to internal viscera, particularly liver, spleen, adrenals,
muscle, and brain (Fig. 14.90).1 Argyria initially presents in the gingivae
as a slate-blue line due to deposition of metallic silver and silver sulfide.1–3
Cutaneous manifestations affect the sun-exposed sites of the face, neck, and
backs of hands.6 The nails may also be involved. Ocular involvement presents
as a bluish-gray to brownish-black coloration.
Localized argyria has been documented due to silver earrings, orthodon-
tic surgery, acupuncture, silver polishing, and the application of topical silver
sulfadiazine.10–19 In the absence of clinical information, a diagnosis of blue
nevus may mistakenly be made.11
Histological features
Argyria results from deposition of metallic silver and silver sulfide. Pigmentation
is intensified by sunlight due to silver reduction analogous to photographic
processing.6 There is also increased epidermal melanin synthesis.
Silver granules are found in association with the vascular and adnexal
basement membranes and adjacent to dermal elastic fibers (Fig. 14.91).2
They measure less than 1.0 μm in diameter and appear brown–black in hema-
toxylin and eosin stained sections.6 Ultrastructurally, the silver granules may
be membrane bound within macrophage lysosomes or lie freely in the der-
mis.8 The diagnosis can be confirmed by X-ray microanalysis.6,9
Fig. 14.91
Argyria: note the fine silver granules outlining the basement membrane of the
sweat gland epithelium.
Mercury
Clinical features
Mercury exposure is encountered under a variety of circumstances.1–3
It occurs in three different forms: metallic, inorganic, and organic
mercury.1
• Metallic mercury, which is a liquid at room temperature, is present in
vapor from heating amalgam and paints and in mercury thermometers.4
• Inorganic mercurial salts may be present in laxatives, pesticides,
antiseptics and germicides.1,5
• Organomercurials are used as industrial antifungal agents.4
Dermatological reactions to metallic mercury include mercury granu-
loma and mercury exanthem (acute generalized exanthematous pustulosis).
Mercury granuloma follows penetrating skin wounds as might result from a
broken thermometer, attempted homicide or suicide. Patients present with a
flesh-colored to red or hyperpigmented nodule at the site of implantation.6–10
Membranous fat necrosis following subcutaneous mercury injection has also
been documented.11 Mercury exanthem follows exposure to metallic mercury
(as may follow breaking a thermometer) in a previously sensitized patient.12–22
620 Cutaneous adverse reactions to drugs
The eruption presents as a vivid erythema, which particularly affects the flex-
ural sites of the body (so-called ‘Baboon syndrome’).17 An inverted V-shaped
erythema affecting the upper anteromedial aspects of both thighs is charac-
teristic.12,16 Sterile pustules commonly develop and a purpuric element may
develop. Pyrexia and peripheral leukocytosis are typically present. The der-
matosis resolves by desquamation.
Topical mercury cream has been used as a skin-bleaching agent.6,23,24
Continuous and protracted use results in slate-gray pigmentation affect-
ing the flexures. The eyelids, nasolabial folds, and neck creases are sites of
predilection.25,26
Parenteral use of mercury results in pigmentation of the gingivae.26
A  lichenoid drug reaction has been documented following acute mercury
poisoning.27
Dental workers are at risk of allergic contact dermatitis from exposure to
mercury or mercury salts.28
Mercury may also be associated with palmar/plantar peeling in chil-
dren (pink disease, acrodynia, erythredema), palmar/plantar hyperkeratosis,
and acanthosis nigricans-like skin lesions.29 Pink disease is rarely encoun-
tered nowadays due to control of mercury in medications and in the envi-
ronment.30–32 The condition is still occasionally seen and may be a problem
in developing countries. It presents in infants and young children following
chronic mercury exposure, for example in diaper powders, laxatives, paint,
fluorescent light bulbs or other household sources.1 It is characterized by the
development of characteristic painful swelling and pink coloration of the tip
of the nose, fingers, and toes.1,11 As the condition resolves, the palms and
soles show intense sweating and desquamation.1 Sterility in males is a poten-
tial long-term sequel.31
Lichenoid and granulomatous inflammatory reactions may complicate
use of mercuric sulfide (cinnabar) to provide the red color in tattoos.33–35
Pseudolymphomatous reactions to mercury have also been documented.36,37
Amalgam tattoo reactions are discussed elsewhere.
Histological features
Mercury pigment is brown–black, round and opaque, and measures up to
340 μm in diameter (Fig. 14.92).5–7,38 The granules are found within mac-
rophages in addition to extracellular dermal deposition. They are localized
around the superficial vasculature and in association with the connective tis-
sue elements.38
Mercury granulomata are characterized by local necrosis associated with
free mercury globules surrounded by an intense foreign body granulomatous
reaction with lymphocytes, histiocytes, plasma cells, and varying numbers of
eosinophils.6,7,9 Ulceration is common and the epidermis may show pseudoep-
itheliomatous hyperplasia.
Fig. 14.92
Mercury pigmentation: there are multiple round black deposits of mercury
associated with abscess formation.
Mercury exanthem is characterized by subcorneal and/or intraepidermal
pustules which may contain acantholytic keratinocytes in addition to large
numbers of neutrophils.13 Background spongiosis is usually evident. The der-
mal papillae are often edematous and occasionally subepidermal vesiculation
is a feature. A perivascular infiltrate of lymphocytes and histiocytes with con-
spicuous neutrophils and variable numbers of eosinophils is present in the
superficial dermis. Leukocytoclastic vasculitis may be a feature in a signifi-
cant proportion of cases.13
Cutaneous pigmentation following chronic local exposure to mercury is
characterized by increased melanin pigment in the epidermis accompanied by
mercury granules in the papillary dermis.26 Iron stains are negative.1
Pink disease is characterized by sweat gland hyperplasia and a non-specific
dermal inflammatory cell infiltrate.1
Bismuth
Clinical features
Bismuth may be used for gastrointestinal complaints including gastritis and
peptic ulceration.1–3 Adverse cutaneous reactions include erythroderma, exan-
themata, purpuric eruptions, stomatitis, and urticaria.2,3 Generalized pig-
mentation may follow prolonged parenteral and oral use. Patients develop a
generalized blue–gray pigmentation, which also affects the conjunctivae and
oral mucosa.1 A blue–black line at the gingival margin is pathognomonic.1
Transient black lingual pigmentation has also been reported.4
Histological features
Bismuth appears as small dark granules in the dermis and within sweat gland
basement membranes.3 Transfollicular elimination has been documented.2
Voriconazole
Clinical features
Voriconazole is a second-generation broad-spectrum triazole antifungal
that acts by inhibiting fungal cytochrome 450 enzymes. It is well tolerated
and it is commonly used to treat fungal infections, particularly in immuno-
compromised patients. It may be associated with a number of side effects
including nausea, vomiting, diarrhea, visual disturbances, cheilitis, ery-
thema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis,
pseudoporphyria, blistering, facial erythema, and mucocutaneous retinoid-
like effects.1–4 One of the most important side effects is photosensitivity,
initially reported to occur in around 1–2% of patients and after long-term
therapy.5–7 Although the photosensitivity subsides when the treatment is
stopped, photoaging also occurs and it persists. The latter is associated
with multiple lentigines and premature dermatoheliosis.5–7 Furthermore,
some patients, even children, have developed aggressive squamous cell car-
cinomas and, most recently, melanomas in-situ have been reported in two
adults.8–11
Histological features
All the cutaneous manifestations of voriconazole therapy show the same his-
tological features of their counterparts not induced by drugs.
Lithium
Clinical features
Lithium therapy is associated with cutaneous side effects in up to 45% of
patients.1,2 It is known to precipitate or aggravate psoriasis, in particular
pustular lesions.3–6 Other cutaneous adverse affects include maculopapular
eruptions, seborrheic dermatitis, exfoliative dermatitis, atypical acneiform
lesions (predominantly affecting the forearms and legs), pustular erup-
tions, hidradenitis suppurativa, keratosis pilaris-like lesions, palmoplantar
hyperkeratosis, bullous disorders, and hair, nail and mucosal changes.7–12
Exacerbation and the development of Darier’s disease has rarely been
documented.13

Barbiturates and coma blisters
Clinical features
Barbiturates may be associated with a wide range of adverse drug reactions
including erythema multiforme, toxic epidermal necrolysis, hypersensitivity
syndrome, and pseudolymphoma.1,2
In company with many other sedative drugs, including chlorpromazine, imi-
pramine, and meprobamate, barbiturates, particularly when taken in overdose,
may result in blisters (coma blisters), related especially to sites of trauma.3–8
Pathogenesis and histological features
These lesions probably develop as a result of focal persistent hypoxia and
ischemia due to chronic localized pressure. They may develop in a coma-
tose patient whatever the cause. Direct toxic effect may be of importance in
some patients, since similar blisters have complicated localized barbiturate
extravasation.
Histologically, the blisters are subepidermal in location and are often
accompanied by infarction of the overlying epidermis (Fig. 14.93). Sweat
gland necrosis is characteristic.
Chemotherapeutic agents
Clinical features
The rapid rate of epidermal and mucosal turnover results in a high degree
of susceptibility to the effects of chemotherapeutic agents. Among the most
commonly encountered adverse responses are stomatitis, alopecia, and pig-
mentary changes.1–8
Stomatitis is very common and presents as burning erythema, followed by
the development of extremely painful erosions and ulcers.2 Commonly impli-
cated drugs include cyclophosphamide, methotrexate, bleomycin, cytarabine,
doxorubicin, daunorubicin, dactinomycin, 5-fluorouracil, IL-2, hydroxyu-
rea, and mercaptopurine.5,7 Secondary infection, such as with herpes simplex
virus or Candida albicans, is an important complication.
Proliferating hair follicles are highly susceptible to chemotherapeutic agents
and as a consequence anagen effluvium (in which there is loss of much of the
body hair) is a common and distressing complication.7,8 This is reversible once
treatment is completed although subsequent regrowth of hair may be accom-
panied by a change in color or texture.1 Concomitant premature catagen and
telogen effluvium can result in total baldness.2 Drugs most often implicated
include bleomycin, cyclophosphamide, daunorubicin, docetaxel, doxorubi-
cin, etoposide, ifosfamide, mechlorethamine, methotrexate, mitoxantrone,
and paclitaxel.1 Nail changes, including pale transverse ridges (Beau’s lines)
Fig. 14.93
Coma blister: there is a subepidermal blister. Re-epithelialization along the floor is
present.
Chemotherapeutic agents 621
develop as a result of mitosis inhibition with consequent temporary growth
arrest and may be due to bleomycin, cyclophosphamide, and doxorubicin.5
Onycholysis can follow treatment with docetaxel, fluorouracil, and mitoxan-
trone.7 Transverse striate leukonychia (Mees’ lines), which result from peri-
odic disruption of nail plate keratinization, classically have been described in
association with arsenic poisoning.9 Similar lesions have been documented
with a number of agents including ciclosporin and daunorubicin.10,11
Maculopapular eruptions may be caused by several chemotherapeutic
drugs including azathioprine, 5-fluorouracil, chlorambucil, melphalan, and
hydroxyurea.6 These are frequently a source of clinical diagnostic difficulty,
as infectious diseases – including viral exanthemas and, in patients who have
undergone transplantation, acute GVHD – are often within the differential
diagnosis.
Cutaneous hyperpigmentation is a common complication of chemothera-
peutic agents and often affects the hair, nails, and mucosae in addition to the
skin.1–8,12–14 Hypopigmentation is less commonly seen.5 The mechanism for
increased melanin synthesis by melanocytes is unknown. Alkylating agents
including busulfan, cyclophosphamide, ifosfamide, hydroxyurea, 5-fluorou-
racil, and methotrexate are among the most often implicated agents.5,15,16 Nail
changes (including diffuse pigmentation, longitudinal and transverse banding
or streaks) are particularly seen with cyclophosphamide, daunorubicin, dox-
orubicin, 5-fluorouracil, and hydroxyurea.2,9 Cyclophosphamide also causes
hyperpigmentation of the palms and fingers.14 Immediate or delayed tanning
following sun exposure is a frequent complication of 5-fluorouracil. Rarely,
patients may develop linear erythema, complicated by pigmentation around
an injection site, so-called serpentine supravenous hyperpigmentation.7,16,17–19
Similar lesions have followed treatment with actinomycin and nitrosourea.20,21
Hair pigmentation can result from tamoxifen therapy.1,22 Bleomycin therapy
is associated with cutaneous pigmentation affecting between 30% and 60%
of patients.2,23 Pathognomonic linear flagellate streaks may develop on the
skin of the trunk and proximal extremities.24–31 It is suggested that lesions
develop as a consequence of trauma-induced vasodilatation with resultant
local increased concentration of bleomycin. An early inflammatory phase,
due to scratching, has occasionally been documented, suggesting that the pig-
mentation occurs as a consequence of postinflammatory changes. A simi-
lar problem of patterned hyperpigmentation has been documented following
treatment with thio-TEPA (triethylene thiophosphoramide). Localized occlu-
sion during treatment (as for example with adhesive bandages) may cause
retention of thio-TEPA-rich sweat and subsequent reversible hyperpigmenta-
tion confined to the occluded surfaces.32,33 Transverse banding of hair shafts
following therapy with methotrexate – the so-called ‘flag sign’ – has also been
documented.34
Chemotherapeutic agents may interact with radiation therapy to result in
various unusual manifestations including photosensitivity, radiation enhance-
ment, radiation recall, and reactivation.
Photosensitivity may be induced by dacarbazine, 5-fluorouracil, hydroxyu-
rea, and vinblastine.7
Radiation enhancement, which may be a feature of both dactinomycin
and doxorubicin therapy, is due to impaired repair of radiation-induced sub-
lethal cellular damage.2,5 As a consequence, the effects of radiation therapy
are amplified. Clinical manifestations include increased erythema, hyper-
pigmentation, erosions, blistering, and necrosis at the site of radiation ther-
apy.32 Radiation enhancement has also been encountered following therapy
with adriamycin, bleomycin, cisplatin, 5-fluorouracil, hydroxyurea, and
methotrexate.5,7
Radiation recall presents as erythema, vesiculation, and desquamation
at the site of previous irradiation and may develop months or years after
completion of treatment.2 The mechanism is unknown. Dactinomycin is par-
ticularly incriminated.2 A similar response has also been reported following
therapy with adriamycin, bleomycin, cytarabine, doxorubicin, etoposide,
5-fluorouracil, hydroxyurea, melphalan, methotrexate, tamoxifen, and vin-
blastine.7,35,36 Recently, radiation recall reactions have been described follow-
ing treatment with paclitaxel, gemcitabine, docetaxel, IFN-α2b, dacarbazine,
acyclovir, and capecitabine.37–45
Reactivation of ultraviolet light-induced erythema has been described as a
complication of methotrexate and suramin therapy.7,46 Manifestations include
vesiculation and erythema.
622 Cutaneous adverse reactions to drugs

Inflammatory changes affecting pre-existing actinic keratoses and seb-

orrheic keratoses have been described following treatment with cispla-
tin, cytarabine, dacarbazine, dactinomycin, doxorubicin, 5-fluorouracil,
6-thioguanine, and vincristine.4,5 The affected keratoses become pruritic and
erythematous. It is suggested that such changes are analogous to radiation
recall phenomena.4
Hypersensitivity reactions (including urticaria, angioedema, serum sick-
ness, anaphylaxis, generalized dermatitis, and fixed drug eruption) are
uncommon complications of chemotherapy. Although a wide range of agents
may result in these responses, L-asparaginase, intravenous melphalan, and
cisplatin have been particularly incriminated.2,47,48 Cyclophosphamide,
daunorubicin, doxorubicin, methotrexate, and procarbazine have also been
implicated.48 Dacarbazine and procarbazine may cause fixed drug reactions.1
Immune complex-mediated reactions including vasculitis and some cases of
erythema multiforme or toxic epidermal necrolysis may rarely be a result of
treatment with hydroxyurea and mechlorethamine.5 Contact dermatitis is an
uncommon but important complication of topical mechlorethamine (mus-
tard) therapy.49
An interstitial granulomatous maculopapular eruption following low-dose
methotrexate in the treatment of collagen vascular diseases including lupus Fig. 14.94
Chemotherapy-related drug reaction: there are discrete palmar bullae with a rim
erythematosus and rheumatoid arthritis has been described.50 The buttocks
of erythema. The patient had been taking sorafenib. By courtesy of R. Lee, MD,
and limbs are commonly affected.
Virginia Commonwealth University, Richmond, Virginia, USA.
Newer chemotherapeutic agents have emerged which selectively target
specific cellular pathways. Their increasing use has also resulted in diverse
cutaneous side effects.51 One class of such drugs is the epidermal growth fac-
tor receptor (EGFR) inhibitors which are used to treat non-small cell lung
cancer, breast, colon, pancreatic, and squamous cell carcinoma of the head
and neck.52 Examples include cetuximab, gefitinib, and erlotinib. Since
EGFR is expressed in keratinocytes, follicular epithelium, eccrine glands, and
sebaceous cells, adverse effects on the skin and appendages are common.53
Acute folliculitis on the face and trunk is most common.51,52,54 Other poten-
tial side effects include dry skin, nail alterations (paronychia, ingrown nails,
nail fold fissures, onycholysis, splinter hemorrhages, pyogenic granulomas),
and hair changes (frontal alopecia, trichomegaly of eyelashes, altered hair
texture).51,52,55–57
Another class of medication is the tyrosine kinase inhibitor. Imatinib, dasa-
tinib, and nilotinib treat chronic myeloid leukemia (CML).51 Imatinib is also
approved for treatment of gastrointestinal stromal tumor (GIST) and some
cases of dermatofibrosarcoma protuberans. A wide range of cutaneous effects
have been reported with these medications, the more common being hyper-,
hypo- and de-pigmentation and macular–papular exanthems.51,58,59
Sorafenib and sunitinib are multikinase inhibitors currently approved for
treatment of renal cell carcinoma.51,60 Additional uses include hepatocellular Fig. 14.95
carcinoma and imatinib-resitant GIST for sorafenib and sunitinib, respec- Chemotherapy-related drug reaction: there are interface changes with basal cell
tively. A distinct cutaneous finding with both of these medications is hand– hydropic degeneration and apoptosis.
foot reaction developing in up to two-thirds of patients, typically 2 to 4 weeks
after initiating treatment, and characterized by painful erythema and edema of
the palms and soles (Fig. 14.94).51,53,61–63 There may be associated paresthesia
and desquamation. The lesions are discrete and accompanied by hyperkera-
tosis, in contrast to the acral erythema associated with traditional chemo-
therapeutic agents.53 Other cutaneous reactions linked to sorafenib include
pruritus, alopecia, actinic keratoses, and squamous cell carcinoma.51,60,64,65

Histological features
Interface dermatitis represents the most frequently encountered histological
appearance in chemotherapy adverse drug reactions (Figs 14.95–14.97).66–69
In addition to the epidermis, both follicular and sweat gland/duct epithe-
lium may be affected. Appearances are variable, ranging from lichen planus-
like changes (including hyperkeratosis, hypergranulosis, acanthosis, basal cell
hydropic degeneration, and apoptosis) to lupus erythematosus-like reactions
in which the epidermis is markedly atrophic. The combination of interface
changes with severe maturation arrest (dysmaturation) is pathognomonic
of chemotherapy-related reactions. It is particularly a feature of patients
receiving long-term chemotherapy, high-dose chemotherapy, and multiagent
chemotherapy. In addition to impaired maturation, the epidermis appears Fig. 14.96
disorganized and individual keratinocytes are enlarged with pleomorphic Chemotherapy-related drug reaction: there is striking dyskeratosis and abnormal
nuclei containing conspicuous nucleoli. These changes are particularly maturation. The latter is a common feature of chemotherapy reactions.

Fig. 14.97
Chemotherapy-related drug reaction: close-up view.
associated with bleomycin, busulfan, and hydroxyurea. Squamous metapla-
sia of the dermal sweat ducts may be seen with methotrexate therapy.69
Etoposide, a podophyllin derivative, in addition to causing maturation
abnormalities, can cause metaphase arrest with characteristic fragmented
nuclear chromatin resulting in so-called ‘starburst cells’.70
Hyperpigmentation complicating busulfan therapy predominantly
affects the basal layer of the epidermis but also may extend throughout the
full thickness and is often accompanied by pigmentary incontinence due
to melanocyte toxicity.71 Similarly, bleomycin-induced hyperpigmentation
is characterized by epidermal hyperpigmentation and pigmentary incon-
tinence.72 Melanocytes are present in normal numbers. The early inflam-
matory phase is characterized by a superficial perivascular infiltrate of
lymphocytes, histiocytes, occasional neutrophils, plasma cells, and eosino-
phils. Some authors, however, have described basal cell pigmentation in the
absence of pigmentary incontinence.27,73 Lymphocytic vasculitis has also
been reported.28
Thio-TEPA-induced pigmentation is similarly characterized by melanin
pigment within all layers of the epidermis including the stratum corneum,
accompanied by basal cell hydropic degeneration and pigmentary incon-
tinence.32 A mild perivascular lymphohistiocytic infiltrate is present in the
superficial dermis. The melanocyte concentration is normal.
Radiation recall is characterized by epidermal atrophy, basal cell hydropic
degeneration, and superficial dermal vascular ectasia.
In addition to anagen alopecia and interface changes, pustular folliculi-
tis and allergic contact dermatitis (5-fluorouracil) may be a feature of che-
motherapy-associated adverse reactions, particularly with dactinomycin and
5-fluorouracil.74,75
Hypersensitivity reactions including urticaria, angioedema, and maculo-
papular eruptions are histologically no different from other drug-induced
lesions (see above).
Dermal sclerosis may be a feature of bleomycin and docetaxel therapy.76
Extravasation of chemotherapeutic agents including cisplatin, dactino-
mycin, daunorubicin, doxorubicin, etoposide, idarubicin, mechlorethamine,
mithramycin, paclitaxel, vinblastine, and vincristine may result in chemical
cellulitis and tissue necrosis.1
Spongiotic dermatitis is rarely seen as a complication of systemic che-
motherapy but has been described following treatment with methotrexate,
5-fluorouracil, and dacarbazine.67,68 It is much more commonly encoun-
tered following topical chemotherapeutic agents including 5-fluorouracil and
mechlorethamine.
The interstitial granulomatous reaction associated with low-dose metho-
trexate therapy is characterized by a largely histiocytic interstitial infiltrate
with small numbers of neutrophils.46 Vasculitis is not a feature. The histio-
cytes may surround neutrophil aggregates, and a characteristic feature is his-
tiocytes forming a palisade around collagen fibers.65
Chemotherapy-associated eccrine gland reactions 623
Pustular folliculitis secondary to EGFR inhibitors demonstrates a dilated,
hyperkeratotic follicular infundibulum.63 The perifollicular infiltrate initially
contains lymphocytes and later becomes neutrophilic.
The histological features of hand–foot eruption seen with multikinase
inhibitors sorafenib and sunitinib include vacuolar interface alteration along
the dermal–epidermal junction, dyskeratotic keratinocytes, and a thin to
absent granular cell layer with variable parakeratosis.53,62 Mitotic figures
may also be seen predominantly in the spinous layer. Intraepidermal cleavage
occurs as a consequence of epidermal cell necrosis. Intradermal perivascular
inflammation is sparse and contains mononuclear cells with inconspicuous
eosinophils. Vasculitis is not seen.
Chemotherapy-induced acral erythema
Clinical features
Chemotherapy-induced acral erythema (acral erythema, hand-foot syndrome,
palmoplantar erythrodysesthesia syndrome, toxic erythema of the palms and
soles) in which the patient presents with circumscribed, extremely painful
and tender erythematous macules on the palms, fingertips and soles has been
described following treatment with 5-fluorouracil, cyclophosphamide, cytar-
abine, daunorubicin, doxorubicin, and vincristine.1–12 Etoposide, mercap-
topurine, methotrexate, and vinblastine have also been incriminated. Patients
subsequently develop blisters followed by desquamation.
Histological features
The histological features include basal cell liquefactive degeneration, kerati-
nocyte necrosis, and mild spongiosis.1–3,13 There is papillary dermal edema,
vascular dilatation, and a mild superficial perivascular lymphohistiocytic
infiltrate. Features of syringosquamous metaplasia and eccrine neutrophilic
hidradenitis are rarely seen.14,15
In one case, immunohistochemistry of the dermal lymphocytes disclosed a
CD3+, CD16+, CD56+, leukocyte function antigen-1 positive phenotype sug-
gestive of natural killer T-cells.16 The eccrine ducts expressed HLA-DR and
intercellular adhesion molecule-1 (ICAM-1).16
Differential diagnosis
The features are indistinguishable from graft-versus-host disease. Distinction
is dependent upon clinicopathological correlation. Compared to hand–foot
reaction associated with multikinase inhibitors, there is no diminution of the
granular cell layer, parakeratosis or intraepidermal mitoses.17
Chemotherapy-associated eccrine
gland reactions
Although there is some histological overlap between neutrophil eccrine
hidradenitis and eccrine syringosquamous metaplasia, more often they present
independently of one another and, as such, they are considered separately.
Neutrophilic eccrine hidradenitis
Clinical features
This rare eccrine gland reaction was initially reported in a patient receiv-
ing induction chemotherapy including doxorubicin and cytarabine in the
treatment of acute myelogenous leukemia.1 Subsequently, a similar erup-
tion was described in patients with a number of other malignancies such as
Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, breast carcinoma, Wilms’s
tumor, osteosarcoma, and testicular tumors including embryonal carci-
noma and teratoma.2–7 Further cases developing in association with acute
myelogenous leukemia have also been documented.8,9 It was soon appreci-
ated that additional chemotherapeutic agents including bleomycin, chloram-
bucil, daunorubicin, dactinomycin, vincristine, lomustine, mitoxantrone,
thioguanine, cis-platinum, vinblastine, topotecan, cyclophosphamide, and
5-fluorouracil might be responsible, although cytarabine has been most com-
monly implicated.10 A case following the use of GM-CSF has been reported.11
624 Cutaneous adverse reactions to drugs
It should be noted, however, that neutrophilic eccrine hidradenitis has also
been described as a prodromal manifestation of acute myelogenous leuke-
mia in the absence of chemotherapy.12 The condition has been described in
­HIV-positive patients receiving zidovudine and as a complication of treat-
ment with acetaminophen.13–16
Clinically, patients (who are commonly febrile) develop a polymorphous
eruption consisting of variably asymptomatic or tender erythematous to
violaceous macules, papules, plaques, nodules, and pustules which most often
presents within 1 or 2 weeks of starting chemotherapy.4 Lesions may be very
numerous and, although there does not appear to be a site predilection, the
trunk and upper limbs are most often affected.5 Facial involvement may also
occur, manifesting as periorbital edema, violaceous plaques, and lesions that
mimic cellulitis.17–19 Ear involvement seen as bilateral tender erythema has
been documented.20 An atypical presentation with symmetrical, erythematous
plaques isolated to the breasts has also been reported.21 The lesions desqua-
mate and usually heal spontaneously within 1–3 weeks.4 Postinflammatory
hyperpigmentation and scarring are not usually features. Recurrence follow-
ing the reintroduction of chemotherapy has been documented.1,8 Clinically,
an infectious condition, leukemia cutis, bullous pyoderma, atypical pyoderma
gangrenosum or Sweet’s disease is most often suspected.8
Pathogenesis and histological features
The pathogenesis of this condition is unknown but it has been proposed that
the drug may be concentrated in the sweat glands, thereby exerting a direct
toxic effect on the secretory epithelial cells.1,2 Alternatively, the condition
may represent part of the spectrum of acute neutrophilic dermatoses which
also includes Sweet’s syndrome and pyoderma gangrenosum.4 Presentation
as a prodromal manifestation of leukemia before the introduction of chemo-
therapy and its development in an otherwise healthy person as a probable
complication of prolonged pressure suggests that the etiology is likely to be
multifactorial.12,16
The most significant histological features are seen in the deeper reticular
dermis and subcutaneous fat where a dense neutrophil polymorph infiltrate
surrounds the eccrine secretory coils (Fig. 14.98). The coiled and straight der-
mal ducts are typically unaffected. Leukocytoclasis is sometimes evident.4,22
The glandular epithelium shows neutrophil infiltration, nuclear pyknosis,
cytoplasmic eosinophilia or vacuolation and often appears sloughed off into
the lumen of the gland.7 Syringosquamous metaplasia may additionally be
present; rarely, necrosis of the eccrine gland is seen in the absence of signifi-
cant inflammation.8,17,23,24 The periadnexal fibroadipose tissue stroma typi-
cally shows mucinous degeneration and a variable infiltrate of neutrophils,
lymphocytes, histiocytes, and eosinophils.8 Recently, it has been shown that
the apocrine glands may be affected in addition to the eccrine glands.25 There
is no evidence of vasculitis.
Fig. 14.98
Neutrophil eccrine hidradenitis: there is a neutrophil infiltrate involving the eccrine
gland. Note the sparing of the duct in the center of the field.
Differential diagnosis
Idiopathic plantar hidradenitis (idiopathic recurrent palmoplantar hidradeni-
tis in children, neutrophilic eccrine hidradenitis in children) is a rare derma-
tosis in which tender, painful, erythematous papules, plaques, and nodules,
0.5–3.0 cm in diameter, develop on the soles of the feet of children.26–30
Pustular lesions have been reported.31 Less often, concomitant palmar involve-
ment has been documented.27 Recurrences are not uncommon. The condition
shows a predilection for females (2:1).26 Incidence shows seasonal variation,
lesions developing most often in spring and autumn. Adults may also rarely
be affected.32 Although trauma does not appear to be an etiological factor,
chronic pressure is probably of importance. Prolonged immersion in hot bath
water preceded the development of lesions in a number of cases. Pyrexia is
not usually present and the patients are otherwise well. The condition gener-
ally clears spontaneously.
In contrast to eccrine neutrophilic hidradenitis, the changes are centered
on the coiled duct and proximal straight duct, the secretory apparatus usu-
ally being spared or only minimally affected.26 There is an intense neutrophil
infiltrate surrounding and involving the ductal epithelium associated with
epithelial degenerative changes and necrosis. Abscess formation may also be
a feature. Eccrine syringosquamous metaplasia is not seen.
Rarely, neutrophilic eccrine hidradenitis may represent a primary infec-
tious process, for example Serratio spp., Enterobacter cloacae, Staphylococcus
aureus, and Nocardia asteroides.33–35
Eccrine squamous syringometaplasia
Clinical features
Eccrine squamous syringometaplasia (syringosquamous metaplasia) is a his-
tologically distinctive eruption that may rarely develop following chemo-
therapy.1–3 Patients present with erythematous papules often in a generalized
distribution following the administration of a number of chemotherapeutic
agents including bleomycin, cytarabine, daunorubicin, doxorubicin, and cis-
platinum (Fig. 14.99). A similar response has been seen more recently with
the kinase inhibitors sunitinib and imatinib.4,5 Pustules and vesicles are some-
times seen. Presentation as acral erythema has also been documented.6,7
Histological features
The changes primarily affect the upper portion of the eccrine duct and con-
sist of squamous metaplasia associated with apoptosis of the lining epithe-
lium (Figs 14.100, 14.101).1 Periductal edema and fibrosis may also be seen.
A perivascular infiltrate consisting of lymphocytes and occasionally neutro-
phils is present in the surrounding dermis.
Fig. 14.99
Eccrine squamous syringometaplasia: there is an erythematous patch with a dusky
center on the thigh and in the inguinal fold.

Fig. 14.100
Eccrine squamous syringometaplasia: the eccrine ductal wall is replaced with
squamous epithelium.
Fig. 14.101
Eccrine squamous syringometaplasia: high-power view.
Differential diagnosis
Eccrine squamous syringometaplasia may occur in a wide variety of settings.
It may be found adjacent to cutaneous ulcers, following severe burns, as a
feature in panniculitis, linear scleroderma, and pyoderma gangrenosum, in
fibrous hamartoma of infancy, in recall phenomenon, in association with
tumors including squamous cell carcinoma and keratoacanthoma, and in
infections including herpes virus, cytomegalovirus, and human immunodefi-
ciency virus.8–15 It has also been described as a complication of benoxaprofen
therapy.16
Adverse reactions to cytokine therapy
Clinical features
A very wide range of adverse reactions to the large number of recombinant
cytokines available as therapeutic agents has been described.1 These are very
comprehensively documented in the review article of Asnis and Gaspari.2 The
majority of these agents have to a greater or lesser extent been associated with
local injection site reactions (painful or pruritic erythematous wheals).2 Only
a limited number of cytokines, which may be associated with more specific
dermatological manifestations, are included in this section.
Adverse reactions to cytokine therapy 625
Granulocyte colony-stimulating factor (G-CSF, filgrastim; a glycopro-
tein that stimulates proliferation and differentiation of neutrophils) therapy
has been associated with a number of dermatological conditions including
bullous pyoderma gangrenosum, folliculitis, leukocytoclastic vasculitis, and
Sweet’s syndrome.2–9 G-CSF and GM-CSF have also been incriminated in
exacerbation of pre-existent leukocytoclastic vasculitis, psoriasis, a general-
ized erythematous eruption, erythematous plaques, and a localized lichenoid
reaction.10–15
A number of adverse reactions have been described following treatment
with GM-CSF (a growth factor which stimulates proliferation and differ-
entiation of neutrophils, monocytes, and eosinophils) including localized
angioedema, facial flushing, and generalized erythematous, maculopapu-
lar, exfoliative, urticarial, pruritic and pustular cutaneous reactions.2,16–19
Localized pustular and vasculitic reactions, generalized folliculitis, epider-
molysis bullosa acquisita, and alopecia have also followed treatment with
GM-CSF.2,7,18–21
The use of IFN-α may be followed by localized erythema and less often
skin necrosis. It is followed by the development of alopecia in up to 10% of
patients.22 Psoriasis, pyoderma gangrenosum, localized granulomatous and
suppurative lesions, ulcers, vasculitis, systemic lupus erythematosus, eosino-
philic fasciitis, eczematous lesions, photosensitivity, and paraneoplastic pem-
phigus have also complicated its use.2,23–29 Sarcoidosis induced by IFN-α is
also well documented.30,31 Cutaneous and systemic disease may occur as a
consequence of enhanced helper T-cell type 1 (Th1) immune response, result-
ing in granulomatous inflammation.
Pegylated IFN-α, used increasingly for its improved bioavailabity com-
pared to traditional interferon, has been linked to hyperpigmentation.32–34
Expression of α-melanocyte stimulating hormone receptors is increased by
interferon, and is thought to be the cause of lingual and cutaneous darkening.
Cutaneous lesions are reported to occur at sites of injection and elsewhere,
including the face, trunk, extremities, and nails. Lesions develop weeks to
months after starting therapy.
Single case reports have documented instances of fatal pemphigus vulgaris
and allergic facial contact dermatitis following treatment with IFN-β.35,36
Erythematous plaques, cutaneous ulceration, necrosis, vasculitis, scleroder-
miform lesions, and lobular panniculitis have also been documented.37–43
IFN-γ may induce psoriatic plaques at the injection site and its use has been
shown to induce erythema nodosum leprosum in patients with leprosy.44,45
IL-2, which is produced by activated T lymphocytes, stimulates the pro-
duction of a number of cytokines including IFN-γ, tumor necrosis factor and
GM-CSF in addition to inducing differentiation of an activated killer cell
population which has a cytotoxic effect on tumor cells.46,47 Dermatological
complications of recombinant IL-2 (r IL-2) therapy include a desquamating,
diffuse erythematous macular eruption, pruritus, purpura, telogen effluvium,
mucositis with aphthous ulcers, and glossitis.2,46 Toxic epidermal necrolysis-
like blistering dermatoses, pemphigus vulgaris, linear IgA disease, vitiligo,
and erythema nodosum have also been reported.2,29,48–52 IL-2 therapy may be
associated with exacerbation of psoriasis.53,54
Pruritus, facial edema, and a transient acantholytic dermatosis-like erup-
tion affecting the chest, back, and proximal extremities have been described
following treatment with IL-4 and there is a case report describing the devel-
opment of vitiligo in association with recombinant IL-4 therapy.55,56
Histological features
Histologically, the erythematous lesions associated with G-CSF show epi-
dermal acanthosis, parakeratosis, eosinophilic spongiosis with abscess for-
mation, and interface changes.14 The lichenoid eruption is characterized by
hyperkeratosis, dyskeratosis, and interface change accompanied by a lym-
phocytic infiltrate.15 An atypical dermal histiocytic infiltrate characterized by
nuclear pleomorphism and mitotic activity has recently been documented.57
The erythematous maculopapular eruption associated with GM-CSF is
characterized by edema and a superficial perivascular and interstitial inflam-
matory cell infiltrate composed of T-helper lymphocytes, histiocytes, eosino-
phils, and conspicuous neutrophils accompanied by epidermal spongiosis
and lymphocyte/neutrophil exocytosis.16–18 Focal dyskeratosis may also be a
feature.16
626 Cutaneous adverse reactions to drugs

The histological features of hyperpigmentation from pegylated IFN-α Histological features

include increased melanin along the basal layer of the epidermis and papil-
lary dermal melanophages.33 There is no associated iron deposition.
Lobular panniculitis associated with IFN-β demonstrates a spectrum of
changes.43 Early on, there is a neutrophil-rich lobular panniculitis with sterile
microabcess formation. Intravascular thrombi without vasculitis, increased
interstitial mucin, and microcalcification may be seen. Areas of fat saponi-
fication with microcalcification are typical and must be distinguished from
pancreatitis-associated panniculitis. As lesions become longstanding, there is
less inflammation, predominantly comprised of mononuclear cells with septal
fibrosis and calcification surrounding adipocytes.
IL-2 skin reactions are characterized by interface vacuolar degeneration
with rare necrotic keratinocytes accompanied by lymphocyte exocytosis and
focal spongiosis.3,46,54 Papillary dermal edema is present with a superficial
perivascular lymphohistiocytic infiltrate. Rarely, epidermal necrosis may be
extensive.46
The infiltrate consists predominantly of CD3+/CD4+/CD25-/HLA-DR+
T-helper cells with a small subpopulation of CD8+ lymphocytes. Endothelial
cells and keratinocytes express ICAM-1.46
Histologically, the transient acantholytic dermatosis-like eruption associ-
ated with IL-4 therapy is characterized by acantholysis and suprabasal cleft
formation with dyskeratosis, spongiosis, and a superficial perivascular lym-
phohistiocytic infiltrate with rare eosinophils.55 Immunofluorescence studies
have not been performed.
Cutaneous reaction of lymphocyte recovery
Clinical features
This unusual condition follows return of lymphocytes to the general circula-
tion and skin after induction or augmentation chemotherapy.1,2 It has been
described most often following combined cytarabine and daunorubicin treat-
ment and also following treatment with amsacrine, etoposide, interferon,
cyclophosphamide, and vincristine.3 Patients present with a pruritic, ery-
thematous maculopapular eruption associated with pyrexia.1 The eruption
resolves with desquamation.2
Histological features
The histological features include mild spongiosis with lymphocyte exocytosis
associated with interface change, keratinocyte atypia with impaired matura-
tion (chemotherapy effect) and minimal dyskeratosis.1,2 There is vascular dil-
atation and a perivascular lymphocytic infiltrate is present in the superficial
dermis. Eosinophils are absent.2 Exceptionally, epidermal lymphocyte infil-
tration may be very marked so as to mimic mycosis fungoides.4
The infiltrate is composed of CD3+/CD4+ T-helper cells with a smaller
subpopulation of CD8+ cells.2 The lymphocytes may also express CD25.4
Epidermal Langerhans cells are reduced in number and there is minimal to
absent keratinocyte HLA-DR and ICAM-1 expression.2,4
Nuclear pleomorphism with hyperchromatism and expression of CD30,
CD25, and HLA-DR has been described in the eruption of lymphocyte recov-
ery in patients who have also received human recombinant cytokines includ-
ing GM-CSF and IL-3.5
Amalgam tattoos, which consist of mercury and silver, sometimes accompa-
nied by tin, present as fine to globular, brown to black deposits lying free or
within macrophages and also deposited on the elastic tissue fibers and blood
vessels within the lamina propria.2–4
Tumor necrosis factor-a inhibitors
The use of tumor necrosis factor-α (TNF-α) inhibitors has rapidly expanded
over the past decade. Etanercept, infliximab, and adalimumab are FDA
approved for treatment of plaque-type psoriasis, rheumatoid arthritis, and
ankylosing spondylitis. Other indications for its use include Crohn’s disease,
ulcerative colitis, and juvenile idiopathic arthritis. As use of these medications
has increased, so too has the side effect profile.
The most common adverse dermatological effect is injection site reaction,
occurring in up to one-third of patients.1,2 Erythematous, edematous, eczem-
atous lesions are described most commonly, although discoid lupus erythe-
matosus and localized vasculitis have been reported.1–3 Generalized vasculitis
may also occur, either following localized lesions or de novo, involving the
skin and other organ systems (kidneys, central and peripheral nervous sys-
tems, serosa, myocardium, lung, gall bladder).4,5
Paradoxically, a common cutaneous side effect seen distant from the injec-
tion site is psoriasis.6 Both psoriasis vulgaris and palmar-plantar pustular pso-
riasis have been described, predominantly in patients treated for rheumatoid
arthritis, ankylosing spondylitis and Crohn’s disease (Figs 14.102–14.104).7
Most psoriasiform reactions occur 6 to 10 months after starting therapy.7,8
The proposed mechanism is increased IFN-α production by plasmacytoid
dendritic cells (PDC) as a consequence of TNF-α inhibition, which has been
shown to induce psoriasis lesions.9–11
There is clinical overlap between the psoriasiform and lichenoid derma-
titides associated with the TNF-α inhibitors. The clinical appearance of the
lichenoid eruptions may resemble lichen planus, psoriasis, or be non-specific
erythematous macules and papules.12 The mechanism for development of
these lesions is not well understood but is thought to be a consequence of
cytokine imbalance.13 The eruption begins weeks to months after starting
TNF-α inhibition therapy.
Cutaneous infections are a well known risk with TNF-α inhibitor ther-
apy and include folliculitis, herpes simplex, tinea corporis, and tinea
versicolor.14–16
An emerging reaction seen in the setting of TNF-α inhibition is granu-
lomatous inflammation. Case reports describe cutaneous, pulmonary, and

Differential diagnosis
The features are indistinguishable from exanthematous drug reactions, viral
infections, and acute graft-versus-host disease.6

Dental amalgam tattoos

Clinical features
Dental amalgam tattoos develop following the accidental implantation of
dental amalgam into the soft tissue of the mouth following a dental proce-
dure. Lesions, which are most commonly found on the buccal, gingival, and Fig. 14.102
alveolar mucosa, measure from 0.10 to 1.5 cm and present as flat gray to Tumor necrosis factor-α inhibitor reaction: there are thin psoriasiform plaques on
blue–gray or slate-colored lesions.1 the lower legs.

Fig. 14.103
Tumor necrosis factor-α inhibitor reaction: erythematous, psoriasiform plaques
are present on the lower leg. Courtesy of J. Nunley, MD, Virginia Commonwealth
University, Richmond, Virginia, USA.
Fig. 14.104
Tumor necrosis factor-α inhibitor reaction: there are tense palmar pustules identical
to those seen in palmar-plantar psoriasis.
nodal sarcoidosis which improves upon discontinuation of therapy.17,18
Additional reports include interstitial granulomatous dermatitis and granu-
loma annulare.19,20
Lupus-like syndromes may also occur as a consequence of therapy with
TNF-α inhibitors.21
Histological features
Injection site reactions are characterized by dermal edema, a perivascular
lymphocytic infiltrate with eosinophils.1–3 Immunohistochemical studies dem-
onstrate CD8-predominant T cells.1
Vasculitis in the setting of TNF-α inhibitor therapy may involve small or
medium sized vessels with leukocytoclastic changes.7 Necrotizing features
and extravascular granulomatous inflammation have been described.
Psoriasis induced by TNF-α inhibitors resembles typical psoriasis, with
variable presence of spongiosis and lichenoid inflammation.10 The dermal
infiltrate contains mononuclear cells, although eosinophils may be present.10
The few histological descriptions of TNF-α inhibitor-associated lichenoid
dermatitis available closely resemble lichen planus, with a lichenoid
Esthetic microimplants 627
Fig. 14.105
Tumor necrosis factor-α inhibitor reaction: there is hyperkeratosis, hypergranulosis,
psoriasiform hyperplasia, and interface change with a superficial perivascular
lymphohistiocytic infiltrate.
Fig. 14.106
Tumor necrosis factor-α inhibitor reaction: in this example, the features are
indistinguishable from sarcoidosis.
infiltrate of mononuclear cells, melanophages involving a hyperplastic epider-
mis, hyperkeratosis, and hypergranulosis.12 Psoriasiform hyperplasia may be
superimposed (Fig. 14.105).
TNF-α inhibitor associated sarcoidosis is characterized by noncaseat-
ing granulomata in the dermis and/or subcutis (Figs 14.106, 14.107).17
Necrotizing foci are rarely described. Interstitial granulomatous dermatitis
demonstrates a diffuse intradermal infiltrate of histiocytes and lymphocytes
with a variable number of eosinophils and occasional neutrophils.19 There is
no increased dermal mucin or vasculitis. Interface changes occur but are not
common.
Esthetic microimplants
Cosmetic dermatology is a rapidly evolving industry. The demand for ‘non-
surgical’ rejuvenation has seen a rise in the number of implants and inject-
able materials available to patients. Unfortunately, inflammatory reactions to
these agents occur.
628 Cutaneous adverse reactions to drugs

Fig. 14.107 Fig. 14.108

Tumor necrosis factor-α inhibitor reaction: high-power view. Restylane nodules: linear arrangement of nodules along the neck creases.

There are several categories of fillers which may be permanent or resorb-

able (Table 14.1). Fillers are either polymers, which function as volumizers, As a consequence of the ban on silicone, bovine collagen was developed.
creating effect by taking up space, or a combination of degradable polymer There is a 1–3% rate of allergic reactions, despite double skin testing.4 Many
and microparticles.1 The microparticles serve as a lattice upon which the host’s such reactions are localized erythema and edema which occur in the first
response (often collagen induction) contributes partially or completely to the weeks to months after injection, although recurrent inflammation, years later,
filler’s effect. The microparticles may or may not be degraded over time. has been described. Other potential complications include localized glabellar
Silicone was one of the first agents used for soft tissue augmentation, in necrosis, granulomata, and abscess formation.5 Granulomata present as ery-
the 1950s. It was banned in the United States in 1982 due to concerns over thematous nodules at the site of treatment and are seen within a few months
adverse effects such as migration to distant locations.2,3 Inflammatory nod- following injection. Sometimes, lesions are seen years later. Abscesses typi-
ules (‘siliconomas’) may also develop, sometimes years later. Presently, two cally occur weeks to months after injection.4
new forms of liquid silicone are available, Silikon 1000 and Adatosil 5000, Hyaluronic acid is commonly used to correct facial creases and wrinkles.
for treatment of retinal detachment.1 The former is more easily injected and There are two types of hyaluronic acid fillers: nonanimal, derived from fer-
is used off-label for cosmetic purposes. Polydimethylsiloxane/polyvinyl pyr- mentation of bacteria (Streptococcus equi) and animal, derived from chicken
rolidone (Bioplastique) contains particles of solid silicone and is available for combs.6 Hypersensitivity reactions, although rare, have been reported in
injection into the subcutaneous fat (Fig. 14.108).4 up to 0.8% of patients.4,7 Injection site reactions are most common, with
temporary erythema, edema, and bruising within the first 14 days follow-
ing injection.8 Delayed reactions are less common and present as erythema-
Table 14.1 tous, firm nodules along the sites of injection weeks to months later.6–11 There
Esthetic microimplants
are two types of nodules: granulomatous and nongranulomatous. The etiol-
ogy of the granulomatous response is unclear. There is speculation that it
Chemical Ingredient Product Name(s) could be secondary to impurities related to the fermentation process in the
Resorbable: ­nonanimal-derived form.12 Additional side effects to hyaluronic acid include
Bovine collagen Zyderm, Zyplast sterile abscesses, hyperpigmentation, and a livedoid, reticular pattern in the
Human collagen Cosmoderm, Cosmoplast, area of injection.7
Cymetra Foreign-body granulomata have also been seen following injection with
Porcine collagen Evolence
poly-L-lactic acid (Newfill, Sculptra) and polyacrylamide gel (Aquamid).4,5
Hyaluronic acid (non-animal) Restylane, Captique, Perlane,
Juvederm
Hydroxy-polyethylene/hydroxyl-polypropylene (Profill) is also associated
Hyaluronic acid (animal) Hylaform, Hylaform plus with lipoatrophy.4
Poly-L-lactic acid Newfill, Sculptra Polytetrafluoroethylene (Gore-Tex) has been used for lip augmentation
Hydroxy-polyethylene/ Profill and has resulted in ulcerated nodules with pustules.14
hydroxyl-polypropylene Immediate-type reactions such as erythema, edema, and bruising have also
Calcium hydroxylapatite Radiesse, Radiance been described with other fillers, including hydroxy-polyethylene/hydroxyl-
Permanent: polypropylene (Profill), polyacrylamide-containing products, and poly-L-lactic
Bovine collagen/polymethyl Artecoll, Arteplast, Artefill, acid.4,13
methacrylate microspheres (PMAA) Metacril Infection is a potential complication following any cosmetic procedure.13
Hyaluronic acid/ DermaLive, DermaDeep Early infections, occurring within 2 weeks, are typically secondary to bac-
polyhydroxyethylmethacrylate (HEMA) / teria such as Staph. aureus or Streptococcus.3,13 Later infections may be due
ethylmethacrylate (EEMA) to atypical mycobacteria such as Mycobacteria chelonae, M. fortuitum, and
Silicone (dimethyl polysiloxane) Silikon 1000, Silskin, Adatosil abscesses.13
5000
Polydimethylsiloxane /polyvinyl Bioplastique
pyrrolidone Histological features
Polyacrylamide gel (PAAG) Aquamid Silicone nodules contain multiple vacuoles in the dermis, subcutis, and
Polyacrylamide and polyvinyl acid Evolution skeletal muscle.3,4,13 Vacuoles are variable in size and shape and resemble
Polyalkylimide gel BioAlcamid Swiss cheese. These are actually empty spaces where silicone was lost dur-
Polytetrafluoroethylene Gore-Tex ing processing. They are surrounded by giant cells and histiocytes which
 Esthetic microimplants 629

contain intracytoplasmic vacuoles. Additionally, impurities in the silicone Ulcers caused by polytetrafluoroethylene (Gore-Tex) demonstrate variably
result in birefringent foreign material within giant cells.3,4 Surrounding sized threads of material surrounded by neutrophils and granulation tissue
fibrosis may also be noted.3 The silicone particles in polydimethylsiloxane/ (Fig. 14.111).14
polyvinyl pyrrolidone are too large to be phagocytosed by histiocytes.1 The Infectious lesions demonstrate variable findings depending on the caus-
material induces a foreign body giant cell reaction and fibrosis. The par- ative organism. Mycobacterial infections may present as granulomatous nod-
ticles are identified as translucent, jagged structures within cystic spaces.4 ules, and appropriate tissue stains and culture are necessary.
Bovine collagen is distinguished from human collagen by its lighter eosino-
philic color, thicker bundles, and more amorphous, acellular appearance.4
When recurrent inflammatory reactions develop in hypersensitive patients, Alpha-melanocyte stimulating hormone
there is a perivascular mononuclear cell infiltrate with a mixture of neutro- analogues (melanotan I and II)
phils, mononuclear cells, and eosinophils within implanted collagen.4
Early granulomatous nodules are comprised of a mixture of ­mononuclear Melanotan I and II are superpotent analogues of alpha-melanocyte stimulat-
cells, giant cells, eosinophils, neutrophils, and plasma cells surrounding but not ing hormone that have photoprotective effects. They appear to be increas-
infiltrating the collagen implant.4 Later lesions have a denser and deeper infil- ingly used by patients who want to develop a prominent tan. Although they
trate. Birefringent material is not seen. In contrast, nodules due to bovine col- are not licensed for this purpose, they can be obtained through the Internet.
lagen with polymethyl methacrylate microspheres (PMAA) (Artecoll) contain Their administration not only induces prominent tanning but also induces
a diffuse and nodular granulomatous infiltrate which surrounds cystic spaces, enlargement and darkening of pre-existing nevi. Histology of these nevi has
mimicking fat cells and with a Swiss cheese appearance.3 Located in the cen- not been described in detail but the few removed lesions in two patients did
ter of the spaces are nonbirefringent, round, translucent, well-­circumscribed not show evidence of malignancy.1
foreign bodies (Fig. 14.109). This foreign material is the PMMA microsphere
which also induces surrounding fibrosis. The fibrosis contributes to the fill-
ing-effect. Hyaluronic acid with polyhydroxyethylmethacrylate (HEMA)/eth-
ylmethacrylate (EEMA) (DermaLive, DermaDeep) reactions are very similar
histologically to Artecoll, as they also contain methacrylate microspheres.3
Calcification of the foreign material has been described with DermaLive.1
Asteroid bodies may be present in both reactions.
Abscesses seen as a consequence of collagen implants show a dense neutro-
philic infiltrate with admixed plasma cells, histiocytes, and mononuclear cells.4
Giant cells surround implanted collagen, and granulomata may be present.
Nongranulomatous inflammatory nodules related to hyaluronic acid
injection are characterized by a superficial and deep perivascular and peri-
adnexal infiltrate of mononuclear cells with several eosinophils.13 Implanted
hyaluronic acid is not seen. In contrast, the granulomatous nodules con-
tain a striking nodular infiltrate of foreign body giant cells, histiocytes, and
eosinophils surrounding pools of basophilic foreign material which stain with
Alcian blue (pH 2.7).4,13 Polyacrylamide gel (PAAG) (Aquamid) has similar
features, but is distinguished from injected hyaluronic acid by the presence of
necrotic tissue admixed with the basophilic foreign material.13
Poly-L-lactic acid (Newfill, Sculptra) nodules are granulomatous and are
distinguished by spiky, long translucent bodies within giant cells.4,13 They are
irregular in shape and birefringent.
Reactions to bioAlcamid (polyalkylimide gel) display palisading granulo- Fig. 14.110
mas with scattered giant cells and a central area of amorphous material that Reaction to Bioalcamid: the central necrobiosis with a surrounding rim of
may mimic deep granuloma annulare or rheumatoid nodule (Fig. 14.110). histiocytes shows a striking resemblance to granuloma annulare.

Fig. 14.109
Reaction to Artecoll: note the foreign body granulomatous reaction and the typical Fig. 14.111
swiss cheese appearance. Reaction to Gore-Tex: the mesh is surrounded by dense fibrous tissue.
630 Cutaneous adverse reactions to drugs

latter changes may mimic epidermolysis bullosa (Fig. 14.112). By electron

EMLA cream (prilocaine-lidocaine microscopy, the appearances mimic a lysosomal storage disorder with empty
emulsion) lisosomal inclusions.6 The latter change has been attributed to the castor oil
contained in EMLA cream.
Clinical features
EMLA is a eutectic mixture of prilocaine and lidocaine that is used widely
as a cream to provide local anesthesia, particularly in children and in adults
in genital areas. Very few side effects occur with its application, among them
a petechial eruption, contact urticaria, allergic contact dermatitis, and irri-
tant contact dermatitis.1–4 For dermatopathologists, however, what is more
important about EMLA are the subtle changes that it can cause at a micro-
scopic level, leading to difficulties in interpretation.5 These changes appear to
be related to the time that the cream is applied to the patient and they may
be more common in skin in which the biopsy is performed as a result of an
inflammatory process.

Histological features
In cases of irritant contact dermatitis, the features consist of confluent necro-
sis of the upper layers of the epidermis, focal interface change with hydropic
degeneration of basal cells and clefting at the dermoepidermal junction and
an upper dermal mixed inflammatory cell infiltrate with neutrophils.4 The
changes mimic a necrolyic erythema or graft-versus-host disease. In cases
with no clinical evidence of a side effect, there is vacuolization of the gran- Fig. 14.112
ular cell layer and upper stratum spinosum and focal areas with hydropic Reaction to EMLA cream: in this example, there are multiple small foci of
degeneration of basal cells and clefting at the dermoepidermal junction.5 The subepidermal vesiculation.
 Neutrophilic and eosinophilic Chapter

See
www.expertconsult.com
for references and
additional material
dermatoses
15
Pyoderma gangrenosum  631 Seabather’s eruption and coelenterate Eosinophilic cellulitis  649
stings  643
Acute febrile neutrophilic dermatosis  636 Eosinophilic pustular folliculitis  651
Erythema marginatum rheumaticum  644
Neutrophilic dermatoses associated Incontinentia pigmenti  652
with gastrointestinal and hepatobiliary Still's disease  644
Toxic erythema of the neonate  655
disease  639
Urticaria  645
Hidradenitis suppurativa  655
Rheumatoid neutrophilic dermatitis  640
Papular urticaria  649
Arthropod and arachnid bite reactions  641
Hypereosinophilic syndrome  649

Pyoderma gangrenosum
Clinical features
Pyoderma gangrenosum is an uncommon disease of obscure etiology.1–11 It
appears to be somewhat more common in women and, although it may occur
at any age, most patients are in their fourth or fifth decade.4 Presentation
in children is uncommon, but it has been seen even in infants,12–21 and rare
­familial cases have been documented.22–24 The disease may also present in
pregnancy and in this setting it is associated with an underlying disease
­process in about 50% of the cases.25–28 Large, necrotic ulcers, often 10 cm or
more in ­diameter, characterize the disease (Fig. 15.1). Lesions may arise from
­acneiform ­pustules or on a background of erythematous nodules. Typically,
the ulcers have undermined edges and red–purple borders (Fig. 15.2).
They may be ­solitary or multiple, and occur most often on the lower limbs,
although other sites such as the trunk, face, arms, and buttocks are sometimes
affected (Fig. 15.3).29–30 Rare sites of involvement include the oropharyngeal
region, hand, eyelid, eye, vulva, penis, scrotum, and the ­cervix.31–44 The ulcers
are ­painful and tender, and may persist for months or years. Complications
­usually result from the site of the lesion and include cranial osteolysis and nasal
­perforation.17,45 Recurrent attacks are not uncommon.2 Cribriform ­scarring
often follows healing. Systemic involvement has rarely been ­documented,
affecting the lungs, liver, bone, joints, pancreas, and heart.46–51

Fig. 15.2
Pyoderma gangrenosum:
this shows an area of
ulceration with a typical
undermined purplish
Fig. 15.1 border. By courtesy
Pyoderma gangrenosum: this unusually severe example is associated with very of R.A. Marsden, MD,
extensive tissue destruction resembling necrotizing fasciitis. By courtesy of R.A. St George’s Hospital,
Marsden, MD, St George’s Hospital, London, UK. London, UK.
632 Neutrophilic and eosinophilic dermatoses
Fig. 15.3
Pyoderma gangrenosum: an extensive lesion with marked crusting and
undermining in the proximal and medial margins. By courtesy of R.A. Marsden, MD,
St George's Hospital, London, UK.
Occasionally bullous or pustular variants are encountered.4,52–60 One large
study found that bullous lesions are more common on the upper ­extr­emities
and they appear to be more frequently associated with hematological
­malignancy.4 Such lesions are sometimes designated atypical pyoderma gangr­
enosum.4,53 A vegetative form has also been described.61–65
A particularly interesting feature seen in as many as 50% of cases is
­development of lesions in traumatized areas (pathergy).4,66,67 Lesions may
occur at sites of surgery and have been reported after cholecystectomy, breast
reduction or augmentation, splenectomy, hysterectomy, cesarian section, fol­
lowing aortic valve replacement, at the site of a fasciocutaneous flap, a lap­
aroscopic port insertion site, and in an amputation stump (Fig. 15.4).68–81
They also occur following rather trivial trauma such as injection or intrave­
nous access site, ­arteriovenous dialysis shunt, blood-drawing, ­acupuncture
Fig. 15.4
Pyoderma gangrenosum:
multiple early lesions
at the site of previous
surgery. By courtesy
of R.A. Marsden, MD,
St George’s Hospital,
London, UK.
or a tattoo.4,82–85 Pressure from use of seat belts in automobiles has been
­associated with subsequent lesion development.86 Presentation has even been
documented at the location of a spider bite.87 One case reports involvement
of the scalp after receiving hair highlights at a salon, which could be due to
physical and/or chemical trauma.88
A few publications have implicated drugs in the etiology of the disease,
including:
• alpha-2b interferon (IFN-α2b),
• isotretinoin,
• sulpiride,
• propylthiouracil.89–94
In a single case report, pyoderma gangrenosum developed after
­combination therapy with cytosine arabinoside, aclarubicin, and granu­
locyte colony-stimulating factor for myelodysplastic syndrome.95 Another
single report associates gefitinib, an EGFR inhibitor, with pyoderma gan­
grenosum.96 A granulomatous and suppurative dermatitis that may mimic
pyoderma gangrenosum has been documented at the site of interferon-
alpha (IFN-α) ­injections.97 Sclerotherapy has also been complicated by
pyoderma gangrenosum on rare occasions.98 Association with sunitinib
was reported in a single case study.99
Of particular importance is the known association of pyoderma gangreno­
sum with a variety of conditions4,11,100 (in up to 50% of patients2) as outlined
in Table 15.1. Of these, inflammatory bowel disease (both Crohn’s disease
and ulcerative colitis) and arthritis show the most well-established links.101–103
Pyoderma gangrenosum is reported to complicate around 1–2% of inflam­
matory bowel disease patients.104–106 In one study, 27% of patients had asso­
ciated inflammatory bowel disease and 20% of patients had arthritis.4 In this
same study, 27% of patients with superficial ‘atypical’ pyoderma gangrenosum
had an associated hematological disorder.4 In another large study, idiopathic
pyoderma gangrenosum and that associated with chronic inflammatory
bowel disease were found to be more common in females, whereas pyoderma
gangrenosum associated with hematological malignancy was more common
in males.5 While pyoderma gangrenosum can fluctuate with inflammatory
bowel disease activity, it may also be a presenting or heralding feature. The
presence of pyoderma gangrenosum as a complication of inflammatory bowel
disease does not appear to be an independent ­predictor of severity of the
bowel disease.107,108 Although pyoderma gangrenosum lesions may improve
as inflammatory bowel disease is brought under control, specific treatment
is usually required.109 Most of the other numerous, rare associations men­
tioned in Table 15.1 are likely to be fortuitous, as a report of simple coex­
istence does not strictly imply a meaningful association.110 In any event, a
diagnosis of pyoderma ­gangrenosum should always prompt an evaluation for
an underlying disease association. Pyoderma gangrenosum-like lesions have
been reported as the presenting feature of antiphospholipid antibody syn­
drome.111 Other underlying conditions causing lesions that mimic pyoderma
gangrenosum are also well described including inflammatory and infectious
processes, vasculopathies, and malignancies, stressing the importance of care­
ful c­ linical investigation.112–122
The disease may also occur in association with other neutrophilic derma­
toses including Sweet’s syndrome.123–125
Pyoderma gangrenosum is one of the components of a recently
described autosomal dominant syndrome known as PAPA (pyogenic ster­
ile arthritis, pyoderma gangrenosum and acne).126 This syndrome has been
mapped to chromosome 15q and is associated with mutations in the gene
CD2BP1/PSTPIP1.127–131 These mutations increase the binding affinity of
this gene product to pyrin, overcoming the autoinhibition of this homotrimer
and allowing activation of the downstream innate immune response.132–134
Ultimately, this mutation leads to an increase in caspase-1 activation, an
underlying feature of multiple inherited autoinflammatory syndromes.135
Cases lacking a mutation in this gene have also been reported.136 These find­
ing indicate that pyoderma gangrenosum may be best regarded as an autoin­
flammatory or autoimmune disease and the pathways being studied in PAPA
syndrome may also eventually shed light onto the pathogenic mechanisms of
sporadic pyoderma gangrenosum.
Para- and peristomal involvement in patients with ileostomy or colostomy
for inflammatory bowel disease is a well-recognized phenomenon.4,137–141 In a
large series, 13% of patients had peristomal pyoderma.4 Both Crohn’s disease
 Pyoderma gangrenosum 633

Table 15.1 Superficial granulomatous pyoderma is believed to represent a ­superficial

Conditions associated with pyoderma gangrenosum (alphabetical order) and rare variant of pyoderma gangrenosum.3,143–148 Patients develop single
or sometimes multiple superficial ulcerated lesions with vegetative borders
• Acne fulminans, acne conglobata and hidradenitis suppurativa184–188 (for this reason this variant is sometimes referred to as ‘vegetative variant of
• Acquired ichthyosis189
­pyoderma gangrenosum’) as a consequence of trauma, frequently ­surgical
• Acute myeloid leukemia190
(Fig. 15.5). Pain is an occasional feature. The ulcers have a cleaner base than
• Allergic contact dermatitis from rubber191
• Anaplastic large cell lymphoma192 those seen in classic pyoderma. Lesions are most commonly found on the
• Antineutrophil cytoplasmic antibodies193–195 trunk and upper extremities and heal with cribriform scarring (Fig. 15.6).
• Arthritis (either seronegative or rheumatoid arthritis), ankylosing Draining sinuses are occasionally evident. Often there is no evidence of under­
spondylitis and osteoarthrosis 4,196–198 lying systemic disease. Superficial granulomatous pyoderma is more likely to
• Autoimmune neutropenia of infancy199 follow a chronic course compared with classic pyoderma gangrenosum.149
• Behçet’s disease200 So-called ‘malignant pyoderma’ is a controversial designation which we
• Bullous systemic lupus erythematosus201 believe should be avoided. Some authors have used the term to describe a vari­
• Burns / scalding202,203 ant of pyoderma gangrenosum predominantly affecting the head and neck.150–
• C7 deficiency204 152 More recently, however, it has been postulated that at least some cases
• Chronic idiopathic myelofibrosis205
of so-called malignant pyoderma more likely represent cutaneous Wegener’s
• Chronic myelomonocytic leukemia206
• Chronic renal failure207 granulomatosis.153
• Chlamydia pneumoniae208 One study found that over 50% of patients with pyoderma gangreno­
• Cogan’s syndrome (interstitial keratitis and vestibuloauditory sum required long-term therapy to control their disease.5 The disease may be
dysfunction) 209
• Collagenous colitis210, 211
• Colorectal carcinoma212
• Cutaneous T-cell lymphoma213
• Cryofibrinogenemia214
• Cryoglobulinemia6
• Diverticular disease215
• Essential thrombocythemia 216
• Fanconi’s anemia217
• Factor V Leiden deficiency214
• Gastric carcinoma154,218
• Grave's disease219
• Glomerulonephritis220
• Hepatitis, autoimmune and viral156, 221–225
• Human immunodeficiency virus (HIV) infection226–228
• Hypertrophic osteoarthropathy229
• Hypogammaglobulinemia230, 231
• Inflammatory bowel disease: both ulcerative colitis and Crohn’s disease2,4,104
• Juvenile idiopathic arthritis232
• Kartagener’s syndrome233
• Klinefelter's syndrome234
• Lupus anticoagulant235
• Monoclonal gammopathy (most often IgA); usually benign but may
lead to multiple myeloma2,54,196,236 Fig. 15.5
• Multiple sclerosis237 Superficial granulomatous pyoderma: crusted superficial lesion with a cribriform
• Myelodysplastic syndrome238,239 appearance. By courtesy of the Institute of Dermatology, London, UK.
• Myelofibrosis240
• Myeloid leukemia54,56,155,241
• Osteomyelitis12,242
• Paroxysmal nocturnal hemoglobulinuria243
• Polycythemia rubra vera198
• Psoriasis244
• Renal transplant245,246
• SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis)247,248
• Sarcoidosis249
• Sjogren syndrome250
• Subcorneal pustular dermatosis251,252
• Systemic lupus erythematosus253
• Systemic sclerosis254
• Tuberculosis255
• Varicella (chickenpox)256
• Vasculitis, including Takayasu’s disease, erythema elevatum diutinum
and Wegener’s granulomatosis257–263

and ulcerative colitis are associated with this complication.4,140,142 It should be

noted that peristomal pyoderma gangrenosum has been seen in the absence
of inflammatory bowel disease.137,138 It has been documented in patients with
ostomy for gastrointestinal carcinoma and diverticular ­disease.137,138 Pyoderma
gangrenosum may also occur at urostomy sites following ­cystectomy for
­bladder carcinoma.138
Fig. 15.6
Superficial granulomatous pyoderma: this field shows extensive ulceration of the
breast. By courtesy of R.K. Winkelmann, MD, Mayo Clinic, Scottsdale, Arizona, USA.
634 Neutrophilic and eosinophilic dermatoses

fatal in some cases, particularly if diagnosis is delayed.6,154 In another study,

2 of the 21 patients reported died of pyoderma gangrenosum secondary to
­pulmonary involvement.6

Pathogenesis and histological features

The precise pathogenesis of pyoderma gangrenosum is uncertain. The current
state of knowledge suggests that it is due to immune dysfunction, perhaps
innate, and/or that it develops on a vasculitic basis.10,128,155–160 A variety of
immunological abnormalities have been described including:
• absent delayed hypersensitivity reactions to common antigens such as
mycobacteria and Candida albicans,
• defective neutrophil chemotaxis,
• impaired neutrophil phagocytosis,
• diminished lymphokine (migration inhibition factor) production,155,156,158
• overexpression of interleukin-8, a potent chemotactic polypeptide for
neutrophils, has been reported in lesional tissue and may be an important
pathogenetic factor,161,162
• reduction in interleukin-8 and related molecules has been noted following
successful therapy,163
• aberrant neutrophil trafficking and metabolic integrin β2-CR3 and -CR4
oscillations in lesional tissue,164,165
• elevated levels of HIF2a and downstream effectors VEGF and Ang-2
have been noted in disseminated disease, suggesting that angiogenesis
in improper control of the neutrophil oxidative burst may be
involved,166
• elevated TNF-α, MMP-9, and MMP-10 have also been noted,167
• TNF-α may have some of its effects mediated by keratinocyte
secretion of elafin, an elastase inhibitor.168 Indeed anti-TNF-α
therapy has been described to show some efficacy;169–173 however, a case
has also been described in association with TNF-α antagonists used to
treat rheumatoid arthritis and the relationship may be complex.174
The results of immunofluorescence studies in large series of patients have
revealed both immunoglobulins (usually IgM) and complement in blood ves­
sel walls in the dermis of the leading edge of the ulcer.175,176 Another study,
however, failed to substantiate this finding.2 There is no evidence to support
an infective pathogenesis.177
Expanding T-cell clones in both the skin and circulation have been
described in a small series of patients indicating that T-cell response plays
a role in the disease and may be triggered by a local stimulus in the skin.178
T-cell clonality has been described in pyoderma gangrenosum in the absence
of an underlying myeloproliferative disease.179
In general, the histopathology is that of non-specific ulceration with abscess
formation (Fig. 15.7). The adjacent dermis shows acute and chronic inflam­
mation. A pseudo-Pelger-Huet phenomenon with hyposegmented neutrophils
Fig. 15.8
Pyoderma gangrenosum: early acneiform lesion showing a subcorneal pustule.
­ aking recognition difficult has been described in one patient.180 Early lesions
m
may present with subcorneal pustulation (Fig. 15.8). Although the histological
features of both leukocytoclastic and lymphocyte-mediated vasculitis have been
described, it is our experience that any vasculitis present is usually located within
the floor of the ulcer or in the immediate adjacent tissues and is, therefore, more
likely to be a consequence, rather than a cause, of the lesion (Fig. 15.9).1,181
Giant cells appear to be a common feature of pyoderma gangreno­
sum in patients with Crohn’s disease.7 In one study, they were present in
6 of 13 patients with associated inflammatory bowel disease; of these,
5 had Crohn’s disease and 1 had ulcerative colitis.7 Giant cells were not
found in any ­biopsies from 22 patients without associated inflammatory
bowel disease.
Superficial granulomatous pyoderma is characterized by a zoned inflamma­
tory infiltrate in the superficial dermis.3 Focal and sterile abscesses are surrounded
by a zone of granulomatous inflammation bordered by a rim of lymphocytes and
plasma cells (Figs 15.10–15.12).3 Hemorrhage is often present and eosinophils
may be evident. Any vasculitic change is thought to be secondary. The adjacent
tissues may show scarring. Acanthosis and pseudoepitheliomatous hyperplasia
are frequently noted. Foreign material including starch, sutures, vegetable mat­
ter, wood, and hair has been identified in a large proportion of these cases.3
It should be noted that not all cases of pyoderma gangrenosum with granu­
lomatous inflammation are limited to the superficial dermis. Some cases show
involvement of the deep dermis and even subcutaneous tissue.

A B

Fig. 15.7
(A, B) Pyoderma gangrenosum: in this biopsy from the edge of an ulcer, there are massive intradermal inflammatory changes, with abscess formation.

Fig. 15.9 Fig. 15.12
Pyoderma gangrenosum: acute necrotizing vasculitis. It is likely that any active
inflammation of the blood vessel walls is a result of the surrounding inflammation
rather than its cause.
Fig. 15.10
Superficial granulomatous pyoderma: low-power view showing an undermining ulcer.
Fig. 15.11
Superficial granulomatous pyoderma: the zoned inflammatory reaction is clearly
seen. Note the central abscess and surrounding granulomatous inflammation.
Pyoderma gangrenosum 635
Superficial granulomatous pyoderma: high-power view showing multinucleate giant
cells. There are also conspicuous plasma cells.
Differential diagnosis
The histopathological findings in pyoderma gangrenosum are non-specific
and the diagnosis is primarily one of exclusion.182 Since surgery is used to
manage some of the disorders considered in the histological and clinical dif­
ferential diagnosis – but is contraindicated in the treatment of pyoderma
gangrenosum – early and accurate diagnosis is critical. Surgery, which tends
to exacerbate the disease, is generally contraindicated in pyoderma cases
because of the pathergic response. The mainstay of therapy is medical man­
agement, such as corticosteroids. Unfortunately, patients with pyoderma are
often misdiagnosed early in the course of their disease and the diagnosis is
sometimes made only after multiple unsuccessful (and damaging) surgeries
have been performed. In one study, an average of five physicians had exam­
ined the patient before a correct diagnosis was rendered.29 To avoid this error,
obtaining accurate clinical information on wounds and debridement speci­
mens is essential.
Culture is required to exclude infection (bacterial, mycobacterial, fun­
gal). Necrotizing fasciitis tends to affect deeper fascial and subcutaneous
tissue, while pyoderma is centered in the dermis (albeit some spillover
into the subcutis may be seen). Usually, sheets of bacteria are evident
in untreated necrotizing fasciitis. Distinguishing these two conditions
is critical since the treatments are diametric opposites with surgery and
antibiotics for necrotizing fasciitis and avoidance of surgery with sys­
temic anti-immune treatment and supportive wound care for pyoderma
gangrenosum.183
Sweet’s syndrome is generally not associated with ulceration and shows
more prominent karyorrhexis relative to the number of neutrophils. Bite
reactions, particularly resulting from the brown recluse or other spiders,
may show similar histological features. Clinical information is necessary
to distinguish pyoderma from many other forms of ulcer such as those due
to trauma.
Although some authors have noted lymphocytic or neutrophilic vascu­
litis in lesions of pyoderma gangrenosum, this finding, in our experience,
is limited to areas adjacent to the ulcer and likely represents a second­
ary finding.5 Indeed, it has been our experience that ‘secondary’ vasculitis
is frequently present at the border of ulcers of many different etiologies
in patients without any genuine underlying ‘primary’ vasculitic process.
Evaluation for vasculitis as a cause of ulceration therefore depends upon
examination of blood vessels in areas of dermis and subcutaneous tissue
away from the ulcer.
It cannot be overemphasized how important accurate clinical information
is in establishing the correct diagnosis. Failing to recognize this disease early
in its course can be disastrous for the patient.
636 Neutrophilic and eosinophilic dermatoses

Occasionally, the lesions may become bullous or pustular.32,33 The

Acute febrile neutrophilic dermatosis
Clinical features
Acute febrile neutrophilic dermatosis (Sweet’s syndrome) is an uncommon
disease of unknown etiology and pathogenesis.1–11 It is associated with a
marked female predilection (5:1) and most patients affected are in their third
through sixth decades. It may, however, occasionally be seen in children and
a few cases presenting in infancy have been documented.12–22 Infant broth­
ers who both had Sweet’s syndrome have been reported.23 Patients present
with variable numbers of asymmetrically distributed, frequently bilateral, cir­
cumscribed, tender and painful red plaques or nodules, particularly on the
face, neck, and upper and lower limbs (Figs 15.13–15.15). An acral form
of this condition is now termed neurophilic (or pustular) dermatosis of the
dorsal hands (Fig 15.16).24–31 Whether this represents a distinct disease or a
­peculiarly localized variant of Sweet’s syndrome is uncertain.
plaques vary from about 1 to 4 cm in diameter and typically heal without
scarring. Recurrences develop in approximately one-third of patients and
postinflammatory hyperpigmentation is sometimes seen.34,35 Pathergy and
­koebnerization are occasional features and necrosis with ulceration may
rarely be encountered.7,36–38 Sweet’s syndrome may present with lesions
mimicking ­palmoplantar pustulosis and sometimes erythema nodosum-like
lesions are present.32,39,40 A Sweet’s syndrome-like eruption has been described
in a­ ssociation with exposure to light.41
Sweet’s syndrome often follows an upper respiratory tract infection. In
some cases it is a complication of drug treatment, for example carbamazepine,
furosemide, hydralazine, co-trimoxazole, abacavir, azathioprine, ofloxacin,
doxycycline, clindamycin, minocycline, trimethoprim-sulfamethoxazole, bort­
ezomib, lenalidomide, imatinib mesylate, nilotinib, etanercept, granulocyte
­colony-stimulating factor (G-CSF), radiocontrast agent, some vaccines, oral
contraceptives, all-trans retinoic acid, isotretinoin, nitrofurantoin, diazepam,
clozapine, and celecoxib.32,33,42–69 The temporal relationship with administra­
tion, development of symptoms, and resolution with withdrawal of the offend­
ing drug establishes the cause in drug-induced cases.42,65 The disease has also
been reported after chemotherapy in patients with acute ­myeloid ­leukemia.70,71

Fig. 15.13
Sweet’s syndrome: an erythematous plaque on the forearm. By courtesy of R.A.
Marsden, MD, St George’s Hospital, London, UK.

Fig. 15.15
Sweet’s syndrome: close-up view of typical plaques. By courtesy of the Institute of
Dermatology, London, UK.

Fig. 15.14
Sweet’s syndrome:
characteristic edematous
red plaques (some
showing ulceration and
pustulation) are widely
distributed on the trunk
and proximal limbs. By
courtesy of R.A. Marsden, Fig. 15.16
MD, St George’s Hospital, Sweet’s syndrome: acral lesions on the dorsal surface of the hands and fingers, some
London, UK. with a hemorrhagic appearance. By courtesy of J.C. Pascual, MD, Alicante, Spain.

Sweet’s syndrome can be broadly reviewed as falling into three general
categories:
• classic (and often idiopathic),
• malignancy-associated (paraneoplastic),
• drug-induced.10
Patients may also have conjunctivitis, episcleritis, iritis, polyneuropathy,
oral involvement (superficial ulcers), and arthralgias.32,72–76 The larger joints
are usually affected and involvement tends to be migratory.5 Patients with
concurrent Sweet’s syndrome and erythema nodosum have been described
and it is possible that these two disorders share common pathogenetic mecha­
nisms.77 Dyssynchronous and synchronous Sweet’s syndrome and erythema
nodosum may occur.78–81
Sweet’s syndrome is of particular importance since 10–40% of cases are
associated with hematological malignancy such as leukemia (monocytic or
myelomonocytic, including leukemia cutis), myelodysplasia, lymphoma, and
multiple myeloma.82–93 Development of the disease may herald a relapse of the
leukemia.94 Sweet’s syndrome has also been reported in patients with mono­
clonal gammopathy and myelodysplasia in the absence of frank leukemia or
lymphoma.95 Hemophagocytic syndrome is also a reported association.96 The
clinical lesions of Sweet’s syndrome are said to be more severe in patients with
underlying hematological disease.88 An association with urticaria pigmentosa
has also been documented.7
Solid tumors may also be associated with Sweet’s syndrome in up to 7%
of patients, including:
• testicular,
• bladder,
• gastrointestinal,
• breast,
• lung,
• ovary,
• prostate.7,32,35,79,82–85,88,95,97–99
Association with oral squamous cell carcinoma has been reported,36,100
as has a rare case following treatment of herpes simplex in a patient with
metastatic breast carcinoma.101 Sweet’s syndrome has been described in
conjunction with numerous conditions, some of which are listed in Table
15.2. While its association with hematologic and internal malignan­
cies, upper respiratory tract infections, drugs, and certain inflammatory
­disorders such as erythema nodosum, rheumatoid arthritis, and sarcoido­
sis appears repeatedly, many of the others listed in the literature could be
coincidental.
Systemic involvement may be a feature of Sweet’s syndrome with lesions
described in the eye, lung, kidney, central nervous system, vagina, liver, gas­
trointestinal tract and skeletal muscle.7,86,102–110 Neural involvement appears
to be strongly associated with HLA-Cw1.110 An exceptional case with gin­
gival hyperplasia and myositis in the absence of cutaneous involvement has
been documented.111
Associated features include pyrexia, neutrophilia, and a raised ESR. In
one study, six of seven patients had antineutrophil cytoplasmic antibodies
(ANCA).112 Other studies, however, have not found an association between
Sweet’s syndrome and ANCA.7 This finding has not been further explored in
the more recent literature.
Pathogenesis and histological features
The etiology of Sweet’s syndrome is unknown; however, the disease most prob­
ably represents an unusual hypersensitivity reaction.113 Cytokine mediation
is likely, as anti-inflammatory agents are generally useful.113 The occasional
presence of immune complexes in blood vessel walls may have pathogenetic
significance.32 It has been suggested that neutrophils are activated by interleu­
kin (IL)-1 and that Sweet’s syndrome represents a cytokine-mediated inflam­
matory reaction to a wide variety of different antigens including bacteria,
viruses, drugs, and malignancies.114–116 Demonstration of elevated serum
IL-1α, IL-1β, IL-2, and interferon-gamma (IFN-γ) but not IL-4 suggests that
type 1 (but not type 2) helper T cells (Th) play a role in the pathogenesis.117
Not surprisingly, since exogenous treatment with G-CSF is associated with
Sweet’s syndrome, endogenous G-CSF has been shown to be elevated in some
cases.118
Acute febrile neutrophilic dermatosis 637
Table 15.2
Conditions associated with Sweet’s syndrome
Common associations
Drugs58
Hematologic malignancies (and myelodysplastic syndrome)91
Hepatitis B142
Inflammatory bowel disease (including ulcerative colitis and Crohn’s
disease) 143,144
Non-tuberculous mycobacterial infection145,146
Pregancy147
Sarcoidosis148,149
Scrofuloderma150
Sjögren’s syndrome151
Tuberculosis152
Upper respiratory tract infection10
Rare associations
Bacille-Calmette–Guérin (BCG) vaccination153
Pigmented villonodular synovitis154
Behçet’s disease155,156
Bronchiolitis obliterans157
Celiac disease158
Chronic granulomatous disease159
Dermatomyositis160, 161
Encephalitis162
Erythema nodosum80
Generalized granuloma annulare163
Hashimoto thyroiditis164
Infection with Apnocytophaga canimorsus, Chlamydia pneumoniae,
Coccidiodes immitis, Cytomegalovirus, Francisella tularensis,
Helicobacter pylori, Hepatitis C, human immunodeficiency virus (HIV),
Pasteurella multocida, Salmonella enteritidis, and Staphylococcus
epidermidis and Staphylococcus aureus165–178
Polycythemia rubra vera179,180
Prothrombin gene (G20210A) mutation181
Relapsing polychondritis182, 183
Sarcoidosis184
Solid tumor malignancy87, 97
Still’s disease185
Surgery186
Subacute and systemic cutaneous lupus erythematosus187–189
Thyroid disease (Grave’s disease and Hashimoto’s thyroiditis)190
Urticaria pigmentosa7
One study demonstrated clonality in the skin infiltrate of a patient with
Sweet’s syndrome and acute myelogenous leukemia, undergoing treatment
with G-CSF.119 The authors concluded that Sweet’s syndrome in patients with
myelogenous leukemia may result from therapy-induced differentiation of
neoplastic cells.119 However, a further study has demonstrated clonality in
four patients in the absence of myeloproliferative disease.120
Histologically, the epidermis in Sweet’s syndrome is usually unaffected
although occasionally slight spongiosis is present; rarely, vesiculation and
spongiform pustules have been described.32 Necrotic keratinocytes are also
sometimes evident.32 The cardinal feature, however, is an intense neutrophil
polymorph infiltrate within the reticular dermis (Fig. 15.17).3,121 This may be
diffuse or perivascular in distribution and often surrounds the sweat ducts.
Typically, leukocytoclasis is marked (Fig. 15.18). Admixed with the neutro­
phil polymorphs are variable numbers of eosinophils, lymphocytes, and his­
tiocytes. Ingestion of nuclear debris by histiocytes is sometimes a conspicuous
feature. A histiocyte-rich form of the disease has increasingly been recog­
nized.32,122–130 This is more likely to represent a stage in the evolution of the
disease rather than a specific variant of Sweet’s syndrome. It has been pos­
tulated that the histiocyte-like cells seen represent immature granulocytes.130
Awareness of this form of presentation is important to avoid a misdiagno­
sis. Given the presence of a ­mononuclear cell infiltrate in these cases, it is
extremely important to exclude leukemia cutis.
Often, the papillary dermis shows very marked edema, which sometimes
results in subepidermal vesiculation (Fig. 15.19). Rarely, the presence of
638 Neutrophilic and eosinophilic dermatoses

Fig. 15.17
Sweet’s syndrome: an intense inflammatory cell infiltrate is present in the dermis. Fig. 15.20
Sweet’s syndrome: the
occasional presence of
dermal papillary neutrophil
microabscesses can
result in confusion with
dermatitis herpetiformis.

dermal papillary neutrophil microabscesses may cause diagnostic confusion

with dermatitis herpetiformis (Fig. 15.20).121 In Sweet’s syndrome the blood
­vessels are dilated and may show endothelial swelling but changes of frank
vasculitis are generally absent in our experience (and certainly not promi­
nent). However, others have reported features of vasculitis such as nuclear
dust, extravasation of erythrocytes, and fibrin deposition in and around ves­
sels walls in the majority of their series of 31 cases and thus argue that the
presence of vasculitis should not exclude this diagnosis.131–133 Purpura, how­
ever, is sometimes evident.134 Immunofluorescence examination of skin biop­
sies in Sweet’s syndrome is usually negative for immunoreactants in the walls
of the vasculature. Recently, a case associated with leukocytoclastic neutro­
philic lobular panniculitis has been reported.135
Fig. 15.18 In some cases, an inflammatory infiltrate is noted within subcutaneous tis­
Sweet’s syndrome: the infiltrate consists largely of neutrophils. There is edema and sue. This infiltrate may be composed of lymphocytes and histiocytes and, less
marked leukocytoclasis. commonly, neutrophils.121,129 Sweet’s syndrome has also been associated with
an erythema nodosum-like panniculitis.136 Elastophagocytosis and cutis laxa
have been reported with resolution of Sweet’s syndrome lesions.137–140

Fig. 15.19
Sweet’s syndrome: marked papillary dermal edema is commonly present and
sometimes this is associated with subepidermal vesiculation.
Differential diagnosis
The presence of prominent fibrinoid vascular change can distinguish necrotiz­
ing vasculidities such as leukocytoclastic vasculitis, erythema elevatum diuti­
num, and granuloma faciale from Sweet’s syndrome; the clinical presentation
and distribution of disease are also extremely helpful. In granuloma faciale,
fibrinoid necrosis is often minimal and eosinophils tend to be prominent. Late
lesions of erythema elevatum diutinum and granuloma faciale show fibrosis,
a feature not seen in Sweet’s syndrome. Clinically, the presence of character­
istic large ulcers helps distinguish pyoderma gangrenosum from Sweet’s syn­
drome. Also, pyoderma gangrenosum does not usually show the extent of
karyorrhexis that is a typical feature of Sweet’s syndrome. A Gram stain and
periodic acid-Schiff (PAS) or culture may be necessary to exclude ­infection.
Distinction from some other forms of neutrophilic dermatosis including
bowel bypass syndrome may be a definitional issue since the clinical setting
determines the terminology applied.7 Behçet’s disease may also be associated
with lesions similar to those seen in Sweet’s syndrome. Clinical correlation
should ensure the correct diagnosis. CD30-positive forms can sometimes be
found in Sweet’s syndrome, raising the possibility of lymphomatoid papulosis.
However, neutrophils are usually rare in the latter condition and the ­number
of CD30-positive cells in lymphomatoid papulosis is not prominent.141
 Neutrophilic dermatoses associated with gastrointestinal and hepatobiliary disease 639

Neutrophilic dermatoses associated with

gastrointestinal and hepatobiliary disease
Clinical features
Pyoderma gangrenosum, the most common neutrophilic dermatosis affect­
ing patients with gastrointestinal disease (particularly ulcerative colitis), is
discussed above. The spectrum of lesions described in this section shares
many histological (and likely pathogenetic) features with pyoderma gan­
grenosum but lack the characteristic progressive ulceration. Neutrophilic
dermatoses associated with gastrointestinal disease may best be regarded
as a continuum, with pyoderma gangrenosum representing an extreme end
of the spectrum.
A syndrome of arthritis and pustular skin lesions was initially
described in patients with inflammatory bowel and liver disease, and also
in patients who have undergone jejunoileal bypass or Billroth II surgery
for morbid obesity, but now has been described in other gastrointesti­
nal disorders.1–7 Up to 20% of patients with jejunoileal bypass develop
this condition.4,8 It has also been noted in association with peptic ulcer­ Fig. 15.21
(A, B) Neutrophilic
ation, appendicitis, and diverticular disease.9,10 An increasing number of
dermatosis associated
papers call this process bowel-associated dermatosis-arthritis syndrome with gastrointestinal
(BADAS); this terminology currently appears to be that preferred by the disease: there is
majority of authors. an intense dermal
The skin lesions may be papular or vesicular, or form large necrotic neutrophilic infiltrate
lesions resembling pyoderma gangrenosum. They are usually found on A indistinguishable from
the trunk or extremities. Oral involvement has also been described.2 Sweet’s syndrome.
Associated panniculitis, which may resemble erythema nodosum, is a fea­
ture in some patients. Cutaneous manifestations often recur with exacer­
bation of the associated gastrointestinal disease.4 Some patients have an
elevated ESR.4 The disease occasionally responds to antibiotic or steroid
therapy.
A recurring vesiculopustular eruption may be seen in patients with hepa­
tobiliary disease.11 The lesions – which can be pruritic and sometimes heal
with an atrophic scar – often present on the extremities. In some patients
the ­eruption represents a necrotizing folliculitis.11 Occasionally, the cutaneous
lesions precede the features of the hepatobiliary disease.
Of interest, patients with Crohn’s disease complicated by disseminated
abscesses (involving the spleen, lymph nodes, liver, pancreas, and brain)
have recently been described.12 In some of these, the abscesses occurred
before the diagnosis of Crohn’s disease. Histologically, a granulomatous ele­
ment was commonly present. Successful treatment with immunosuppressive
therapy suggests that such lesions may represent an unusual extraintestinal
­manifestation of Crohn’s disease.12
The description of these entities suggests that they are overlapping or B
­perhaps represent a disease continuum. BADAS is the most rigorously defined
among these and this terminology can probably be employed for all of the
conditions mentioned above. Differential diagnosis
The main differential diagnoses include infection, Sweet’s syndrome, ­pyoderma
Pathogenesis and histological features gangrenosum, and rheumatoid neutrophilic dermatitis. Clinical history is essen­
The presence of circulating immune complexes in occasional patients has led tial to distinguish these conditions.
some authors to postulate a pathogenic role.13,14 It is postulated that bacterial The literature relating to bowel-associated dermatosis-arthritis and
overgrowth may play a role in the development of such circulating immune Sweet’s syndromes is often confusing and it seems likely that some patients
complexes.4 who have been reported as the former would actually have been better clas­
The histopathological findings, which are non-specific, are those of a neu­ sified as the latter. Contrariwise, occasional patients who presented with
trophilic dermatosis. The lesions show variable dermal edema and necrosis features more typical of bowel-associated dermatosis-arthritis syndrome
associated with a perivascular and interstitial neutrophilic infiltrate. Variable have, in fact, been reported as Sweet’s syndrome.17,18 In many patients
numbers of lymphocytes and histiocytes may also be present. Abundant kary­ such a distinction is semantic. In others, however, the clinical lesions are
orrhexis gives rise to a histological pattern similar to acute febrile neutrophilic quite inconsistent with Sweet’s syndrome and in these patients a designa­
dermatosis (Sweet’s syndrome) (Fig. 15.21). Leukocytoclastic vasculitis and tion of bowel-associated dermatosis-arthritis syndrome is probably more
pustular vasculitis have also been documented.15,16 The inflammation is often appropriate.
limited to the dermis but in some patients it may be seen to involve the sub­ Pyoderma gangrenosum is another neutrophilic dermatosis which patients
cutaneous fat, resulting in erythema nodosum or an erythema nodosum-like with gastrointestinal disease are at risk of developing. Clinically, it may be
panniculitis. distinguished by the progressive expansile nature of the cutaneous ulcers.4
The small number of cases described in patients with hepatobiliary disease Since the biopsy findings may be similar, clinical correlation is ­essential
has shown bullae associated with a dermal neutrophilic infiltrate, sometimes to distinguish this condition from bowel-associated dermatosis-arthritis
accompanied by eccrine hidradenitis or folliculitis.11 syndrome.
640 Neutrophilic and eosinophilic dermatoses
It is likely, given the histological and clinical spectrum encountered in the
neutrophilic dermatoses associated with gastrointestinal and hepatobiliary
disease, that they result from similar or shared pathogenetic mechanisms.
Clearly, more research may clarify their precise pathogenesis and contribute
to a more satisfactory classification system.
Rheumatoid neutrophilic dermatitis
Clinical features
Rheumatoid neutrophilic dermatitis is an uncommon eruption seen in
patients with rheumatoid arthritis.1 It presents most often as papules, nod­
ules, and plaques on the extensor surfaces of the extremities, neck, and
trunk. In some patients it may clinically resemble urticaria.2–7 Bullous lesions
have also been described.8,9 The lesions, which can ulcerate, are often pru­
ritic or painful, and sometimes show an annular configuration.3,10 The dis­
ease is uncommon, as evidenced by documentation in just two of 142 and
two of 215 patients with rheumatoid arthritis seeking medical attention for
skin disorders in academic clinics in Japan and Turkey, respectively.4,11 The
presence of rheumatoid neutrophilic dermatitis correlates with the severity
of the patient’s joint disease.4
Typically, lesions last for up to several weeks.2 In some patients, the condi­
tion resolves spontaneously; in others, it responds to steroid, dapsone or sul­
famethoxypyridamine therapy.2,5,10
Patients with seronegative arthritis but with cutaneous findings similar to
rheumatoid neutrophilic dermatitis have recently been reported.12–15
Magro and Crowson have described sterile neutrophilic folliculitis
associated with a Sweet’s syndrome-like histology in a setting of systemic
disease including rheumatoid arthritis, Crohn’s disease, connective tissue
disease, hepatitis, Behçet’s disease, atopy, hematological dyscrasia, and
mycobacterial infection.16,17 A similar folliculocentric acute ­inflammatory
process has also been documented in patients with ulcerative ­colitis.18,19
It would seem probable that these reports reflect a similar ­condition
or ­spectrum of disease that likely shares common histopathogenic
mechanisms.
Pathogenesis and histological features
The pathogenesis of rheumatoid neutrophilic dermatitis is not understood
but some authors have suggested that it may represent an immune complex-
mediated disease.3,5
Histologically, it is characterized by a dermal neutrophilic infiltrate with
variable karyorrhexis (Fig. 15.22). In some cases, however, karyorrhe­
xis is ­minimal or absent. Variable numbers of histiocytes, plasma cells, and
A B
Fig. 15.22
(A, B) Rheumatoid neutrophilic dermatitis: there is an intense upper dermal neutrophilic infiltrate with conspicuous karyorrhexis. By courtesy of J. Cohen, MD,
Dermatopathology Laboratory, Tucson, USA.
e­ osinophils may be present; abscess formation is sometimes a feature.2,3,5
Occasionally, the inflammatory infiltrate extends into the subcutaneous
fat.3,7 The overlying epidermis may show spongiosis and intraepidermal
vesiculation.5
Differential diagnosis
Infection must be considered in the differential diagnosis, particularly as
patients are often at risk of infection as a result of immunosuppressive ther­
apy. Furthermore, the cutaneous eruption may be treated with steroids, and
failure to diagnose an underlying infective process could have disastrous
consequences. Gram, AFB/acid fast, and silver stains for microorganisms
should be routinely performed and the diagnosis made only after infection
has been excluded. We have encountered several patients with rheumatoid
arthritis on steroid therapy who developed pustular infiltrates associated with
Mycobacterium chelonei infection.
Pyoderma gangrenosum may show similar, if not identical, features but
differs by progressive ulceration. It should be remembered that patients
with rheumatoid arthritis may also develop pyoderma gangrenosum.4
Clinical correlation is necessary to distinguish these entities. Pyoderma
gangrenosum may form part of a continuum that may eventually prove
to share similar pathogenetic mechanisms. To those who hold this view,
documentation of a patient with concurrent typical features of both
­pyoderma gangrenosum and rheumatoid neutrophilic dermatitis should
not be surprising.20
Some authors have pointed out that rheumatoid neutrophilic derma­
titis might be classified as a variant of Sweet’s syndrome.2 Certainly, the
biopsy findings may be very similar. The lack of fever and the general mal­
aise that accompany Sweet’s syndrome are distinguishing clinical findings.
The presence of gastrointestinal disease distinguishes rheumatoid neutro­
philic dermatitis from bowel-associated dermatosis-arthritis syndrome.
As with pyoderma gangrenosum, one might consider Sweet’s syndrome
and rheumatoid neutrophilic dermatitis to form a spectrum of disease.2
It is the characteristic clinical settings that allow these disorders to be
distinguished.
Patients with rheumatoid arthritis may sometimes develop lesions
which show histological overlap with rheumatoid neutrophilic dermatitis
but which can be distinguished by the presence of a palisading necrobiotic
and granulomatous component (termed palisaded neutrophilic granuloma­
tous dermatitis).21 This spectrum, also includes interstitial granulomatous
dermatitis encountered in a setting of systemic disease (including rheuma­
toid arthritis). Patients, predominantly adults, present with papules and
nodules which particularly affect the extremities or trunk; these are often
distributed in a linear pattern.22,23 The presence of necrobiosis associated

with a histiocytic response reminiscent of granuloma annulare or necrobi­
osis lipoidica in addition to acute inflammation and ­variable ­karyorrhexis
helps distinguish these lesions from typical ­rheumatoid ­neutrophilic
dermatitis.
Lesions in which the neutrophilic infiltrate is associated with dermal pap­
illary abscess formation may be mistaken for dermatitis herpetiformis, linear
IgA disease, and bullous systemic lupus erythematosus. Immunofluorescence
staining may be necessary in problematic cases.
The presence of vascular necrosis and fibrinoid change distinguishes rheu­
matoid neutrophilic dermatitis from vasculitis.24 It must be emphasized that
a careful search for evidence of vasculitis is not simply an academic exercise,
since patients with rheumatoid arthritis are also at risk of developing vas­
culitis. In fact, patients with rheumatoid arthritis may present with lesions
histologically showing extravascular palisading granulomas, diffuse neutro­
philic infiltrates or vasculitis (neutrophilic, lymphocytic or granulomatous).
The different patterns may overlap and classification should be based on the
dominant histological pattern.
Arthropod and arachnid bite reactions
Clinical features
The vast majority of insect bites pose little more than a minor annoyance. The
reaction that results from a given bite depends on the nature of the offend­
ing insect and the patient’s immune response. The clinical response to a bite
may vary from a trivial erythematous papule to a large nodule associated
with marked pruritus and ulceration. Vesicles are sometimes seen in severe
­reactions (Fig. 15.23). Careful inspection will often reveal a punctum at the
site where insect mouth parts entered skin.
While arthropod bites are rarely of clinical importance, reactions ­following
the bite of certain arachnids can lead to a more serious clinical lesion
(Fig. 15.24). Many different species of spiders may bite humans, and reac­
tions to the most significant and well described – the brown recluse and the
black widow – are detailed below.1–4
Brown recluse spider
The brown recluse spider (Loxosceles reclusa) bite begins as a painful ­bluish
macule, papule or nodule, often with a bruise-like appearance. A central
punctum is commonly observed. The lesion is often trivial. The thigh was the
involved site in almost 50% of cases with the arm and abdomen accounting
for most of the remainder in a large series from a single center of more than
50 patients with presumed bites.5 However, in some patients, blistering and
Fig. 15.23
Bullous insect bite reaction: there are large fluid-filled bullae in this close up view
from the lower leg. From the collection of the late N.P. Smith, MD, the Institute of
Dermatology, London, UK.
Arthropod and arachnid bite reactions 641
Fig. 15.24
Spider bite: note the central eschar and surrounding erythema. Courtesy of
Al Mahmoud, MD, Doha, Qatar.
ulceration, often progressing to a large necrotic lesion, is a feature.6 Chronic
ulceration mimicking pyoderma gangrenosum may rarely ensue.7 The brown
recluse is most commonly encountered in rural areas of the Midwest, south-
central, and southeastern United States and is easily identified by a violin-
shaped marking on the cephalothorax that gives it its vernacular name of
‘fiddleback’ spider.8 However, other spiders are often misidentified as brown
recluse and the diagnosis may be overused as the spider is often not identi­
fied at the time of the bite.9–13 This makes much of the existing literature
suspect.14
Sphingomyelinase-D in the venom of the brown recluse spider is
thought to be responsible for the extensive necrosis that results in some
patients.15 Spider bites may be associated with morbilliform rash, malaise,
fever, nausea, hemoglobinuria, arthralgias, and vomiting.6,16–18 More seri­
ous complications (e.g., renal failure, shock, disseminated intravascular
coagulation, acute hemolytic anemia, and intravascular hemolysis) have
also been described.16,19,20 Many of the effects of the venom appear to
be dose-dependent rather than idiosyncratic.21,22 ELISA-based assays to
detect the Loxosceles venom at the site of the bite are available and can
be helpful to confirm the diagnosis, as detectable toxin may persist for
more than 2 weeks.23–27 Anti-loxoscelic sera are available for use in severe
cases.28,29
Widow spiders
The five species of widow spiders found in the United States, including the
notorious black widow (Latrodectus mactans), are most commonly encoun­
tered in the southern states. Compared with the brown recluse, bites by
widow spiders are much less commonly encountered by healthcare provid­
ers. Many presumed or self-reported arachnid bites are ultimately discov­
ered to be skin and soft tissue infections.30 The bite often shows a targetoid
appearance with a pale center surrounded by an outer erythematous rim.31
A bite from a black widow spider is commonly associated with severe pain
in the vicinity of the bite as well as systemic symptoms such as general mal­
aise, abdominal pain, nausea, headache, and muscle spasms.6,16,31 Priapism
has been noted as a rare complication.32 Occasionally, patients die as a result
of the bite.19,33
Alpha-latrotoxin is an active component of the venom that binds to pre­
synaptic nerve terminals and stimulates massive neurotransmitter release.
The neurological symptoms are termed latrodectism and consist of pain,
diaphoresis, and non-specific systemic symptoms sometimes combined with
additional autonomic or neurological dysfunction.34 Equine-derived antisera
is available and effective as a treatment.35 Recombinant antisera are under
development.36
642 Neutrophilic and eosinophilic dermatoses

Hobo spider
Recently, the Hobo spider (Tegenaria agrestis) has been implicated as a
cause of significant bite reactions in the Pacific Northwest with migration to
Montana and Colorado and evidence of continuing eastward expansion.37,38
While bites from this spider are believed to cause dermonecrotic injuries,
additional study is necessary to confirm this impression.39,40

Histological features
Just as there is a spectrum of clinical response to an insect bite, the histo­
pathological features also vary.
The typical arthropod bite reaction, such as follows a mosquito bite, is
characterized by a wedge-shaped polymorphic inflammatory cell infiltrate
composed of lymphocytes, histiocytes, eosinophils, and sometimes neutro­
phils (Figs 15.25, 15.26). Spongiosis (occasionally with vesicle formation)
and variable dermal edema are also seen (Figs 15.27–15.30). Ulceration
with scale-crust commonly forms in excoriated lesions. In some cases,
insect mouth parts are identified in the center of the lesion. In our experi­
ence, this is more common in biopsies from tick bites than arachnid bites
Fig. 15.26
(Figs 15.31–15.33). Arthropod bite reaction: note the conspicuous eosinophils.
As with arthropod bite reactions, the histological sequelae from arach­
nid bite are variable. Compared with the former, arachnid bite reactions are
typically associated with more extensive necrosis and suppurative inflam­
mation. Necrosis may extend to involve the subcutaneous fat and muscle.6
Variable numbers of eosinophils and lymphocytes are present and marked
dermal edema is often a feature.6 Secondary vasculitis, involving vessels
within the lesion or in the immediate surrounding tissue, may be a feature
in some cases. Injection of brown recluse spider venom into rabbits results
in ‘mummified’ coagulation necrosis, a mixed inflammatory cell infiltrate,
and vasculitis.41

Differential diagnosis
The histological findings in biopsies of insect bites, short of identifying
mouth parts in the specimen, are non-specific. The main differential diagno­
sis includes hypersensitivity reactions. The characteristic wedge shape of the
infiltrate is an important clue to the diagnosis. The presence of large ­atypical
lymphocytes helps distinguish lymphomatoid papulosis from an arthropod
bite reaction. Bite reactions with a dense eosinophil-rich infiltrate may be

Fig. 15.27
Bullous arthropod bite reaction: massive subepidermal edema has resulted in a
multiloculated subepidermal blister.

Fig. 15.25
Arthropod bite reaction:
there is a heavy Fig. 15.28
perivascular and interstitial Bullous arthropod bite reaction: eosinophilic spongiosis is present at the edge of
infiltrate. the lesion.
 Seabather’s eruption and coelenterate stings 643

Fig. 15.29 Fig. 15.32

Bullous arthropod bite reaction: there is a lymphocytic and eosinophilic perivascular Tick bite reaction: high-power view showing tick parts and multiple flame figures.
and interstitial infiltrate.

Fig. 15.30 Fig. 15.33

Bullous arthropod bite reaction: high-power view showing a flame figure. Tick bite reaction: there is a dense infiltrate of lymphocytes, histiocytes, and
conspicuous eosinophils.

indistinguishable from Wells’ syndrome. The occasional presence of flame

figures heightens the similarity. Clinical correlation may be necessary to
­distinguish these two conditions.
The histological findings associated with arachnid bite are also non-spe­
cific. Arachnid bites must be distinguished from pyoderma gangrenosum,
factitial disease, primary vasculitis, and infections including cellulitis and
necrotizing fasciitis. Arachnid envenomation appears to be over-reported;
thus, some cases have been reported in regions where the spiders have never
been documented to exist. ELISA-based assays may be helpful to confirm
the ­diagnosis. Without definitive evidence of involvement of an arachnid,
the diagnosis must be considered one of exclusion so as not to overlook
­important clinical alternatives with a different treatment approach.

Seabather’s eruption and coelenterate

Fig. 15.31
Tick bite reaction: low-power view showing a heavy dermal inflammatory cell
infiltrate. Tick parts are seen in the center of the field.
stings
Clinical features
Seabather’s eruption, sometimes referred to as ‘sea lice’, is attributed
to stings from larval forms of coelenterates, often the thimble jellyfish
644 Neutrophilic and eosinophilic dermatoses
(Linuche unguiculata scyphomedusae).1–4 Typically, patients develop a
papular eruption in areas covered by the bathing suit, often accentuated
where the suit is tight fitting, such as the waistline.5 The eruption is usu­
ally pruritic and may cause a burning sensation. Patients sometimes expe­
rience systemic symptoms such as malaise, fever, nausea, diarrhea, and
vomiting.
Reactions to coelenterates such as jellyfish vary from minor irritation to
fatal reactions following stings by highly venomous species such as the ‘box
jellyfish’ (Chironex fleckeri and Chiropsalmus quadrigatus).6 Jellyfish stings
are often erythematous and show a ‘whiplash-like’ appearance.6,7 Certain spe­
cies may have more serious consequences, such as the Portugese man-of-
war (Physalia physalis), where systemic effects from neurotoxins can be seen,
including cramping of muscles, respiratory distress, profound ­hypotension,
and even death in extreme cases.8–11
A topically applied envenomation inhibitor based on the mucous coat of
clown fish is effective in dramatically reducing both some coelenterate stings
and seabather’s eruption, though it may lack efficacy against certain coelen­
terate species.12,13
Histological features
Biopsy of papules of seabather’s eruption shows a non-specific perivascular
inflammatory cell infiltrate composed of variable numbers of lymphocytes,
eosinophils, and neutrophils.2 Epidermal changes are apparently not usually
a feature.2
Only few authors have reported the histological findings following reac­
tion to coelenterate stings. Non-specific perivascular inflammation with
lymphocytes and variable numbers of eosinophils appear to be characteris­
tic. Some cases show dense, sheetlike aggregates of lymphocytes and histio­
cytes.14 Variable dermal edema may be an additional feature. Spongiosis and
vesicle formation are also sometimes described.14–16 One fatal case showed
only vascular congestion without significant inflammation, a ­histological
picture that likely reflects the fact that the patient died only 40 minutes
after being stung.6 Only occasionally are nematocyst capsules and tubes
identified.6,16
Differential diagnosis
The histological differential diagnosis of reactions to coelenterates includes
other hypersensitivity reactions. Short of finding nematocysts, the diagnosis
depends entirely on clinical correlation.
Erythema marginatum rheumaticum
Clinical features
Once a common disease, it was thought that, with the effective antibiotic
treatment of the causative infection, rheumatic fever would become of histor­
ical interest only. However, there has been a resurgence of the condition over
the past few decades, particularly in developing countries.1–5
Rheumatic fever is an immunologically mediated disease that follows an
infection with Lancefield group A beta-hemolytic streptococcus. The infec­
tion causes pharyngitis and carditis. Additional features include polyarthritis,
a neurological movement disorder known as Sydenham’s chorea, and sub­
cutaneous nodules.6 Carditis, characterized by a valvular disease, is a major
cause of morbidity and mortality.
Erythema marginatum rheumaticum is the designation given to the dis­
tinctive annular or polycyclic eruption of rheumatic fever. The lesions are
nonpruritic, multiple, flat, erythematous maculopapules which change
and spread over hours, and are often recurrent. The trunk and proximal
extremities are most frequently affected.2 The hands and face may also be
involved.4 By definition, erythema marginatum rheumaticum is associated
with rheumatic fever, but occurs in only 1–18% of patients.1 Some studies
have failed to identify significant human leukocyte antigen (HLA) associa­
tions.3,7 However, there are conflicting reports of certain HLA subtypes and
the disease.8
Pathogenesis and histological features
The pathogenesis of rheumatic fever is incompletely understood. It appears
likely that it results from a hypersensitivity reaction triggered by streptococ­
cal infection. Specifically, patients develop autoantibodies that cross-react
with streptococcal antigen due to molecular mimicry.9 For example, autoan­
tibodies cross-react with cardiac muscle, causing carditis. Mice immunized
with the streptococcal M protein develop myocarditis.9 Bradykinin in dense
deposits can be seen in stromal and endothelial tissues, suggesting it may
mediate some facets of this condition.10
Variable numbers of neutrophils (sometimes associated with leukocyto­
clasis) and mononuclear cells are present in the infiltrate.7,11 Importantly,
however, there is no evidence of vasculitis. Dermal papillary neutrophil
microabscesses have occasionally been described.7
It has been reported that rare cases are devoid of neutrophils and the
­infiltrate is instead composed of lymphocytes and histiocytes.12
Differential diagnosis
The biopsy findings in erythema marginatum are non-specific. Similar his­
tological features may be seen in patients with Still’s disease and acute lupus
erythematosus. Careful search for vascular damage is necessary to exclude
leukocytoclastic vasculitis. Special stains and culture to rule out an infec­
tious etiology are sometimes required. Urticaria can demonstrate ­perivascular
­neutrophils but additionally it shows significant dermal edema, and an
­interstitial inflammatory cell infiltrate, including neutrophils, eosinophils,
and lymphocytes
Still's disease
Clinical features
Juvenile rheumatoid arthritis or systemic juvenile idiopathic arthritis (Still’s
disease) is a heterogeneous group of disorders which share in common an
inflammatory arthritis with many features similar to rheumatoid arthritis in
adults. Juvenile rheumatoid arthritis patients, however, are seronegative for
rheumatoid factor.1 There are marked differences in prevalence from region
to region. Whites in Europe, the United States, and Australia (4 per 1000)
have the highest prevalence.2,3 One study has suggested that the incidence of
the disease is decreasing.4 This same study also documented incidence peaks
indicating a possible cyclical pattern.4 Other studies have found seasonal
­variation in certain regions such as the Canadian prairies.5 However, such
seasonal onset has not been apparent in other areas of Canada, in Denmark
or in Japan.5–8
Juvenile rheumatoid arthritis is classified into three variants: ­pauciarticular,
polyarticular, and systemic onset.
• The pauciarticular (oligoarticular) form is characterized by arthritis
involving up to a maximum of four joints. Systemic manifestations are
uncommon. Uveitis, however, is frequently present.
• The polyarticular form is manifest by symmetrical arthritis typically
involving the knees, wrists, and ankles. Fever and hepatosplenomegaly
are sometimes present.
• The systemic-onset form is a severe variant in which lymphadenopathy,
fever, and rash precede development of polyarteritis which most often
affects the knees, ankles, and wrists.9 Additional features may include
hepatosplenomegaly and effusions. In general, the term Still’s disease is
restricted to this form of juvenile rheumatoid arthritis; however, some
authors use it for any of the variants. The majority of patients with the
systemic form have the characteristic rash in contrast to the pauci- and
polyarticular variants in which only 20–40% are affected.9
The rash of Still’s disease is evanescent, and is characterized by a faint
erythematous (salmon-colored), sometimes pruritic, macular eruption involv­
ing the trunk, extremities, head, and neck.9–11 Often, there is an association
between onset of rash and febrile episodes, particularly in the late afternoon
or evening.9,11 The rash is typically present for only a short period of time,
usually a matter of a few hours; however, some lesions persist for more than
24 hours.9,11 It characteristically reappears without regard for its former dis­
tribution.11 Macules are often only a few millimeters in size but frequently

become confluent to form larger lesions. Central pallor is sometimes a feature
of the latter.10 The eruption – which may persist for weeks to years – tends to
localize to areas of mild trauma and pressure.9,11
Laboratory abnormalities include elevated ESR and C-reactive protein.
Serum immunoglobulins may also be raised. Patients sometimes have leuko­
cytosis, anemia, and thrombocytosis. Occasional patients have rheumatoid
factor and some authors consider this to represent bona fide juvenile rheu­
matoid arthritis. Antinuclear antibodies are commonly found in patients with
pauci- and polyarticular variants of the disease.8 In contrast, antinuclear anti­
body is usually not present in the systemic-onset form.
It is very difficult to predict the outcome of this disease in the individual
patient. Approximately 50% of patients experience symptoms into adulthood.
Progression of juvenile rheumatoid arthritis to systemic lupus ­erythematosus
(SLE) has been documented.12 Serious complications ­including uveitis,
­cardiac tamponade, portal vein thrombosis, liver failure, and ­disseminated
­­intravascular coagulation have been documented.13–17
Despite the name juvenile rheumatoid arthritis, Still’s disease is not lim­
ited to the pediatric population. Adult onset is well described in the literature
(Fig. 15.34).18–22 Patients with the adult form of the disease may develop per­
sistent papules and plaques and hyperpigmentation.23 Lesions are mainly seen
on the face, neck, trunk, and extensor surfaces of the extremities.
Pathogenesis and histological features
The pathogenesis of juvenile rheumatoid arthritis is poorly understood. It would
seem likely, however, that the various subtypes have different etiologies. Thus:
• IL-2 mRNA is detected more often in pauciarticular juvenile rheumatoid
arthritis than in the polyarticular form.24
• IFN-γ mRNA may be detected in 33% of systemic-onset juvenile
rheumatoid arthritis in contrast to 85% in the other forms.24 IL-6 and
other cytokines can also be involved.25
Recently, it has been suggested that nucleotide-binding and oligomerization
domain (NOD)-like receptors (NLR) that detect microbes and help constitute
the inflammasome (a complex of proteins which initiates an inflammatory
reaction) may be involved in autoimmune disease generally and in Still’s dis­
ease in particular.26
Data suggesting that the incidence of the disease is decreasing with cyclical
peaks raise the possibility that environmental factors could play a role in the
pathogenesis.4 Demonstration of T-cell oligoclonal expansions within synovial
tissue suggests that an antigen or group of antigens may trigger the disease.27
The nature of such triggering factors, however, has not yet been identified.
The prevalence of autoimmune disease is increased in relatives of patients
with juvenile rheumatoid arthritis compared with control subjects, suggesting
that shared susceptibility genes may be of importance in the pathogenesis of
juvenile rheumatoid arthritis and other autoimmune diseases.28
Fig. 15.34
Still’s disease in an adult: there are multiple erythematous macules. By courtesy of
J.C. Pascual, MD, Alicante, Spain.
Urticaria 645
The influence of various HLA alleles and their association with juve­
nile rheumatoid arthritis has been an area of considerable interest and has
yielded a complex picture of the relationship between certain HLA alleles and
risk of disease.29 HLA-A2, DR8, DR5, and DPB1*0201 are associated with
increased risk of pauciarticular disease early in life.31 While B27 and DR4
may be protective in the early years, these alleles seem to confer increased risk
of disease later in life.30
CD4-reactive T lymphocytes are the predominant cell type in the inflamed
synovium.31 As with other autoimmune disorders, production of predomi­
nantly Th1 cytokines (IFN-γ and IFN-β) has been observed in the synovium
of juvenile rheumatoid arthritis patients.31,32
The biopsy findings are non-specific and variable. There is often a perivas­
cular neutrophilic infiltrate.10 In some cases, mononuclear cells are the pre­
dominant cell type.9,11 A neutrophilic panniculitis may be associated with
the disease.33 In adult-onset Still’s disease, distinctive histologic features have
been described particularly in the persistent papules and plaques sometimes
seen in the disease.24 The epidermis displays dyskeratotic keratinocytes in
single units or aggregates. They tend to be present mainly in the upper layers
of the epidermis and even in the stratum corneum.23,34 Other changes include
subcorneal pustules, upper dermal lymphocytes and neutrophils and, in a
single case report, excess dermal mucin.23,34
Differential diagnosis
The histological findings, as indicated above, are variable and non-specific.
Clinical correlation is necessary to establish the diagnosis. The differential
diagnosis includes infection, and culture and stains for microorganisms should
be performed when necessary. The absence of fibrinoid change and necrosis of
blood vessel walls distinguishes the lesions from leukocytoclastic vasculitis.
Urticaria
Clinical features
Urticaria is an extremely common group of disorders that share common
clinical and histological features.1 The lifetime incidence approaches 1 in 5
people.2 As will be seen later, urticaria has many different etiologies but, more
often than not, the cause remains unknown and the disease is then classi­
fied as idiopathic. In some patients, more than one stimulus may elicit symp­
toms.3 The clinical common denominator in urticaria is the development of
‘hives’ or ‘wheals’ – raised edematous lesions – which are often surrounded
by a zone of erythema and are commonly pruritic (Figs 15.35–15.37).4,5
Dermatographism – pressure or light scratching resulting in linear urti­
carial lesions – is a common symptom. Urticaria may develop in only sec­
onds. Lesions usually resolve in less than a few hours. By definition, lesions
Fig. 15.35
Urticaria: erythematous, edematous, coalescing plaques on the trunk and proximal
extremities of an infant. By courtesy of J.C. Pascual, MD, Alicante, Spain.
646 Neutrophilic and eosinophilic dermatoses

Solar urticaria
Solar urticaria is characterized by development of wheals and pruritus at sites
exposed to light (Fig. 15.38).7 A sensitizing agent, such as a drug, may be
necessary.8 In some patients lesions even arise in areas covered by light cloth­
ing.9 ‘Fixed solar urticaria’ is a designation given to a rare form of urticaria
seen in patients who develop lesions at the same sites with repeated light
exposure.10,11 Solar urticaria has also been described following exposure to
infrared and ultraviolet radiation.12,13

Fig. 15.36
Urticaria: in this patient,
the erythematous border
is well demonstrated.
By courtesy of the
Institute of Dermatology,
London, UK.
Aquagenic urticaria
‘Aquagenic urticaria’ is a bizarre variant of physical urticaria in which patients
develop lesions following exposure to water (regardless of temperature).14,15
Extracutaneous manifestations such as migraine headache and familial occur­
rence has been described on rare occasion.16–18 Thankfully, patients do not
develop symptoms from drinking water.5,19 Application of petrolatum oint­
ment or other barrier cream prior to water exposure helps to prevent lesion
development.14,20 It has been postulated that a water-soluble epidermal anti­
gen may be responsible for such symptoms, since aqueous extracts of callus
cause symptoms in patients’ skin but not in that of controls.21 Increased water
salinity has also been implicated.22
Cold urticaria
Placing an ice cube on the skin of patients may elicit a wheal – a condition desig­
nated ‘cold urticaria’.5,23 Some patients, however, develop symptoms only after
generalized cooling of the body.5,24 Occasionally, drinking cold liquids or bath­
ing in cold water elicits symptoms.5 The condition can be associated with other
types of physical urticaria. Very rarely, there is associated cryoglobulinemia and
in some cases the condition follows a viral infection or drug ingestion.23,25,26
Familial cold urticaria (familial cold autoinflammatory syndrome) which
­follows exposure to cold is an autosomal dominant condition characterized by:27–30
• urticaria,
• fever,
• arthralgias,
• arthritis,
• conjunctivitis,
• leukocytosis.
Patients with this syndrome develop symptoms with a decrease in body
temperature but do not develop wheals at the site of an ice cube applied to
skin. Recently, patients have been shown to have mutations in the NLRP3
gene (also known as CIAS1) on chromosome 1q44 encoding the protein cryo­
pryin. This protein is part of the cytosolic inflammasome protein complex and
involved in its activation.31–38 Interestingly, Muckle-Wells syndrome is associ­
ated with the same gene and consists of periodic fever, frequent ­sensorineural

Fig. 15.37
Urticaria: in this extreme
example there is intense
erythema. By courtesy
of the Institute of
Dermatology, London, UK.

in patients with chronic urticaria, however, persist over a period in excess of

6 weeks.5,6 In addition, individual lesions in patients with chronic urticaria
often last longer – up to 36 hours.4
Given that urticaria is best viewed not as a single disease but as a group of
related disorders, it comes as no surprise that the natural history of ­urticaria
is highly variable.2 Resolution is seen in 50% of patients within a few years
of onset; however, in some patients the disease persists for decades.2,5 The
severity of symptoms is also variable. For many patients, the disease is a
minor annoyance; for others, however, severe reactions may be associated
with ­life-threatening anaphylaxis. Fig. 15.38
Physical causes of urticaria include sunlight, cold, heat, pressure, and Solar urticaria: in this patient, urticaria developed after exposure to sunlight.
vibration. By courtesy of the Institute of Dermatology, London, UK.

hearing loss, amyloidosis, and recurrent urticaria not linked to cold expo­
sure.32,39 In addition, neonatal-onset multisystem inflammatory disease also
maps to this gene.40 The spectrum of autoinflammatory disorders is now
referred to as the cryopinopathies.41
Urticaria induced by heat has rarely been documented.42–44
Delayed pressure urticaria
Patients with ‘delayed pressure urticaria’ develop lesions at sites of pressure,
such as areas of tight clothing.5,45 This form of urticaria is seen in 40% of
patients with chronic urticaria (see below).5,46,47
Cholinergic urticaria
Cholinergic urticaria – one of the most common subtypes of urticaria – is
thought to result from release of cholinergic substances by nerves.48–50 Evidence
in support of this theory includes the observation that wheals may be elicited
by the injection of cholinergic compounds, and injection of anticholinergic
agents blocks wheal formation.48 Furthermore, wheals do not develop in skin
innervated by nerves injected with local anesthetic, and application of sco­
polamine to skin prevents aquagenic urticaria.19,48 Common causes of cho­
linergic urticaria include increase in body temperature (e.g., following a hot
bath or shower), emotional stress, exercise or consumption of spicy food (Fig.
15.39).5,48,51 Familial cases of cholinergic urticaria have been reported.52
Contact urticaria
Contact urticaria may be divided into two main subtypes: allergic and irritant.5
• Allergic contact urticaria is a hypersensitivity reaction following
exposure to an allergen such as chemicals, foods, latex, plants, fruits and
vegetables, and animal-derived antigens.53,54 Not surprisingly, this form of
urticaria often occurs in patients with a history of atopy.53,55
• Irritant contact urticaria is a nonimmunologically mediated form of
urticaria secondary to a wide variety of substances found in cosmetics,
food and medications.53
Urticarial angioedema
Patients with urticaria often develop angioedema characterized by edematous
swelling of the lips, eyelids, and tissues of the oropharynx.5,56,57 Two main sub­
types of angioedema are recognized: hereditary and nonhereditary (acquired).
• Hereditary angioedema is rare, autosomal dominantly inherited, and due
to C1-esterase inhibitor deficiency.58
• Acquired angioedema is caused by drug reactions, allergic reactions,
reaction to physical agents, hypereosinophilia, and acquired
(nonhereditary) C1-esterase deficiency.57
An idiopathic variant is also recognized.
Fig. 15.39
Cholinergic urticaria: in this variant, urticaria follows heat, emotional stress or a
spicy meal. By courtesy of the Institute of Dermatology, London, UK.
Urticaria 647
Physical urticaria, secondary to vibration, cold, and sunlight, as well as
contact (type I) hypersensitivity reaction and cholinergic urticaria may be
associated with angioedema.57
Urticarial vasculitis
Urticarial vasculitis is an uncommon condition which combines clinical
­features of chronic urticaria and histological findings of leukocytoclastic
venulitis.59–62 A type III hypersensitivity reaction (caused by antibody–antigen
complexes) appears to be the underlying etiology in a subset of patients.63,64
In many patients, however, no underlying cause is discovered.
Urticarial vasculitis is associated with a female predominance (2:1)
and is most often seen in young to middle-aged adults. Urticarial lesions
tend to last 24–72 hours and may be associated with pruritus, a burning
­sensation or pain.65,66 The frequency of attacks varies from daily to monthly.
Hyperpigmentation can be present at resolution.
The spectrum of illness ranges from mild symptoms to a serious ­systemic ill­
ness.67 In addition to urticarial skin lesions, patients can also have angioedema,
gastrointestinal symptoms, and evidence of renal involvement. Necrotic skin
lesions are not usually seen. Other systemic manifestations/associations include
joint pain, stiffness, and swelling; however, frank arthritis is extremely rare. Some
patients have proteinuria and hematuria. Rarely, renal biopsy reveals the features
of focal or diffuse proliferative glomerulonephritis. Crescentic glomerulonephri­
tis and mesangial and membranous nephropathy have been described in some
patients.67–69 The erythrocyte sedimentation rate (ESR) is frequently raised.
Rarely, urticarial vasculitis has been documented in association with malig­
nancy, a relationship which may be coincidental.67,70–75
Hypocomplementemia is seen in many patients and the presence of this sign
correlates with systemic involvement and a high prevalence of autoantibod­
ies to endothelial cells.63,67,76–78 Patients with Schnitzler’s syndrome have urti­
carial vasculitis and monoclonal IgM gammopathy.79–86 Hepatosplenomegaly,
elevated ESR, raised white blood cell count, fever, and joint pain are charac­
teristic features.80–82 Occasional patients have an associated lymphoprolifera­
tive disorder.79 This disease is associated with anti-C1q autoantibodies which
likely mediate the disease.87
Urticarial vasculitis (especially the hypocomplementemic variant) is often asso­
ciated with or precedes development of a variety of systemic ­diseases, including
myeloma, hepatitis B and C, SLE, arthritis, interstitial lung ­disease, peri­carditis,
mixed connective tissue disease, inflammatory bowel ­disease, serum sickness,
polyarteritis nodosa, Wegener’s granulomatosis, viral ­infections, Sjögren’s syn­
drome, cryoglobulinemia, polycythemia rubra vera, ­reaction to drugs, and as a
response to sunlight.67,76,77,88–96 Urticarial vasculitis has also been documented in
association with pregnancy, exercise, and cocaine use.97–99 Ocular disease (includ­
ing uveitis, scleritis, conjunctivitis or episcleritis) is a very common ­feature.67,100
Patients with hypocomplementemia appear to be at risk of developing more
severe disease.88 Obviously, a diagnosis of urticarial ­vasculitis in any patient
should initiate an evaluation for underlying disease.101
Drug-induced urticaria
Drug-induced urticaria is fairly common. It is present in 0.16% of medical
inpatients and in 9% of cases of chronic urticaria or angioedema seen in der­
matology outpatient departments.102,103 The drugs most commonly implicated
are sulfonamides, penicillins, and non-steroidal anti-inflammatory medica­
tions.102 Aspirin may induce acute urticaria, worsen chronic urticaria or act
as a cofactor to induce anaphylaxis.104 Other less common drug associations
include antipsychotics, alendronate, recombinant IFN-β, cetirizine, bleomycin,
and IL-3.105–110 Many of these reactions are mediated by IgE antibodies, but
some result from direct activation of mast cells or interact with another path­
way that augments the urticaria reaction.111 In this last category, modulation
of arachidonic acid metabolites by aspirin and other agents can help initiate or
exacerbate urticaria.112 Specifically, in some cases polymorphism in the leukot­
riene C4 synthase gene can be associated with aspirin-induced urticaria.113–115
Other urticarial associations
Urticaria has also been documented in association with autoimmune pro­
gesterone dermatitis, dermatophytosis, candidiasis, parasites (anisakiasis),
consumption of tonic water, nicotine, alcohol consumption, and hepatitis
B vaccination (Table 15.3).116–122
648 Neutrophilic and eosinophilic dermatoses

Table 15.3 histamine, eosinophil chemotactic factor, prostaglandin, leukotrienes, ­platelet

Classification of urticaria subtypes (presenting with wheals and/or activating factor, and enzymes.53,123,124,126,127 Similarly, IgE-mediated mast cell
angioedema) degranulation also underlies the pathogenesis of allergic contact urticaria
Types Subtypes Definition
in which direct contact with allergens on skin bind to the surface IgE on
mast cells causing release of histamine and other inflammatory mediators.
Spontaneous Acute spontaneous Spontaneous wheals and/or Autoantibodies against the IgE high-affinity receptor (FcεRI) or to IgE itself
urticaria urticaria angioedema < 6 weeks
are present in about 30% of patients with chronic urticaria, designated auto­
Chronic spontaneous Spontaneous wheals and/or
urticaria angioedema > 6 weeks
immune urticaria, a type II hypersensitivity reaction.123,128–131 Patients with
physical urticaria or with connective tissue or autoimmune bullous disease
Physical Cold contact urticaria Eliciting factor: cold objects/ may also have anti-FcεRI. However, in the last group of patients, the autoan­
urticaria air/fluids/wind
tibodies are nonfunctional (nonhistamine releasing), whereas in chronic urti­
Delayed pressure Eliciting factor: vertical
caria, the antibodies are functional (histamine releasing).131,132 A type III
urticaria pressure (wheals arising with
a 3-12 h latency) hypersensitivity reaction, caused by circulating antigen–antibody immune
Heat contact urticaria Eliciting factor: localized heat complexes, underlies a form of urticaria associated with serum sickness.
Solar urticaria Eliciting factor: UV and/or A role for Helicobacter pylori in the causation of chronic urticaria has
visible light been suggested but other studies have challenged this theory.133–138
Urticaria factitia/ Eliciting factor: mechanical The pathogenesis of irritant contact urticaria is not well understood but
dermographic shearing forces (wheals evidence suggests that degranulation of mast cells due to direct, nonimmu­
urticaria arising after 1-5 min) nologically mediated contact causes release of vasogenic mediators.53,124
Vibratory urticaria/ Eliciting factor: vibratory forces, Similarly, it is thought that the physical urticarias (heat, cold, pressure,
angioedema e.g. pneumatic hammer
vibration, water) also result from a direct effect on mast cells in susceptible
Other urticaria Aquagenic urticaria Eliciting factor: water individuals.127
types Cholinergic urticaria Elicitation by increase of body Some investigators have suggested that solar urticaria results from a type
core temperature due to I hypersensitivity reaction to a photoinduced antigen eliciting IgE-mediated
physical exercises, spicy food mast cell degranulation.9 An intriguing study has shown that most patients
Contact urticaria Elicitation by contact with
(77%) develop an urticarial reaction when challenged with autologous serum
urticariogenic substance
Exercise induced Eliciting factor: physical
that has been irradiated using the same spectrum of light that induces lesions
anaphylaxis/urticaria exercise in each particular patient.139 Furthermore, patients with ‘fixed’ urticaria
develop lesions at the same specific sites that are affected by light exposure
Table 2 from Zuberbier T, Asero R, Bindslev-Jensen C, et al. EAACI/GA2LEN/EDF/WAO
guideline: definition, classification and diagnosis of urticaria. Allergy 2009; following injection with irradiated plasma.14 Consistent with these observa­
64:1417–1426. tions, some patients with severe solar urticaria may be effectively treated by
plasma exchange.140,141
A type III hypersensitivity reaction (caused by antibody–antigen com­
plexes) appears to be the underlying etiology in some patients with urti­
Pathogenesis and histological features carial vasculitis; however, no underlying cause is discovered in many
As has been stated above, urticaria is probably best viewed as a group of dis­ patients.64,67 More recently, urticarial vasculitis has been excluded from
orders sharing common clinical and histological features. The pathogenesis the formal urticaria group of disorders by some authors due to its variant
of some forms of urticaria (e.g., allergic contact urticaria) is well understood; pathogenic mechanism, but is still considered in this section for historical
however, the precise pathogenesis of many cases of urticaria is obscure.123 Mast purposes.2
cell degranulation with perhaps some involvement of basophils appears to be The biopsy findings in urticaria are non-specific. Dermal edema may be
a common denominator in the pathway of most types of urticaria.124,125 mild or severe and its presence is confirmed by separation of dermal retic­
Release of histamine following a hypersensitivity reaction after exposure ular collagen fibers. An often sparse dermal perivascular and interstitial
to an allergen is the basis for allergic contact urticaria.56 In sensitized patients, mixed inflammatory infiltrate composed of variable numbers of lympho­
an allergen binds to IgE on mast cells causing degranulation and the release of cytes, ­neutrophils, and eosinophils is present (Fig. 15.40). Of interest, mast­

A B

Fig. 15.40
Urticaria: (A) at low-power examination, the features are easily overlooked. There is a light perivascular infiltrate and the collagen fibers appear separated; (B) at high power,
there is edema and a light perivascular infiltrate of lymphocytes with scattered eosinophils.

cells – which play such an important role in the pathogenesis of urticaria –
do not appear to be increased in number except in chronic urticaria.130,142
Usually, more inflammatory cells are seen in lesions of chronic urticaria com­
pared to those of acute urticaria.142
Urticarial vasculitis combines histological features of urticaria with super­
imposed vascular damage. The vasculitis affects the superficial vascular
plexus and shows features of a leukocytoclastic subtype; however, compared
with typical leukocytoclastic vasculitis, the histological findings tend to be
subtle and are easily overlooked. Mild or focal fibrinoid change apparent on
only a few sections associated with few neutrophils and sparse karyorrhexis
is typical. Some authors have shown that endothelial ­necrosis is unusual.64
Occasionally, impressive necrotizing vasculitis (features of ­typical leukocy­
toclastic vasculitis) may be seen. In summary, urticarial vasculitis appears as
a continuum, ranging from urticaria with very mild vascular injury to frank
necrotizing vasculitis.143
Differential diagnosis
The diagnosis requires careful clinical correlation. The biopsy findings are
often very subtle: the dermal edema and sparse inflammatory infiltrate
may be easily overlooked. A definitive diagnosis sometimes requires test­
ing for response to particular antigens. Other forms of hypersensitivity
reaction such as arthropod bite and drug eruption can show similar fea­
tures and require clinical correlation to distinguish them from ­urticaria.
Clinical correlation is necessary to distinguish urticarial vasculitis from
other forms of leukocytoclastic vasculitis. Although urticarial vasculi­
tis is often associated with subtle low-grade vascular injury, this pattern
should not be relied upon in the distinction from other forms of vasculitis.
In short, the pathologist’s role in diagnosis is to confirm the presence of
vasculitis.
Papular urticaria
Clinical features
Although papular urticaria (prurigo mitis) is often described as a variant
of urticaria, and the histologic picture is that of an urticarial dermatitis,
the lesions are persistent and patients do not fulfill the criteria for the
diagnosis of urticaria. In the latter, lesions are self-limited even in cases
of chronic urticaria. The condition is generally regarded as a variant of
an insect bite reaction.1–4 Papular urticaria has no sex predilection and
although the age range is wide, it tends to be more frequent in children.
It presents as small, itchy, red papules that tend to appear in crops. Most
lesions are no more than a few millimeters in diameter but larger lesions
may be seen. They are more usually seen on exposed areas of the body and
tend to be more prevalent during the summer months. Changes secondary
to scratching including excoriations are frequent. There are no associations
with systemic disease.
Pathogenesis and histological features
The pathogenesis is not entirely clear but it is generally believed that the
condition is triggered by a hypersensitivity reaction to insect or arthropod
bites.5,6 Many insects and arthropods have been implicated in the disease
including fleas, carpet beetles, lice, bedbugs, mosquitoes, and even caterpil­
lars. This is further supported by the rash clearing after the patient returns
from ­holidays or after moving to a new house. A recent study found evidence
of IgG against bedbugs (Cimex lectularius) in affected patients suggesting a
role in the pathogenesis of the disease.6
The histological features are fairly non-specific. In intact lesions the epi­
dermis is unremarkable or slightly acanthotic. Changes of excoriation may be
evident. In the dermis there is a mild to moderate, superficial and deep, often
wedge-shaped, mainly perivascular inflammatory cell infiltrate composed of
lymphocytes, histiocytes, and eosinophils.7 Neutrophils can be seen in some
cases.7 The presence of the latter is required for a histological ­diagnosis of
­papular urticaria to be made. A few CD30-positive lymphocytes are some­
times present.
Eosinophilic cellulitis 649
Hypereosinophilic syndrome
Clinical features
The hypereosinophilic syndrome is defined as an idiopathic condition
­characterized by persistent eosinophilia (more than 1.5 × 109/L) for at least 6
months and with involvement of one or more organs.1–4 The diagnosis should
be made only after other causes of eosinophilia, particularly parasitic infec­
tions, have been excluded. The heart, lungs, central and peripheral nervous
system, liver, and skin are commonly affected. The disease, which may some­
times prove fatal, generally presents in adults.
Cutaneous lesions are seen in up to 53% of patients and usually consist
of either pruritic papules and nodules or urticaria and angioedema.5 Rarely,
skin lesions represent an initial manifestation and in this setting, annular ery­
thema and erythroderma have been reported.6–10 Oral and genital erosions
are quite characteristic and can be the first manifestation of the disease.11,12
Other rare cutaneous features include livedo reticularis, cutaneous infarction,
deep vein thrombosis, blisters, aquagenic pruritus, erythema gyratum repens,
and Wells’ syndrome.13–19 Hypereosinophilic syndrome has been reported in
­association with lymphomatoid papulosis, T-cell lymphoma, systemic mast
cell disease, SLE, and HIV infection.20–25
Pathogenesis and histological features
The etiology is unknown. It has sometimes been categorized into:
• idiopathic,
• clonal,
• secondary types.26
Some forms of clonal eosinophilia (malignancy-associated) harbor activat­
ing mutations or rearrangements of fibroblast or platelet derived growth fac­
tor receptors (FGFR1, PDGFRA, PDGFRB) and are amenable to targeted
therapies.27,28 Secondary causes result from other causes such as an under­
lying infection. Idiopathic is what remains when these first two categories
are excluded. Elevated serum levels of IL-10 and soluble IL-2 receptor have
been documented.29 IL-2 stimulates release of eosinophilic cationic protein
from eosinophils which contain IL-2 receptor (CD25) and this results in tis­
sue damage.
The histological findings vary according to the type of lesion biopsied.
Urticarial and papular lesions show a superficial and deep perivascular
and interstitial mixed inflammatory cell infiltrate with variable numbers of
eosinophils and scattered lymphocytes, histiocytes, and occasional plasma
cells. Rare flame figures may be present. Dermal edema is seen particularly
in urticarial lesions. Eosinophils are not always prominent and the findings
can be entirely non-specific. Microthrombi are present in some cases and
­sometimes correlate with the severity of the disease.13,30
Eosinophilic cellulitis
Clinical features
Eosinophilic cellulitis (Wells’ syndrome) is an uncommon disorder, character­
ized by recurrent erythematous and edematous plaques.1–6 It occurs with an
equal sex ratio and there is a large age range, with a mean age of 37 years.7
It is sometimes also encountered in children and rare cases have been docu­
mented in neonates.7–11 It appears that cases occurring in childhood may be
particularly severe. Scalp involvement, with alopecia and scarring, is a feature
in some patients.7,8
The disease particularly affects the extremities and trunk. Although it pres­
ents most commonly as well-defined (cellulitis-like) annular erythematous
plaques, which are edematous and firm, a wide variety of clinical ­appearances
have been described including blistering, nodular, papulovesicular ­eruptions,
and itchy excoriated inflammatory papules (Figs 15.41–15.43).7,12–14 The
plaques, which cause pain and pruritus in some patients, typically heal with­
out scarring.7 Eosinophilic cellulitis has been associated with urticaria.15
Dermatographism can be a feature.16 With progression, the lesions sometimes
adopt a greenish hue. Clinically, the lesion may occasionally be mistaken for
an infective process.17 The disease tends to be episodic, with remissions and
relapses, which can last from months to years.
650 Neutrophilic and eosinophilic dermatoses
Fig. 15.41
Eosinophilic cellulitis: there is a large erythematous swollen plaque. The limbs are
commonly affected. From the collection of the late N.P. Smith, MD, the Institute of
Dermatology, London, UK.
Fig. 15.42
Eosinophilic cellulitis: in this patient, there is striking symmetry. From the collection
of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig. 15.43
Eosinophilic cellulitis: bullous lesion with a hint of greenish discoloration in the adjacent
skin. From the collection of the late N.P. Smith, MD, Institute of Dermatology, London, UK.
Large bullae are seen in rare patients.18 An unusual pattern of involvement
following Blaschko's lines has been reported and it has been proposed that
this form represents cutaneous mosaicism.19
Rarely, eosinophilic cellulitis is associated with a malignant neoplasm.
Cases accompanied by eosinophilic leukemia, colonic carcinoma, squamous
cell carcinoma of the lung, and non-Hodgkin’s lymphoma have been
described.20–23 Associations with HIV, hypereosinophilic syndrome, ulcerative
colitis, tetanus or thiomersal-containing vaccine and varicella infection have
occasionally been documented.24–30
Exceptional familial cases have been reported.31,32 In one family, the ­disease
showed an autosomal dominant pattern of inheritance and was associated
with mental retardation and dysmorphic body habitus.31 In another family,
the lesions were first noted during infancy.33
Pathogenesis and histological features
The pathogenesis is unknown and may simply represent an eosinophil-rich
inflammatory reaction to a variety of insults. The only consistent associa­
tion appears to be a peripheral eosinophilia, manifested either as an elevated
total eosinophil count or as an increased percentage of eosinophils. Clinical
activity appears to correlate with increased eosinophil cation protein and
IL-5 levels in the peripheral blood in addition to blood and bone marrow
eosinophilia.31,32
An elevated ESR is occasionally present. It is possible that some patients
represent the benign end of the spectrum of the hypereosinophilic syndrome
discussed in the previous section.
Histologically, early lesions of eosinophilic cellulitis are characterized by
a diffuse and heavy dermal infiltrate of eosinophils: this occurs either in the
superficial dermis, as a bandlike infiltrate, or in the deep dermis with exten­
sion into the underlying subcutaneous tissue, fascia, and muscle (Figs 15.44,
15.45).2,34 In addition, lymphocytes and plasma cells may be present. There
is sometimes edema of the papillary dermis to such an extent that subepi­
dermal bullae develop (Fig. 15.46).35 The epidermis can be spongiotic and
occasionally intraepidermal vesicles are present.35 Over a period of 1–3 weeks
the eosinophils degranulate and degenerate, and eosinophilic material and
nuclear debris are deposited on collagen fibers to produce ‘flame figures’ (Fig.
15.47).35, 36 Sometimes these are surrounded by histiocytes and multinucleated
giant cells (Fig. 15.48). There is no evidence of primary collagen degenera­
tion. It is likely that flame figures represent a non-specific eosinophil reaction
pattern to a variety of different provoking stimuli.36 Later, the lesion becomes
more granulomatous and giant cells are occasionally prominent.37 Vasculitis is
not usually a feature, although extravasation of red blood cells is sometimes
evident.35
Indirect immunofluorescence studies have shown that flame figures con­
tain extracellular eosinophil granule major basic protein.36,38 Ultrastructural
Fig. 15.44
Eosinophilic cellulitis: there is a light, deep dermal chronic inflammatory cell
infiltrate. A flame figure is present.

Fig. 15.45
Eosinophilic cellulitis: the infiltrate is composed of lymphocytes and histiocytes
with conspicuous eosinophils and extends into the subcutaneous fat.
Fig. 15.46
Eosinophilic cellulitis: subepidermal vesiculation as seen here is not uncommon.
The blister cavity may contain numerous eosinophils reminiscent of bullous
pemphigoid.
Fig. 15.47
Eosinophilic cellulitis: flame figures are typically present.
Eosinophilic pustular folliculitis 651
Fig. 15.48
Eosinophilic cellulitis: in this example, a flame figure is surrounded by an intense
granulomatous infiltrate.
investigation confirms that the eosinophil granules invest the associated
­collagen fibers.39 Direct immunofluorescence has demonstrated immu­
noglobulins and/or complement in blood vessel walls in a minority of
cases.2,7,17,36
Differential diagnosis
The histological features of eosinophilic infiltration with 'flame figures',
although characteristic of Wells’ syndrome, are not pathognomonic.40
Similar features may be seen in arthropod bite reactions, spider bites,
onchocerciasis, drug hypersensitivity reactions, diffuse erythema, tinea
infection, atopic eczema, allergic contact dermatitis, urticarial vasculi­
tis, eosinophilic pustular folliculitis, bullous pemphigoid, herpes gestatio­
nis, the hypereosinophilic syndrome, and cutaneous mastocytoma.2,36,41–47
Prominent flame figures are also seen in eosinophilic ulcer of the oral
mucosa.48–50 It should be emphasized that in regions where parasitic infec­
tions are endemic, lesions with the histological appearance of eosinophilic
cellulitis have a high likelihood of representing parasitic infection such
as giardiasis, toxocariasis, and onchocerciasis.51–53 In eosinophilic fasciitis,
diffuse fibrosis of the deep dermis with extension into the fibrous septa of
the subcutaneous fat and involvement of the fascia allow for easy distinc­
tion from Wells’ syndrome.
Eosinophilic pustular folliculitis
Clinical features
Eosinophilic pustular folliculitis (Ofuji’s disease) is a rare dermatosis seen
primarily in Japanese and Chinese, although occasional reports from Europe
and the USA are encountered.1–5 It is a disease which particularly affects
the seborrheic regions and, therefore, lesions are predominantly present on
the face and back.6 The extensor surfaces of the upper limbs are also fre­
quently affected. Acral involvement is exceptional.7–9 Patients present with
crops of occasionally pruritic, sterile follicular papulopustules measuring
1–2 mm in diameter, grouped to form small plaques, which characteristi­
cally spread centrifugally to produce an annular or serpiginous lesion.1,6 The
disease is typically recurrent and spontaneous resolution within months to
several years is characteristic.10,11 Healing is often associated with residual
postinflammatory hyperpigmentation.1 Males are predominantly affected
(5:1) and the peak incidence is in the third and fourth decades, although
children and infants can be affected.12,13 Sometimes there is a past or present
history of acne vulgaris.
Extensive laboratory investigations reveal leukocytosis with hypereosino­
philia.14 Serum IgE levels may be increased.5,15
652 Neutrophilic and eosinophilic dermatoses

Similar cases have been reported in Caucasians in association with HIV

infection.3,4,16–23 However, based on the clinical and histological findings,
many authors regard HIV-associated eosinophilic folliculitis as a separate
entity.20,22 Pruritus, which is always present in patients with HIV-associated
eosinophilic folliculitis, is seen only in occasional patients with Ofuji’s
disease.24
A small number of childhood cases of eosinophilic pustular folliculitis,
including several in neonates, have also been reported.15,25–31 Some authors
prefer to categorize these as a separate entity, others feel that this category
does not form a distinct condition.5,12,28,32 In children, the scalp is particularly
involved. There is less of a tendency to affect the seborrheic regions and poly­
cyclic patterns are not evident.25
Eosinophilic pustular folliculitis has been described in association with
non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, polycythemia rubra
vera, myelodysplastic syndrome, bone marrow transplant for aplastic ane­
mia, eosinophilic cellulitis, hepatitis C viral infection, and the nevoid basal
cell ­carcinoma ­syndrome.13,33–41 A few cases induced by allopurinol, time­
pidium bromide, and chemotherapy for breast carcinoma has also been
documented.42–44

Pathogenesis and histological features

The etiology and pathogenesis of eosinophil pustular folliculitis are unknown. Fig. 15.49
(A, B) Eosinophilic
The possibility of an inherited or contagious cause for the disease has been
pustular folliculitis: there
raised by the observation of the disease in siblings.45 However, there is no firm
is spongiosis associated
evidence of an infective cause. A variety of immunological abnormalities have with an eosinophil-rich
A
been described including: abscess.
• raised IgE levels,
• low immunoglobulin levels,
• defects of neutrophil motility.6,28
A pemphigus-like antibody and an antibasal keratinocyte antibody have
also been recorded in patients with this disease.46,47
The seborrheic distribution raises a possible role for sebaceous glands in the
pathogenesis.10 A lipid-soluble eosinophil chemotactic factor has been iden­
tified from epidermal surface lipids.48 The association of eosinophil pustular
folliculitis with AIDS (if indeed this is the same disease) raises the interesting
possibility of a diminished T-helper lymphocyte-mediated pathogenesis.
An increased number of mast cells has been described around hair follicles
and sebaceous glands, suggesting a role for these cells in the development of
the disease.49
In early lesions, spongiosis of the outer root sheath of the infundibulum
with an accompanying eosinophil and mononuclear cell infiltrate is char­
acteristic.6 As the disease progresses, vesiculation and pustulation are seen
deep to the stratum corneum, often extending into the sebaceous gland (Fig.
15.49). The epithelium is infiltrated by large numbers of eosinophils with B
an admixture of neutrophils and mononuclear cells. In the superficial dermis
there is a perivascular mononuclear and eosinophil infiltrate. Follicular muci­
nosis has been described.50–54
females is variable, manifestations being dependent on the effects of mosa­
Differential diagnosis icism resulting from X-chromosome lyonization.5 It has occasionally been
As mentioned above, there is considerable overlap between eosinophilic folli­ described in identical twins.6 The disease is rarely transmitted from father
culitis associated with HIV infection and Ofuji’s disease. The latter condition to daughter.7
tends to form arcuate plaques. Histologically, well-developed large eosino­ Most males with incontinentia pigmenti die in utero and only very rare
philic pustules in the pilar canals are characteristic of Ofuji’s disease but are patients survive. As with females, it is associated with the same phenotypic
less common in HIV-associated eosinophilic folliculitis.55 mosaicism.8 In the majority of cases of male involvement it develops in asso­
Identical histology may be seen in epidermal fungal infections and special ciation with Klinefelter’s syndrome.9,10,32 Half chromatid mutation, or more
stains are essential to exclude this possibility.49,56–59 recently an unstable pre-mutation, has been offered as explanations for
affected males with a normal karyotype.11,12
Typically, the condition has four stages: 13,14
Incontinentia pigmenti • Stage 1, comprising erythema and linear vesiculation on the trunk and
extremities, is apparent at birth or during the first 2 weeks of life
Clinical features (Fig. 15.50).15 Characteristically, the face is unaffected. Patients usually
Incontinentia pigmenti (Bloch-Sulzberger syndrome) is a rare systemic illness show associated leukocytosis and eosinophilia. On average, the blistering
with a striking female bias (in excess of 37:1), as affected males usually die stage completely resolves within 4 months.5
in utero.1–3 It has an X-linked dominant mode of inheritance.4 Cutaneous • Stage 2, which is uncommon and usually transitory, consists of
­manifestations usually present at birth or during the first few weeks of life.1 hyperkeratotic verrucous papules and plaques most frequently found on
There may also be lesions affecting the hair, teeth, nails, eyes, skeleton and the extremities (Fig. 15.51). The verrucous lesions develop at sites of
the central nervous system in up to 80% of patients.1,4 The phenotype in previous blistering.15 They may resemble linear epidermal nevi.16 This

Fig. 15.50
Incontinentia pigmenti: the inflammatory stage is characterized by erythema, linear
clusters of intact vesicles, crusts, and scaling. By courtesy of J.C. Pascual, MD,
Alicante, Spain.
stage (when present) appears during the second to sixth weeks of life and
usually resolves completely by 6 months.5
• Stage 3, which is pathognomonic of incontinentia pigmenti, presents
as bizarre reticulated pigmentation, generally between the twelfth and
twenty-sixth weeks after birth. It sometimes occurs de novo. The brown
to slate-gray pigmentation appears as splashes, streaks, and whorls
(sometimes referred to as ‘Chinese lettering’) on the torso and extremities
(Fig. 15.52). The nipples are typically hyperpigmented and involvement
of the groin and axillae is characteristic.5 The pigmentation appears to
develop independently of the bullous lesions or verrucous plaques and
follows Blaschko's lines.15,16 Resolution of lesions is associated with
atrophy and the pigmentation is usually imperceptible by adulthood.
• Stage 4, usually present in adulthood, shows only residual changes
that may be visible as occasional atrophic, hypopigmented, hairless,
reticulated patches and streaks best seen on the lower legs.1,5,17
Additional cutaneous lesions include mild nail dystrophy (40%), scalp alo­
pecia at the vertex, and the woolly hair nevus.4,5 A whorled scarring alopecia
following the lines of Blaschko has been documented.2 At this point, the skin
lesions cease to be problematic and other issues such as ocular involvement
are the focus of concern.18,19
Fig. 15.51
Incontinentia pigmenti: verrucous lesions, seen in the second stage, predominantly
affect the extremities. By courtesy of the Institute of Dermatology, London, UK.
Incontinentia pigmenti 653
Fig. 15.52
Incontinentia pigmenti: the whorl-like distribution of the pigment is characteristic.
From the collection of the late N.P. Smith, MD, the Institute of Dermatology,
London, UK.
Painful subungual digital verrucous nodules are occasional late ­features of
incontinentia pigmenti.17,20 They are usually multiple, affect the hands more
often than the feet and, in addition to nail destruction, they can also be asso­
ciated with scalloped resorption of the underlying phalanx.21 Spontaneous
regression is sometimes seen. Clinically, these nodules may be mistaken for a
wart, subungual fibroma, keratoacanthoma or squamous cell carcinoma.22
Dermatoglyphic patterns presenting in patients and also in nonaffected
family members have been described.23
Some patients develop episodes of late reactivation of the disease in hyperpig­
mented streaks and this appears to be related to a preceding infection.24 It sug­
gests that the mutated cells persist in the epidermis for a long period of time.
There can be widespread systemic involvement (Table 15.4). Dental
abnormalities include hypodontia, delayed eruption, impaction, and crown
malformations such as conical forms and accessory cusps.5,16,25–27
The most characteristic ocular changes are strabismus, ­microphthalmos,
cataract, and optic atrophy.28 Retinal detachment with a fibrovascular
­retrolental membrane is the commonest intraocular abnormality.29–32
Central nervous system involvement may result in encephalopathy,
­seizures, mental retardation, microcephaly, cerebellar ataxia, and motor
effects including spastic quadriplegia, hemiplegia, slow motor develop­
ment, and psychomotor retardation.1,33–35 There is some evidence to suggest
that incontinentia pigmenti can be associated with chromosomal instabil­
ity and a slightly increased susceptibility to cancer; cutaneous squamous cell
­carcinoma has been described in a 16-year-old.36,37 A unique case associated
with t­ wenty-nail dystrophy has been reported.38
Table 15.4
General manifestations of incontinentia pigmenti
System Abnormality
Scalp Scarring
Alopecia of variable severity
Nails Occasional dystrophy
Teeth Partial/complete absence
Conical (pegged)
Eyes Strabismus
Blindness
Cataracts
Atrophy of optic nerve
Central nervous system Spastic paralysis
Mental retardation
Convulsions
654 Neutrophilic and eosinophilic dermatoses

Pathogenesis and histological features

Considerable new data have been published which sheds much light on the
pathogenesis of this disease:
• Linkage analysis has demonstrated two incontinentia pigmenti loci that
reside within the long arm of the X chromosome at Xq11 (IP1) and
Xq28 (IP2).5,39,40
• Mutations in the gene for the inhibitor of kappa light polypeptide gene
enhancer in B-cells, kinase gamma (IKBKG) also called nuclear factor
(NF)-κ,B gene modulator (NEMO), which plays a role in inhibiting
tumor necrosis factor (TNF)-induced apoptosis, has been shown to be
responsible for development of the disease.41–44
• A mouse model has been created by disruption of NEMO, which leads
to lethality in males and heterozygous females with skin and eye lesions
similar to incontinentia pigmenti.45,46 Biopsy of skin lesions of diseased
animals shows increased keratinocyte apoptosis, inflammation, and
pigment incontinence.45
• A relationship between incontinentia pigmenti and the osteopetrosis,
lymphedema, anhidrotic ectodermal dysplasia, immunodeficiency
(OL-EDA-ID) syndrome has recently been suggested in a patient who Fig. 15.54
presented with the latter syndrome born to a mother with features of Incontinentia pigmenti: there is dyskeratosis and an upper dermal eosinophil-rich
incontinentia pigmenti.47 Both diseases are associated with mutations infiltrate.
in NEMO / IKBKG.48,49 Male patients with the disease often have
less deleterious mutations and present with ectodermal dysplasia and
immunodeficiency.10
• Eotaxin (an NF-kappaB-activated chemokine) is strongly expressed in the
suprabasal epidermis of involved skin in patients with the disease.50 This
expression is concomitant with the upper epidermal accumulation of
eosinophils, suggesting a pathogenetic role for this chemokine.
Histological examination of lesions in the vesicular stage (stage 1) shows
eosinophilic spongiosis (Fig. 15.53). Occasionally, aggregates of dyskeratotic
cells are evident (Fig. 15.54).4 A chronic inflammatory cell infiltrate with
conspicuous eosinophilia may be present within the dermis.
The verrucous lesions (stage 2) are characterized by hyperkeratosis, acan­
thosis, papillomatosis, and focal dyskeratosis (Fig. 15.55).21 The dyskeratotic
cells are typically arranged in a whorled configuration.
Stage 3 lesions manifest marked pigmentary incontinence with numerous
melanophages in the dermis associated with epidermal basal cell degeneration.
End-stage lesions display epidermal atrophy and there may be loss of the
adnexae.45 Melanocytes appear to be present in reduced or normal num­
bers and ultrastructurally have shown no significant lesion except for one
report in which small nondendritic forms with degenerate melanosomes were
described.6,51 Some authors have recommended biopsy of these late lesions in
adulthood as helpful for diagnosis.52
A

Fig. 15.53 Fig. 15.55

Incontinentia pigmenti: vesicular stage showing a subcorneal eosinophil pustule (A, B) Incontinentia pigmenti: verrucous stage showing massive hyperkeratosis,
and intraepidermal eosinophils. papillomatosis, acanthosis, and numerous dyskeratotic cells.
 Hidradenitis suppurativa 655

Molecular testing is available for confirmation of difficult cases and such

techniques can also be applied to prenatal testing.3,53–55
The subungual verrucous nodules show hyperkeratosis, hypergranulosis,
pseudoepitheliomatous hyperplasia, and striking dyskeratosis throughout the
epidermis.21,22

Differential diagnosis
Clinically, incontinentia pigmenti may be confused with hypomelanosis of Ito
(incontinentia pigmenti achromians), and the central nervous system involve­
ment in both diseases is similar.56 The latter condition, however, is character­
ized by cutaneous pigmentary changes in the absence of either vesicular or
verrucous lesions.
Many conditions are associated with eosinophilic spongiosis, but with ade­
quate clinical information none should pose diagnostic problems. Toxic erythema
of the neonate can be distinguished histologically from incontinentia pigmenti by
the absence of spongiosis in the former condition.

Fig. 15.56
Toxic erythema of the neonate Hidradenitis suppurativa:
early lesion presenting as
Clinical features an erythematous nodule
discharging clear fluid.
Toxic erythema of the neonate (erythema toxicum, erythema toxicum neonato­ The axilla is a commonly
rum) is a very common, self-limiting disorder that presents as an asymptomatic affected site. By courtesy
erythematous macular rash usually in the first few days of life. Very rarely, the of R.A. Marsden, MD,
eruption occurs a week or more after birth.1 It affects up to 50% of neonates. St George’s Hospital,
In survey studies from Japan, Australia, China, and India, toxic erythema was London, UK.
found in 40.8%, 34.8%, 33.7% and 20.6% of infants, respectively.2–5
It may be associated with papules, and occasionally pustule formation is
evident. It most often involves the forehead, face, chest, trunk, and extremi­
ties.6 Lesions usually resolve in a few days.

Pathogenesis and histological features

The etiology of this condition is obscure, but some have suggested an immune
reaction to postnatal cutaneous comensural microbial colonization, perhaps
partially mediated by mast cells.7,8
Early erythematous lesions show a somewhat nondescript perivascular
inflammatory cell infiltrate with conspicuous eosinophils, which can be seen
penetrating the epidermis in close proximity to hair follicles. The pustules
are characteristically intrafollicular, sometimes subcorneal or intraepidermal,
and contain large numbers of eosinophils and occasional neutrophils.9

Differential diagnosis
Toxic erythema of the neonate must be distinguished from incontinentia pig­
menti. The latter, however, is characterized by eosinophilic spongiosis, a fea­
ture not seen in toxic erythema. In miliaria rubra the vesicles are related to
sweat ducts rather than hair follicles and typically contain mononuclear cells
rather than eosinophils.
Hidradenitis suppurativa
Clinical features
Hidradenitis suppurativa (acne inversa, apocrine acne) is a common dis­
ease.1–3 Studies from Denmark have found the prevalence to be around 4%,
while that in France is approximately 1%.4–6
It is a chronic relapsing suppurative inflammation of regions where apo­
crine glands occur, i.e., the axilla, inguinal folds, perineum, genitalia, and
periareolar region (Fig. 15.56).7,8 It occurs postpubertally in both sexes,
but is more common in women.5 Karl Marx was famously afflicted.9–11 The
­disease is seen most frequently in young adults, although its first presentation
may be in older individuals and also before puberty.12,13 Initially, there is a
firm painful nodule in the groin or axilla. The nodule can involute slowly or
else discharge pus through the skin; the discharge of pus is not copious, but
is chronic and often malodorous. In the late stages a complex interconnecting
system of sinuses extends deeply into the dermis and subcutaneous fat with
extensive dense fibrosis (Fig. 15.57).14
Fig. 15.57
Hidradenitis suppurativa:
in this very severe
example, there is marked
scarring and numerous
sinuses are present.
By courtesy of R.A.
Marsden, MD, St George’s
Hospital, London, UK.
Axillary lesions are more common in women and genitoinguinal lesions
are more common in men. Changes may be confined to one region or occur
in both, but the axillary region is involved in over 70% of cases.15 Some
reports have attached etiological importance to axillary shaving and the
use of deodorants, but this is not generally accepted.15,16 In women, obesity
appears to be a predisposing factor and smoking is closely associated, but it
is not clear whether this is a cause or effect.6,17–19 In one study, nearly 90% of
German patients were smokers (expected prevalence rate 27%).12 Whether
cessation of smoking improves the course of the disease is unknown.20 Patients
with the hidradenitis suppurativa appear to be at increased risk of developing
­nonmelanoma skin cancer.21
656 Neutrophilic and eosinophilic dermatoses
The lesions are clearly maintained by bacterial infection as various
­ rganisms are often grown. Symptomatic improvement can be achieved with
o more commonly found than apocrine involvement and yet others think that
long-term antibiotics. Perineal lesions are often severe and complicated by
abscesses, fistulae, and draining sinus tracts.15
Lesions are also rarely seen on the malar region of the face and even on the
eyelids (glands of Moll), sites with modified apocrine glands.
Hidradenitis suppurativa can be present in association with conditions
which are said to be pathologically similar, namely acne conglobata and dis­
secting folliculitis of the scalp. These three conditions have been referred to
collectively as the ‘follicular occlusion triad’.22 Any one condition, however,
may occur separately. Acne conglobata, an extremely severe nodulocystic
variant of acne, occurs extensively on the trunk, buttocks, and limbs with
predilection for males.23 The disease has been described in association with
HIV and following pregnancy.24,25 Dissecting folliculitis (folliculitis capitis
abscedens et suffodiens) is centered on the vertex of the scalp and is char­
acterized by boggy tender lesions that tend to become confluent with for­
mation of draining sinuses and suppuration.26–29 The disease presents more
commonly in black males and it is very rarely familial.30 Radical surgery is
often the only satisfactory means of terminating the process. All the dis­
eases in the follicular occlusion triad can occasionally be complicated by
progression to cellulitis and septicemia. Squamous carcinoma (including the
verrucous variant) is a rare and late additional complication.31–38 As with
Marjolin’s ulcer–cancer, the carcinomas are capable of aggressive invasion
and metastasis (50%) and are generally associated with a poor prognosis.15
Such tumors arise most frequently on the buttocks and are more often seen
in males.34 Hidradenitis has been shown to be rarely associated with sys­
temic granulomatous lesions, in particular Crohn’s disease.17,39–41 An associa­
tion with spondyloarthropathy, Dowling-Degos disease, and lithium therapy
has also been documented.42–44
Treatment of this disease is difficult due to its chronic relapsing nature.
Surgery is often used to remove affected areas but the cure rate in some
studies is very low.45 Nevertheless, occasional patients are satisfied with
the relief of symptoms, albeit temporary, afforded by surgery.45 Other
studies have shown a low recurrence rate following wide excision.46,47
Early surgical treatment appears to increase the chance of success.48
Recently, new-generation immunosuppressive agents have shown some
efficacy.49 Hormonal regulation has also been employed with more ­limited
success.50
Pathogenesis and histological features
The pathogenesis of hidradenitis suppurativa remains poorly understood.51–56
It has generally been thought that the earliest lesion is an acute inflamma­
tory process involving the apocrine duct and gland, which extends into the
surrounding connective tissue with subsequent abscess and sinus formation
A B
Fig. 15.58
(A, B) Hidradenitis suppurativa: early lesion showing acute inflammation involving the apocrine gland.
(Fig. 15.58).51 Other authors, however, believe that eccrine hidradenitis is
the primary event is follicular obstruction.34,53 Some data suggest overacti­
vation of the innate immune system, but a deeper underlying cause remains
elusive.57,58
The provocation for the initial ‘apocrinitis’ is believed by some to be
keratin occlusion of the corresponding hair follicle. Certainly, keratin plug­
ging of follicles and sinuses and inflammation in and around the hair fol­
licle are regularly seen.52 In one study, follicular occlusion was present in all
of 118 specimens examined in patients with disease duration that ranged
from as little as 1 month to many years.54 The anatomic distribution of the
lesions also supports the concept of an underlying apocrine gland defect.
The condition has some similarity to Fox-Fordyce disease, which is more
convincingly associated with an inflammatory process of the apocrine duct.
Fox-Fordyce disease has the same sex predilection, age incidence, and ana­
tomic distribution, and it too is alleviated by pregnancy. Interestingly, some
cases of Fox-Fordyce disease have been reported to progress to hidradenitis
suppurativa.
The other members of the follicular occlusion triad – acne conglobata and
dissecting folliculitis – are both clearly associated with keratin plugging.
There is no doubt that the main symptoms and chronic disability are
related to the sinuses and fibrosis; these are largely due to the chronic second­
ary infection, since injection of sterile apocrine sweat into tissues does not
induce an inflammatory response.
Organisms that may be found include Staphylococcus aureus, Streptococcus
viridans, Escherichia coli, Proteus mirabilis, Klebsiella spp, Pseudomonas
aeruginosa, Streptococcus milleri and anaerobic organisms. Coagulase-
negative S. aureus is the most common bacterium isolated from the depth
of the lesions.59 Anaerobic organisms are responsible for the offensive smell,
which can be a major problem for the patient. Generally, no immune defi­
ciency is detectable, but there have been occasional reports of a functional
neutrophil deficiency.
In considering the pathogenesis of this condition it must also be noted
that some cases clearly develop as an autosomal dominantly inherited ten­
dency.60,61 Others have no suggestion of familial incidence.
The disease has been simulated in 3 of 12 normal volunteers by occlu­
sion of axillary skin with atropine tape following depilation.62 The latter
in itself could be expected to produce some pathology, which is clearly
not seen in the normal individual. The absence of lesions in 75% of these
volunteers shows at least that there is some variation in susceptibility to
developing the disease. This experimental induction of the disease has not
been repeated.
In a study of 42 women with hidradenitis suppurativa, the authors
noted premenstrual exacerbation of symptoms in two-thirds of patients
 Hidradenitis suppurativa 657

and over one-third of patients reported menstrual irregularities.63 In this

same study, testosterone and free androgen index were higher compared
with control patients.63 In contrast, another study was not able to correlate
­hyperandrogenism and development of hidradenitis in women.8,64 Pregnancy
may relieve the ­symptoms of the disease.
In summary, the precise pathogenesis of hidradenitis suppurativa is not
well understood. It seems likely, however, that while many patients have a
tendency to follicular occlusion with resultant acne-like lesions, some indi­
viduals show an additional, occasionally inherited, tendency for follicular
obstruction to cause, or be associated with, inflammation of the apocrine
duct. With the additional occlusive effects of obesity and secondary infec­
tion, often by mixed organisms, there is a resultant florid destructive fol­
liculitis centered on, or also involving, the apocrine glands. The secondary
bacterial infection perpetuates the chronic inflammatory and scarring nature
of the process. A defect in the immune system would be expected to exac­
erbate this vicious circle, but no consistent abnormality has yet been identi­
fied.65,66 The changes with pregnancy and menstrual cycle can be attributed
to the hormonal effects on the apocrine gland and do not appear to be of
primary importance.
Biopsies of established hidradenitis suppurativa show sinus tracts with Fig. 15.59
Hidradenitis suppurativa: the sinuses are lined by stratified squamous epithelium
marked suppuration and frank abscess formation. The sinus tracts are lined
and surrounded by fibrosis and inflammation.
by a mixture of granulation tissue and squamous epithelium (Fig. 15.59).
The latter extends from the associated follicular epithelium. These inflam­
matory sinus tracts usually contain desquamated keratin and sometimes hair experience, this is an uncommon finding in routine surgical specimens.
shafts, and are surrounded by dense fibrosis.54 The suppuration may extend Others have also found primary inflammation of apocrine glands in only a
into adjacent connective tissue where there can also be a chronic inflam­ minority of specimens.53,67
matory infiltrate frequently including histiocytes and giant cells that are
sometimes related to keratin fragments. At this stage apocrine glands are Differential diagnosis
conspicuously absent in the scarred and inflamed area, although ­adjacent The main differential diagnoses are primary infection, a response to a ­ruptured
apocrine glands often appear quite normal. Although some authors have epidermal inclusion cyst, or wounds. Clinical correlation and special stains
emphasized the presence of acute inflammation of apocrine glands, in our for microorganisms are necessary to establish the correct diagnosis.
Chapter

16 Vascular diseases See

www.expertconsult.com
for references and
additional material

Introduction  658 Thromboangiitis obliterans  688 Disseminated intravascular coagulation  701

Leukocytoclastic vasculitis  658
Henoch-Schönlein purpura  664
Infantile acute hemorrhagic edema  665
Urticarial vasculitis  666
Polyarteritis nodosa and microscopic
polyangiitis  667
Wegener's granulomatosis  673
Allergic granulomatosis with angiitis  677
Mucocutaneous lymph node
syndrome  679
Granuloma faciale  681
Erythema elevatum diutinum  684
Behçet's disease  686
Temporal arteritis  689 Cryoglobulinemia  703
Juvenile temporal arteritis  692 Antiphospholipid antibody syndrome and
Sneddon's syndrome  705
Takayasu's arteritis  692
Thrombotic thrombocytopenic purpura and
Infection-related vasculitis  694
hemolytic uremic syndrome  706
Paraneoplastic vasculitis  695
Immune thrombocytopenic purpura  707
Vasculitis associated with palisaded
Factor V Leiden mutation  708
neutrophilic and granulomatous
dermatitis  696 Hypergammaglobulinemic purpura  708
Lymphocytic vasculitis  696 Hyperimmunoglobulinemia D
syndrome  709
Malignant atrophic papulosis  697
Superficial thrombophlebitis  709
Atrophie blanche  699
Sclerosing lymphangitis  709
Dermatological manifestations of cholesterol
crystal embolism and embolism from atrial Senile purpura  710
myxoma  700

of vascular disease may manifest as diverse histological patterns. For

Introduction
Vasculitis and other forms of vascular damage are the subjects of this chapter.
Although minimal criteria for the diagnosis of vasculitis may differ among
experts, the presence of inflammation and some evidence of vascular damage
in the form of vessel wall/endothelial cell necrosis or fibrinoid change fulfill
most authorities' criteria for a diagnosis of vasculitis. Some, however, apply
the term less restrictively to vascular inflammation associated with non-
specific histological features such as extravasated red cells, endothelial
swelling, or karyorrhexis but without fibrinoid change or necrosis. When
encountering such cases, we prefer to designate them as ‘low-grade vascular
damage’ and include a comment that, although the findings may represent
very early vasculitis, they do not meet strict criteria for necrotizing vasculitis.
That inflammatory vascular disease is represented by a broad spectrum of
histological changes cannot be overemphasized.
The histological features of most forms of vasculitis are not specific for an
entity per se. A specific diagnosis requires careful clinical, histological, and
serological (i.e. presence of antineutrophil antibodies) correlation.1 The role
of the pathologist in evaluating a biopsy is to confirm or deny the presence
of vasculitis, and to describe the nature of the inflammatory infiltrate and
the type(s) and size(s) of the vessel(s) involved. A histological differential
diagnosis is established to guide patient evaluation. Correct biopsy technique
and timing are important to allow for adequate assessment for vasculitis.
Incisional biopsies to include sufficient subcutis and larger subcutaneous
vessels within the first 48 hours after development of the lesion yield the best
results.1
A pathological diagnosis of vasculitis may indicate a primary or secondary
disease (i.e. in the setting of connective tissue disease). Secondary forms
example, connective tissue diseases may be associated with either a small-
vessel leukocytoclastic disease or a large vessel vasculitis. Likewise, different
histological patterns may be seen in association with a given primary
vasculitis. As an example, Wegener's granulomatosis may be linked with
either leukocytoclastic or granulomatous vasculitis.
The myriad schemata for the classification of the vasculitides are a reflection
of the complexity of this controversial class of diseases. Over the last decade
or so, several new classifications have emerged that attempt to combine both
histological and clinical information (Table 16.1).2 Undoubtedly, these will
continue to be refined as a more complete understanding of the pathogenesis
of these diseases is gained.
Leukocytoclastic vasculitis
Clinical features
Leukocytoclastic vasculitis (allergic vasculitis, hypersensitivity vasculitis,
leukocytoclastic angiitis) is the commonest form of vasculitis.1–6 It is not a
disease entity but represents a vascular reaction pattern due to circulating
immune complexes that may either be idiopathic or caused by a number
of underlying disorders. The antigens possibly involved are summarized
in Table 16.2.1–7 The most frequent associations are drugs in addition to
infections.8,9 In over 40% of cases, however, no underlying condition can be
identified.10 Although the condition may be limited to the skin, it is important
to recognize that it can also be associated with systemic manifestations
involving the joints, kidneys, and gastrointestinal system in between 15%
and 50% of patients.5,10–12 The disease occurs equally in men and women, and
may present in any age group.
 Leukocytoclastic vasculitis 659

Table 16.1
Types and definitions of vasculitis adopted by the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis*

Type of vasculitis Essential components/nonessential components

Large vessel vasculitis
Giant cell (temporal) arteritis Granulomatous arteritis of the aorta and its major branches, with a predilection for the extracranial
branches of the carotid artery. Often involves the temporal artery. Usually occurs in patients older than
50 and often is associated with polymyalgia rheumatic.
Takayasu arteritis Granulomatous inflammation of the aorta and its major branches. Usually occurs in patients younger
than 50.
Medium-sized vessel vasculitis
Polyarteritis nodosa† (classic Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in
polyarteritis nodosa) arterioles, capillaries, or venules.
Kawasaki disease Arteritis involving large, medium-sized and small arteries, and associated with mucocutaneous lymph
node syndrome. Coronary arteries are often involved; aorta and veins may be involved. Usually occurs in
children.
Small vessel vasculitis
Cutaneous leukocytoclastic angiitis Isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis.
Henoch–Schönlein purpura Vasculitis, with IgA-dominant immune deposits, affecting small vessels (i.e. capillaries, venules or
arterioles). Typically involves skin, gut, and glomeruli, and is associated with arthralgias
or arthritis.
Microscopic polyangiitis† Necrotizing vasculitis, with few or no immune deposits, affecting small vessels (i.e. capillaries, venules or
(microscopic polyarteritis)‡ arterioles). Necrotizing arteritis involving small and medium-sized arteries may be present. Necrotizing
glomerulonephritis is very common. Pulmonary capillaritis often occurs.
Wegener's granulomatosis‡ Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to
medium-sized vessels (e.g. capillaries, venules, arterioles and arteries). Necrotizing glomerulonephritis is
common.
Churg-Strauss syndrome‡ Eosinophil-rich and granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis
affecting small to medium-sized vessels, and associated with asthma and eosinophilia.
Essential cryoglobulinemic vasculitis Vasculitis, with cryoglobulin immune deposits, affecting small vessels (i.e. capillaries, venules or arterioles),
and associated with cryoglobulins in serum. Skin and glomeruli are often involved.

Reproduced with permission from Jennette, J.C., et al. 1994 Seminars in Diagnostic Pathology, 18, 3–13.
* Large vessel refers to the aorta and the largest branches directed toward major body regions (e.g. to the extremities and the head and neck); medium-sized vessel refers to the
main visceral arteries (e.g. renal, hepatic, coronary, and mesenteric arteries); small vessel refers to venules, capillaries, arterioles, and the intraparenchymal distal arterial radicals that
connect with arterioles. Some small and large vessel vasculitides may involve medium-sized arteries, but large and medium-sized vessel vasculitides do not involve vessels smaller
than arteries. Essential components are represented by normal type; italicized type represents usual, but not essential, components.
† Preferred term.

‡ Strongly associated with antineutrophil cytoplasmic autoantibodies.

Skin lesions are typically polymorphic, but palpable purpura (nonblanching
erythematous papules) is the commonest manifestation (Fig. 16.1). Urticarial,
bullous or vesicular, ulceroinfarctive, nodular, pustular, livedoid, and annular
lesions may also be encountered (Figs 16.2–16.8).13–17 The lesions measure
from 1 mm to several centimeters in diameter. Occasionally, annular erythema
multiforme-like lesions occur (Fig. 16.9). The lower legs are affected most
often, but lesions can present at a wide variety of sites, including the buttocks,
arms, feet, ankles, trunk, and face, particularly in more seriously affected
patients (Figs 16.10, 16.11). Lesions may be noted in the skin of dependent
areas of bedridden patients, such as the back and buttocks. A frequent
accompaniment is edema of the lower legs or ankles (Fig. 16.12). Patients
either experience a single occurrence or develop frequent recurrences over
months or years. The eruption often occurs in episodes at irregular intervals,
each lasting 1–4 weeks. Lesions usually heal completely, although on occasions
atrophic scars and hyperpigmentation may occur. Rarely, leukocytoclastic
In one study, drug therapy, often following an upper respiratory tract
infection, was the inciting event in 45% of patients.20 Numerous drugs
have been implicated as a trigger including non-steroidal anti-inflammatory
drugs (aspirin, ibuprofen, naproxen, phenylbutazone), phenytoin, quinidine,
amiodarone, potassium iodide, allopurinol, sulfonamides, griseofulvin,
penicillin, erythromycin, clindamycin, oxacillin, vancomycin, ofloxacin, clarithro­
mycin, furosemide (frusemide), thiazides, cimetidine, omeprazole, gabapentin,
orlistat, zidovudine, indinavir, efavirenz, lisinopril, sotalol, insulin, retinoids,
propy­lthiouracil, thiouracil, mefloquine, methotrexate, azathioprine,
sirolimus, granulocyte colony-stimulating factor, haloperidol, cytarabine, erlo­
tinib, rituximab, cinacalcet, famciclovir, rifampin, pyrazinamide, insulin
aspart, metformin, gold and disulfiram.2,21–63 Levamisole has been described
as producing a vasculitis localized to the ears in children.64, 65 Localized
leukocytoclastic vasculitis may occur at the site of interferon alpha injection.66,
67

vasculitis shows an erythema gyratum repens gross morphology.18 Collagen vascular disease (most often rheumatoid arthritis and lupus
Although occasional cases are asymptomatic, patients not uncommonly erythematosus) is commonly associated with leukocytoclastic vasculitis,
complain of pruritus or burning; less frequently, pain is a feature. Additional 2,68 and in one study it was found in 21% of patients.2 The presence of

features, which are sometimes present, include abdominal pain and
gastrointestinal bleeding, joint pains with associated erythema and swelling,
and evidence of renal involvement.19 In severe cases, the features resemble
acute glomerulonephritis and the nephrotic syndrome may even supervene.
Rarely, patients have respiratory involvement (nodular or diffuse infiltrative
lesions on X-ray examination), and very exceptionally the central or peripheral
nervous system is affected, causing symptoms such as headache, diplopia, and
dysphagia.
leukocytoclastic vasculitis in a patient with dermatomyositis raises the
possibility of associated malignancy.69
Infection is also commonly associated with leukocytoclastic vasculitis, with
bacterial, fungal, and viral infection all being implicated.70 Associated bacterial
infections include streptococci, Klebsiella pneumoniae, Mycobacterium
tuberculosis, and Mycoplasma pneumoniae.71–73 Systemic cat scratch disease
presenting as leukocytoclastic vasculitis has been documented.74 Hepatitis
C infection is a particularly frequent association. It should be noted that
660 Vascular diseases

Table 16.2
Possible causes of allergic vasculitis

•  Infection
–  bacterial: Streptococcus
–  mycobacterial: Mycobacterium tuberculosis
–  viral: hepatitis, influenza
–  cytomegalovirus
–  HIV infection
–  leprosy
•  Drugs
–  aspirin, phenacetin, sulfonamides, penicillin, iodides, phenothiazines
•  Chemicals
–  insecticides, weed killers, petroleum products
•  Foreign proteins
–  serum sickness
–  hyposensitization antigens
•  Associated diseases
– autoimmune diseases: systemic lupus erythematosus, inflammatory
bowel disease Fig. 16.2
–  hemolytic anemia Leukocytoclastic vasculitis: close-up view showing small erythematous lesions. By
–  Hodgkin's lymphoma, carcinoma courtesy of the Institute of Dermatology, London, UK.
–  rheumatoid arthritis
–  mixed connective tissue disease
–  dermatomyositis
–  relapsing polychondritis
–  Sjögren's syndrome
–  Henoch-Schönlein purpura
–  cryoglobulinemia
–  polyarteritis nodosa
–  Wegener's granulomatosis
–  Churg-Strauss disease
–  granuloma faciale
–  erythema elevatum diutinum
–  Waldenström's hypergammaglobulinemia
–  sarcoidosis

Fig. 16.3
Leukocytoclastic vasculitis: in this patient an extensive purpuric eruption showing
central necrosis is evident. By courtesy of R.A. Marsden, MD, St George's Hospital,
London, UK.

Fig. 16.1
Leukocytoclastic vasculitis: typical erythematous maculopapular lesions are present
on the medial aspect of the ankle. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.

hepatitis C is also often associated with cryoglobulins (see section on

cryoglobulinemia).75–77
Inflammatory bowel disease, both ulcerative colitis and Crohn's disease,
may be coupled with leukocytoclastic vasculitis.78,79 Further rare associations
include sarcoidosis, α1-antitrypsin deficiency, cystic fibrosis, and the Wiskott-
Aldrich syndrome.15,80,81
Fig. 16.4
Leukocytoclastic vasculitis: here confluent purpura with ulceration is present.
By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 16.5
Leukocytoclastic
vasculitis: this patient
presented with bullous
lesions which developed
as a consequence
of thrombosis with
epidermal infarction. By
courtesy of the Institute
of Dermatology, London,
UK.
Fig. 16.6
Leukocytoclastic vasculitis: Nodular lesions. By courtesy of the Institute of
Dermatology, London, UK.
Physical exercise has also been related to the development of leukocytoclastic
vasculitis. Outdoor activities in hot weather such as walking, running, and
golfing (Golfer's vasculitis) have especially been implicated and middle-aged
to elderly individuals are more frequently affected.82–84 Leukocytoclastic
vasculitis rarely represents a paraneoplastic manifestation of an underlying
malignancy, especially leukemia and lymphoma.85 Hairy cell leukemia is
particularly often associated with leukocytoclastic vasculitis but other
forms of vasculitis may also be seen. In one study of 42 patients with hairy
cell leukemia and vasculitis, 21 had leukocytoclastic vasculitis and 17 had
polyarteritis nodosa.86 In addition, four patients had direct infiltration of
vessel walls by leukemic cells (see also section on paraneoplastic vasculitis).
Although uncommon, leukocytoclastic vasculitis may also be seen in patients
with a variety of solid tumors including non-small cell carcinoma of lung, and
adenocarcinoma of breast, colon, prostate, and kidney.87, 88
Leukocytoclastic vasculitis can be a manifestation of human immuno­
deficiency virus (HIV) infection.89 Unusual associations of this condition
Leukocytoclastic vasculitis 661
Fig. 16.7
Leukocytoclastic vasculitis: in this patient, there are extensive ulceroinfarctive
lesions. By courtesy of the Institute of Dermatology, London, UK.
Fig. 16.8
Leukocytoclastic vasculitis: close-up view of a hemorrhagic blister. By courtesy of
the Institute of Dermatology, London, UK.
include the use of a nicotine patch, drug additives, sodium benzoate, protein
A column pheresis, interleukin-12 receptor beta-1 deficiency, prolonged
exercise, and as a complication of an infected hip prosthesis.90–96
Laboratory investigation may reveal an elevated erythrocyte sedimentation
rate (ESR), proteinuria or hematuria. In some idiopathic cases and in those
associated with systemic disease (e.g. rheumatoid arthritis, systemic lupus
erythematosus (SLE), and Sjögren's syndrome), hypocomplementemia
is sometimes evident.5 Urinalysis may reveal proteinuria or hematuria.
Cryoglobulins have been found in up to 25% of patients.2 Perinuclear staining
antineutrophil antibodies are present in about 20% of patients.2,97
The outcome of leukocytoclastic vasculitis is variable, ranging from
a mild, self-limiting illness through to a serious, potentially fatal disorder
due particularly to renal involvement.19 About 1.9% of patients die of
systemic disease.2 Most patients have a benign outcome. An acute clinical
course is seen in approximately 50% of patients.2,10 A chronic course or one
characterized by relapses and remissions is seen in some patients.2 In one
study of patients with hypersensitivity vasculitis, 54 did not require therapy,
26 were treated with non-steroidal anti-inflammatory medications, and 14
required immunosuppressive agents, most often corticosteroids.20
Specific syndromes associated with leukocytoclastic vasculitis, such as
urticarial vasculitis and Henoch-Schönlein purpura, are discussed under
separate headings in this chapter.
662 Vascular diseases

Fig. 16.9 Fig. 16.10 Fig. 16.11

Leukocytoclastic vasculitis: these urticarial lesions Leukocytoclastic vasculitis: lesions may be widely Leukocytoclastic vasculitis: this patient
on the back of the arm resemble those of erythema disseminated in severely affected patients. By has serological evidence of systemic lupus
multiforme. By courtesy of R.A. Marsden, MD, St courtesy of R.A. Marsden, MD, St George's Hospital, erythematosus.
George's Hospital, London, UK. London, UK.

lysosomal enzymes, including elastases and collagenases, resulting in blood

Fig. 16.12
Leukocytoclastic
vasculitis: in addition to
the typical maculopapular
eruption there is marked
swelling of the legs. By
courtesy of R.A. Marsden,
MD, St George's Hospital,
London, UK.
Pathogenesis and histological features
Leukocytoclastic vasculitis is an immune complex-mediated disorder
similar to the classic Arthus reaction.98 Immune complexes are deposited in
the walls of small blood vessels.5 This is associated with activation of the
complement cascade and the production of C5a (a neutrophil polymorph
chemotactant). The resultant polymorph influx is associated with release of
vessel wall damage, fibrin deposition, and the release of red blood cells
(purpura) into the perivenular connective tissue. Thrombosis may ensue and,
in particularly severe examples, epidermal ischemic damage results. Lesions
are particularly seen on the lower legs because of hydrostasis and blood vessel
flow sludging.5
Evidence for an immune complex-mediated pathogenesis is convincing.1
Patients have been clinically proven to have high levels of circulating
immune complexes, and these are shown to correlate with vasculitic
lesions. Immunoglobulin and complement can be identified in vitro, by
immunofluorescence or immunoperoxidase techniques, and in biopsies from
blood vessel wall lesions less than 24 hours old (Fig. 16.13).99 Immune
complexes can be identified ultrastructurally as clumps of electron-dense
material, usually within the basement membrane between endothelial
cells and pericytes of postcapillary venules. Examination of apparently
uninvolved skin from patients with leukocytoclastic vasculitis sometimes
shows immunoglobulin and complement within the walls of dermal blood
vessels. If histamine is injected into uninvolved skin 3–4 hours previously,
all the features of leukocytoclastic vasculitis are evident at biopsy, including
neutrophil degeneration; this suggests that the immunoreactants are a cause
rather than a consequence of the vasculitis.1
The findings of immunofluorescence studies vary according to the age of
the lesion. Immunoglobulins have been described in up to 81% of patients.8
In early lesions, C3 and IgM predominate, in fully developed lesions there is
predominance of fibrinogen and IgG, and in late lesions fibrinogen and C3
are detected.8
Some authors, noting that early lesions may contain abundant CD3+, CD4+
and CD1a+ cells, have suggested that cell-mediated immune mechanisms may
also play a role in the pathogenesis of leukocytoclastic vasculitis.8 Consistent
with this hypothesis is the demonstration of Langerhans cells in the late phase
of vasculitis.100 Expression of 72 kD heat shock protein and the presence of
gamma/delta T cells in patients with vasculitis associated with infection have
led one group of authors to postulate that the cell-mediated immune response
plays an important role in that subset.101
 Leukocytoclastic vasculitis 663

Fig. 16.13 Fig. 16.15

Leukocytoclastic vasculitis: IgM is present in the blood vessel walls (direct Leukocytoclastic vasculitis: high-power view showing complete vessel wall destruction.
immunofluorescence). By courtesy of B. Bhogal, FIMLS, Institute of Dermatology,
London, UK.

In leukocytoclastic vasculitis, it is the postcapillary venule and the capillary

loops (and not the arteriole) which are primarily affected, usually within the
superficial dermis (Figs. 16.14, 16.15). In severe cases, particularly those
associated with malignancy or connective tissue disease, the inflammatory
changes extend into the vasculature of the deep reticular dermis or even the
subcutaneous fat.9 The histological features are similar irrespective of the
underlying etiology.
The histological features of leukocytoclastic vasculitis are those of fibrinoid
necrosis associated with endothelial cell swelling and infiltration of the blood
vessel walls by neutrophils and conspicuous nuclear dust (Fig. 16.16).2,102,103
Variable numbers of mononuclear cells and eosinophils may be seen. In early
lesions, nuclear dust is associated with a perivascular neutrophilic infiltrate
but multiple tissue sections may be needed to identify fibrinoid vascular
changes. The former features, even without unequivocal fibrinoid change,
are suggestive of an evolving leukocytoclastic vasculitis.
Intravascular thrombi and ischemic necrosis of the overlying epidermis
(often with bullae formation) may sometimes be seen (Figs 16.17–16.19).
Occasionally, one may encounter intradermal or subepidermal pustules. Fig. 16.16
In patients with associated hypocomplementemia, neutrophils are predom­ Leukocytoclastic vasculitis: high-power view showing fibrinoid necrosis and a mixed
inant with far fewer lymphocytes; patients who are normocomplementemic inflammatory cell infiltrate composed of neutrophils, eosinophils, and lymphocytes.
There is marked leukocytoclasis (karyorrhexis, nuclear dust).

Fig. 16.14 Fig. 16.17

Leukocytoclastic vasculitis: the blood vessels show florid fibrinoid necrosis and Leukocytoclastic vasculitis: vascular thrombosis as seen in this field is not uncommon.
intense inflammation.
664 Vascular diseases
Fig. 16.18
Leukocytoclastic vasculitis: in this example, there is incipient subepidermal
vesiculation.
Fig. 16.19
Leukocytoclastic
vasculitis: vascular
thrombosis is
accompanied by
epidermal infarction.
Note the cytoplasmic
eosinophilia and loss of
nuclei.
may show lymphocyte predominance. In the surrounding connective tissue, red
cell extravasation, edema, and an inflammatory neutrophil infiltrate associated
with karyorrhexis (leukocytoclasis) are typically present (Fig. 16.20).
The severity of the histopathological changes in the cutaneous lesions of
leukocytoclastic vasculitis does not predict extracutaneous involvement.104
Differential diagnosis
The diagnosis is relatively straightforward. It is critical to understand that
leukocytoclastic vasculitis is not a disease sui generis. Rather, it represents
a reaction pattern due to circulating immune complexes that may be caused
by myriad underlying disorders. Furthermore, leukocytoclastic vasculitis is
frequently encountered in association with other forms of vasculitis. For
example, it is much more commonly encountered in patients with Wegener's
granulomatosis than granulomatous vasculitis. Therefore, a biopsy showing
leukocytoclastic vasculitis does not exclude diseases that may be associated
with other forms of vasculitis. Sometimes it coexists with a large-vessel
Fig. 16.20
Leukocytoclastic vasculitis: note the marked red cell extravasation.
vasculitis. An inadequate biopsy that does not include deep dermis and
subcutaneous tissue containing large vessels can produce misleading results.
The presence of leukocytoclastic vasculitis in a superficial biopsy does
not exclude an associated large-vessel vasculitis; therefore the report of a
superficial biopsy from a patient suspected of having large-vessel vasculitis
should comment on the lack of larger vessels for evaluation.
Sweet's syndrome may resemble leukocytoclastic vasculitis; however, the
presence of a diffuse (rather than predominantly perivascular) neutrophilic infiltrate
without fibrinoid vascular change or necrosis favors the former condition.
Henoch-Schönlein purpura
Clinical features
Henoch-Schönlein purpura is a syndrome characterized by abdominal
pain, joint symptoms, and palpable purpura secondary to leukocytoclastic
vasculitis, and caused by circulating IgA immune complexes. The disease
typically involves children (males more often than females), although adults
may also be affected.1–4 Occurrence during pregnancy has only rarely been
documented.5 In a large study of children with Henoch-Schönlein purpura,
92% of patients were less than 10 years of age.6
It often complicates an upper respiratory tract infection and is characterized
by a seasonal incidence with a peak in winter.1 Clustering of cases has
been described, leading one group of authors to postulate that person-to-
person spread of an infectious agent plays a role in the pathogenesis of
this syndrome.7 Although it may follow a streptococcal throat infection, it
sometimes develops after a wide variety of other infective conditions including
amebiasis, chickenpox, hepatitis, HIV, yersiniosis, and infection by Toxocara
canis, Helicobacter pylori, Pseudomonas aeruginosa, Staphylococcus aureus,
Escherichia coli, and erythrovirus (formerly parvovirus) B19.8–13 Additional
causes include adverse reactions to drugs such as ampicillin, penicillin,
erythromycin, and clarithromycin.14,15 An association with cocaine inhalation
has also been described.16 In one study, drug therapy may have been a
precipitating cause in 26% of patients.17
As noted above, classic Henoch-Schönlein purpura is characterized by
a triad of purpura, abdominal pain, and arthralgia. The cutaneous clinical
findings are those of leukocytoclastic vasculitis. Cutaneous lesions are
most frequently the presenting symptom and comprise palpable purpura
predominantly affecting the lower limbs, thighs, and buttocks (Fig. 16.21).1,18–20
Targetoid lesions are often present.21 Hemorrhagic bullae are rare.22–24
Subcutaneous nodules have also been documented.25 A prodrome of itchy
urticaria is sometimes described.2 Children often have edema, particularly of
the feet and lower legs, although it may be more widespread.
In one large study, arthritis was seen in 82% of patients and was the
presenting feature in 24%.6 Joint involvement consists of migratory arthralgia

A an underlying malignancy in older patients (especially males of 40 years or
B to a diagnosis of Henoch-Schönlein purpura. A vasculitis with the presence
Fig. 16.21
(A, B) Henoch-Schönlein purpura: palpable purpura in the classical distribution on
the buttocks and thighs. From the collection of the late N.P. Smith, MD, the Institute
of Dermatology, London, UK.
predominantly affecting the large joints of the lower limbs. In one study, 37%
also had involvement of the upper extremities, with the hand and wrist being
more often affected than the elbow.6
Intestinal involvement with resultant red cell extravasation or hemorrhage
leads to abdominal pain and gastrointestinal bleeding. Abdominal pain was
noted in 63% of patients in one study of 100 consecutive children presenting
with the condition.6 Gastrointestinal disease develops as a consequence of acute
vasculitis. Bleeding may be either occult or in the form of bloody or melanotic
stools.6 Intussusception is an occasional complication.26,27 Abdominal pain
was the presenting complaint in 19% of patients in one study.6 Endoscopy
may reveal hemorrhage, ulceration, and erosions.28 IgA is often noted in
capillaries of the gastrointestinal tract but frank necrotizing vasculitis was
not seen in any patients in two series.28,29 Rarely, gastrointestinal involvement
with minimal skin lesions is encountered.30
Renal symptoms are variable and include microscopic hematuria, acute
nephritic syndrome, nephrotic syndrome, and acute or chronic renal failure.
The pathological features seen on renal biopsy range from mild focal glomerulo­
nephritis to necrotizing or proliferative glomerulonephritis.1,6 In a consecutive
series of 100 pediatric patients, a single patient required transplantation.6
Patients older than 7 years are at increased risk of renal involvement.31
Orchitis is a recognized complication of Henoch-Schönlein purpura,
affecting 14% of male patients.6,18
Neurological involvement may be manifested by headaches, seizures, mental
status changes and, less frequently, ataxia and peripheral neuropathy.32
Infantile acute hemorrhagic edema 665
Low serum C3, leukopenia, and thrombocytopenia are rare findings.33
Henoch-Schönlein purpura in children is generally associated with a good
prognosis, with less than 2% suffering long-term morbidity.34,35 However,
patients do occasionally die from renal failure, gastrointestinal infarction or
respiratory involvement. In contrast to pediatric patients, adults are thought
to have a worse prognosis. However, one study found that, although older
patients had more severe symptoms including frequent renal involvement,
prognosis was equally good in young and older patients.36 In another study,
complete recovery was seen in 67% of adults after a median follow-up period
of 36 months.10 In a further series, a third of patients suffered at least one
recurrence of symptoms, usually within a few months of initial presentation.6
Recurrences were also found to be more frequent in patients > 8 years of age
and in those with nephritis.18
Solid tumors including breast cancer and hematological malignancy have
been associated with Henoch-Schönlein purpura.37–41 One study found that
nearly a third of adults with Henoch-Schönlein purpura had an associated
tumor.37 For this reason, the authors concluded that physicians should suspect
more) with Henoch-Schönlein purpura.38
Pulmonary hemorrhage is a rare complication that may prove fatal.42,43
Pathogenesis and histological features
An incomplete picture of the pathogenesis of Henoch-Schönlein purpura
has emerged. As noted above, it seems a wide variety of infective agents
may trigger this disease. Henoch-Schönlein purpura is associated with IgA
deposition in blood vessel walls, both in the dermis and in the renal glomerulus
(mesangium). IgA1 is the major IgA subclass found in the cutaneous blood
vessels.44 Fibrinogen and C3 are also usually present. Raised levels of serum
IgA and IgE are present in some, but not all, patients.6 IgA antineutrophil
cytoplasmic antibodies (ANCA) and IgA anticardiolipin antibodies have
also been documented.45,46 There is evidence that patients have an increased
number of IgA-type B cells.47 More recently, IgA-binding regions from
streptococcal M proteins have been identified in a significant subset of skin
and renal biopsies from patients with Henoch-Schönlein purpura.48
The finding of IgA deposition by immunofluorescence is not equivalent
of IgA deposition in patients lacking other typical features of Henoch-
Schönlein purpura has been described in association with cancer, Wegener's
granulomatosis, and inflammatory bowel disease.49
The observation of an association between DRB1*01 and DRB1*11
and Henoch-Schönlein purpura suggests a genetic susceptibility in some
patients.50,51 Other authors have suggested that DQA1*0301 and C4 deletion
may also represent risk factors for IgA nephropathy as well as Henoch-
Schönlein nephritis.52
Biopsies of cutaneous lesions show features of typical leukocytoclastic
vasculitis (Fig. 16.22).
Differential diagnosis
The histological differential diagnosis includes other forms of leukocytoclastic
vasculitis. Since IgA deposition can be seen in the blood vessel walls of patients
with leukocytoclastic vasculitis but without evidence of Henoch-Schönlein
purpura, this finding is not diagnostic in isolation.53 In one study, only 24%
of patients with vascular IgA deposition had Henoch-Schönlein purpura.53
Careful clinical correlation is necessary to establish the diagnosis.
Infantile acute hemorrhagic edema
Clinical features
Infantile hemorrhagic edema is a form of leukocytoclastic vasculitis that
is mostly seen in newborns but has also been described in the first 3 years
of life and occasionally in older children.1–11 The disease is usually limited
to the skin but mucosal involvement may be an additional feature.10
Transient renal involvement with microscopic hematuria and proteinemia,
hypocomplementemia, abdominal pain, and elevated transaminases are
exceptional additional findings.12,13 It frequently follows vaccination or
666 Vascular diseases
Fig. 16.22
Henoch-Schönlein purpura: this small venule shows striking fibrinoid change. There
is considerable red cell extravasation.
infection including otitis, upper respiratory tract infection or conjunctivitis.1,10,11
An association with cytomegalovirus, herpes simplex virus-1 or rotavirus
infection has been documented.14–16 Since many children had received
antibiotics for infection prior to development of lesions, a subset of cases
may represent reaction to medication.1 This disease has a peak incidence in
the winter months.
Skin lesions are widely distributed, and often involve the head and neck, and
limbs. They present as purpuric lesions that often have a rosette or targetoid
configuration.2,3 The cheeks and ears seem to be sites of predilection.3,11
Resolution within a few weeks is typical and recurrences are not reported.1,11,17
An elevated ESR and leukocytosis are usually present.
Pathogenesis and histological features
The pathogenesis of infantile hemorrhagic edema is unknown; however,
it is likely that the disease is immune mediated. Biopsy shows features of
leukocytoclastic vasculitis with variable fibrinoid necrosis.3
Differential diagnosis
Some authors consider infantile hemorrhagic edema to be a variant of
Henoch-Schönlein purpura. Others do not agree, arguing that the absence
of perivascular IgA on immunofluorescence staining, absence of systemic
involvement in most patients, and the benign clinical course do not support
this view.3,18 However, a very interesting hypothesis possibly linking the two
diseases has been postulated.19 Goraya and Kaur note that, since the IgA
immune system in infants is immature, if acute hemorrhagic edema were related
to Henoch-Schönlein purpura, the patient would be incapable of mounting
an IgA-mediated immune response and this would explain the lack of IgA
on immunofluorescence studies in the majority of patients.19 Clearly, further
study of this disorder is necessary to elucidate its pathogenesis and to clarify its
nosological position in the classification of leukocytoclastic vasculitis.
Urticarial vasculitis
Clinical features
Urticarial vasculitis is an uncommon condition characterized clinically by
urticaria and histologically by leukocytoclastic venulitis.1–5 In addition to
urticarial skin lesions, patients may also experience angioedema, arthralgia,
gastrointestinal symptoms, and evidence of renal involvement.6,7 The term
encompasses a spectrum of illness, with some patients experiencing only mild
symptoms while others develop serious systemic involvement.7,8
Urticarial vasculitis is most often seen in the third to fifth decades and
shows a female predominance.7 The cutaneous lesions are urticarial in
appearance, consisting of edematous, raised, erythematous plaques associated
Fig. 16.23
Urticarial vasculitis: this very large lesion has developed a bizarre outline due to
central clearing. By courtesy of the Institute of Dermatology, London, UK.
Fig. 16.24
Urticarial vasculitis: close-up view. By courtesy of the Institute of Dermatology,
London, UK.
with nonblanchable purpura (Figs 16.23, 16.24). However, in contrast to
uncomplicated urticaria, cutaneous lesions of urticarial vasculitis often last
24–72 hours.9 Patients commonly complain of pruritus, burning or pain. The
frequency of cutaneous symptoms varies considerably, from daily to monthly.
Joint pain, stiffness, and swelling, particularly of the hands, elbows, feet,
ankles, and knees, are seen; however, frank arthritis is extremely rare.10
Hypocomplementemia, which correlates with systemic involvement, is a
feature in many patients.4,7,8,11,12 Proteinuria and hematuria may also be noted.
Rarely, patients develop focal or diffuse proliferative glomerulonephritis.
Crescentic glomerulonephritis, mesangial glomerulonephritis, and
membranous nephropathy have also been documented.8,13–16 Gastrointestinal
symptoms can include abdominal pain, nausea, vomiting and diarrhea, and
an associated peripheral neuropathy has been reported.17
The ESR is raised in many patients with hypocomplementemia. There
may also be depression of the early classic pathway components C1q, C4
and C2. Patients with hypocomplementemic urticarial vasculitis have a high
prevalence of autoantibodies to endothelial cells.18,19
Schnitzler's syndrome is a term that has been applied to patients with urticarial
vasculitis and monoclonal IgM gammopathy.20–25 Hepatosplenomegaly,
elevated ESR, and white blood cell count, fever and joint pain are characteristic
features.21–23 An associated monoclonal IgA gammopathy has been reported and
an underlying lymphoproliferative disorder is present in some patients.20,26,27
 Polyarteritis nodosa and microscopic polyangiitis 667

Importantly, urticarial vasculitis (especially the hypocomplementemic

variant) is often associated with, or heralds the onset of, a variety of systemic
diseases, including SLE, arthritis, interstitial lung disease, pericarditis,
mixed connective tissue disease, systemic sclerosis, relapsing polychondritis,
hepatitis, inflammatory bowel disease, serum sickness, polyarteritis
nodosa and Wegener's granulomatosis, viral infection, Sjögren's syndrome,
cryoglobulinemia, polycythemia rubra vera, reaction to drugs (including
cocaine and diltiazem), and as a response to sunlight.8,13,28–38 The condition
may be exacerbated by methotrexate.39 In one study, more than 50% of
patients had uveitis, scleritis, conjunctivitis or episcleritis.8 It appears that
patients with hypocomplementemia have more severe disease.28 Some authors
have postulated that hypocomplementemic urticarial vasculitis represents a
subset of SLE. Others, however, have failed to confirm this observation.8,40
Urticarial vasculitis has been documented in association with malignancy.8,41
Given the rarity of this association, this may well be coincidental. Nevertheless, a
diagnosis of urticarial vasculitis should always initiate an evaluation for possible
underlying disease. Urticarial vasculitis usually has a benign outcome.8
Pathogenesis and histological features
In many patients, no underlying cause is discovered. In others, antibody–
antigen complexes (a type III hypersensitivity reaction) is implicated.4,5
The vasculitis affects the superficial vascular plexus and is characterized
by a leukocytoclastic pattern (Fig. 16.25). Extravasation of red blood cells is
evidence of vascular damage. A background of dermal edema may be seen.
Often, the histological features are subtle and are easily overlooked, with only
focal fibrinoid vascular change, few neutrophils, and sparse karyorrhexis. In
our experience, the vasculitis is usually low grade or subtle in nature; however,
more impressive necrotizing vasculitis is seen in some patients. Others have
shown that endothelial necrosis is unusual.5
In summary, urticarial vasculitis may show a spectrum of histological
changes ranging from urticaria with very mild vascular injury to frank
necrotizing vasculitis.42
Polyarteritis nodosa and microscopic
polyangiitis
Classic polyarteritis nodosa (Kussmaul-Maier disease) is a rare systemic
vasculitis involving medium-sized and small arteries.1 Some view the disorder
not as a disease sui generis but, less restrictively, as a syndrome with many
triggering causes and disease associations. Classic polyarteritis nodosa
overlaps both clinically and histologically with microscopic polyangiitis
(microscopic polyarteritis nodosa, microscopic polyarteritis). Distinction
between these entities may be difficult and criteria for their distinction are
controversial. Nevertheless, they seem to represent distinctive syndromes that
warrant separate classification to facilitate appropriate treatment.2 In order
to maintain a usable working classification, we – while admitting they are
separate diseases – prefer to describe them in the same section to facilitate
comparisons between them.
Clinical features
Classical polyarteritis nodosa
Classic polyarteritis nodosa is a multisystem disease with protean clinical
manifestations (Table 16.3).1,3–5 It should be noted that the 1990 criteria
from the American College of Rheumatology do not distinguish polyarteritis
nodosa from microscopic polyarteritis. However, in the more recent Chapel
Table 16.3
1990 criteria for the classification of polyarteritis nodosa (traditional format)*
Criterion Definition
Weight loss ≥ 4 kg Loss of 4 kg or more of body weight
since illness began not due to dieting or
other factors

Differential diagnosis Livedo reticularis
Clinical correlation is necessary to distinguish urticarial vasculitis from other
forms of leukocytoclastic vasculitis. Although urticarial vasculitis is often Testicular pain or
tenderness
associated with subtle low-grade vascular injury, this feature should not be
relied upon in its distinction from other forms of vasculitis. In short, the Myalgias, weakness, or leg
pathologist's role in diagnosis is to confirm the presence of vasculitis. tenderness
Mononeuropathy or
polyneuropathy
Diastolic BP > 9  mmHg
Elevated BUN or creatinine
Hepatitis B virus
Arteriographic abnormality
Biopsy of small or medium-
sized artery
Mottled reticular pattern over the skin of
portions of the extremities or torso
Pain or tenderness of the testicles not
due to infection, trauma or other causes
Diffuse myalgias (excluding shoulder
and hip girdle) or weakness of muscles
or tenderness of leg muscles
Development of mononeuropathy,
multiple mononeuropathies or
polyneuropathy
Development of hypertension with the
diastolic BP higher than 90 mmHg
Elevation of BUN > 40 mg/dL or
creatinine > 1.5 mg/dL not due to
dehydration or obstruction
Presence of hepatitis B surface antigen
or antibody in serum
Arteriogram showing aneurysms or
occlusions of the vesical arteries not
due to arteriosclerosis, fibromuscular
dysplasia, or other non-inflammatory
causes
Histological changes showing the
presence of granylocytes or granulocytes
and mononuclear leukocytes containing
PMN in the artery wall

*For classification purposes, a patient shall be said to have polyarteritis nodosa if at

Fig. 16.25
Urticarial vasculitis: the
changes are unusually
florid in this example.
least three of these 10 criteria are present.
The presence of any three or more criteria yields a sensitivity of 82.2% and a
specificity of 86.6%.
BP, blood pressure; BUN, blood urea nitrogen; PMN, polymorphonuclear neutrophils.
Reproduced with permission from Lightfoot, D.W. (1991) Current Opinion in
Rheumatology, 3, 3–7.
668 Vascular diseases

Hill nomenclature this discrimination is made (see Table 16.1). Polyarteritis
nodosa is associated with significant morbidity and mortality even when
treated with corticosteroids. With therapy, survival is in the range of 75–80%.1
Although a wide age group may be affected, patients are most often in their
fifth or sixth decade.6 There is a male predilection (4:1). Patients commonly
present with constitutional symptoms including weight loss, pyrexia, and
anorexia.1
Cutaneous lesions are common and are present in over 40% of patients.6–10
Palpable purpuric lesions and foci of ulceration, particularly involving the
lower limbs, are most often found (Figs 16.26–16.28).10 Livedo reticularis
is also a common cutaneous manifestation (Fig. 16.29). Cutaneous nodules
may also be seen. A maculopapular rash, vesiculation, and pustular lesions
are occasional features (Figs 16.30–16.33).
Joint involvement (arthralgias and arthritis) is often present; arthritis is
usually asymmetrical and particularly affects the lower limbs. Non-specific
muscle pain and weakness are additional features. Muscle wasting is
commonly found.
Both peripheral and central nervous system involvement are often
encountered. The former presents as sensory neuropathies (numbness
or paresthesias), motor neuropathies (wrist or foot drop) and combined

A B

Fig. 16.26 Fig. 16.27

Polyarteritis nodosa: (A) a sharply defined ulcer with an indurated purplish border on the shin; (B) multiple Polyarteritis nodosa: this patient presented with large
ulcers, nodules, and foci of livedo reticularis. By courtesy of R.A. Marsden, MD, St George's Hospital, hemorrhagic lesions on the legs. By courtesy of the
London, UK. Institute of Dermatology, London, UK.

Fig. 16.28 Fig. 16.29

Polyarteritis nodosa: epidermal infarction has resulted in these digital ulcers. Polyarteritis nodosa: this patient shows florid livedo reticularis. By courtesy of the
By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK. Institute of Dermatology, London, UK.

Fig. 16.30
Polyarteritis nodosa: erythematous macules are occasionally seen. By courtesy of
the Institute of Dermatology, London, UK.
Fig. 16.31
Polyarteritis nodosa: erythematous papules are present around this patient's
ankles. By courtesy of the Institute of Dermatology, London, UK.
Fig. 16.32
Polyarteritis nodosa: this patient presented with acral erythematous lesions. By
courtesy of the Institute of Dermatology, London, UK.
Polyarteritis nodosa and microscopic polyangiitis 669
Fig. 16.33
Polyarteritis nodosa: in some patients, an intense neutrophil infiltrate results in
pustular lesions as seen in this patient. By courtesy of the Institute of Dermatology,
London, UK.
sensorimotor lesions (mononeuritis multiplex and polyneuropathy). Central
nervous system involvement may present as confusion, disorientation
or delirium. Eye involvement is a rare feature of polyarteritis nodosa.11
Complications include choroidal infarction, ischemic optic neuropathy,
retinal artery occlusion, episcleritis, ulcerative keratitis, uveitis, and orbital
pseudotumor.11–13
Involvement of the kidney is very common and is of major importance
because its sequelae – renal failure and hypertension – are among the
commonest causes of death in this disease. Patients on occasion have episodes
of loin pain due to renal infarction. Hypertension is often present in patients
with classical polyarteritis nodosa and in some patients it may enter the
malignant phase. Urinalysis for proteinuria, hematuria and red cell casts, and
serum creatinine estimations are therefore mandatory early investigations.
Gastrointestinal involvement is also an important cause of morbidity
and mortality.14,15 Symptoms include nausea, vomiting, and abdominal pain.
Serious complications include gastrointestinal hemorrhage, perforation, and
infarction, the last being a not uncommon cause of death. Involvement of the
hepatobiliary tract may also be seen.16,17 Involvement of the gallbladder and
pancreas has also been reported and can represent an incidental finding or
patients may present with symptoms of acute cholecystitis.18,19
Cardiac manifestations include pericarditis, arrhythmias, and myocardial
infarction due to coronary artery involvement (Fig. 16.34). Although it is
often stated that polyarteritis nodosa does not involve the lung, in exceptional
cases pulmonary involvement is seen and patients occasionally complain of
asthma, hemoptysis, and effusions. Although clinical involvement of the lungs
is rare, autopsy evaluation has shown that arteritis affecting the bronchial
arteries is not uncommon, being seen in 70% in one small series.20
Orchitis, usually unilateral, is a characteristic feature of polyarteritis
nodosa.21–23 Affected patients present with symptoms of acute orchitis or
features that suggest a testicular neoplasm.21,23
Laboratory investigations often reveal anemia, leukocytosis, and a raised
ESR. Low-titer rheumatoid factor and antinuclear antibody are sometimes
features and, in occasional patients, a cryoglobulin is identified. Diminished
serum complement levels may also be detected. ANCAs are uncommonly
seen in patients with classic polyarteritis nodosa. One group with extensive
experience estimates that less than 5% of patients with the classic form of
the disease have ANCAs.24 Others have found a somewhat higher frequency.
Nevertheless, this is in contrast to microscopic polyangiitis, a form of vasculitis
that is usually associated with ANCAs (see below).
Polyarteritis nodosa in children may present in two forms: the infantile
variant, which may be related to Kawasaki syndrome, and a childhood form,
which is similar to adult polyarteritis nodosa (see also section on Kawasaki
syndrome).25
670 Vascular diseases

Fig. 16.34
Polyarteritis nodosa:
coronary arteries showing Fig. 16.35
conspicuous aneurysmal Microscopic polyarteritis: p-ANCA. By courtesy of G. Swana, MD, St Thomas'
dilatation are now very Hospital, London, UK.
rarely seen (museum
specimen). By courtesy
of the Department of with either disease have neither pulmonary nor renal involvement, precise
Pathology, St Thomas' classification can be difficult.24 Microscopic polyangiitis is a diagnosis of
Hospital, London, UK. exclusion; other conditions that may manifest similar renal features include
Wegener's granulomatosis, rapidly progressive glomerulonephritis, Churg-
Strauss syndrome, SLE, classic polyarteritis nodosa, and Henoch-Schönlein
Cutaneous polyarteritis nodosa purpura.18
Microscopic polyangiitis is usually associated with positive neutrophil
In addition to classic polyarteritis nodosa, ‘localized (cutaneous) polyarteritis
cytoplasmic antibodies, typically of the antimyeloperoxidase (perinuclear-
nodosa’ has also been described.26–32 This is a relatively benign variant in
antineutrophil cytoplasmic antibody, p-ANCA) subtype (Fig. 16.35).40 Since
which patients develop cutaneous lesions, often over very prolonged periods,
most (but not all) patients with classic polyarteritis nodosa do not have
but serious visceral involvement is, by definition, never a feature. In one study,
ANCAs, this is useful in distinguishing these conditions.
none of 79 patients with cutaneous polyarteritis nodosa who were followed
This disease is of particular importance due to its high morbidity and
for an average of 6.9 years developed systemic vasculitis.26 It may occur at
mortality, with a 5-year survival of approximately only 65%.38 As a result
any age, including childhood, and shows no sex predilection. The disease has
of improved medical treatment outcome has significantly improved over the
occasionally been associated with minocycline treatment.33–35
past few decades, with a quoted 5-year survival of 81%.41 Severe renal disease
Patients have recurrent episodes during which tender, painful nodules
and disease relapse are the best indicators for poor prognosis.41
develop, particularly on the lower legs, although these may sometimes be
Patients often present with non-specific constitutional symptoms including
quite widespread. Individual lesions vary from 2 mm to 2 cm in diameter. In
malaise, fever, and myalgia. There may be a past history of sore throat
the early stages they are pink or red, while more established nodules may have
or a flulike illness, which obviously raises the possibility of an iatrogenic
a purplish coloration. Patients sometimes also manifest livedo reticularis,
pathogenesis for the subsequent vasculitic process.38 Renal involvement
usually on the lower legs and often related to groups of nodules. Other
may manifest as microscopic hematuria, proteinuria or acute renal failure.
complications include ulceration and, rarely, gangrene. Very occasionally,
Hypertension is present in a large proportion of patients. Pulmonary lesions
patients develop lesions reminiscent of atrophie blanche.30
present as hemoptysis, pulmonary fibrosis, and intrapulmonary hemorrhage,
Other features include fever, malaise, arthralgias, and myalgias, and
which can prove fatal.42,43
peripheral nerves may be affected, but there is never any evidence of more
Dermatological signs, which are found in approximately 40% of patients,
widespread visceral involvement.28,32
include purpura, erythema, splinter hemorrhages, and leg ulceration.10,39,44
Immunofluorescence often reveals IgM and/or complement in the walls
Bullous presentation or urticaria are occasionally encountered but cutaneous
of cutaneous arteries, suggesting a possible immune complex pathogenesis.36
nodules and livedo are rare features of this disease due to absence of involvement
Rare reports of infants of mothers with cutaneous polyarteritis developing the
of larger vessels.10,44–46 Other manifestations such as nervous system lesions,
disease and experiencing subsequent resolution are suggestive of a pathogenic
gastrointestinal bleeding with pain, and diarrhea, are sometimes evident.47–50
circulating factor.37
Laboratory findings in microscopic polyarteritis include a raised
ESR, normochromic normocytic anemia, leukocytosis with neutrophilia
Microscopic polyangiitis
and thrombocytosis, raised C-reactive protein, and raised α-1 and α-2
Microscopic polyangiitis (microscopic polyarteritis) is a more recently described globulins. Rheumatoid factor and immune complexes are present in less
entity, which involves the skin in a significant proportion of patients.2,38–40 than 50% of patients.38 Anti-DNA antibodies are not a feature. Cutaneous
Its definition and relationship to classic polyarteritis nodosa are somewhat immunofluorescence is usually negative.
controversial. The disease essentially consists of small vessel vasculitis in
association with glomerulonephritis. In contrast, renal involvement in classic Pathogenesis and histological features
polyarteritis is a vascular nephropathy. Lung capillaritis is sometimes seen
in patients with microscopic polyangiitis. By way of distinction, classic Polyarteritis nodosa
polyarteritis nodosa is very rarely associated with clinical manifestations of The pathogenesis of polyarteritis nodosa is poorly understood. Classic
pulmonary involvement (although pathological involvement of large vessels polyarteritis nodosa has been suggested to be immune-complex mediated, on
may be more common than suspected: see above) and this, clinical difference the basis of serum immune-complex levels, immunofluorescence investigations
is helpful in distinguishing these entities.24 However, since many patients and ultrastructural studies. However, in many patients immune complexes
 Polyarteritis nodosa and microscopic polyangiitis 671

cannot be demonstrated and their role in the development of this disease infarction (Fig. 16.37). Although the whole circumference and thickness of
is controversial. Important suspect antigens include hepatitis B virus (HBV) the vessel wall is often affected, sometimes the changes are focal. Typically in
surface antigens and cryoglobulins.51–54 It has been shown that a significant polyarteritis nodosa, the vascular changes are discontinuous, with uninvolved
number of patients with polyarteritis nodosa have circulating HBV antigen.9,54 skip lesions between affected segments (Fig. 16.38).
Furthermore, circulating immune complexes containing HBV antigen and The acute changes, those of fibrinoid necrosis, involve the muscle coat and
immunoglobulin have been characterized in occasional patients.9 HBV surface often destroy the internal elastic lamina; this is often best appreciated by the
antigen has also been identified within affected vessels in a small number of use of a stain for elastic tissue (Fig. 16.39). Associated with the necrosis is
patients.9 A decrease in HBV-associated cases of polyarteritis nodosa in France an inflammatory cell infiltrate of neutrophils, eosinophils, and mononuclear
has been reported and it has been suggested that this phenomenon is the cells. Leukocytoclasis is sometimes an additional feature. Thrombosis
result of vaccination programs.55 Rarely, however, polyarteritis nodosa may is common and may be complicated by ischemic necrosis of the surface
also develop following hepatitis B vaccination.56 Human immunodeficiency epithelium. Healing lesions are associated with fibroblastic proliferation and
viral infection has also been reported in cases of polyarteritis nodosa or a eventual fibrous scarring. Endarteritis is often evident and any disruption
polyarteritis nodosa-like syndrome.57–63 of the internal elastic lamina is permanent. A characteristic feature often
Evidence of hepatitis C viral infection has been documented in some present in wedge biopsies that contain multiple vessels is the presence of
patients. In one study, 20% of patients had antibodies against hepatitis lesions at varying stages of evolution. Deep, surgical incisional biopsies are
C virus.62,64 Erythrovirus (parvovirus) infection has been associated with essential for the diagnosis of cutaneous involvement in polyarteritis nodosa.
polyarteritis nodosa in occasional cases.65,66 A punch biopsy will often not sample larger vessels that are typically affected.
In childhood polyarteritis nodosa, there appears to be a striking association Furthermore, the diagnosis is subject to sampling error due to the multifocal
with group A streptococci.67 nature of the disease. Aneurysm formation may sometimes be appreciated
Although there is some evidence to suggest a role for immune complexes microscopically.1
generated during infection, such a relationship cannot be demonstrated in
many cases. Therefore, the pathogenesis of classic polyarteritis nodosa is
unclear in many patients.
As with other ANCA-associated vasculitides, the presence of ANCAs
(usually p-ANCAs) in most patients with microscopic polyangiitis suggests
that these antibodies may play a pathogenic role. In contrast, ANCAs are
not usually seen in patients with classic polyarteritis nodosa. Additionally,
again in contrast to classic polyarteritis nodosa, immune complexes are
not thought to play a role in the pathogenesis of microscopic polyarteritis
nodosa. The presence of ANCAs suggests a shared pathogenic relationship
with other ANCA-associated vasculitides (i.e. Wegener's granulomatosis,
Churg-Strauss syndrome) and there is recent evidence to suggest that
different but overlapping epitopes of myeloperoxidase (MPO) are
recognized by ANCAs in Wegener's granulomatosis and microscopic
polyangiitis.68 HIV infection has been documented in patients with
microscopic polyangiitis.58
The histological features of the cutaneous lesions in both the classic
and localized variants of polyarteritis nodosa are similar and changes are
variable.38,69,70 In some instances, the changes are indistinguishable from
leukocytoclastic vasculitis involving the superficial dermal vessels (Fig.
16.36). More characteristic, however, is the finding of necrotizing vasculitis
involving the muscular arteries of the deep dermis or subcutaneous fat; these Fig. 16.37
are the changes that are also seen in the internal viscera, often associated with Polyarteritis nodosa: high-power view showing fibrinoid necrosis.

Fig. 16.36 Fig. 16.38

Polyarteritis nodosa: in this case the features are those of a superficial Polyarteritis nodosa: while fibrinoid necrosis involves both lateral extremities of this
leukocytoclastic vasculitis. It is important to remember that this histological lesion vascular segment, the middle portion is relatively unaffected.
may represent a serious systemic disease.
672 Vascular diseases

Fig. 16.40
Polyarteritis nodosa: in this kidney section an arcuate artery shows necrotizing
vasculitis and fibrointimal thickening. The inflammatory cell infiltrate contains
conspicuous eosinophils.

Fig. 16.39
Polyarteritis nodosa: (A) there is marked red cell extravasation; (B) elastic–van
Gieson staining shows disruption of the internal elastic lamina.

Internal visceral involvement is based upon the effects of necrotizing

arteritis. Interestingly, nodular swellings (aneurysms) are much more obvious. Fig. 16.41
Polyarteritis nodosa: segmental necrotizing glomerulonephritis.
The effects depend upon the relative interplay of infarction and hemorrhage.
Renal involvement in classical polyarteritis nodosa is predominantly due to
large-vessel vasculitis, with resultant thrombosis and infarction, coupled
with the effects of hypertension (Fig. 16.40).71 Patients may also manifest
focal, segmental proliferative or necrotizing glomerulonephritis similar to
that seen in patients with microscopic polyarteritis nodosa (Fig. 16.41).

Microscopic polyangiitis
Microscopic polyangiitis (microscopic polyarteritis) is characterized by small-
vessel vasculitis, which may predominantly affect the muscular arteriole,
capillaries, and venules (Fig. 16.42).2,40,72 Given the spectrum of vessel types
involved and the absence of arteriolar involvement in some patients, the term
‘microscopic polyangiitis’ is preferred by some authors.2,73 The absence of
involvement of capillaries and venules in classic polyarteritis nodosa is a major
point of distinction from microscopic polyarteritis nodosa. Necrotizing vasculitis
with fibrinoid necrosis and variable numbers of neutrophils and monocytes is
seen. In early lesions, neutrophils associated with karyorrhexis predominate,
while lymphocytes and histiocytes dominate the infiltrate in older lesions. In some
patients, acute lesions are indistinguishable from leukocytoclastic vasculitis.
Renal lesions include focal segmental necrotizing glomerulonephritis (often
with crescents), vasculitis, interstitial inflammation, and tubular atrophy. Fig. 16.42
Large-vessel disease, visceral infarction, and granulomatous inflammation Microscopic polyarteritis nodosa: acute necrotizing vasculitis of a small muscular
are not features. arteriole is evident. Numerous eosinophils are present.
 Wegener's granulomatosis 673

Differential diagnosis Table 16.4

1990 criteria for the classification of Wegener's granulomatosis (traditional
Since other vasculitides may show similar histological features, particularly format)*
cases with only small-vessel involvement (leukocytoclastic vasculitis pattern),
the biopsy findings must never be used in isolation to determine the diagnosis.
Criterion Definition
Only after careful clinical, serological, and histological correlation should a
definitive diagnosis be rendered. Criteria are admittedly definitional and as Nasal or oral Development of painful or painless
inflammation oral ulcers or purulent or bloody nasal
we learn more about this disease (or group of diseases), criteria are likely to
discharge
change. Careful clinical investigation is required to evaluate for underlying
causes/disease associations. Abnormal chest Chest radiograph showing the presence of
As noted above, distinction between classic polyarteritis nodosa and radiograph nodules, fixed infiltrates or cavities
polyangiitis is based on the size of vessels involved, spectrum and type Urinary sediment Microhematuria (> 5 red blood cells per
of organ involvement, and presence of ANCAs. Microscopic polyangiitis high power field) or red cell casts in urine
may also be confused with Wegener's granulomatosis and Churg-Strauss sediment
syndrome. The presence of granulomatous inflammation in the lung favors Granulomatous Histological changes showing
the first of the last two conditions. The presence of blood eosinophilia and inflammation on biopsy granulomatous inflammation within the
asthma favors a diagnosis of Churg-Strauss syndrome. As can be seen, wall of an artery or in the perivascular or
microscopic polyangiitis is a diagnosis of exclusion. In fact, with clinical extravascular area (artery or arteriole)
follow-up, the diagnosis may be revised. For example, patients who
* For purposes of classification, a patient shall be said to have Wegener's
appear to fit criteria for microscopic polyangiitis may eventually develop granulomatosis if at least two of these four criteria are present. The presence of any
manifestations that allow for classification as Wegener's granulomatosis.2 two or more criteria yields a sensitivity of 88.2% and a specificity of 92.0%
Diagnostic criteria are likely to change as we understand more about these Reproduced with permission from Leavitt, R.Y. (1990) Arthritis and Rheumatism, 33,
disorders. 1101–1107.

Wegener's granulomatosis not uncommon and occur either as a consequence of direct extension through
the base of the skull from sinus involvement or as a result of meningeal or
Clinical features intracerebral necrotizing granulomata. Patients may experience myelopathy
or neuropathy.12 Vasculitis involving intracerebral vessels can also result in
Wegener's granulomatosis is a multisystem vascular disease associated
cerebral lesions. Patients develop cranioneuropathy, cerebrovascular accidents
with high morbidity and mortality.1,2 Before the introduction of
or seizures.11 Involvement of the vasa nervora may give rise to mononeuritis
cyclophosphamide therapy it was associated with a dismal prognosis.
multiplex.
Mean survival was of the order of 5 months following diagnosis and
Ocular lesions result in a variety of complications including conjunctivitis,
approximately 80% of patients died within 1 year, most as a consequence
granulomatous keratitis, sclerouveitis, and orbital pseudotumor. Proptosis
of renal involvement.
is sometimes a feature.13 Involvement of the temporal artery results in
Although it may present in a wide variety of age groups, from infancy to
features (i.e. vision loss, jaw claudication) similar to those seen in temporal
the elderly, it is the middle-aged that are predominantly affected, with a peak
arteritis.14
incidence in the fourth decade.1–4 There is a slight predilection for males (3:2).
Cutaneous manifestations are common, occurring in about 14–50%
In one large study, 97% of patients were Caucasians.5
of patients.15–18 Several different types of skin lesion may be encountered,
Wegener's granulomatosis comprises a triad of characteristics:
including vasculitic lesions with purpura, bruising, and nodule formation
• necrotizing, destructive, granulomatous lesions in the upper respiratory (Figs 16.43–16.45). Pyoderma gangrenosum-like lesions with necrosis
tract (nose, nasal sinuses, nasopharynx, and larynx) and/or in the lower
and ulceration that have a predilection for the lower limbs are sometimes
respiratory tract (trachea, bronchi or lungs); frequently, both are present.
encountered. The presence of skin lesions appears to correlate with disease
Similar lesions may also be found in virtually any organ in the body,
activity. Oral ulceration is common.18,19
• a generalized focal vasculitis occurring in a wide variety of sites, but
particularly affecting the lungs,
• glomerulonephritis.6,7
Early in the disease, when patients may not have developed the full clinical
triad, definitive diagnosis can be difficult or impossible (see Table 16.4).
The most common presenting symptoms relate to involvement of the nose
and nasal sinuses, and include severe and often purulent nasal discharge
or evidence of sinusitis with pain and discharge. Clinical examination may
reveal mucosal ulceration, perforated septum, paranasal sinusitis or a saddle-
nose deformity. Serous or purulent otitis media is occasionally a presenting
feature. Middle and inner ear involvement is also a common manifestation
of disease.8–10
Pulmonary lesions are invariably present and patients may have cough,
chest pain or hemoptysis. Radiological examination frequently reveals solitary
or more commonly multiple nodular opacities, which are often bilateral, may
be diffuse or sharply delineated, and are typically transient. Cavitation is
frequently a feature. Lesions may present as large nodules that are clinically
and radiologically suspicious for malignancy.
Renal involvement is common and urinalysis typically reveals hematuria
(often microscopic), proteinuria, and red cell casts.
Joint involvement may present as arthralgia or, less commonly, frank
arthritis. Fig. 16.43
In one large series, 34% of patients developed neurological involvement.11 Wegener's granulomatosis: multiple purpuric macules and papules. By courtesy of
Peripheral neuropathy was seen in 16%.11 Central nervous system lesions are D. McGibbon, MD, St Thomas' Hospital, London, UK.
674 Vascular diseases
Fig. 16.44
Wegener's granulomatosis: cutaneous nodules as seen in this patient are a not
uncommon manifestation. By courtesy of the Institute of Dermatology, London, UK.
Fig. 16.45
Wegener's granulomatosis: this patient has ulcerating plaques and nodules. By
courtesy of the Institute of Dermatology, London, UK.
In addition to the organ-specific features noted above, patients also often
have a variety of constitutional symptoms, including anorexia, weight loss,
fever, and general malaise.
Two limited forms of Wegener's granulomatosis are recognized: pathergic
granulomatosis and limited pulmonary granulomatosis.20–22
• Pathergic granulomatosis is of particular importance because mucosal and
cutaneous lesions may predominate and persist for very long periods of
time before intractable renal failure develops. In the absence of evidence
of pulmonary and renal involvement, there may be a delay in establishing
the diagnosis and administration of appropriate chemotherapy, with
resultant increased morbidity and mortality. Patients with this variant are
at particular risk of facial mutilation; sites especially involved include the
nose, nasopharynx, sinuses, and middle ears (Fig. 16.46).
• In limited pulmonary granulomatosis patients have respiratory symptoms
with associated fever and weight loss. Radiologically, multiple bilateral
discrete nodular infiltrates and thin-walled cavitating lesions are seen,
usually in the lower lobes. No evidence for renal involvement is present.
Patients with this variant appear to have a somewhat better prognosis
than those with classic (generalized) Wegener's granulomatosis.
A further development is the proposed purely granulomatous Wegener's
granulomatosis (PGWG), in which it has been suggested that the presence
of extravascular granulomata (particularly affecting the ears, nose, throat,
Fig. 16.46
Pathergic granulomatosis: gross necrosis and ulceration have resulted in very
disfiguring tissue damage.
Fig. 16.47
Wegener's granulomatosis: c-ANCA. By courtesy of G. Swana, MD, St Thomas'
Hospital, London, UK.
orbit or lung) in association with a positive serum cytoplasmic-antineutrophil
cytoplasmic antibody (c-ANCA) represents the earliest stage in the evolution
of Wegener's granulomatosis.23 Such a concept, if proven viable, should result
in diagnosis at a stage before the development of more serious multisystem
disease and, hence, earlier treatment.
The vast majority of patients with Wegener's granulomatosis have ANCA
detected in their sera; rising titers have been shown to correlate with disease
activity and are a valuable method of predicting relapse.2,24 Typically, the
indirect immunofluorescence shows a cytoplasmic pattern of staining
(c-ANCA) (Fig. 16.47).1 In the majority (70–80%) of patients with active
disease ANCAs are directed against proteinase 3 (PR3) while ANCAs against
myeloperoxidase (MPO) are detected in approximately 10% of patients.25,26
ANCAs have also been detected in patients with Takayasu's arteritis, Churg-
Strauss syndrome, Kawasaki's arteritis, microscopic polyangiitis, and
idiopathic crescentic glomerulonephritis.24,27,28
Pathogenesis and histological features
This rare disease is thought to represent a hypersensitivity reaction to an as yet
unidentified allergen. Response to immunosuppressive therapy is consistent
with this hypothesis. The presence of ANCAs against PR3 and to a lesser amount
MPO in most patients with Wegener's granulomatosis and the correlation
 Wegener's granulomatosis 675

of circulating levels of ANCAs with disease activity suggest a role in the of the necrotic focus (Fig. 16.49). In addition, the features of an active
pathogenesis of this disease. Additionally, although immune complexes have angiitis are present; this may involve both arteries and veins and frequently
not been demonstrated, disease activity is ameliorated with plasma exchange. has a granulomatous component (Fig. 16.50). The adjacent parenchyma is
Thus, there is compelling anecdotal evidence suggesting ANCAs are central to chronically inflamed and often shows severe, diffuse, interstitial fibrosis.
pathogenesis, most likely through activation of neutrophils, lymphocytes, and Early renal lesions are characterized by focal segmental glomerulonephritis.
macrophages.29 In particular, abnormal numbers and function in regulatory T In more advanced cases the glomerulitis becomes generalized, with fibrinoid
cells (Treg) have been demonstrated in patients with Wegener's granulomatosis necrosis and widespread epithelial crescent formation.43 The renal interstitial
and appear to also correlate with disease activity.30–32 However, the precise tissue may contain necrotizing granulomata, and vasculitis is sometimes
mechanism action of ANCAs is not yet fully understood.29 a feature. Immunofluorescence occasionally reveals granular deposits of
It is postulated that exposure to an antigen (or antigens) may trigger immunoglobulin and complement along the glomerular capillary walls.
ANCAs that have pathophysiological effects leading to tissue destruction.33 This is taken as evidence for possible immune complex involvement. Similar
Infectious agents have received some attention as potentially playing a role granulomata and evidence of vasculitis have been described in all organ
in the pathogenesis of Wegener's granulomatosis. It is interesting to note that systems of the body, but are particularly often seen in the spleen.
relapses of the disease may follow infection.29 In some patients, a complete Cutaneous lesions reveal a variety of features including necrotizing
or partial remission is achieved with antibiotic treatment combined with vasculitis, in which small or medium-sized dermal vessels display fibrinoid
immunosuppressive agents.29,34 Trimethoprim-sulfamethoxazole has also necrosis, a neutrophil polymorphonuclear infiltrate, and nuclear dust (Figs
been used to reduce the frequency of relapses in Wegener's patients.35 Patients 16.51, 16.52). In one series, 80% of biopsies from patients with cutaneous
who are chronic nasal carriers of Staphylococcus aureus seem to have a lesions (of 244 patients in this series, 14% had cutaneous lesions) showed
higher relapse rate compared with noncarriers.36 Furthermore, antibodies leukocytoclastic vasculitis.17 In another study, nearly a third showed
against hepatitis C virus, Epstein-Barr virus, and Helicobacter pylori as leukocytoclastic vasculitis and another third showed non-specific chronic
well as IgG antibodies against Toxoplasma gondii and IgM antibodies
against cytomegalovirus are significantly more common in patients with
Wegener's granulomatosis than in unaffected individuals.37 Gastrointestinal
and renal manifestation correlate well with the presence of IgG antibodies to
cytomegalovirus while otolaryngeal manifestation is more common in patients
with IgG antibodies to the EBV early antigen.37 Despite considerable research
to establish a possible relationship between Wegener's granulomatosis and
infection, a categoric role in the disease is elusive.38
In addition to that for infectious agents, a search for putative roles for
physical agents in the environment has also been undertaken. Perhaps most
attention has focused on silicon compounds.39–41 One case-control study
showed that exposure to silicon-containing compounds conferred a sevenfold
risk for the development of Wegener's granulomatosis.40 It has been postulated
that silica-induced apoptosis of inflammatory cells may release lysosomal
enzymes that stimulate ANCAs.29,39
Pulmonary lesions are characterized by necrotizing granulomatous
inflammation that may bear more than a superficial resemblance to the
caseation of pulmonary tuberculosis (Fig. 16.48).42 The similarity is increased
by the presence of large numbers of Langhans giant cells at the periphery

Fig. 16.49
Wegener's granulomatosis: this lung section shows extensive necrosis associated
with a granulomatous infiltrate containing Langhans giant cells. These appearances
resemble pulmonary tuberculosis.

Fig. 16.48
Wegener's
granulomatosis: this
postmortem lung
specimen shows
consolidation and
numerous abscesses.
By courtesy of B. Corrin, Fig. 16.50
MD, Brompton Hospital, Wegener's granulomatosis: a branch of the pulmonary artery shows necrotizing
London, UK. arteritis with fibrointimal thickening.
676 Vascular diseases
Fig. 16.51
Wegener's granulomatosis: leukocytoclastic vasculitis as shown in this field is the
most frequently encountered cutaneous lesion.
Fig. 16.52
Wegener's granulomatosis: large vessel showing intense chronic inflammation,
thrombosis, and intimal fibrosis.
inflammation.44 In this study, nearly 50% of patients had entirely non-specific
findings. Extravasated red blood cells are invariably present.15,16 In severe
cases, the epidermis may show ischemic necrosis. Bone fide granulomatous
vasculitis of skin appears to be a very rare feature. In fact, one study failed
to demonstrate granulomatous vasculitis in 75 skin biopsies from 46
patients.44 In other patients, there may be granulomatous infiltration of the
dermis, which may be related to foci of collagen necrosis and sometimes
resembles the Churg-Strauss granuloma (Figs 16.53, 16.54). In some cases,
extensive geographic zones of necrosis are present, associated with a mixed
inflammatory cell infiltrate including variable numbers of histiocytes, giant
cells, lymphocytes, eosinophils, and plasma cells. Erythema nodosum and
granuloma annulare-like lesions may also be encountered.44
Differential diagnosis
As mentioned above, early in the course of the disease, when patients may
not have developed the full clinical triad, definitive diagnosis is sometimes
impossible.
In those instances where a granulomatous dermal infiltrate occurs
in the absence of vasculitis, a host of conditions enters the differential
Fig. 16.53
Wegener's granulomatosis: low-power view of a necrotizing dermal granuloma.
Fig. 16.54
Wegener's granulomatosis: high-power view of an ill-defined granuloma.
diagnosis including sarcoidosis and infections, particularly mycobacterial
and fungal. Granulomatous vasculitis may also be seen in association with
lymphoproliferative diseases including lymphoma, angioimmunoblastic
lymphadenopathy, and leukemia.45
Microscopic polyangiitis can be confused with Wegener's granulomatosis.
The presence of granulomatous inflammation in the lung would favor the
latter. Microscopic polyangiitis is approached as a diagnosis of exclusion.
In fact, a diagnosis may be revised as the pattern of clinical involvement
changes. For example, patients that appear to fit criteria for microscopic
polyangiitis may eventually develop manifestation allowing for classification
as Wegener's granulomatosis.46
When granulomata and/or allergic vasculitis are the only features, it
may not be possible to histologically distinguish Wegener's granulomatosis
from the Churg-Strauss syndrome. A high eosinophil content, however, is
somewhat suggestive of the latter condition but certainly not diagnostic, as
this finding may sometimes be seen in Wegener's granulomatosis.44 Therefore,
distinction of Wegener's granulomatosis from other forms of granulomatous
inflammation and leukocytoclastic and granulomatous vasculitis requires
careful clinicopathological and serological correlation.

Allergic granulomatosis with angiitis
Clinical features
Allergic granulomatosis with angiitis (Churg-Strauss syndrome) is a very
rare disease that combines the features of asthma, fever, multisystem
necrotizing vasculitis, extravascular granulomata, and hypereosinophilia.1,2
Although there is clinical overlap, it can be distinguished from polyarteritis
nodosa and Wegener's granulomatosis (Table 16.5). The criteria published
by the Chapel Hill Consensus conference differ somewhat.3 In this scheme,
Churg-Strauss syndrome is defined as ‘eosinophil-rich and granulomatous
inflammation involving the respiratory tract, and necrotizing vasculitis
affecting small to medium-sized arteries, and associated with asthma and
eosinophilia’.3 Given differences in classification criteria, it comes as no
surprise that inconsistencies between these classification schemes exist.4,5
One study found good concordance between classification schemes for the
diagnosis of Wegener's granulomatosis but not Churg-Strauss syndrome.4
As we gain further understanding of this disease, refinement of diagnostic
criteria is likely.
Churg-Strauss syndrome may present in a wide range of age groups,
but most patients are adults, those in the third and fourth decades being
most commonly affected. The disease has a slight male predominance.6–9
Presentation in children is very rare.10–12
Asthma and necrotizing vasculitis are invariably present. Asthma
often precedes the onset of vasculitis, sometimes by many years, or these
features develop simultaneously. In one large study, asthma preceded
definitive diagnosis in 94% of patients.1 Asthma may be associated with
transient pulmonary infiltrates (Loeffler's syndrome) or there can be full-
blown chronic eosinophilic pneumonitis.6 There is some evidence to
suggest that patients in whom vasculitis occurs rapidly after presentation
of asthma have a particularly poor prognosis. It has been suggested that,
in some cases, treatment for allergic rhinitis with steroids suppresses the
full-blown syndrome.13,14 Recently, an association between treatment of
asthma with antileukotrienes and development of Churg-Strauss syndrome
has been suggested.2,15 The association is controversial and what role, if any,
antileukotrienes play in development of disease in these patients is unclear.
However, it has also been proposed that it is the withdrawal of the steroids
and not the administration of antileukotrienes that leads to disease.2 Further
investigation is required to resolve this controversy. Churg-Strauss syndrome
has also been described following treatment with anti-IgE antibodies
(omalizumab) for asthma and may represent unmasking of the disease while
reducing steroid treatment.16
Common manifestations of upper respiratory tract involvement include
allergic rhinitis (which is sometimes associated with polyp formation and
sinusitis) and hay fever. A family history of atopy and allergic reactions to
inhaled antigens and drugs is often present.
Chest radiography frequently confirms the presence of pulmonary
involvement, which takes a variety of forms including transient patchy
infiltrates, discrete noncavitating nodular masses, or diffuse interstitial disease.
Table 16.5
1990 criteria for the classification of Churg–Strauss syndrome (traditional format)*
Criterion No. of CSS patients (n = 20)
Asthma 19
Eosinophilia > 10% 20
Neuropathy (mono or poly) 20
Pulmonary infiltrates, non-fixed 20
Paranasal sinus abnormality 14
Extravascular eosinophils 16
* For classification purposes, a patient shall be said to have Churg-Strauss syndrome (CSS) if at least four of these six criteria are positive. The presence of any four or more of the
six criteria yields a sensitivity of 85% and a specificity of 99.7%.
Reproduced with permission from Masi, A.T. (1990) Arthritis and Rheumatism, 33, 1094–1100.
Allergic granulomatosis with angiitis 677
On CT scan, pulmonary infiltrates may take the form of opacification, nodules,
or bronchial wall and interlobular septal thickening.17 Bronchoalveolar
lavage reveals alveolar eosinophilia.1 Certain patients develop an eosinophil-
rich pleural effusion.1
In addition to pulmonary lesions, systemic involvement most commonly
affects the heart, nervous system, gut, and kidneys.6 Cardiac lesions may
be a cause of dysrhythmia or sudden death. Cardiac manifestations also
include valvulopathy, ventricular insufficiency, global cardiac insufficiency,
and endomyocarditis.1,18–20 Pericardial effusion was seen in 23% of patients
in one study.1 Complications relating to cardiac involvement are the most
common cause of death in patients with Churg-Strauss syndrome. Nearly
40% of deaths are due to cardiac involvement.1
Neurological manifestations are frequent, particularly mononeuritis
multiplex and symmetric polyneuropathy.21,22 In one large study, 72% of
patients developed mononeuritis multiplex.1,23 Intracerebral hemorrhage
or infarction sometimes develops.21 Ischemic optic and bilateral trigeminal
neuropathy are rare complications.22 Myalgia, epilepsy, hydrocephalus,
chorea, and vertigo are further occasional features.24
Evidence of gastrointestinal involvement, such as nausea, bleeding,
vomiting, and abdominal pain, is often found. In one study, one-third of
patients experienced gastrointestinal symptoms, usually abdominal pain.1
Diffuse bowel ischemia is an uncommon but serious complication.1
Renal disease in Churg-Strauss syndrome is usually manifest as
glomerulonephritis, most often a focal segmental glomerulonephritis.1,25
Patients with renal involvement show hematuria, proteinuria, and increased
creatinine.1 Renal infarction appears to be a rare complication.1
Rheumatological involvement in the form of polyarthralgia and consti­
tutional symptoms, including fever, anemia, and weight loss, is common.1
Amyloidosis is a rare complication.26,27 Exceptionally, Churg-Strauss
syndrome may present with temporal nongiant cell arteritis.28 Involvement of
the breast occurs exceptionally as eosinophilic mastitis.29 A limited form of
the disease has been described.30,31
Cutaneous lesions are seen in 40–70% of patients and include petechiae,
purpura, papules, vesicles, facial erythema, urticaria, and ulceration.32–37
Cutaneous infarction and bullae are less common manifestations.35,38 Livedo
reticularis involving the lower limbs is occasionally a feature. Patients may
also develop tender nodules, which particularly affect the extensor aspects of
the arms, legs, hands, and feet (Fig. 16.55). The sacrum, buttocks, and scalp
can also be involved. The cutaneous lesions tend to appear in crops with
spontaneous relapses and remissions.
Churg-Strauss syndrome has been seen in association with HIV infection,
hepatitis B, Wells' syndrome, and bronchopulmonary candidiasis.39–42 The
disease has also been described in association with drugs including fluticasone
and cocaine.43,44
Laboratory investigation usually reveals leukocytosis and a raised ESR in
association with peripheral blood eosinophilia.35 Blood eosinophilia often
decreases with treatment but some authors stress that such a response should
not be taken as evidence that disease activity is under control.45 ANCAs are
demonstrated in many patients (see below).
Sensitivity (%) No. of control patients (n = 787) Specificity (%)
100 782 96.3
95 708 96.6
75 781 79.8
40 736 92.4
85.7 366 79.3
81.3 385 84.4
678 Vascular diseases

Fig. 16.55
Churg-Strauss syndrome: this patient presented with painful nodules on the limbs. Fig. 16.56
By courtesy of the Institute of Dermatology, London, UK. Churg-Strauss syndrome:
this early lesion shows
a swollen collagen fiber
Pathogenesis and histological features in the superficial dermis.
Note the surrounding
The etiology and pathogenesis of Churg-Strauss syndrome is poorly multinucleate giant cells.
understood. The presence of perinuclear-antineutrophil cytoplasmic
antibodies (p-ANCA) in many patients is of considerable interest.46–49
ANCAs are detected in approximately 40% of patients.50–52 The ANCAs
seen in these patients usually target myeloperoxidase.52 However, the various
types of ANCA are non-specific, being present in a spectrum of disease.53
Their presence is associated with higher risk of developing renal disease and
peripheral neuropathy, while absence of ANCAs is linked to heart disease
and fever.51,52,54 ANCAs may activate neutrophils, causing degranulation and
vascular injury.55 T lymphocytes can also be stimulated, leading to endothelial
cell injury.55 As with other ANCA-associated vasculitides, it is suspected that
they play a role in the pathogenesis of Churg-Strauss syndrome; however,
the precise mechanism, particularly triggering factors, is not yet known.
Persistence of ANCAs with therapy may be of limited value in making
treatment decisions.56 One group has found that, although there is poor
correlation between ANCA titer and disease activity, disappearance of ANCA
can reflect absent disease activity.57
Pulmonary lesions comprise variably sized (up to 1.5 cm) nodules, ranging
from only a few lesions to hundreds which may coalesce. Histologically,
they are composed of granulomata with central necrosis and surrounding
epithelioid histiocytes with occasional giant cells. Large numbers of
eosinophils with an admixture of lymphocytes, neutrophils, plasma cells, and Fig. 16.57
Churg-Strauss syndrome: medium-power view showing swelling of the dermal
histiocytes infiltrate the adjacent lung parenchyma. Vasculitis involving small
collagen fibers and a perivascular chronic inflammatory cell infiltrate.
arteries and sometimes veins is also present.
Cutaneous lesions are variable. A common feature is the so-called ‘Churg-
Strauss (extravascular) granuloma’. Early lesions are characterized by focal Differential diagnosis
collagen degeneration in association with a varying and mixed inflammatory The histological features encountered in skin biopsies of patients with
cell infiltrate comprising neutrophils, lymphocytes, and histiocytes (Figs Churg-Strauss syndrome are not diagnostic. Careful clinicopathological and
16.56, 16.57). Eosinophils may be sparse or numerous. Leukocytoclasis is serological evaluation is necessary to establish a definitive diagnosis. Although
often a feature. In more advanced examples the granuloma is more mature Churg-Strauss syndrome, polyarteritis nodosa, and Wegener's granulomatosis
in appearance, consisting of a central zone of collagen necrosis surrounded show both clinical and histological overlap, research over the last several
by a peripheral palisade of epithelioid and giant cells (Figs. 16.58,16.59). decades leaves no doubt that they represent distinctive entities. Nonetheless,
In some examples, the features are those of a rather diffuse and ill-defined they form a spectrum of disease with similar pathogenesis, although there are
granulomatous inflammatory process without obvious collagen degeneration. sufficient differences to justify their separate classification:
Commonly, features of necrotizing vasculitis are evident: fibrinoid necrosis • Asthma may be seen in both polyarteritis nodosa and Churg-Strauss
accompanied by an eosinophilic and neutrophilic infiltrate with leukocytoclasis syndrome, but characteristically polyarteritis affects medium-sized and
involving the more superficial small blood vessels (Fig. 16.60). There may small arteries, while Churg-Strauss syndrome typically affects small
be epidermal ischemic necrosis. In one study, 16 of 37 biopsies (taken from arteries and veins.
29 patients) showed leukocytoclastic vasculitis.34 Occasionally, the arteries • The neutrophil dominates the inflammatory cell infiltrate in polyarteritis
in the dermis and subcutaneous fat show changes similar to those seen in nodosa, whereas in Churg-Strauss syndrome it is the eosinophil.
polyarteritis nodosa.35 Additionally, acute and chronic panniculitis with • Necrotizing extravascular granulomata are not a feature of polyarteritis
eosinophils has been described.35 nodosa.
 Mucocutaneous lymph node syndrome 679

Fig. 16.58
Churg-Strauss syndrome: in this field there is a more obvious granulomatous infiltrate.

Fig. 16.60
Churg-Strauss syndrome:
the features of small-
vessel leukocytoclastic
vasculitis are evident.

by both endemic and epidemic variants.4 The incidence among Japanese

children is 16–150/100 000/ year whereas in white children the incidence is
6–10/100 000/year.4,6 The incidence of reported disease in the United States
is rising but has been attributed to increased physician awareness.7,8 The
syndrome shows a male predominance and occurs most frequently in children
aged 6–18 months.9 Adults are only rarely affected.10–12 Kawasaki syndrome
is thought to have an infectious etiology on the basis of symptoms of fever
and exanthem, age distribution, seasonality (peaks in winter and spring), and
occurrence of community-wide epidemics.13

Fig. 16.59
Churg-Strauss syndrome: this florid example shows a granulomatous infiltrate
containing prominent giant cells. By courtesy of E. Wilson Jones, MD, Institute of
Dermatology, London, UK.
Clinical features
The diagnostic features of Kawasaki syndrome are summarized in Table 16.6
and include:
• a spiking fever unresponsive to antibiotic therapy,
• an erythematous polymorphic cutaneous eruption (Fig. 16.61),
• erythema, edema, and induration of the extremities followed by
cutaneous desquamation of the tips of the fingers and toes (Fig. 16.62),

• Patients with Wegener's granulomatosis present with ulceroproliferative

lesions of the upper respiratory tract, chest pain, and hemoptysis rather
Table 16.6
than asthma.
Kawasaki syndrome: diagnostic guidelines
• Marked eosinophilia is uncommon in Wegener's granulomatosis.
Churg-Strauss granulomata may be seen in Wegener's granulomatosis; •  Fever lasting ≥ 5 days plus
however, the necrosis is more often of the tuberculocoagulative type. •  Polymorphous rash
Granulomatous vasculitis is not a feature of Churg-Strauss syndrome. •  Bilaterial conjunctival injection
It must be stressed that Churg-Straus granulomata should not be taken as •  At least one of the following changes of the mucosal membranes:
pathognomonic for Churg-Strauss syndrome. Churg-Strauss granulomata, or –  erythema or fissuring of the lips
–  strawberry tongue
nearly identical lesions, have been described in the setting of other systemic
–  diffuse injection of oral and pharyngeal mucosa
diseases including rheumatoid arthritis, lupus erythematosus, other forms
of vasculitis (Wegener's granulomatosis, polyarteritis nodosa, Takayasu's •  Acute non-purulent cervical lymphadenopathy (at least one node
arteritis), lymphoproliferative disorders, Crohn's disease and ulcerative ≥ 1.5 cm)
colitis, bacterial endocarditis, and hepatitis.35,58–62 •  At least one of the following changes of the peripheral extremities:
–  erythema of palms and soles
–  indurative edema of hands and feet
Mucocutaneous lymph node syndrome –  membranous desquamation from fingertips

Mucocutaneous lymph node syndrome (Kawasaki syndrome) is a multisystem
disease that predominantly affects infants and young children.1–5 Although it
was first described, and shows a marked preponderance, in Japan, it has been
diagnosed worldwide and in all races. Kawasaki syndrome is characterized
Fever plus four of the above criteria must be present for a secure diagnosis; other
illness that can present with similar clinical findings must be excluded.
Reproduced with permission from Wortman, D.W. (1992) Seminars in Dermatology, 11,
37–47.
680 Vascular diseases
Fig. 16.61
Kawasaki syndrome: erythematous macular eruption. By courtesy of W.G. Phillips,
MD, Institute of Dermatology, London, UK.
Fig. 16.62
Kawasaki syndrome:
desquamation of the
skin of the toes is a
characteristic finding.
By courtesy of J. Ross,
MD, Lewisham Hospital,
London, UK.
• oropharyngeal mucosal changes including edema, erythema, and fissuring
of the lips, erythema of the cheeks, and a strawberry (scarletiform)
tongue (Figs 16.63, 16.64),
• bilateral, nonexudative conjunctivitis,
• nonsuppurative cervical lymphadenopathy.
In an appropriate clinical context, children are judged to have Kawasaki
syndrome if they show a high fever plus four of the signs described above.4,14
More recently, this has been amended to include coronary artery aneurysm
plus three of the above features.4
The cutaneous findings are variable and include erythematous, macular,
maculopapular (morbilliform), urticarial, pustular, erythema multiforme-
like (targetoid), and erythema marginatum-like lesions.2,15 A vesiculopustular
eruption has also been reported.16 The skin lesions show a propensity for the
trunk and extremities, but may be more generalized. A diffuse, erythematous
macular or plaquelike eruption involving the perineum is said to be
characteristic.5 This can be pruritic or painful and typically desquamates.
Fig. 16.63
Kawasaki syndrome: the lips are erythematous and swollen. Angular cheilitis is
evident. By courtesy of J. Ross, MD, Lewisham Hospital, London, UK.
Fig. 16.64
Kawasaki syndrome: the tongue shows intense erythema. By courtesy of J. Ross,
MD, Lewisham Hospital, London, UK.
Cervical lymphadenopathy affects 50–75% of patients and may be
unilateral or bilateral and involves one or a group of nodes.
Cardiovascular involvement is characteristic and is the most important
cause of morbidity and mortality.2 Some 50% of patients show evidence of
myocarditis, which may progress to congestive cardiac failure. Pericardial
effusion (subclinical) is not uncommon. Of particular significance is the
development of coronary artery ectasia or aneurysm, a feature that develops
in 15–25% of patients, which may be complicated by coronary artery
ischemia, thrombosis, and infarction. In 2% of patients, it proves fatal.12
In a very large follow-up study of 594 patients, the incidence of coronary
artery aneurysm was 25%.17 Angiographic evidence of regression was seen
in 55% of patients.17 There is an inverse relationship between the size of
the aneurysm and the likelihood of resolution: large aneurysms, especially
giant aneurysms (defined as greater than 8.0 mm), tend to persist, or become
obstructed or stenotic.18
Gastrointestinal involvement presents as abdominal pain, vomiting,
and diarrhea. Liver lesions may result in abnormal liver function tests and,
less often, jaundice. Pancreatitis and hydrops of the gallbladder are seen in
approximately 10% of patients.2
Neurological symptoms develop in about 30% of patients and include
features of aseptic meningitis, seizures, and transient paralyses.2 Arthralgias

Fig. 16.65
Kawasaki syndrome:
disease in an adult is
very rare. In this patient,
the erythema particularly
affects the buttocks
and thighs. By courtesy
of W.G. Phillips, MD,
Institute of Dermatology,
London, UK.
and arthritis are present in up to 30–40%, although chronicity is not a
feature. Renal involvement manifests as sterile pyuria, hematuria, and
infarction.
The features of adult Kawasaki syndrome are essentially those described
above and are illustrated in Figure 16.65. Coronary artery aneurysm,
however, appears to be a less common complication.10 It is important to
differentiate this condition from staphylococcal toxic shock syndrome.19
Occasionally, patients develop a relapse, which may occur years after
initial disease and resolution.20
Pathogenesis and histological features
The etiology of this disease is unknown. Recent evidence points to an
immunoregulatory defect of T cells stimulated by superantigen-producing
strains of Streptococcus pyogenes and Staphylococcus aureus.19,21,22
Superantigens are a class of microbial antigens that are thought to be capable
of stimulating a large number of naive T cells in a non-specific manner by
binding to histocompatibility antigens on antigen-presenting cells leading to
T-cell activation. Superantigens have been postulated to play a role in the
pathogenesis of a number of skin diseases in addition to Kawasaki syndrome,
such as atopic dermatitis, psoriasis and toxic shock syndrome. However, in
one study, superantigen-producing bacteria were found in 56% of cultures
(taken from throat, rectum, and groin) from patients with Kawasaki syndrome
compared with 35% of controls with positive culture.23 These differences did
not achieve statistical significance. Another study found strains of streptococci
and staphylococci in the jejunum of patients with Kawasaki syndrome but
not in controls.24 These same authors, in a follow-up study, found V beta
2+ T cells selectively increased in small bowel mucosa of Kawasaki patients
compared with control subjects.25 Clearly, further research is necessary to
elucidate the precise pathogenesis of Kawasaki disease.
Other infectious agents that have been implicated in the pathogenesis
of Kawasaki disease include retroviruses, rickettsiae, spirochetes and
Propionibacterium acnes.5,26 Additionally favored hypotheses include
exposure to house mites and recently cleaned or shampooed carpet, living in
close proximity to open water or complicating a recent respiratory illness.13 It
is possible that Kawasaki syndrome represents a vasculitic disorder developing
as a consequence of multiple infectious agents.
Of interest, there is a growing body of literature reporting Kawasaki
disease, or a Kawasaki-like syndrome, in patients infected with the human
immunodeficiency virus.27–29
Granuloma faciale 681
Fig. 16.66
Kawasaki syndrome: in this example, the features of severe, acute leukocytoclastic
vasculitis are present in the superficial dermis. This is an uncommon finding. By
courtesy of W.G. Phillips, MD, Institute of Dermatology, London, UK.
The histopathological features of cutaneous lesions in Kawasaki disease
are often non-specific and comprise severe edema of the papillary dermis
accompanied by vascular dilatation, endothelial cell swelling and degeneration
associated with a superficial perivascular mononuclear infiltrate.5 Immuno­
pathological studies have shown the infiltrate is usually composed of CD4+
T lymphocytes and macrophages.30 Occasionally, however, the features of a
leukocytoclastic vasculitis are evident (Fig. 16.66). The epidermis may show
mild basal cell degeneration.5 Vesiculopustular lesions develop on the basis of
subcorneal spongiform pustulation.9
Systemic lesions are characterized by necrotizing vasculitis.19,31,32 Aneurysm
with mural thrombus formation may be evident in advanced lesions.
Lymph node involvement includes vasculitis, focal necrosis, and
infarction.
Differential diagnosis
The mucocutaneous manifestations of Kawasaki disease show considerable
overlap with those seen in the toxic shock syndrome, which is not surprising,
given that they appear to share a similar pathogenesis. Palmoplantar
erythema, cutaneous desquamation, conjunctivitis, and pharyngitis are
therefore common to both.33 The toxic shock syndrome (which is due to a
staphylococcal exotoxin complicating constant tampon use in menstruating
females) is, however, not associated with systemic vascular involvement.
Histologically, it is characterized by a mild, superficial, perivascular
lymphocytic infiltrate associated with edema of the papillary dermis and no
evidence of vasculitis.34
Granuloma faciale
Clinical features
Granuloma faciale is a localized form of leukocytoclastic vasculitis of
uncertain pathogenesis. Although children may be affected, most cases occur
in people who are middle aged or older. There is predilections for males.1
Lesions occur most commonly on the face and are single or more often
multiple, erythematous or brownish red, soft discrete papules, plaques or
nodules up to several centimeters in diameter (Fig. 16.67).2–4 The surface
often shows dilated follicles and fine telangiectasia (Fig. 16.68). Common
sites include the nose, malar prominence, forehead, and ear (Fig. 16.69).
A case simulating rhinophyma has been documented.5 Extrafacial lesions may
occur on the extremities, neck, chest, and scalp (Fig. 16.70).1,6–13 Although
often asymptomatic, patients sometimes report symptoms of mild pruritus or
stinging. There is no evidence of associated systemic involvement. Granuloma
faciale tends to chronicity and is typified by periods of relapse and partial
682 Vascular diseases
Fig. 16.67
Granuloma faciale: multiple brown nodules. From the collection of the late N.P.
Smith, MD, the Institute of Dermatology, London, UK.
Fig. 16.68
Granuloma faciale: the
face is a commonly
affected site. From the
collection of the late N.P.
Smith, MD, the Institute
of Dermatology, London,
UK.
remissions. Treatment is very difficult and recurrences manifest after surgical
excision, even at the site of full-thickness grafting.14
A histologically similar lesion affecting the mucosa of the upper respiratory
tract has been designated ‘eosinophilic angiocentric fibrosis’. Concurrent
cases of granuloma faciale and eosinophilic angiocentric fibrosis have been
described.15–17 This suggests that the two diseases represent part of the same
spectrum.
Granuloma faciale has been documented in a patient with prostate
carcinoma.18 Any relationship with tumors is likely to be coincidental.
Pathogenesis and histological features
Examination of lesional biopsies by immunofluorescence reveals granular
IgG and complement along the epidermal–dermal junction, outlining the
hair follicles, and also within the walls of blood vessels; less often IgA
and IgM are present, and there is abundant fibrin.19–21 Granuloma faciale
is, therefore, a chronic vasculitis and may be immune complex mediated.
However, some authors consider the above immunofluorescence findings
Fig. 16.69
Granuloma faciale: the
lesions are frequently
multiple. By courtesy of K.
Liddell, MD, Eastbourne
District Hospital, East
Sussex, UK.
Fig. 16.70
Granuloma faciale: there are multiple lesions on this patient's neck. By courtesy of
the Institute of Dermatology, London, UK.
non-specific. Immunohistochemistry shows the presence of abundant
eosinophilic cationic protein.22 T-helper lymphocytes represent the main
nonmyelocytic cell in the infiltrate and it has been suggested that they play a
role in the pathogenesis of the disease, being attracted to the site by gamma-
interferon.23
Histologically, granuloma faciale is characterized by a dense cellular
infiltrate, which often has a nodular outline (Fig. 16.71).24 This infiltrate
usually occupies the mid dermis, although the deep dermis and the subcutaneous
fat may be involved; it typically spares the immediate subepidermis and hair
follicles, forming a ‘grenz zone’ (Fig. 16.72). The infiltrate is polymorphic,
being composed of large numbers of eosinophils, neutrophils (often displaying
leukocytoclasis), and an admixture of plasma cells, mast cells, and lymphocytes
(Fig. 16.73).25 Red cell extravasation is often present. Blood vessels, which
often appear increased in number, are dilated and may show infiltration of
their walls by eosinophils with fibrin deposition (Fig 16.74). Diagnostic
features of vasculitis, namely inflammation of vessel walls associated with

Fig. 16.71
Granuloma faciale: a dense inflammatory cell infiltrate is present in the dermis.
Note the conspicuously spared grenz zone.
Fig. 16.72
Granuloma faciale: close-up view of grenz zone.
Fig. 16.73
Granuloma faciale: the infiltrate contains large numbers of eosinophils as well as
lymphocytes, histiocytes, and occasional polymorphs and plasma cells.
Granuloma faciale 683
Fig. 16.74
Granuloma faciale: this dilated blood vessel shows marked endothelial swelling,
fibrin deposition, and disruption of its wall.
Fig. 16.75
Granuloma faciale: there is a well-developed storiform pattern.
fibrinoid change, may be difficult to identify in some lesions. In other cases,
fibrin is widely distributed in the dermis. Older lesions may show fibrosis and
hemosiderin deposition.1 The microscopic picture in late stages overlaps with
that seen in erythema elevatum diutinum (Fig 16.75).1
An ultrastructural study of a case of granuloma faciale has shown that the
cytoplasmic granules in the eosinophils display alterations and Langerhans
cells are absent.26
Differential diagnosis
The morphological features of granuloma faciale are distinctive. The presence
of a mixed infiltrate with a grenz zone distinguishes it from neutrophilic
dermatoses and leukocytoclastic vasculitis. Erythema elevatum diutinum,
another form of localized vasculitis, tends to be located on the extensor
surfaces of the extremities and shows more sclerosis, more neutrophils,
and fewer eosinophils. The presence of large numbers of eosinophils may
raise the possibility of a Langerhans cell proliferative disorder; however, the
presence of only scattered Langerhans cells and a grenz zone (Langerhans cell
proliferative disorders tend to be epidermotropic) with significant numbers of
neutrophils favors granuloma faciale. The grenz zone also helps to distinguish
granuloma faciale from hypersensitivity reactions such as to an arthropod
bite. Angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma)
is distinguished by the presence of highly unusual thick-walled blood vessels
684 Vascular diseases
with prominent endothelial cells. An exceptional case of infection by
Trichophyton rubrum with histology mimicking that of granuloma faciale
has been documented.27
Histological features identical to those of granuloma faciale may be seen
in patients presenting with a solitary lesion (papule, nodule or plaque) that
does not have the clinical appearance or location typical of the disease. The
histological picture in these cases has been described as chronic fibrosing
vasculitis. As there is also histological overlap with erythema elevatum
diutinum, it has been suggested that the microscopic appearances represent
a non-specific inflammatory reaction pattern.28 Therefore, establishing the
diagnosis requires close clinicopathological correlation.
Erythema elevatum diutinum
Clinical features
This uncommon disease represents a localized variant of leukocytoclastic
vasculitis.1–3 Although it can occur in any age group, patients are usually in
their third to fifth decade.4 Incidence is equal in men and women. Patients
present with papules and nodules measuring up to about 1 cm in diameter;
they may also develop round or oval, indurated, elevated plaques 5–6 cm in
diameter. Lesions are red or purple, although some have a yellowish tinge,
which may be confused with a xanthomatous process. Bullous lesions are
occasionally present and an annular distribution has been reported.1,5,6 The
disease is characteristically persistent and the distribution of the lesions often
symmetrical. Large nodules resembling keloids or tumor are sometimes
found.7,8
Lesions are located particularly in relation to the extensor surfaces of the
joints and are, therefore, seen on the backs of the hands and fingers, wrists,
elbows, knees, ankles, and toes (Figs 16.76, 16.77). The buttocks may also
be affected, but the trunk is usually spared.9 We have observed a case with
oral involvement. Although lesions are often asymptomatic, some patients
complain of itching and pain, and symptoms are frequently made worse in a
cold environment. Patients sometimes also have arthralgia. Eye involvement
includes keratolysis and ulcerative keratitis with positive rheumatoid
factor.10,11 Although the disease is chronic and progressive, resolution usually
occurs by 5–10 years. The disease characteristically responds to dapsone.
Systemic involvement does not usually occur but pulmonary infiltrates
have exceptionally been documented.12
Fig. 16.76
Erythema elevatum
diutinum: tuberose
nodules present on the
elbow. From the collection
of the late N.P. Smith,
MD, the Institute of
Dermatology, London, UK.
Fig. 16.77
Erythema elevatum diutinum: the extensor surfaces are commonly affected. From
the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
An association with paraproteinemia is frequently present, often of the
IgA subtype.1,13,14 Hyperimmunoglobulinemia D syndrome is a further rare
association.15 An underlying myelodysplastic syndrome or a hematological
malignancy (e.g. multiple myeloma, B cell lymphoma, and chronic
lymphocytic leukemia) has been found in some patients.1,16–19 Often, the skin
lesions precede development of the hematological disorder.1 In one study, an
average of 7.8 years separated onset of skin lesions and development of a
myeloproliferative disorder.1,20
Erythema elevatum diutinum has rarely also been associated with other
malignancies such as pulmonary lymphoepithelioma-like carcinoma and
breast carcinoma.21,22
Inflammatory bowel disease – both Crohn's disease and ulcerative colitis –
has also been associated with erythema elevatum diutinum.23–25 Interestingly,
in one patient with Crohn's disease, skin lesions seemed to appear during
exacerbation of bowel symptoms.23 In another patient with ulcerative colitis,
onset of erythema elevatum diutinum lesions coincided with presentation of
bowel disease, and skin lesions resolved following colectomy.24 Erythema
elevatum diutinum has also been reported in association with celiac
disease.26–28 In one patient with celiac disease, skin lesions resolved with the
introduction of a gluten-free diet.27
Rheumatoid arthritis has been described in conjunction with erythema
elevatum diutinum.29–31 Other reported associations include Wegener's
granulomatosis, relapsing polychondritis and pyoderma gangrenosum,
cutaneous lupus erythematosus, nodular scleritis and panuveitis, Hashimoto's
thyroiditis, juvenile idiopathic arthritis, and Sjögren's syndrome.32–40 Erythema
elevatum diutinum is also seen in patients with HIV infection.41–46 In HIV-
infected patients, lesions may mimic Kaposi's sarcoma.41 Extensive acro-
osteolysis has been described in a single case.47 The exceptional association
with pityriasis rubra pilaris and mosquito bites is probably coincidental.48
A condition described as ‘neutrophilic dermatosis of the dorsal hands’ is
likely to be part of the spectrum of erythema elevatum diutinum.49
Pathogenesis and histological features
Erythema elevatum diutinum is possibly immune complex mediated. Both
a streptococcal antigen and Escherichia coli have been implicated.2,50 As
mentioned above, the disease has also been recorded in association with
cryoglobulin IgA, monoclonal or biclonal gammopathy, multiple myeloma,
hairy cell leukemia, and polycythemia rubra vera.1,51–53 In addition, IgA
antineutrophil cytoplasmic antibodies (ANCA) and less frequently IgG ANCA
have been identified in patient's serum.54 In early lesions, there is increased
expression of the beta (2)-integrins CR3 and LFA-1 and this diminishes in
older lesions.55 Peripheral blood neutrophils show increased migration in
response to interleukin-8 (IL-8) and decreased responsiveness to the bacterial
peptide analogue N-formyl-methionyl-leucyl-phenylalanine. These findings
 Erythema elevatum diutinum 685

Fig. 16.78
Erythema elevatum
diutinum: early lesion
showing leukocytoclastic
vasculitis in a background
of a Sweet's syndrome-
like neutrophil infiltrate.
suggest that in erythema elevatum diutinum the recruitment of neutrophils
occurs as a result of activation of cytokines such as IL-8.55 Immune complexes
and bacterial peptides sustain the persistent local inflammatory response.55
Biopsy of early lesions reveals typical features of leukocytoclastic vasculitis
(Fig. 16.78).1,56 The epidermis may show acanthosis and parakeratosis.
Fibrinoid necrosis and infiltration of the superficial vessels by neutrophil
polymorphs are present. The perivenular connective tissue contains abundant
fibrin and a dense inflammatory cell infiltrate of neutrophils, histiocytes,
lymphocytes, and eosinophils. Leukocytoclasis is usually evident.
Older lesions are characterized by the development of granulation tissue
and fibrous scarring, although even then, foci of neutrophilic vasculitis may
Fig. 16.79
Erythema elevatum diutinum: older lesion showing scar tissue with a vaguely
storiform growth pattern.
be found after examination of multiple sections (Fig. 16.79). In ‘burnt out’
lesions, vasculitis may not be present. Granulation tissue and dense scarring
mark the site of the previous acute inflammatory process. In older lesions
the scarring often shows a storiform pattern (Fig. 16.80). Interstitial lipid
deposition described in the past as extracellular cholesterolosis is uncommon.
In ocular lesions, leukocytoclastic vasculitis with focal granulomatous
inflammation has been described.11
Rare histopathological features described include palisaded necrotizing
granuloma and pyogenic granuloma-like features.48
Differential diagnosis
Erythema elevatum diutinum typically involves the dermis and must,
therefore, be distinguished from granuloma faciale. Granuloma faciale
usually shows an eosinophil predominance whereas in erythema elevatum
diutinum neutrophils are much more numerous. However, the histological

Fig. 16.80
(A, B) Erythema elevatum diutinum: this example was clinically thought to
represent a keloid. There is a circumscribed dermal nodule composed of spindle
A cells in a hyalinized stroma. Focally perivascular nuclear debris is evident and
there are scattered eosinophils.
686 Vascular diseases

features of late lesions in both entities often overlap and similar appearances Table 16.8
are found in chronic fibrosing vasculitis. The latter represents a non-specific Behçet's disease: diagnostic criteria*
reaction pattern that is occasionally seen in solitary lesions from patients who
have no clinical features of either granuloma faciale or erythema elevatum Criterion Definition
diutinum.57 Distinction from Sweet's syndrome is afforded by the presence of Recurrent oral Minor aphthous, major aphthous, or
neutrophilic vasculitis. Older sclerotic lesions, particularly when they present ulceration herpetiform ulceration observed by physician
as mass lesions, may be mistaken for a neoplastic process or dermatofibroma.8 or patient, and recurrent at least three times
The presence of a leukocytoclastic vasculitis and neutrophilic infiltrate with in one 12-month period
karyorrhexis favors erythema elevatum diutinum. Plus two of:
Recurrent genital Aphthous ulceration or scarring, observed by
Behçet's disease ulceration physician or patient
Eye lesions Anterior uveitis, posterior uveitis or cells in
Clinical features vitreous on slit lamp examination
This rare disease was originally described as a combination of recurrent oral or
Retinal vasculitis observed by
and genital ulceration associated with uveitis. However, it is now known
ophthalmologist
to represent a systemic illness with lesions involving the joints and central
nervous, vascular, respiratory, gastrointestinal, and urogenital systems, in Skin lesions Erythema nodosum observed by physician or
addition to mucous membranes and integument (Table 16.7).1–7 Although it patient, pseudofolliculitis or papulopustular
lesions; or acneiform nodules observed
is seen worldwide, it has a high incidence in Japan, Southeast Asia, the Middle
by physician, patient not on corticosteroid
East, Turkey, and some countries bordering the Mediterranean. Behçet's treatment
disease shows a male predominance and most commonly presents in young
adults with a peak incidence of onset in the third decade.8 Children may Positive pathergy test Read by physician at 24–48 hours
also be affected with an approximately equal sex incidence.9 One study has * Findings applicable only in the absence of other clinical explanations.
suggested that the disease is less aggressive in children.10 Some data appear to Reprinted with permission from Elsevier (International Study Group for Behçet's
indicate that males have a higher mortality rate.11 Disease (1990) Lancet, 335, 1078–1080).
The International Study Group established diagnostic criteria for Behçet's
disease in 1990 and these are summarized in Table 16.8.4 It should be kept
in mind that these criteria are somewhat controversial.12 More research is
necessary before we can fully understand this complex disease.
Recurrent oral ulceration is an invariable feature. Some patients have a
long history of oral ulceration before developing other features that allow
for a definitive diagnosis of Behçet's disease. Ulcers typically measure up to
1 cm across but may be larger. They develop anywhere in the oral cavity,
in the pharynx, and even in the larynx (Fig. 16.81).13 They are exquisitely
painful, and usually regress spontaneously within 14 days although they can
persist for much longer. A yellow, necrotic crust covers the ulcer floor. Some
patients develop ulcerations in a herpetiform configuration.14 Patients with
larger ulcers tend to have greater severity of oral disease with more frequent
relapses.14
Cutaneous lesions are common, recurrent, and comprise a wide variety of
manifestations including erythema nodosum-like lesions, usually on the lower
extremities.15,16 Patients may also develop acneiform papules and pustules,
furuncles, pyoderma, and thrombophlebitis (Fig. 16.82). In one very large
study, papulopustular lesions (followed by erythema nodosum-like nodules)
were the most commonly encountered skin manifestation.7 Patients have also
been described with Sweet's syndrome-like features.17
Fig. 16.81
Behçet's disease: superficial ulcers are present on the inner aspect of both lips. By
Table 16.7 courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Behçet's disease: frequency of organ involvement

Typical of Behçet's disease, and an important diagnostic clue, is

Sign or symptom Incidence (%) development of sterile pustules at sites of mild skin trauma such as injection
Oral ulcers 90–100 sites (pathergic response) (Fig. 16.83).18,19 Paradoxically, some authors have
Genital ulcers 64–88 found that wound healing after 4 mm punch biopsy does not seem to differ
compared with control subjects.20
Ocular lesions 27–90
Genital lesions, similar in appearance to those of the oral mucosa, occur
Cutaneous lesions 48–88 on the scrotum, penis, vagina, and vulva (Figs 16.84, 16.85).7
Joint manifestations 18–64 Ocular involvement is important because, if left untreated, it may
Neurological features 10–29
progress to cataracts and blindness. Both eyes are affected in the majority of
patients. Almost any part of the eye is affected and bilateral inflammation
Intestinal manifestations 0–59 of the anterior segment (anterior uveitis), posterior uveitis with hypopyon
Thrombophlebitis 10–37 and vitritis are said to be pathognomonic.21,22 Uveitis is more common and
is associated with a more severe clinical course in males potentially leading
Reproduced with permission from Arbesfield, S.J. and Kurban, A.K. (1988) Journal
to loss of vision.22 Conjunctivitis, corneal ulceration, choroiditis, and retinal
of the American Academy of Dermatology, 19, 767–779. Copyright © The American
Academy of Dermatology, Inc. vessel involvement (arterial and venous vasculitis) are sometimes additional
features.
 Behçet's disease 687

Fig. 16.82
Behçet's disease: typical pustules on the lower leg. By courtesy of R.A. Marsden, Fig. 16.84
MD, St George's Hospital, London, UK. Behçet's disease: there
is a typical scrotal ulcer
with central slough. By
courtesy of D.A.H. Yates,
MD, St Thomas' Hospital,
London, UK.

Fig. 16.83
Behçet's disease: this ruptured pustule developed at the site of a previous
venipuncture. Such a positive provocation test is virtually pathognomonic for Behçet's
disease. By courtesy of D.A.H. Yates, MD, St Thomas' Hospital, London, UK.

Joint involvement is not uncommon and usually affects the knees, ankles,
elbows, and wrists.23 A mono- or oligoarticular pattern is typical. The affected
joints are swollen, red, tender, and painful. It is of interest that despite many
years of arthritic symptoms, joint deformities do not develop.
Vascular disease in Behçet's disease takes the form of both thrombo-
occlusive disease and frank vasculitis. Vascular involvement is an important
cause of both morbidity and mortality and is seen in approximately one-third
of patients.24,25 Males appear to be at an increased risk.25 Thrombophlebitis is
common and can affect both superficial and deep veins of the limbs. Superior
and inferior vena caval obstruction are not uncommon complications. A
particularly perilous form of vascular involvement is hepatic vein occlusion
(Budd-Chiari syndrome), which is associated with a high mortality.26
Pulmonary artery aneurysm occurs in approximately 1% of patients and is
associated with a 50% mortality rate.27,28
The inflammation may affect virtually any artery and the development of
an aneurysm with subsequent rupture is an important cause of death.
Respiratory involvement presents as dyspnea, cough, pleuritic chest
pain, and hemoptysis.29 The last, due to pulmonary artery–bronchial fistula
formation, is an important cause of death. Lung involvement occurs in up to
5% of patients.29
Fig. 16.85
Behçet's disease: multiple
superficial vulval ulcers
are present. By courtesy
of R.A. Marsden, MD,
St George's Hospital,
London, UK.
Intestinal involvement particularly affects the ileocecal region; ulcers may
be complicated by perforation, presenting as an intra-abdominal emergency
necessitating surgical intervention.30 The esophagus is uncommonly affected
by ulcers and erosion, stenosis or esophagitis.31
Involvement of the nervous system, which is associated with a poor
prognosis, occurs in up to 25% of patients.24 Lesions develop anywhere in the
central and peripheral components and, therefore, virtually any neurological
sign or symptom may be seen, including sensory losses, strokes, and spinal
cord, cranial and peripheral nerve lesions. Dural sinus thrombosis is a ­well-
recognized complication.32
688 Vascular diseases
The kidney is affected in up to 55% of patients and manifestations include
amyloidosis, glomerulonephritis, interstitial nephritis, and vasculitis.33
A study of relative organ system involvement has led to a subclassification
of a spectrum of Behçet's disease.34,35 The mortality of Behçet's disease is,
however, surprisingly low, of the order of 2–4%.
Pathogenesis and histological features
The precise etiology and pathogenesis are unknown. Recent interest has
focused on the possibility of an altered immune response in patients with
Behçet's disease. It has been suggested that heat shock proteins may play an
important role in its pathogenesis.36,37 They have been found to be elevated
in serum together with increased levels of vascular endothelial growth factor
(VEGF) and antiphospholipid antibodies independent of disease activity.38
Heat shock proteins reactive in Behçet's patients induce uveitis in rats.37
Increased VEGF levels correlate significantly with the presence of vascular
or ocular disease.38 Oligoclonal expansion of T cells in some patients with
Behçet's disease has been documented.39 In one study, serum IL-12 and
peripheral Th1 lymphocyte levels correlated with disease activity.40
Complement components C3 and C9 have been identified in blood vessel
walls in oral biopsies.35 Increased interleukin levels associated with increased
B-cell activity have also been described.41 Of possible importance in the
pathogenesis is the frequent presence of high levels of circulating immune
complexes and the common detection of immunoglobulins (particularly
IgM) and complement in blood vessel walls.42–44 Behçet's disease is associated
with human leukocyte antigen (HLA)-B5, -B12, -B27, and particularly with
HLA-BW51.24 Anticardiolipin antibodies have been described.24
Despite the accumulation of considerable immunological and genetic data,
the underlying antigen or other stimulus that drives these changes, and is
ultimately responsible for the disease, remains elusive.
The histological features are in themselves largely non-specific.35,41,45,46
The diagnosis of Behçet's disease is essentially clinical. The pathological
features that may be detected include both lymphocytic and necrotizing
vasculitis affecting the superficial postcapillary venules with associated
fibrinoid necrosis (Fig. 16.86).45 In one study, nearly 50% of patients had
evidence of vasculitis.47 Often, however, such vasculitic changes appear to be
a consequence, rather than a cause, of the dermal or mucosal inflammatory
changes.46 Endothelial swelling may be a feature and there is often an
associated lymphocytic perivascular infiltrate although sometimes neutrophils
are abundant.48 Venulitis and phlebitis were the most common forms of
vasculitis seen in one series of patients.12 In this study, phlebitis/venulitis was
seen in 48% of patients while leukocytoclastic vasculitis and lymphocytic
vasculitis were seen in 17% and 31% of patients, respectively.47
Non-specific features include a diffuse neutrophil polymorph dermal
infiltrate with or without abscess formation, corresponding clinically to pustular
Fig. 16.86
Behçet's disease: this field shows a superficial vulval ulcer with an intense
neutrophilic infiltrate and changes of acute vasculitis.
Fig. 16.87
Behçet's disease: there is florid suppurative acute folliculitis.
lesions, acute folliculitis, and acneiform folliculocentric pustular changes (Fig.
16.87).12,49,50 Biopsy after needle trauma in one study showed a neutrophilic
infiltrate with intraepidermal pustules. Vasculitis was not seen in pathergic
lesions in this study.51 Other authors have found that the pathergic lesions may
show leukocytoclastic vasculitis or Sweet's syndrome-like features.18
The erythema nodosum-like lesions correspond to necrotizing vasculitis
of the subcutaneous vessels, usually associated with thrombosis. Septal and
lobular panniculitis have also been described.13 Superficial thrombophlebitis
is present in up to 30% of patients (Fig. 16.88).34 Oral lesions and genital
ulcers show non-specific ulceration, accompanied in some instances by
leukocytoclastic or lymphocytic vasculitis.
Pulmonary involvement is characterized by pulmonary artery vasculitis,
sometimes also affecting the veins and capillaries.29 Thrombosis, infarction,
hemorrhage, and the development of aneurysm are important sequelae. The
inflammation is usually transmural and may be associated with damage to the
associated elastic tissue. Older destructive vascular lesions are characterized
by fibrous scarring.
Cerebral lesions in the early stage are characterized by a perivenular
lymphocytic infiltrate. In the more advanced lesions there is extensive
demyelination resembling multiple sclerosis.24
Differential diagnosis
Given the myriad non-specific histological manifestations that Behçet's
disease may produce, it comes as no surprise that the histological differential
diagnosis is usually broad. The authors of one large study stated that clinical
data are most important in establishing a diagnosis and suggested that the
role of biopsy is to confirm the clinical impression.7 Others propose that
biopsy is critical to evaluate for vessel-based pathology as clinical distinction
from pustular (non-vascular) lesions may be important.12 It is likely that the
criteria for diagnosis of Behçet's disease will continue to be refined.
The differential diagnosis includes other causes of folliculitis, infection,
erythema nodosum, connective tissue disease, neutrophilic and lymphocytic
vasculitis, and neutrophilic dermatoses. There are no pathognomonic
histological changes. Both clinical and pathological data must be considered
before arriving at a final diagnosis.7
Thromboangiitis obliterans
Clinical features
Thromboangiitis obliterans (Buerger's disease) is most often seen in young
adults and is much more common in males than in females.1 However, the
ratio of men to women is shifting, with the disease becoming more common
in women.2,3 In one large study, 23% of patients were female.2 In addition,
the disease is seen more frequently in older patients.2 Buerger's disease occurs

B histiocytes, and giant cells.19,24 Immunohistochemical studies have confirmed
Fig. 16.88
(A, B) Behçet's disease: this section shows thrombophlebitis involving a vein in the
subcutaneous fat. The vessel is infiltrated by large numbers of lymphocytes.
almost exclusively in smokers. Although most patients are considered ‘heavy’
smokers, some smoke less than a pack of cigarettes a day.4 In fact, some
authors view a history of smoking a necessary criterion for diagnosis. In
one study from Japan, nonsmokers with Buerger's disease were more likely
to be women.5 In Bangladesh, smoking bidis (a hand-rolled, additive-free,
unprocessed form of tobacco) is particularly associated with this disease.6
The worldwide incidence of Buerger's disease differs dramatically from
region to region. For example, the incidence is 50-fold greater in Nepal
compared with North America.7 This disease has its highest prevalence in
Eastern Europe, the Middle East, and Asia. Patients most often present with
painful cyanotic lesions of the extremities, especially the fingers or toes, which
may ulcerate and become gangrenous (Fig. 16.89). Sensitivity to cold is a
common complaint.
Resolution of disease usually follows cessation of smoking.8,9 Patients who
continue to smoke suffer autoamputation of digits and distal extremities.
In one study, only 2% of patients who quit smoking had amputations. In
contrast, 42% of those that continued to smoke required amputation.2
In most patients, the disease is limited to the extremities; however, some
patients develop visceral involvement,10–13 and this can prove fatal.10 The
vessels of the brain, intestine, heart, kidney, and lung may therefore be
affected.14–17 Occasional patients have involvement of multiple organs.18
Pathogenesis and histological features
The pathogenesis of Buerger's disease is poorly understood. Clearly, the
strong association with smoking suggests that this habit plays an important
role in eliciting thrombosis and resultant ischemia.19 It is unclear if tobacco
Temporal arteritis 689
Fig. 16.89
Buerger's disease: digital gangrene is present in this amputation specimen.
products are toxic to endothelial cells or elicit immune reactions that
damage vessels. Of interest, the disease has been described in patients who
use smokeless tobacco.20 Antiendothelial antibodies are elevated in a subset
of patients with Buerger's disease.21 Furthermore, disease activity correlates
with antiendothelial cell antibody titers.21 Response to acetylcholine, an
endothelium-dependent vasodilator, is diminished in ‘nondiseased’ extremities
of Buerger's patients compared with control subjects.22 IgG, IgM, and IgA are
present along the internal elastic lamina.23
Lesions are characterized by thrombosis of small or medium-sized
arteries and, less commonly, veins associated with a variable inflammatory
infiltrate composed of a mixture of neutrophils, lymphocytes, eosinophils,
the heterogeneous nature of the infiltrate. T cells, B cells, macrophages, and
dendritic cells may all be present.23 CD4-positive T cells outnumber CD8-
positive cells and T cell-mediated inflammation appears to be of significance
in the development of the disease.25 A characteristic finding is the presence of
a microabscess associated with an intraluminal thrombus. Inflammatory cells
may be seen in all layers of the vessel wall (Fig. 16.90). Preservation of the
internal elastic lamina is a typical feature.19
As lesions age, thrombi become organized and are replaced by fibrosis, and
eventually the vessel is recanalized (Fig. 16.91). A definitive diagnosis based
on biopsy findings is not possible during the later stages of organization.
Differential diagnosis
The histopathological features are probably not specific for Buerger's disease,
and differential diagnosis includes other thrombotic vasculopathies. Clinical
correlation is advised before rendering a definitive diagnosis. Preservation
of the internal elastic lamina is a characteristic feature and is said to help in
distinction from other vasculitides.19,26
Temporal arteritis
Clinical features
Temporal arteritis (giant cell arteritis) is a disease of the elderly that shows
a marked female predominance (3:1).1,2 It is a generalized vasculitis that
predominantly affects large and medium-sized arteries.3 It is mainly seen in
Caucasians and its etiology is unknown.2,3
Five of the American College of Rheumatology 1990 criteria are outlined
in Table 16.9.1 Classically, the temporal arteries are primarily affected,
but giant cell arteritis may also affect the occipital or facial arteries and,
in fact, has the potential to involve virtually any medium-sized or large
vessel, including the aorta and its branches.3 Patients with giant cell arteritis
present with pyrexia, severe headache, and throbbing scalp pain. Clinical
690 Vascular diseases

A A

B B

Fig. 16.90  (A, B) Buerger's disease: this acute lesion shows pan-mural Fig. 16.91  (A, B) Buerger's disease: old lesion showing luminal obliteration and
inflammation with abscess formation and thrombosis. recanalization. Note the intact elastic lamina.

The vast majority of patients have an elevated ESR.16 C-reactive protein

examination may reveal scalp tenderness and the skin overlying the affected
is also typically elevated.16 Elevated levels of anticardiolipin antibodies are
vessel may be erythematous, edematous or appear bruised.4 Palpation
frequently present.17–20 Some studies suggest that the presence of anticardiolipin
often reveals a cordlike and nodular vessel. Pulsation can be diminished or
antibodies correlates with more severe vascular damage.19,20 In most patients,
absent.
anticardiolipin antibody titers return to normal range with steroid therapy.18
Visual disturbance due to involvement of the ophthalmic or retinal vessels
is an important complication which sometimes results in blindness. Lesions
of the central nervous system may result in stroke, subarachnoid hemorrhage
Table 16.9
or mental confusion, and aural involvement can cause deafness. In one large
1990 criteria for the classification of giant cell (temporal) arteritis (traditional
study, neurological problems were present in nearly one-third of patients.5
format)*
Peripheral neuropathic syndromes are evident in 14% of patients.4 Often the
associated lymph nodes are enlarged and tender. Symptoms of polymyalgia
Criterion Definition
rheumatica (i.e. stiffness, weakness, aching and pain in the muscles of the
Age at disease Development of symptoms or findings beginning at
neck, limb girdles, and upper limbs) are extremely common, occurring in up
onset ≥ 50 years age 50 or older
to 75% of patients.6 Laboratory investigations typically reveal mild anemia,
neutrophilia, and a very high ESR. Elevated levels of von Willebrand factor are New headache New onset of or new type of localized pain in the head
characteristic.7 Temporal artery Temporal artery tenderness to palpation or decreased
Cutaneous lesions other than those mentioned above are uncommon, abnormality pulsation, unrelated to arteriosclerosis of cervical arteries
presumably reflecting the vast collateral circulation of the integument.8,9 Elevated ESR ESR ≥ 50 mm/hour by the Westergren method
Patients may occasionally manifest ulcers (sometimes quite widespread),
Abnormal Biopsy specimen with artery showing vasculitis
massive necrosis, bullae, and gangrene (Fig. 16.92).10,11 Involvement of the
artery biopsy characterized by a predominance of mononuclear cell
lingual artery can cause glossitis or gangrene of the tongue.12,13 Masticatory
infiltration or granulomatous inflammation, usually
claudication is an additional feature. with multinucleated giant cells
Rare patients with disseminated visceral arteritis with giant cell arteritis-
like histological features have been described.14 The heart, lungs, kidneys, *For purposes of classification, a patient shall be said to have giant cell (temporal)
stomach, pancreas, and liver may be involved.14 It is debatable what arteritis if at least three of these five criteria are present. The presence of any three or
more criteria yields a sensitivity of 93.5% and a specificity of 91.2%.
terminology should be applied to such rare and unusual cases.
Reproduced with permission from Hunder, G.G. (1990) Arthritis and Rheumatism, 33,
Life expectancy does not seem to be adversely affected by having temporal 1122–1128.
arteritis.15
 Temporal arteritis 691

Fig. 16.92
Giant cell arteritis: severe ischemic necrosis with ulceration has destroyed most
of this patient's scalp. By courtesy of D. McGibbon, MD, St Thomas' Hospital,
London, UK.

Pathogenesis and histological features

The pathogenesis of temporal arteritis is poorly understood. Although an
immunological mechanism has been suggested, it has not been proven. Evidence
of familial aggregation and an increased incidence of the HLA-DR4 antigen have
raised the possibility of a genetic influence.3 However, consistent reproducible
HLA associations have not been demonstrated in all populations.
It has been suggested that giant cell arteritis is an autoimmune disease
perhaps directed, at least in part, against the vascular elastic lamina.3
T cells in the infiltrate are predominantly of the helper subclass and B
expression of HLA-DR has been recorded, thereby suggesting that they
are activated.3 The lymphocytes have been shown to respond to antibodies Fig. 16.93
against transferrin and IL-2 receptors.21 Proliferation of mononuclear cells (A, B) Giant cell arteritis: this scalp biopsy showed multiple affected vessels.
following incubation in cultures containing elastin-derived peptides is By courtesy of P.A. Burton, MD, Southmead Hospital, Bristol, UK.
increased compared with control subjects.22 This finding suggests elastin-
derived peptides are the targets of T cells in giant cell arteritis.22 Disease
activity has been shown to correlate with plasma concentrations of IL-6.23
The demonstration by some authors of a fluctuating cyclical pattern of
incidence has raised the possibility of an infectious agent or other triggering
factor playing a significant pathogenetic role.24–26 A study from the Mayo Clinic
showed a variation in incidence with peak periods occurring approximately
every 7 years.24 Similarly, a study from Denmark demonstrated marked
variation in the incidence of temporal arteritis with five peak periods.26 Of
these, there appeared to be association with two epidemics of Mycoplasma
pneumoniae infection, two possibly related to erythrovirus (parvovirus)
B19 epidemics and one peak that may have been related to an epidemic
of Chlamydia pneumoniae.26 Another study showed a threefold increased
likelihood of infection in patients with temporal arteritis compared with
control subjects.27 An association between temporal arteritis and antibodies
to parainfluenza type 1 has been demonstrated.28,29 A different hypothesis
implicated altered endogenous material due to age- or sun damage-related
changes.30–32 Despite these observations, the precise triggering factors and the
pathogenesis of temporal arteritis remain unclear.
The lesions of giant cell arteritis are typically focal in distribution; therefore,
the vessel should be carefully palpated to find an obviously affected segment
before a biopsy is undertaken. Even then, false negatives are not uncommon
(see below). The lesion is granulomatous in nature and may affect only part
or the whole circumference of the vessel wall (Fig. 16.93).33 The infiltrate,
which particularly affects the intima and media, is composed of lymphocytes, Fig. 16.94
plasma cells, histiocytes, and variable numbers of giant cells of both foreign Giant cell arteritis: the intima and media are infiltrated by a dense chronic inflammatory
body and Langhans type (Fig. 16.94). Giant cells are sometimes relatively cell infiltrate containing conspicuous Langhans giant cells. By courtesy of P.A. Burton,
sparse and multiple levels have to be examined before they are identified. MD, Southmead Hospital, Bristol, UK.
692 Vascular diseases
On occasion, they are absent. Typical of giant cell arteritis is damage to the
internal elastic lamina, which appears swollen and fragmented, and portions
may be identified within the cytoplasm of giant cells (Fig. 16.95).4
A second, less common form consists of a panarteritis composed of lymphocytes,
macrophages, neutrophils, and eosinophils but giant cells are absent. Varying
degrees of vessel wall necrosis are evident and the vessel is often thrombosed.
In the late stages of the disease, fibrous scarring takes place and a
reconstituted, often multilayered, internal elastic lamina may be identified. In
cases of doubt, an elastic tissue stain can prove invaluable. The thrombus is
on occasions recanalized.
Initiation of corticosteroid treatment before biopsy influences the histological
appearances.34 Giant cells are rare or entirely absent, there are large circumferential
defects in the elastic lamina, and there is a mantle of lymphocytes and epithelioid
histiocytes between the outer muscular layer and the adventitia.34 These changes
can be noted as early as 1 week following steroid treatment.34
It is crucial to note that patients with classic symptoms of temporal arteritis
may have a negative biopsy, most likely due to the multifocal nature of the
arteritis and sampling bias. In one study, 44% of patients who were regarded
as having clinical manifestations of temporal arteritis, which improved with
steroid treatment, had negative biopsies.35 Therefore, a negative biopsy does
not necessarily exclude this disease. Given the consequences of delayed or no
treatment, it is often necessary to treat selected patients even without definitive
biopsy diagnosis. One study found that patients with temporal arteritis who have
constitutional symptoms or an abnormal temporal artery detected by physical
examination are more likely to have a positive biopsy.36 Doppler flow studies
may be used to improve the sensitivity of biopsy.37 Given the multifocal nature of
giant cell arteritis, the diagnostic yield, not surprisingly, is likely improved with
longer artery length biopsied and increased number of sections examined.38
Differential diagnosis
The histological findings are identical to those seen in some patients with
Takayasu's disease, another form of giant cell arteritis. Careful clinical
correlation is required to distinguish these conditions and, since overlap
exists, many cases are not easily subclassified. Some authors consider these
diseases part of a continuum of giant cell vasculitis, with patient age being
an important discriminator: patients under age 40 are more likely to have
Takayasu's arteritis; those over 50 are more likely to have temporal arteritis.
It should be noted that fragmentation of the internal elastic lamina may
result from either age-related changes or atherosclerosis and these conditions
may be difficult to distinguish from healed arteritis. The presence of medial
scarring is suggestive of temporal arteritis. The extent of destruction,
particularly confluent loss of the internal elastic lamina, is said to correlate
with probability of healed arteritis.6
Fig. 16.95
Giant cell arteritis: there is fragmentation of the internal elastic lamina. By courtesy
of P.A. Burton, MD, Southmead Hospital, Bristol, UK.
Juvenile temporal arteritis
Clinical features
Juvenile temporal arteritis is a rare and poorly defined entity first reported
in 1975.1 Thus far, only approximately 20 cases have been reported in the
literature.2–10 The disease is unrelated to classic temporal arteritis and is not
associated with abnormal erythrocyte sedimentation rate or signs of systemic
involvement. It occurs in patients under the age of 40, most commonly
manifesting as a unilateral painless nodule or swelling of a few centimeters
in the temporal area.1–10 Painful presentation and bilateral involvement are
rare features.2–4 The disease may be accompanied by blood eosinophilia and
it may be related to or associated with Kimura's disease.4,5,7,9,10
Histological features
Juvenile temporal arteritis is characterized by intimal proliferation and
disruption of the media of the temporal artery associated with a heavy
chronic inflammatory infiltrate composed predominantly of lymphocytes and
eosinophils. Endothelial proliferation is an additional finding and formation
of lymphoid follicles and germinal centers may be present. Giant cells as seen
in classical temporal arteritis are not a feature.
Takayasu's arteritis
Clinical features
Takayasu's arteritis (pulseless disease, giant cell arteritis) is a rare
granulomatous disease that predominantly affects the aorta and its major
branches and results in vascular stenoses with bruits and diminished or
absent pulses (hence the term ‘pulseless disease’).1,2 Aneurysm formation
may be an additional feature. It predominantly affects females (7:1), most
often involves the upper limbs, and usually presents in the second or third
decade. Although most patients are young adults, the disease is also seen in
children.3,4 It is rare in Europe and the United States, occurring more often
in Japan, China, Korea, Southeast Asia, India, and Mexico.2 It appears to
have two stages:
• an acute systemic illness characterized by fever, malaise, arthralgias,
myalgias, and ocular lesions including uveitis and episcleritis,
• a chronic stage of large-vessel involvement.5
Current diagnostic criteria are shown in Table 16.10. In addition to the
obligatory criterion, the presence of two major criteria, one major plus two
or more minor, or four or more minor criteria, is associated with a high
probability of Takayasu's arteritis.6
Table 16.10
Takayasu's arteritis: diagnostic criteria
•  Obligatory criterion
–  age < 40 years
•  Major criteria
–  left mid subclavian artery lesion
–  right mid subclavian artery lesion
•  Minor criteria
–  high ESR
–  carotid artery tenderness
–  hypertension
–  aortic regurgitation or annuloaortic ectasia
–  pulmonary artery lesion
–  left mid common carotid lesion
–  distal brachiocephalic trunk lesion
–  descending thoracic aorta lesion
–  abdominal aorta lesion
Reproduced with permission from Bentsson, B.A. and Anderson, T. (1991) Current
Opinion in Rheumatology, 3, 15–22.
 Takayasu's arteritis 693

A B
Fig. 16.96
Takayasu's arteritis: (A) this patient presented with
multiple lesions as seen here on the lower legs; (B) a large
ulcerated inflammatory nodule is present on the left thigh.
By courtesy of P. Godeau, MD, and C. Francès, MD, Groupe
Hospitalier, Pitié-Salpêtrière, Paris, France.

Cutaneous manifestations have been described in up to 50% of patients

and include Raynaud's syndrome (due to large-vessel involvement), acute
inflammatory nodules and erythema nodosum-like features (particularly in
Europe and North America), pyoderma gangrenosum-like lesions (especially
in the Japanese), pseudoerythema induratum, superficial phlebitis, tuberculid
eruptions, and purpura (Figure 16.96).5,7,8 Patients may present with
cutaneous necrotizing vasculitis.8
Cases have been reported describing an overlap between Takayasu's
arteritis and polyarteritis nodosa.6 Rare patients with a lupus-like malar flush
and an urticarial reaction with livedo reticularis have been documented.7
Renal artery involvement with stenosis causes severe hypertension secondary
to renin secretion. Stroke due to severe hypertension is a serious complication
in some patients. Patients with Takayasu's arteritis also have an increased
incidence of associated Crohn's disease.9

Pathogenesis and histological features A

The etiology and pathogenesis of Takayasu's arteritis is poorly understood.
Occasionally, other diseases are seen in association with Takayasu's arteritis
including tuberculosis, inflammatory bowel disease, polymyositis, sarcoidosis,
and rheumatoid arthritis.1,5,10–12 Coexpression with polyarteritis nodosa raises
the possibility of an autoimmune phenomenon.13
The diagnosis is usually made by clinical and radiological
correlation; however, in some cases tissue is sent to the pathologist. The
histological features are variable and include granulomatous vasculitis
indistinguishable from giant cell arteritis, leukocytoclastic vasculitis,
lymphocytic vasculitis, and polyarteritis nodosa-like features ( Figs
16.97, 16.98).5–7,13,14
Septal and lobular panniculitis with granulomatous vasculitis may be the
underlying histology of erythematous nodules and erythema nodosum-like
lesions.7 Features of Churg-Strauss granulomata have also been reported.5

Differential diagnosis
As can be seen from the above discussion, several different patterns of vasculitis B
may be encountered in Takayasu's arteritis. Furthermore, the histological findings
seen in this disease may be identical to other forms of vasculitis. Therefore, Fig. 16.97
careful clinical and radiological correlation is necessary to establish the correct (A, B) Takayasu's arteritis: this occluded artery was present with a thickened
diagnosis. septum of the subcutaneous fat from the thigh of a young woman.
694 Vascular diseases

Table 16.11
Infections known to be associated with clinically defined vasculitis

Vasculitic syndrome Infective agent

Leukocytoclastic vasculitis Bacterial
(including Henoch-Schönlein   Streptococcus
purpura)   Staphylococcus
  Salmonella
  Yersinia
  Mycobacterium
Viral
  varicella-zoster
  hepatitis B
  cytomegalovirus
  influenza
Polyarteritis nodosa Bacterial
  Streptococcus
Viral
  hepatitis A, B, C
Fig. 16.98
  human immunodeficiency virus
Takayasu's arteritis: high-power view showing granulomatous inflammation.
  cytomegalovirus
The features are indistinguishable from giant cell arteritis.
  human T-cell leukemia
  erythrovirus
Isolated granulomatous vasculitis Treponema pallidum
Infection-related vasculitis of the central nervous system Mycobacterium tuberculosis
Fungal
Infection must be considered in the evaluation of many forms of vasculitis,   Coccidioides
particularly leukocytoclastic vasculitis. Infective vasculitis is caused by a wide   Actinomyces
variety of agents including bacteria, fungi, protozoa, viruses, spirochetes,   Cryptococcus
and rickettsiae (Table 16.11). The relationship between particular   Histoplasma
microorganisms and vascular lesions is covered under the specific infection in   Nocardia
Chapter 18. In general terms, vessel wall damage may occur as a consequence
  Aspergillus
Borrelia burgorferi (Lyme)
of direct microbial toxic damage or else develop as a complication of an Varicella-zoster
immunologically mediated injury (Table 16.12).1
Kawasaki disease Bacterial
Bacterial arteritis can develop as a result of embolization from valvular
lesions in patients with infective endocarditis. Although many different
  Streptococcus
  Salmonella
organisms are of etiological importance in the latter condition, staphylococcal   Yersinia
and streptococcal infections remain the most important.2 It may also occur by   Mycoplasma
direct spread from an adjacent septic focus, by lymphatic spread, or represent Viral
a manifestation of underlying bacteremia or septicemia. There also appears   parainfluenza
to be a significant relationship between group A streptococci and childhood   rotavirus
polyarteritis nodosa, both cutaneous and generalized.3 In addition, Kawasaki
Reproduced with permission from Mader, R. and Keystone, E.C. (1992) Current
syndrome has been reported in association with group A streptococci, Opinion in Rheumatology, 4, 35–38.
possibly as a result of superantigen stimulation.4 Gonococcal bacteremia due
to Neisseria gonorrhea is another important cause of vasculitis. Neisseria
meningitis infection may result in vasculitis associated with considerable
morbidity and mortality. Table 16.12
The histological features of small-vessel involvement are variable and depend Mechanisms for infection-associated vasculitis
to some extent on the nature of the causative organism. Suppurative features
are most likely to be due to staphylococcal, streptococcal, Pseudomonas or •  Direct microbial toxicity
Klebsiella infection.2 A Gram stain is advisable in all suspected cases. –  direct endothelial infection
–  effect of microbial toxins
Obviously, in the context of immunosuppressed patients, the range of
bacteria and fungi that can be implicated is very broad. In cases of suspected •  Immune mediated
cutaneous infective vasculitis, especially in immunosuppressed patients, a –  humoral: soluble immune complexes; in situ complex formation
detailed clinical history is essential and the judicious use of special stains is – cellular: cytotoxic cell reaction (T cell, NK cell, other); polyclonal T- or
B-cell response; monoclonal T- or B-cell response
highly advisable.
Candidiasis, aspergillosis, cryptococcosis, and mucormycosis are of NK, natural killer. Reproduced with permission from Calabrese, L.H. (1991) Rheumatic
special importance. Mycobacterium tuberculosis is also sometimes a cause of Disease Clinics of North America, 17, 131–147.
vascular damage. It tends to affect veins rather than arteries.2 The features are
usually those of a granulomatous thrombophlebitis, usually in the absence
of caseation necrosis, although sometimes this is a feature. Occasionally,
however, arteries are primarily affected (Fig. 16.99). fever.2,5 The histological features include endothelial swelling and a mixed
Lepra bacilli are very commonly seen in endothelial and vascular smooth inflammatory cell infiltrate of T lymphocytes, macrophages, and occasionally
muscle cells in lepromatous leprosy. Vasculitis in the setting of leprosy neutrophils.2 Thrombosis is sometimes present.
(erythema nodosum leprosum) is a common cause of vasculitis in regions of Small-vessel vasculitis may be seen in all three stages of syphilis. The features
the world where this disease is endemic. vary from a non-specific lymphocytic inflammation through to necrotizing
Vascular lesions in the skin accompany a variety of rickettsial infections granulomatous angiitis.6–8 Treponema pallidum, however, is very rarely
including epidemic typhus, scrub typhus, and Rocky Mountain spotted identified.2 Cutaneous vasculitis is an occasional feature of Lyme disease.2

A B
Fig. 16.99
(A, B) Tuberculous vasculitis: this patient with miliary tuberculosis presented with ischemic cutaneous lesions. Note the granulomatous inflammation.
The best known viral association with vasculitis is hepatitis B, which has
been described in association with polyarteritis nodosa, leukocytoclastic
vasculitis, and mixed cryoglobulinemia, and hepatitis C associated mixed
cryoglobulinemia and leukocytoclastic vasculitis.1,9–12 Evidence of HBV
infection is found in approximately 35% of all patients with polyarteritis.1
Human immunodeficiency virus (HIV) may be present in a very wide
spectrum of vasculitic lesions including polyarteritis nodosa, Churg-
Strauss syndrome, leukocytoclastic vasculitis, Henoch-Schönlein purpura,
lymphomatoid granulomatosis, and primary angiitis of the central nervous
system.13,14 Whether these represent a direct effect of HIV, or are a consequence
of coexisting viral infections known to cause vasculitis (e.g. cytomegalovirus,
HBV or Epstein-Barr virus), is unknown.10 The identification of HIV within
endothelial cells adds some support to the former possibility.15
Paraneoplastic vasculitis
Clinical features
Occasionally, cutaneous vasculitis is a marker of an underlying systemic
malignancy (Table 16.13).1–11 Although there have been reports of an
association with solid tumors, this relationship is tenuous (with the possible
exception of squamous carcinoma of the bronchus): such cases probably
represent nothing more than coincidence.1,4,6,12 Vasculitis has nevertheless
been reported in patients with carcinoma of the kidney, breast, ovary, lung,
nasopharynx, stomach, small bowel, colon, and prostate. Leukocytoclastic
vasculitis is the most common pattern of vasculitis associated with
Table 16.13
Vasculopathic syndromes associated with malignancy
•  Migratory superficial thrombophlebitis
•  Deep venous thrombosis
•  Nonbacterial thrombotic endocarditis
•  Anticardiolipin antibody syndrome
•  Embolic features associated with atrial myxoma
•  Raynaud's phenomenon
•  Erythema nodosum
•  Hyperviscosity syndrome
•  Cryoglobulinemia
•  Lambda light chain vasculopathy
•  Cutaneous vasculitis
•  Systemic vasculitis
Reproduced with permission from Mertz, L.E. and Conn, D.L. (1992) Current Opinion in
Rheumatology, 9, 39–46.
Paraneoplastic vasculitis 695
malignancy but large-vessel vasculitis may also be seen. Of interest, vasculitis
can be present at the time of initial diagnosis and also herald the onset of
relapse.4 Solid tumors and hematological malignancy have been associated
with Henoch-Schönlein purpura.7,10,11 One study found that nearly a third of
adults with Henoch-Schönlein purpura had an associated malignancy.10 For
this reason, the authors concluded that physicians should suspect underlying
malignancy in older patients (especially men of more than 40 years) with
Henoch-Schönlein purpura.10
In contrast to solid tumors, there does appear to be a genuine relationship
between cutaneous vasculitis and hematological and lymphoreticular
neoplasms including hairy cell leukemia, acute and chronic myeloid leukemia,
multiple myeloma, and non-Hodgkin's lymphoma.1
In general, patients present with the features of leukocytoclastic vasculitis,
and occasionally arthralgia or arthritis is evident. Cutaneous manifestations
include maculopapular eruptions, purpura, urticaria, peripheral ulcers,
and gangrene.13 Although vasculitis is seen in patients with a spectrum of
hematological malignancies, hairy cell leukemia is particularly associated with
leukocytoclastic vasculitis and a polyarteritis nodosa-like picture, including
systemic lesions.4–6 In one study of 42 patients with hairy cell leukemia and
vasculitis, 21 also had leukocytoclastic vasculitis and 17 had polyarteritis
nodosa.4 In addition, four patients had direct infiltration of vessel walls
by leukemic cells. Hodgkin's lymphoma has occasionally been linked to
erythema nodosum, and myelodysplasia has been found in conjunction with
leukocytoclastic vasculitis.14,15 Multiple myeloma is particularly associated
with nonthrombocytopenic purpura.16 It has recently been documented
that lymphocytic vasculitis is a relatively common form of paraneoplastic
vasculitis associated with lymphoproliferative disorders.17
It is important to note that these vasculitic phenomena may antedate the
clinical manifestations of the underlying malignancy. Therefore, patients with
an unexplained vasculitic rash should be investigated with this in mind.2 In
hairy cell leukemia, vasculitis often follows splenectomy.5,13
Pathogenesis and histological features
The pathogenesis of paraneoplastic vasculitis has not been well studied, but
could include immune complexes, cross-reacting antigens, and direct tumor
(leukemic blast) infiltration of blood vessel walls.
Leukocytoclastic, polyarteritis nodosa-like, and lymphocytic forms
of paraneoplastic vasculitis have all been described and show histological
features similar to their nonparaneoplastic counterparts.17
Recently, cases of vasculitis in the setting of myelomonocytic or
monocytic leukemia cutis have been described in which the vascular injury
was mediated by leukemic blasts.18 The term ‘leukemic vasculitis’ has
been proposed for this form of vasculitis.18 In these cases, the vasculitis
ranged from mild microvascular injury to frank necrotizing vasculitis.18,19
696 Vascular diseases

The former was characterized by low-grade vascular injury with endothelial It is arguable that the term ‘vasculitis’ should not be applied to lesions
cell swelling and focal fibrin deposition. Frank necrotizing vasculitis with minimal vascular damage. Regardless of terminology, it is important
shows infiltration of the vessel wall by neoplastic cells associated with for the pathologist to render a report that distinguishes cases of low-grade
necrosis and fibrin deposition in a pattern that resembles polyarteritis vascular injury associated with a lymphocytic infiltrate from frank necrotizing
nodosa. Hairy cell leukemia may also show infiltration of vessel walls by vasculitis. Furthermore, it is important to distinguish lymphocytic from
leukemic cells.4,5 neutrophilic vasculitides.
In cases with low-grade vascular injury, we often apply the term low-
grade lymphocytic vasculitis and mention in our report that frank necrotizing
Vasculitis associated with palisaded vasculitis is not present to avoid any ambiguity. If strict criteria are used –
neutrophilic and granulomatous dermatitis requiring vascular necrosis or significant fibrinoid change for a diagnosis
of vasculitis – frank necrotizing lymphocytic vasculitis is an uncommon
Clinical features condition. The differential diagnosis of lymphocytic vasculitis is broad and
many entities associated with a perivascular lymphocytic infiltrate may, on
Occasionally, granuloma annulare, necrobiosis lipoidica, and rheumatoid
occasion, cause vascular changes that warrant a diagnosis of non-necrotizing
nodule-like lesions associated with vasculitis are encountered.1,2 This group
lymphocytic vasculitis (Table 16.14). Entities that exceptionally show features
of disorders, which is almost always associated with systemic disease,
of lymphocytic vasculitis are discussed in their appropriate chapters. Diseases
is also discussed in Chapter 9. A number of different terms have been
commonly associated with lymphocytic vasculitis include Degos' disease,
applied including palisaded neutrophilic and granulomatous dermatitis
perniosis, Behçet's disease, livedo vasculitis, and Kawasaki syndrome. Other
(of immune complex disease), interstitial granulomatous dermatitis
rare associations of lymphocytic vasculitis include leukemia and the tumor
with arthritis, rheumatoid papules, superficial ulcerating rheumatoid
necrosis factor receptor-associated periodic syndrome. The latter is a periodic
necrobiosis, cutaneous extravascular necrotizing granuloma, and Churg-
fever syndrome associated with a skin eruption presenting with macules and
Strauss granuloma.1–6 Many types of underlying systemic disease have
plaques in early life. It results from mutations in the TNFRSFIA, the gene
been reported in association with these lesions, including rheumatoid
encoding the tumor necrosis factor receptor.7,8
arthritis, lupus erythematosus, Sjögren's syndrome, thyroiditis, Raynaud's
syndrome, hepatitis, inflammatory bowel disease, lymphoproliferative
disorders, myelodysplastic syndrome, vasculitis (Wegener's, Churg-Strauss,
Takayasu's arteritis, periarteritis nodosa), hemolytic uremic syndrome,
thrombotic thrombocytopenic purpura, mixed cryoglobulinemia, drug
reactions, carcinoma, diabetes mellitus, and infection (streptococcal, HIV,
Epstein-Barr virus, erythrovirus).1–4
The lesions are usually papules and nodules, or plaques with a predilection
for the extremities or trunk in an adult.2,6,7 They are often arranged in a linear
pattern, which may be confluent linear bands or cords that are said to have
a ‘ropelike’ quality.

Pathogenesis and histological features

The pathogenesis of palisaded neutrophilic and granulomatous dermatitis
likely depends on the associated/underlying disease. An autoimmune-
mediated vasculitis probably plays an important role in at least a subset of
cases.
As noted above, this is not a single disease but rather a group of disorders
showing a broad spectrum of histology sharing the common denominator of
a prominent neutrophilic infiltrate with or without vasculitis in a background
of palisading granulomatous inflammation. When present, vasculitis usually A
shows the features of leukocytoclastic vasculitis.

Differential diagnosis
The precise terminology that is preferred by the dermatopathologist is
probably not important. More significant than the nosological nuances is
rendering a report that alerts the clinician to the possibility that the patient
may have underlying systemic disease, and when such lesions are encountered
appropriate clinical evaluation is necessary.

Lymphocytic vasculitis
Lymphocytic vasculitis is sometimes diagnosed in cases in which a perivascular
lymphocytic infiltrate is associated with vascular damage (Fig. 16.100). In
many cases, the vascular changes are subtle and minimal, including only
endothelial swelling and extravasated blood cells and sometimes focal
fibrin deposition. Not surprisingly, the concept of lymphocytic vasculitis is
somewhat controversial.1–5 This category of vasculitis has been embraced by B
some authors and rejected by others. To a large extent, the controversy is
the result of a lack of precisely defined criteria for diagnosis. Kossard has Fig. 16.100
defined lymphocytic vasculitis as an overlapping spectrum of changes varying (A, B) Lymphocytic vasculitis: there is mural fibrinoid necrosis accompanied by a
from angiodestruction to endovasculitis and including a pattern defined as dense lymphocytic infiltrate. These images come from a patient with very severe
lichenoid lymphocytic vasculitis.6 perniosis.
 Malignant atrophic papulosis 697

Table 16.14 face, and scalp are spared. The papules are usually asymptomatic and do not
Causes of lymphocytic vasculitis ulcerate or scar. With progression, they develop a characteristic appearance:
•  Behçet's disease discrete small patches composed of a central zone with a depressed white,
•  Connective tissue disease porcelain-like appearance and a fine scale, surrounded by a narrow red or
•  Degos' disease violaceous rim associated with fine telangiectasia (Fig. 16.101). On rare
•  Drug eruptions occasions, similar lesions are found on the buccal and genital mucosa. Penile
•  ‘Gyrate erythemas’ (e.g. erythema annulare centrifugum) ulceration has rarely been documented.19 Sometimes, avascular conjunctival
•  Infection (especially viral and rickettsial) pale patches are seen.20
•  Insect bite reactions Intestinal manifestations are variable. While any segment of the intestinal
•  Kawasaki syndrome system from the oral cavity to the anus may be involved, it is predominantly
•  Livedo vasculitis/atrophie blanche
the small intestine that is affected.13 Some patients are asymptomatic
•  Lymphomatoid papulosis
•  Perniosis (chilblains)
while others complain of indigestion, diarrhea, constipation or abdominal
•  Pityriasis lichenoides distension and pain. Laparoscopy usually reveals characteristic subserosal
•  Pigmented purpuric dermatoses white, yellow or pinkish plaques, typically slightly depressed and several
•  Polymorphic eruption of pregnancy centimeters in diameter. Of great importance, some patients develop small
•  Polymorphous light eruption intestinal perforation with resultant peritonitis. Fistulae involving the small
•  Prurigo of pregnancy bowel may develop as a complication.21 Rarely, intestinal involvement
precedes the cutaneous features.22 Acute small bowel perforation can be the
first manifestation of the disease.23 In addition, intestinal lesions sometimes
develop many years after an initial cutaneous presentation.
Malignant atrophic papulosis The condition may involve both the peripheral and central nervous system
and occasionally such lesions dominate the clinical features.24–27 Symptoms
Clinical features are variable and are occasionally multiple due to various sites being affected.
Malignant atrophic papulosis (Degos' disease, lethal intestinocutaneous For example, hemi- and quadriplegias, sensory losses, and cranial nerve
syndrome,) is a rare disorder affecting multiple systems and usually lesions may all be encountered.28,29
associated with a poor prognosis.1–4 It is of unknown etiology, shows a male Malignant atrophic papulosis is a truly systemic illness in most patients.
predominance (3:1), and usually affects the young and middle aged. The mean At autopsy, lesions are found in a variety of sites including the heart, lungs,
age at presentation is 33 years; however, a wide age range at diagnosis (from kidneys, bladder, and liver.30–33
infancy to 67 years) has been described.5,6 Occasional instances of familial Although this disease is usually associated with a poor prognosis and high
involvement have been recorded.7–9 Presentation during pregnancy may rarely mortality, there does appear to be a subset of patients in whom the cutaneous
occur.10 features are the sole manifestation and evolution is benign.10,34–40 Intestinal
The cutaneous lesions are distinctive, although similar lesions can involvement appears to correlate particularly with a poor outlook.41
be a manifestation of other diseases including SLE, systemic sclerosis, Malignant atrophic papulosis has been reported in a patient with acquired
dermatomyositis, rheumatoid arthritis, and Crohn's disease.11–17 Recently, it immunodeficiency syndrome.42
has been proposed that malignant atrophic papulosis represents a reaction
pattern mainly seen in lupus erythematosus and not a specific disease per se.17,18 Pathogenesis and histological features
Lesions, which may be quite numerous, appear in crops, initially as pinkish The precise etiology is unknown, although viral, genetic, autoimmune
or yellow–gray papules up to 5 mm in diameter and showing a predilection mechanisms, and fibrinolysis have all been implicated.43 Since lesions are
for the trunk and proximal extremities. Characteristically, the palms, soles, sometimes not associated with significant inflammation, it is debatable

Fig. 16.101
A (A, B) Degos' disease: note the typical small papules with depressed centers
and fine white scaling. By courtesy of the Institute of Dermatology, London, UK.
698 Vascular diseases
whether classification as a true vasculitis is appropriate. The pathogenesis is
that of vascular thrombosis, the essential pathology of the lesions being that
of infarction.1 A focal fibrinolytic defect within the center of the infarcted
lesions and alterations of fibrinolysis and platelet function have been
described, but these are not consistent findings.1,44,45 It has been proposed
that endothelial swelling and proliferation with secondary thrombosis is the
primary pathogenesis.1 Consistent with this hypothesis is the documentation
of a patient with malignant atrophic papulosis associated with elevated
anticardiolipin antibodies.46 Others, however, have not been able to
corroborate this finding.47
In most cases, the cause of the initial endothelial vascular insult is
unknown, but a mononuclear vasculitis may play a role in the pathogenesis.4
Most authors regard the mucin deposition described below as a secondary
event developing as a consequence of dermal ischemia.
The established cutaneous lesion has a characteristic appearance.48,49 The
overlying epidermis is hyperkeratotic and atrophic. Immediately beneath this is
a wedge-shaped zone of dermal infarction with the base parallel to the surface
epithelium: it is typically pale in color, relatively acellular, and associated with
mucin deposition (Figs 16.102, 16.103).50 The latter is metachromatic with
toluidine blue and demonstrates hyaluronidase-sensitive Alcian blue staining.
Older lesions are frequently ulcerated. Often, the vessels adjacent and deep
Fig. 16.102
Degos' disease: there is hyperkeratosis and epidermal atrophy associated with a
zone of dermal infarction. Note the ectatic vessels.
Fig. 16.103
Degos' disease: high-power view showing hyalinized fat necrosis.
to the infarct are hyalinized and show a perivascular lymphocytic infiltrate
(Figs 16.104, 16.105). Usually, but not invariably, an endovasculitis can
be demonstrated in the blood vessels at the apex of the lesion: this consists
of endothelial cell hyperplasia, sometimes complicated by thrombosis.
The internal elastic lamina, media, and serosa are usually not involved.
A panniculitis mimicking lupus erythematosus profundus has been described.51
Microscopic examination of the bowel lesions reveals transmural intestinal
inflammation with ulceration and hemorrhage. The latter may involve the
small and large intestines including the rectum (Figs 16.106–16.109).
Vascular changes have included gross intimal thickening with consequent
severe diminution in the lumen diameter, thrombosis, and acute vasculitis.52
Differential diagnosis
As mentioned above, the cutaneous findings are distinctive and diagnosis
should be relatively straightforward. However, it should be kept in mind that
although the cutaneous lesions of malignant atrophic papulosis are typical,
similar lesions have been described in patients with other diseases such as
SLE, systemic sclerosis, rheumatoid arthritis, dermatomyositis, and Crohn's
disease.11–16,53 A search for underlying or associated disorders is therefore
advised.
Fig. 16.104
Degos' disease: high-power view showing blood vessel wall hyalinization and a
heavy lymphocytic infiltrate.
Fig. 16.105
Degos' disease: the superficial blood vessels are thickened and hyalinized.

Fig. 16.106
Degos' disease: section of jejunum showing ulceration of the mucosa with
surrounding intense congestion. By courtesy of C.J.J. Mulder, MD, Rijnstate
Hospital, Arnhem, The Netherlands.
Fig. 16.107
Degos' disease: histological section of jejunum shown in Figure 16.106. Note
the acute inflammation and ulceration. By courtesy of C.J.J. Mulder, MD, Rijnstate
Hospital, Arnhem, The Netherlands.
Fig. 16.108
Degos' disease: section of rectum showing focal congestion and ulceration.
By courtesy of C.J.J. Mulder, MD, Rijnstate Hospital, Arnhem, The Netherlands.
Atrophie blanche 699
Fig. 16.109
Degos' syndrome: histological section of the submucosa of the rectum. There
is acute vasculitis with thrombosis. By courtesy of C.J.J. Mulder, MD, Rijnstate
Hospital, Arnhem, The Netherlands.
Atrophie blanche
Clinical features
Atrophie blanche (livedo vasculitis, livedoid vasculitis, segmental hyalinizing
vasculitis) is a common dermatosis that usually occurs in the elderly,
particularly females.1–4 In its fully established state it consists of one or more
irregular, smooth, atrophic plaques surrounded by a hyperpigmented border
and telangiectases (Figs 16.110, 16.111). Ulcerative lesions of two types may
precede it:
• small (1–5 mm diameter), very painful erythematous purpuric areas that
ulcerate and heal slowly,
• chronic large areas of ulceration up to 5 cm in diameter, which, after a
long period of time, heal to form extensive areas of atrophic plaque.
Atrophie blanche shows seasonal variation, typically worsening in the
summer months. Lesions recur at periodic intervals and are predominantly
located on the lower legs, ankles, and the dorsal surfaces of the feet.
Occasionally, however, they are found around the forearms, fingers, and
hands or even in a more widespread distribution.3,5,6 The disease is often
associated with signs of venous stasis.
Atrophie blanche has been reported in association with lupus erythematosus
and antiphospholipid syndrome.7,8 One study found 17% of lupus patients
were affected.8 This study also noted that the pattern of cutaneous lesions was
somewhat unusual, with involvement of the knees, elbows, fingers, soles, and
the back.8 The same study suggested that patients with lupus erythematosus
who have atrophie blanche are at an increased risk of developing lupus central
nervous system involvement.8
Pathogenesis and histological features
The pathogenesis of atrophie blanche is not well understood but it appears
that ischemia may be the end result. Although increased hydrostatic
pressure certainly contributes to the development of this condition, the
finding of both immunoglobulin (usually IgM, less often IgG and IgA)
and complement within the blood vessel walls raises the possibility of
an immunological pathogenesis.9 It has been associated with a localized
defect of tissue plasminogen activator.3,10 The location of the lesions
certainly suggests that trauma may also play some role in development
of lesions. Recently, patients with atrophie blanche and disorders of
coagulation such as factor V Leiden mutation, raised anticardiolipin
antibodies, protein C or protein S deficiency, prothrombin mutation, and
raised levels of fibrinopeptide A  have been described, suggesting that,
at least in some patients, an underlying coagulopathy is the basis of
disorder.4,11–17
700 Vascular diseases
B In the fully established atrophic plaque, in addition to the vascular changes,
Fig. 16.110
Atrophie blanche: (A) there is ulceration with erythema and scaling; (B) this example shows
marked hyperpigmentation with scarring and atrophy around the ankle and extending onto
the dorsum of the foot. By courtesy of the Institute of Dermatology, London, UK.
Fig. 16.111
Atrophie blanche: an
extensive ivory-white
area of scarring overlies
the medial malleolus. By
courtesy of R.A. Marsden,
St George's Hospital,
London, UK.
Fig. 16.112
Atrophie blanche: the vessels in the papillary dermis are increased in number and
show mural fibrin deposition. There is underlying scarring.
Early and ulcerative lesions are characterized by the presence of increased
numbers of dermal vessels containing fibrin within their walls in addition to
intraluminal fibrinoid plugs (Figs 16.112–16.114). The latter are typically
diastase-resistant and periodic acid–Schiff (PAS) positive, and can also be
highlighted by use of the phosphotungstic acid–hematoxylin stain (Fig.
16.115). Inflammatory destruction of blood vessels is, however, not a
feature and therefore this disorder is not a true vasculitis. Variable degrees
of red cell extravasation are evident and hemosiderin pigment is often
present. A perivascular lymphohistiocytic infiltrate of varying intensity
is usually found and dermal mast cells are often increased in number.
Ulcerative lesions show infarction of the superficial dermis and epidermis.
the epidermis is atrophic and the dermis shows dense scleroderma-like
scarring.
Differential diagnosis
The histological features in the appropriate clinical setting are diagnostic.
Coagulopathies are associated with intraluminal fibrinoid plugs but not
extensive fibrinoid change of the vessel wall. Atrophie blanche shows some of
the features seen in stasis dermatitis such as clustering of vessels in the superficial
dermis; however, uncomplicated stasis does not show fibrinoid change.
Dermatological manifestations of
cholesterol crystal embolism and embolism
from atrial myxoma
Clinical features
Cholesterol crystal embolism is a disease of the elderly and typically occurs
in males (4:1), thereby reflecting the demographics of atherosclerosis.1,2
Cholesterol embolism may occur spontaneously or complicate trauma to the
aorta.1 It can be seen following warfarin therapy.3 Systemic symptoms due to
infarction are variable and depend upon the organ embolized. Necrotizing
vasculitis has been described following cholesterol crystal embolization.4
Multisystem involvement sometimes results in an initial diagnosis of
vasculitis.
Patients commonly manifest pyrexia, myalgia, and a sudden onset of
systemic hypertension as well as renal failure and cutaneous lesions.5 An
increased ESR, blood eosinophilia, and raised serum creatinine are additional
features. Cutaneous manifestations are common and include:
• livedo reticularis, often bilateral, affecting the feet and legs and
sometimes extending up to involve the trunk,6
• gangrene of the toes (Fig. 16.116),
 Disseminated intravascular coagulation 701

Fig. 16.113 Fig. 16.114 Fig. 16.115

Atrophie blanche: high-power view of vessels. Atrophie blanche: occluded vessels are present. Atrophie blanche: the vessel walls are strongly PAS
There is marked red blood cell extravasation. positive, diastase resistant.

Cardiac myxomas are rare but represent the most frequent primary
cardiac tumor. Although benign, they are a marker of Carney's syndrome
and early recognition is imperative as distant embolization is an important
complication associated with high mortality. Cutaneous symptoms include
erythematous macules and papules predominantly of acral sites, digital
cyanosis, petechiae, splinter hemorrhages, telangiectasia, and livedo
reticularis.7–14

Pathogenesis and histological features

Cholesterol emboli are found in the small to large arteries and arterioles
of the deep dermis or subcutaneous fat (Figs. 16.117, 16.118). Diagnosis
depends upon the identification of typical biconvex cleft- or needle-shaped
empty spaces (representing evanescent cholesterol crystals dissolved during
tissue processing) often associated with atheromatous debris or luminal
thrombosis. It is essential, therefore, that deep biopsies are taken. Multiple
levels should also be examined because emboli tend to be patchily distributed
and are often difficult to detect. The skin supplied by the occluded vessel may
be infarcted.
Emboli from atrial myxomas are characterized by the presence of myxoid
material within medium-sized vessels. Due to vascular occlusion, this is
accompanied by fibrin deposition and a reactive vascular proliferation.
Fig. 16.116 Demonstration of the myxoid substance is often difficult and commonly
Cholesterol embolism: requires examination of multiple levels.
there is extensive
infarction of the toes of
this elderly male patient.
Disseminated intravascular coagulation
• cyanosis, Clinical features
• purple discoloration of the toes, Disseminated intravascular coagulation (DIC) is a consumptive coagulopathy
• cutaneous ulceration, that is associated with a wide variety of underlying disorders, many of them
• nodules on the legs, thighs, feet, and toes, life threatening. It is not uncommonly seen in very ill patients and may
• purpuric lesions on the legs and feet. be acute, subacute or chronic. Purpura fulminans is a term that has been
The cutaneous lesions of cholesterol crystal embolism therefore mimic applied to infection-associated DIC in children. More recently, some authors
many other vascular lesions, and biopsy is essential for diagnosis. Mortality have applied the term less restrictively to a severe form of DIC associated
is very high due to cardiac and central nervous system involvement. with high morbidity and mortality.1,2 Purpura fulminans is characterized by
702 Vascular diseases

A B

Fig. 16.117 Fig. 16.118

Cholesterol emboli: there is ulceration and dermal Cholesterol embolism: (A) the overlying epidermis shows full-thickness infarction; (B) high-power view of
scar tissue extending into the septa of the cholesterol clefts.
subcutaneous fat. Needle-shaped crystals are present
in the lumen of an artery in the middle of the field.

an acute syndrome of rapidly progressive and extensive hemorrhagic skin fibrin, clotting factors and platelets, vascular occlusion, tissue ischemia, and
necrosis associated with dermal vascular thrombosis and vascular collapse hemorrhage. Clotting factors may be consumed at a rate that exceeds the
due to DIC.3,4 A common presentation is symmetrical purpura of the fingers ability of the liver for synthesis. The coagulopathy, in turn, causes a hemolytic
and toes. anemia by damaging red blood cells.
DIC is commonly associated with complications of pregnancy and Purpura fulminans is sometimes a manifestation of hereditary protein
delivery such as abruptio placentae, sepsis, and amniotic fluid embolism. C deficiency, protein S deficiency, coumadin therapy, and antiphospholipid
A wide variety of infections including bacterial sepsis, meningococcemia, antibodies.3
and fungal infections may also be associated. Massive trauma, heat stroke,
shock, snakebite, poisoning, and burns can cause DIC. Malignant neoplasms
(including carcinoma of the stomach, breast and colon, small cell carcinoma
of the lung, brain, and pancreas) and hematological malignancies have also
been associated with this condition.5–14
Purpura fulminans occurs predominantly in children and has an equal
incidence in males and females. It develops as a complication of a prodromal
infectious illness, most commonly meningococcemia, scarlet fever, viral upper
respiratory tract infection, chickenpox, rubella, and other exanthemata.15
The disease shows some seasonal variation, being more common in winter
and spring. Children develop large confluent ecchymoses, which particularly
affect the buttocks, legs, and feet, and commonly appear on the upper limbs
and abdomen (Fig. 16.119). The ecchymoses frequently become necrotic,
and blood-filled blisters are often found. On occasion the limbs become
gangrenous (Fig. 16.120). Fever and hypotension accompany the cutaneous
lesions.
Hematological studies reveal thrombocytopenia, anemia, and often
a leukocytosis. The prothrombin and bleeding times are prolonged.
Fibrinogen levels are low and fibrin–fibrinogen degradation products
elevated.
Fig. 16.119
Pathogenesis and histological features Purpura fulminans:
bilateral extensive
As stated above, DIC is not a disease sui generis but represents a coagulopathy ecchymoses are present
resulting from a large number of disorders. These conditions trigger DIC on this child's legs. By
either by causing direct injury to endothelial cells, which causes platelet courtesy of D. McGibbon,
aggregation, or by increasing circulating procoagulant factors, often tissue MD, St Thomas' Hospital,
factor. The consequences are thrombosis, fibrinolysis leading to depletion of London, UK.

Fig. 16.120
Purpura fulminans: there
is complete gangrene
of the skin. By courtesy
of D. McGibbon, MD,
St Thomas' Hospital,
London, UK.
Biopsy of skin lesions in patients with DIC are characterized by fibrin,
platelet or mixed thrombi in the capillaries and venules, particularly of the
skin, but also commonly affecting the internal viscera including the kidneys,
bowel, bladder, and brain (Figs 16.121, 16.122).3 The number of vessels
containing thrombi ranges from scattered to nearly all vessels being involved.
Variable numbers of extravasated red blood cells are seen. In patients with
purpura fulminans, the thrombi are associated with diffuse and extensive
hemorrhage. Early lesions usually show few or no perivascular inflammatory
cells. Older lesions are often characterized by epidermal necrosis and
subepidermal blood-filled bullae. A mild perivascular inflammatory cell
infiltrate of lymphocytes and polymorphs may be present. Infective DIC or
purpura fulminans sometimes shows features of a leukocytoclastic vasculitis.
Immunofluorescence studies for immunoglobulins and complement are
uniformly negative.
Fig. 16.121
Purpura fulminans: there is epidermal infarction.
Cryoglobulinemia 703
Fig. 16.122
Purpura fulminans: numerous small thrombi are seen in the superficial vessels.
Differential diagnosis
The differential diagnosis includes other causes of coagulopathy or
leukocytoclastic vasculitis. Serological evaluation for disorders of coagulation
is required to support the diagnosis. Finally, since successful treatment is both
supportive and aimed at the underlying disorder, patients must be evaluated
to determine the underlying causes of the DIC.
Cryoglobulinemia
Cryoglobulins are immunoglobulins that precipitate at low temperatures
(4°C) and which redissolve on warming (Fig. 16.123). Typically, the greater
their concentration, the higher the temperature at which they precipitate.
This has obvious clinical implications, particularly for plasmapheresis
therapy.
Cryoglobulins may be subdivided into three classes: 1,2
• Type I cryoglobulin is composed solely of monoclonal immunoglobulin
(either kappa or lambda) and is usually, though not invariably, associated
with a variety of lymphoproliferative disorders, including multiple
myeloma, Waldenström's macroglobulinemia, chronic lymphocytic
leukemia, and lymphocytic lymphoma.
• Type II (mixed) cryoglobulin is composed of monoclonal (usually IgM)
immunoglobulin reacting against polyclonal IgG.
• Type III (polyclonal) cryoglobulin is composed of polyclonal
immunoglobulins (usually IgG and IgM).
The last two subtypes (mixed cryoglobulins) function as immune
complexes and clinical manifestations are therefore due, at least in part, to
allergic vasculitis. Mixed cryoglobulinemia may be clinically subdivided into
two forms:
• Essential mixed cryoglobulinemia, in which most patients are infected
with the hepatitis C virus.2,3 Hepatitis B virus has been also described in
association with essential mixed cryoglobulinemia.2,4
• Secondary mixed cryoglobulinemia, which develops as a complication of
a variety of conditions, including connective tissue diseases such as SLE,
lymphomas or infective disease processes (e.g. infective endocarditis and
glandular fever).5
Clinical features
The eponym ‘Meltzer’s triad' has been applied to the combined features
of purpura, arthralgia, and weakness that are often present.4 Cutaneous
manifestations are common to all classes of cryoglobulinemia and are often
the presenting complaint.1,4,6 Purpura is the most frequent initial sign.
Type I cryoglobulinemia is usually characterized by purpuric lesions
including inflammatory macules and papules on the extremities, accompanied
704 Vascular diseases
A B
Fig. 16.123
Cryoglobulinemia: (A) there is a large quantity of precipitated cryoglobulin in this plasmapheresis specimen;
(B) a cryoprecipitate. By courtesy of N. Slater, MD, St Thomas' Hospital, London, UK.
by foci of ulceration (Fig. 16.124).7 Additional features may include
livedo reticularis, Raynaud's phenomenon, scarring, and infarction, which
particularly affects the digits, ears, and nose.7 Renal lesions are uncommon,
but some patients may manifest hematuria, proteinuria (occasionally
amounting to the nephrotic syndrome) and, rarely, anuria.8
Mixed cryoglobulinemia is characterized by joint involvement (arthralgia
and arthritis), Raynaud's phenomenon, fever, purpura, weakness, renal
involvement, hepatosplenomegaly, and generalized vasculitis. Cutaneous
manifestations include palpable purpura, inflammatory macules and papules,
necrotizing vasculitis, crural ulcers and, occasionally, cold urticaria.7,9
Additional rare manifestations include follicular pustular purpura, erythema
multiforme, and necrobiotic xanthogranuloma.7,10,11 Renal involvement, most
frequently in the form of type 1 mesangioproliferative glomerulonephritis,
may be identified by proteinuria, hematuria, and red cell casts.2 Patients can
also have polyneuropathies.2 Prognosis is variable. Renal involvement, which
occurs in 50% of cases, is associated with high morbidity and mortality.
Given the frequent association of hepatitis virus infection with
cryoglobulinemia, it comes as no surprise that some patients develop
hepatocellular carcinoma.12,13
Pathogenesis and histological features
In keeping with an immune complex-mediated pathogenesis, hypocomple­
mentemia is the rule. The cryoprecipitate is composed of polyclonal IgG with
either monoclonal or polyclonal IgM and is associated with rheumatoid factor
properties.14 In some patients, hepatitis B virus surface antigen or antihepatitis
B antibodies are identified in either the serum or the cryoprecipitate,
suggesting a possible causal relationship. Both hepatitis C and hepatitis B
viruses have been reported in cases of mixed cryoglobulinemia.15–17 Since
most patients with essential mixed cryoglobulinemia are infected with the
hepatitis C virus, it appears likely that this represents the cause of this form
of the disease and consequently this aspect has received much investigative
attention. Hepatitis C virus and hepatitis C virus antigen–antibody complexes
have been demonstrated in cryoprecipitates.18 Hepatitis C viral RNA is
detected by polymerase chain reaction (PCR) in peripheral blood monocytes
of 81–90% of patients with mixed cryoglobulinemia.19,20 Hepatitis C
Fig. 16.124
Cryoglobulinemia: there is purplish discoloration
of the third toe. By courtesy of N. Slater, MD, St
Thomas' Hospital, London, UK.
genome has also been demonstrated in the bone marrow cells of patients
with mixed cryoglobulinemia.21 Interestingly, the E2 envelope protein of the
hepatitis C virus binds to CD81, which is present on B lymphocytes.22 What
role this interaction plays in the pathogenesis of cryoglobulinemia is poorly
understood.22
Other infective agents can also be associated with cryoglobulinemia
including protozoa, fungi, bacteria, Chlamydia, and rickettsiae. Cryoglo­
bulinemia has been reported in patients infected with the HIV virus.23–27
However, in HIV patients with circulating cryoglobulins, the clinical symptoms
usually associated with cryoglobulinemia are often lacking.23 Another study
has shown that in HIV-infected patients the presence of cryoglobulins is
significantly associated with increased mortality and risk of developing
neoplasia (including B-cell lymphoproliferative disorders).24 Interestingly,
disappearance of the symptoms of cryoglobulinemia following infection with
the HIV-1 virus has also been reported. The authors of this report speculate
on a significant role for CD4+ T cells in the pathogenesis of cryoglobulinemia
in a subset of patients.28
The histological features of monoclonal cryoglobulinemia are those of
vascular dilatation, endothelial swelling, and plugging of vascular lumina by
hyaline material, which is diastase resistant and PAS positive (Fig. 16.125).
Intravascular rouleaux formation may also be a feature.7 On occasion,
monoclonal cryoglobulinemia may be associated with leukocytoclastic
vasculitis.7
In addition to occasional intracapillary hyaline thrombi, patients with severe
renal involvement sometimes manifest features of membranoproliferative
glomerulonephritis.
Mixed cryoglobulinemia is associated with immune complex-mediated
acute leukocytoclastic vasculitis. The cryoglobulins precipitate in small
vessels at low temperature and the resultant complement activation ensures
the changes of acute vasculitis. Immunofluorescence is positive for IgG, IgM,
and complement (Fig. 16.126). Occasionally, intravascular hyaline thrombi
are present in early lesions. Red cell extravasation is often a feature.
In biopsies from acute cases, the renal glomeruli show intracapillary
thrombi. Other renal manifestations include membranoproliferative glomerulo­
nephritis and vasculitis.
 Antiphospholipid antibody syndrome and Sneddon's syndrome 705

Differential diagnosis
The histological differential diagnosis of monoclonal cryoglobulinemia
includes other causes of thrombotic vasculopathy, for example DIC,
thrombotic thrombocytopenic purpura, protein C deficiency, and warfarin
(coumadin) necrosis. Although subtle histological clues may suggest
cryoglobulinemia, such as the waxy hyaline texture of the casts, definitive
diagnosis is based on serological testing for cryoglobulins. The differential
diagnosis of mixed cryoglobulinemia includes other causes of leukocytoclastic
vasculitis.

Antiphospholipid antibody syndrome and

Sneddon's syndrome
Clinical features
A The circulating anticoagulant known as the antiphospholipid antibody is
associated with paradoxical thrombosis, spontaneous abortion, premature
labor, intrauterine death, labile hypertension, cutaneous necrosis, gangrene,
ecchymoses, purpura, leg ulcers, atrophie blanche, livedo reticularis, and
false-positive syphilis serology – the lupus anticoagulant syndrome.1–6
The last, also known more accurately as the antiphospholipid syndrome
because not all patients have associated SLE, is due to the presence of
circulating antiphospholipid antibodies, which inhibit coagulation in vitro,
and are associated with a greatly increased risk of thrombotic phenomena
affecting both arteries and veins. The most common autoantigen in the
antiphospholipid syndrome is the protein beta-2 glycoprotein 1.7 In addition
to the ‘lupus anticoagulant’, another important type of antiphospholipid
antibody is the anticardiolipin antibody, named for its ability to bind
cardiolipin.
Although this syndrome is most often encountered in young adult women,
it has been documented in children as well as the elderly. This demographic
pattern is certainly a reflection of the association with lupus erythematosus,
which shows a marked predilection for young women (Table 16.15).
Cutaneous involvement is often the first manifestation of disease. Patients
B develop necrosis of skin, which, in some cases, is widespread and severe.8 In
addition to disfiguring necrosis, these patients suffer pain and are at risk of
Fig. 16.125 superimposed infection.9 Livedo reticularis is due to thrombotic involvement
Monoclonal cryoglobulinemia: (A) crusted ulcer with occluded vessels at its base;
of arterioles and arteries.
(B) high-power view of a hyaline thrombus.
Systemic involvement includes deep venous thrombosis, often complicated
by pulmonary embolism, renal infarcts, cerebral vascular occlusion with
resultant strokes, transient ischemic attacks, multi-infarct dementia,
myocardial infarction, and gangrene.3 The term ‘catastrophic antiphospholipid
syndrome’ is applied to patients who develop complications resulting from
multiorgan involvement.9,10 The prognosis for this pernicious form of the
disease is poor: in one study, 60% of patients died.10
The association of cutaneous thrombotic lesions, hypertension, and
cerebrovascular disease is sometimes referred to as Sneddon's syndrome.3,11
Not all patients with Sneddon's syndrome have antiphospholipid antibodies –
the prevalence in various publications has ranged from 0% to 85%.11
In addition to lupus erythematosus, the antiphospholipid syndrome has also
been documented in association with other autoimmune diseases including
rheumatoid arthritis, hemolytic anemia, thrombocytopenic purpura, and
ulcerative colitis.12 It may also complicate treatment with a number of drugs
including phenothiazines and procainamide, or develop during viral illnesses,
and can present with an underlying lymphoma.12
There is a growing body of literature documenting systemic vasculitis
in patients with antiphospholipid and anticardiolipin antibodies including
Takayasu's arteritis, temporal arteritis, polyarteritis nodosa, and Wegener's
granulomatosis.13–18 A patient with Degos' disease and anticardiolipin
antibodies has also been described.19
Carcinomas arising in lung, ovary, gastrointestinal tract, and kidney have
been reported in association with antiphospholipid syndrome.20–25
Fig. 16.126 The syndrome has been reported in patients infected with the human
Mixed cryoglobulinemia: in this example, the features of acute leukocytoclastic immunodeficiency virus.26–28 Some HIV-infected patients have antiphospholipid
vasculitis are evident. antibodies without clinical features of the antiphospholipid syndrome.26
706 Vascular diseases

Table 16.15
Preliminary criteria for the classification of the antiphospholipid syndrome*

Clinical criteria†
1. Vascular thrombosis: One or more clinical episodes of arterial, venous or small vessel thrombosis, in any tissue or organ. Thrombosis must be confirmed
by imaging or Doppler studies or histopathology, with the exception of superficial venous thrombosis. For histopathological confirmation, thrombosis
should be present without significant evidence of inflammation in the vessel wall.
2.  Pregnancy morbidity:
(a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology
documented by ultrasound or by direct examination of the fetus, or
(b) One or more premature births of a morphologically normal neonate at or before the 34th week of gestation because of severe pre-eclampsia or
eclampsia, or severe placental insufficiency, or
(c) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities
and paternal and maternal chromosomal causes excluded.
In studies of populations of patients who have more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of
subjects according to (a), (b) or (c) above.
Laboratory criteria
1. Anticardiolipin antibody of IgG and/or IgM isotype in blood, present in medium or high titer, on two or more occasions, at least 6 weeks apart, measured
by a standardized enzyme-linked immunosorbent assay for β2-glycoprotein I-independent anticardiolipin antibodies.
2. Lupus anticoagulant present in plasma, on two or more occasions, at least 6 weeks apart, detected according to the guidelines of the International Society
on Thrombosis and Hemostasis (Scientific Subcommittee on Lupus Anticoagulants/Phospholipid-Dependent Antibodies), in the following steps:
(a) Prolonged phospholipid-dependent coagulation demonstrated on a screening test, e.g. activated partial thromboplastin time, kaolin clotting time,
dilute Russell's viper venom time, dilute prothrombin time, Textarin time.
(b)  Failure to correct the prolonged coagulation time on the screening test by mixing with normal platelet-poor plasma.
(c) Shortening or correction of the prolonged coagulation time on the screening test by the addition of excess phospholipid.
(d) Exclusion of other coagulopathies, e.g. factor VIII inhibitor or heparin, as appropriate.
Definite antiphospholipid antibody syndrome is considered to be present if at least one of the clinical criteria and one of the laboratory criteria are met.

* No exclusions other than those contained within the above criteria are needed. However, because of the likelihood that thrombosis may be multifactorial in patients with the
antiphospholipid antibody syndrome, the workshop participants recommend that: (a) patient populations being studied should be assessed for other contributing causes of
thrombosis, and (b) such populations should be stratified according to identifiable or probable risk factors (e.g. age or comorbidities). Specific limits were not placed on the interval
between the clinical event and the positive laboratory findings. However, it was the view of many at the workshop that: (a) information about such intervals should be assessed when
relevant, and (b) the relatively strict definition of laboratory criteria (including the requirement that results again be positive on repeat tests performed at least 6 weeks after the initial
test) would help to exclude antiphospholipid antibody positivity that represents an epiphenomenon to the clinical events.
† These criteria were mainly developed by Branch and Silver.
Reproduced with permission from Wilson, W.A. (2001) Rheumatic Diseases Clinics of North America, 27, 499–505.

Pathogenesis and histological features

Antibodies (IgM or IgG) that are reactive with phospholipids clearly play a
role in the pathogenesis of this disorder; however, the precise pathogenesis
is not well understood. Theories include inhibition of protein C (a natural
vitamin K-dependent anticoagulant) function and a suppressive effect on
endothelial cell prostacyclin.29 Endothelial cell injury and platelet activation
may also play a role. The role of beta-2 glycoprotein, a glycoprotein with
antithrombotic properties, has been investigated. Some antiphospholipid
antibodies bind to beta-2 glycoprotein 1, which can lead to inhibition of factor
XII and platelet activation and also decrease prothrombinase activity.
Patients with the antiphospholipid antibody are predisposed to thrombosis
and have prolonged partial thromboplastin and kaolin clotting times;
however, it is important to note that not all patients with the antiphospholipid
antibody develop thrombosis. In one study, 28% of lupus patients with
antiphospholipid antibodies had no evidence of antiphospholipid antibody
syndrome.30
Biopsy shows features of a thrombotic vasculopathy, i.e. vascular occlusion
of arterioles and arteries with a fibrinoid plug, which may be associated with
variable numbers of intraluminal inflammatory cells. Generally, there is
minimal or no inflammation of the blood vessel wall or surrounding tissue.
Marked dermal necrosis is sometimes a feature. It should be noted that false-
negative biopsies may occur.11 Therefore a negative biopsy does not exclude
underlying disease.
Differential diagnosis
The biopsy findings are non-specific and the differential diagnosis includes
other forms of thrombotic vasculopathy. Serological studies are required to
evaluate for antiphospholipid and anticardiolipin antibodies as well as to
evaluate for underlying associated disorders.
Thrombotic thrombocytopenic purpura and
hemolytic uremic syndrome
Clinical features
Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome
(HUS) are related disorders that are due to nonimmune thrombocytopenia.1–4
TTP is a very rare disease of unknown etiology associated with high morbidity
and mortality.5,6 It shows a predilection for females (2.5:1) and tends to affect
younger age groups, with a peak incidence in the third decade. In its fully
developed form it consists of thrombocytopenic purpura, microangiopathic
hemolytic anemia, neurological symptoms, renal involvement, and fever.
Hemolytic uremic syndrome is similar to TTP except that it includes severe
renal involvement and milder CNS symptomatology.7 However, precise
classification into one or the other category is sometimes difficult; therefore
these related disorders are discussed together.8,9 Hemolytic uremic syndrome
is often seen in patients with infectious colitis.10,11
The most common presenting symptoms are transient and usually
recurrent neurological complaints including headaches, confusion, pareses,
dysphasia, and aphasia. Renal involvement includes hematuria, proteinuria,
and occasionally acute renal failure. Cardiac involvement is important and
may precipitate left ventricular failure with resultant pulmonary congestion
and edema. The hemorrhagic tendency is manifest predominantly in the skin
as petechiae, purpura, and ecchymoses, but hemorrhage may also be seen
in the retina, conjunctiva, and mucous membranes, including those of the
gastrointestinal tract (Fig. 16.127).
TTP/HUS can be associated with connective tissue disease (especially lupus
erythematosus), contraceptive use, neoplasia, chemotherapy, adverse drug
reaction, bone marrow transplantation, and antiphospholipid antibodies.4,7,12–17
 Immune thrombocytopenic purpura 707

Fig. 16.127
Thrombotic Fig. 16.128
thrombocytopenic Thrombotic thrombocytopenic purpura: microthrombi are present and there is
purpura: sheeted extensive red cell extravasation.
ecchymoses are present
in the groin. By courtesy
of N. Slater, MD, St
Thomas' Hospital,
London, UK.

Although most patients develop TTP for no apparent reason, it occasionally

complicates drug therapy with, for example, penicillin or sulfonamides, or may
develop after an upper respiratory tract infection. Quite a high proportion of
patients with TTP are pregnant, but the significance of this is uncertain. Rare
cases may be associated with lupus erythematosus.
Familial cases of TTP/HUS, with both autosomal dominant and recessive
patterns of inheritance, have been described.7
Laboratory investigations reveal gross thrombocytopenia and normo­
chromic, normocytic anemia. Examination of peripheral blood smears
commonly demonstrates fragmented and misshapen red blood cells, typically
schistocytes and helmet cells. Coagulation studies are usually normal or
minimally disturbed with occasionally elevated fibrinogen–fibrin degradation
products. The Coombs' test is consistently negative.
Fig. 16.129
Pathogenesis and histological features Thrombotic thrombocytopenic purpura: the occlusions contain abundant fibrin
The pathogenesis of TTP/HUS is poorly understood. It appears that platelet (Martius scarlet blue).
activating substances result in thrombus formation without activation of
the coagulation cascade (hence the normal coagulation studies). Direct
endothelial injury could also play a role in this group of disorders. At autopsy the organs most severely involved include the pancreas, adrenal
TTP has been shown to be associated with deficiency of von Wille­ glands, heart, brain, and kidney.
brand factor-cleaving metalloprotease, ADAMTS13 (a disintegrin and
metalloprotease with thrombospondin 1 repeats-13).18–22 Most cases Differential diagnosis
in adulthood are acquired and caused by autoantibodies inhibiting the
Distinction from other thrombotic vasculopathies requires clinicopathological
function of ADAMTS13.21–23 Familial cases of TTP are due to mutations in
correlation. In contrast to disseminated intravascular coagulation, coagulation
ADMATS13, resulting in constitutional absence of this enzyme.18,21,22 HUS
studies (prothrombin time, partial thromboplastin time) tend to be normal in
is often seen in patients with colitis associated with verotoxin-producing
patients with TTP/HUS.
E. coli.1,24 In one study, 80% of patients with HUS had positive E. coli O157
lipopolysaccharide antibody titers.10 Investigators have shown that verotoxin
enhances platelet adhesion and thrombogenesis using a microvascular
endothelial cell line.25 A minority of patients with HUS have been shown to Immune thrombocytopenic purpura
have mutation in the gene coding for factor H, an alternative complement
pathway regulatory protein.26 Clinical features
The histological features of thrombotic thrombocytopenic purpura are Immune thrombocytopenic purpura (idiopathic thrombocytopenic purpura,
those of hyaline intravascular thrombi composed of aggregates of platelets ITP) is a rare disease, of which two forms – acute and chronic – are
in addition to a variable amount of fibrin (Figs 16.128, 16.129).27 They recognized:
are associated with extravasated red blood cells, but there is no evidence of • Acute ITP is a disorder that characteristically affects children following
vasculitis. There may be foci of necrosis, but true infarcts are uncommon. a viral illness.1 Patients present with petechiae, purpura, and bleeding.
708 Vascular diseases
Fig. 16.130
Idiopathic thrombocytopenic purpura: these legs show purpura, petechiae, and
bruising. By courtesy of N. Slater, MD, St Thomas' Hospital, London, UK.
Most cases are self-limiting with the majority of patients recovering
within weeks to months.2,3 A rare but serious complication is intracranial
hemorrhage.
• Chronic ITP is the term used when the disorder persists for 6 months
or longer.2 The chronic form tends to affect adults and is associated
with connective tissue diseases such as lupus erythematosus or
lymphoproliferative disorders.
Thrombocytopenic purpura has also been described in patients with
thyroid disorders, including Graves' disease and Hashimoto's thyroiditis.4,5
The condition may occur in association with multiple concurrent
autoimmune diseases such as diabetes mellitus, pernicious anemia, and
systemic sclerosis.6 Some patients have had associated antiphospholipid
antibody syndrome.7–9 Patients with Helicobacter pylori infection or those
infected with the human immunodeficiency virus may also develop immune
thrombocytopenia.10–13
The chronic form shows a predilection for women, and presents with a
tendency to bruise easily following mild trauma and bleeding (Fig. 16.130).
In severely affected patients, lesions develop in the mucous membranes of
the respiratory, genitourinary, and gastrointestinal systems in addition to the
integument.
Laboratory examination reveals thrombocytopenia and a prolonged
bleeding time. Partial thromboplastin time and prothrombin time are not
affected.
Pathogenesis and histological features
Immune thrombocytopenic purpura is an autoimmune disease caused by
IgG antiplatelet antibodies, which lead to destruction of platelets.14–16 More
recently, a cytotoxic T cell-mediated process has also been implicated in platelet
destruction.17 Molecular mimicry between HIV glycoproteins (GP120/160)
and membrane antigens (i.e. glycoprotein GPIIb/IIIa) on platelets may play
a role in the development of thrombocytopenia in occasional HIV-infected
patients.14,16,18,19
The cutaneous (and other) lesions are characterized by perivascular
hemorrhage; there is no evidence of vasculitis (Fig. 16.131). Bone marrow
examination reveals increased numbers of rather immature megakaryocytes.
The spleen is congested and shows reactive follicular hyperplasia and
sometimes conspicuous megakaryocytes.
Differential diagnosis
Biopsy findings are entirely non-specific. Serological and clinical correlation
is necessary to arrive at a diagnosis.
Fig. 16.131
Idiopathic
thrombocytopenic
purpura: there is
hemorrhage but no
evidence of vasculitis is
seen.
Factor V (Leiden) mutation
Clinical features
Mutation of factor V Leiden is the most common inherited condition
predisposing to thrombosis.1 The mutation is associated with a prothrombotic
state caused by factor V resistance to inactivation by protein C. It can be
identified by PCR.
Patients with this mutation are at particular risk of deep venous thrombosis
and may also develop pulmonary embolism, stroke, and peripheral vascular
disease.2 Women with recurrent miscarriage have an increased incidence of
this condition.3,4 Among patients with no known explanation for deep venous
thrombosis, factor V Leiden mutation is a common cause. Patients may also
develop skin ulcers.
Histological features
Biopsy of skin lesions shows features of thrombotic vasculopathy. IgM and
C3 deposition has been demonstrated by immunofluorescence staining.5
Hypergammaglobulinemic purpura
Clinical features
Hypergammaglobulinemic purpura (of Waldenström) is a rare disorder
that shows a marked female predilection and tends to affect the young and
middle aged.1 Patients present with recurrent, symmetrical crops of purpura,
particularly affecting the lower limbs although the arms and abdomen may
also be involved (Fig. 16.132).2 Wearing tight-fitting garments, heat, and
strenuous exercise may provoke lesions. The frequency of attacks is highly
variable, ranging from several times a week to as infrequent as a single episode
per year.3,4
The clinical findings are those of petechiae measuring from pinhead size
up to several millimeters. Various symptoms may be experienced, including
tingling, itching, burning, and pain. The petechiae resolve over the course
of a few days to leave hyperpigmented macules. The purpuric attacks are
recurrent and tend to great chronicity. Ecchymoses are not a feature.1
Laboratory investigations usually reveal a raised ESR, mild anemia
and leukopenia, and polyclonal hypergammaglobulinemia (usually IgG,

Fig. 16.132
Hypergammaglobulinemic purpura: scattered, tiny, purpuric lesions. By courtesy of
J. Newton-Bishop, MD, St Thomas' Hospital, London, UK.
but sometimes IgM or IgA). Antinuclear antibodies, anti-Ro, anti-La, and
rheumatoid factor are present in many patients.1,3,5,6 Platelet levels, coagulation
studies, and bone marrow examination are typically normal. Cryoglobulinemia
is an occasional feature. There are no known HLA associations and family
history is negative.1 Lymphadenopathy and splenomegaly are sometimes a
feature.1
It is important to note that hypergammaglobulinemic purpura may be
classified into two categories: idiopathic (Waldenström; not to be confused
with Waldenström's macroglobulinemia) and secondary. In the latter group,
patients have a wide variety of conditions, including SLE, polymyositis,
Hashimoto's thyroiditis, Sjögren's syndrome, rheumatoid arthritis,
hepatitis, chronic lymphocytic leukemia, monoclonal gammopathies, and
sarcoidosis.1 The purpura may precede the associated illness for many
years. Patients with this disorder, therefore, merit a careful and prolonged
follow-up.
Pathogenesis and histological features
Direct immunofluorescence examination of skin lesions reveals IgM and
C3 in blood vessel walls.7 Circulating immune complexes, with both IgG
and IgM, have also been demonstrated in patients with this disorder.8 It is
likely, therefore, that hypergammaglobulinemic purpura is another variant
of immune complex-mediated vasculitis, namely, a type III hypersensitivity
reaction. The precise etiology, however, remains poorly understood.
Histological examination of the purpuric lesions usually reveals the typical
features of acute leukocytoclastic vasculitis with red cell extravasation.9
Occasionally, however, lymphocytic perivasculitis is all that is evident.
Differential diagnosis
The histological changes are not specific and other causes of leukocytoclastic
vasculitis must be considered.
Hyperimmunoglobulinemia D syndrome
Clinical features
Hyperimmunoglobulinemia D syndrome is a rare autosomal recessive disease
due to mutations in the mevalonate kinase (MVK) gene, a key enzyme
located on chromosome 12 and involved in the biosynthesis of cholesterol
and isoprenoid.1,2
The disease is most common in Europe and presents in childhood as
recurrent episodes of high fever lasting for 3–7 days. Vaccinations and
Sclerosing lymphangitis 709
minor infections may be inciting events. Fever attacks are accompanied
by abdominal symptoms, headaches, generalized lymphadenopathy, and
arthralgias of large joints.3,4 Amyloidosis is a rare complication.3 Cutaneous
manifestations include erythematous macules, papules, and nodules as well
as urticarial lesions.5 Elevated IgD levels can be demonstrated in the majority
of patients.3
Histological features
The skin biopsy findings are variable and most frequently show a mild acute
vasculitis. Rarely, the features are reminiscent of Sweet's syndrome, cellulitis
or erythema elevatum diutinum.4–6
Superficial thrombophlebitis
Clinical features
Superficial thrombophlebitis is a common disease presenting as painful,
erythematous, thickened areas with a cordlike morphology. Most cases involve
the lower limbs, particularly below the knees, and there is a predilection for
females. Multifocal segmental disease is frequent and recurrent episodes
are often seen. The disease is usually associated with hypercoagulable
states. Predisposing factors are numerous and include varicose veins,
pregnancy, the use of oral contraceptives (particularly those with a higher
concentration of estrogen), cancer (mainly breast, colonic, pancreatic, gastric,
cholangiocarcinoma, hematological as well as cutaneous), Behçet's disease,
factor V (Leiden) mutation, essential thrombocythemia, anticardiolipin
antibodies, and deficiencies of protein C, protein S, factor XII, antithrombin
III, and heparin cofactor 2C.1–17 Superficial thrombophlebitis developing
in association with secondary syphilis has been documented.18 Superficial
suppurative thrombophlebitis occurs mainly in children and it is caused by a
wide variety of microorganisms, mainly bacteria (both aerobic and anaerobic)
and, less commonly, fungi.19–23 The most common bacteria isolated include
S. aureus, E. coli, and P. aeruginosa.19,20 Candida is by far the most common
fungus associated with the disease.
Superficial thrombophlebitis may be associated with deep vein
thrombosis but the risk of this happening appears to be small unless there
are additional risk factors.24,25 The chance of a patient with superficial
thrombophlebitis developing pulmonary embolism is low, but it has been
documented and the risk appears to be greater in patients with disease
affecting the thigh.26–28
Histological features
Superficial thrombophlebitis typically involves veins located in the superficial
subcutaneous tissue. Early lesions are characterized by an infiltrate
predominantly composed of neutrophils obscuring the vessel walls. The
neutrophils are progressively replaced by lymphocytes, histiocytes, and
occasional giant cells. An organizing thrombus is initially present and this
is followed by recanalization and fibrosis. The infiltrate tends to remain
localized and there is very little involvement of the surrounding subcutaneous
tissue. Arteries are not affected.
Sclerosing lymphangitis
Clinical features
Sclerosing lymphangitis (Mondor's disease) is probably a misnomer as it likely
represents a variant of superficial thrombophlebitis that most commonly affects
the genitalia, chest wall or breasts. Women with large pendulous breasts seem to
be particularly predisposed.1 In these cases, and in others, trauma probably plays
a significant role in development. Some authors have reported an association
with breast carcinoma.2 Intravenous drug abuse may be an occasional cause
and sclerosing lymphangitis of the penis has been documented in association
with an underlying sexually transmitted disease.3,4 Sickle cell disease and
protein S deficiency are rare associations.5,6 Patients present with sometimes
710 Vascular diseases

painful linear cordlike lesions. Typically, lesions are a few centimeters in length
but sometimes may be much larger. The overlying skin is erythematous without
color change. The disorder is self-limiting and usually resolves in a few weeks.7
Rarely, persistent disease requires surgical intervention.8

Histological features
The pathology is characterized by organizing thrombus with variable
inflammation.

Senile purpura
Clinical features
Senile purpura affects the extensor surfaces of the forearms, hands, and lower
legs of the elderly.1,2 Corticosteroid therapy (topical or systemic) contributes
to its development in some patients. Lesions are persistent, lasting 1–3 weeks,
and consist of asymptomatic purpuric macules up to several centimeters
in diameter, in a background of actinically damaged or atrophic skin (Fig.
16.133). Senile purpura develops because of damage to the connective tissue
of the dermis, which fails to support the vasculature, rendering it more Fig. 16.133
susceptible to mild trauma. Senile purpura: trauma-
induced deep purple
ecchymoses on sun-
Histological features damaged skin. By
The lesions are characterized by red cell extravasation unassociated with courtesy of J. Newton-
any significant inflammatory cell reaction. There is usually marked solar Bishop, MD, St Thomas'
elastosis. Hospital, London, UK.
 Idiopathic connective Chapter

See
www.expertconsult.com
for references and
additional material
tissue disorders
Bostjan Luzar and Eduardo Calonje
17
Lupus erythematosus  711 Atrophoderma of Pasini and Pierini  748 Mixed connective tissue disease  756
Systemic sclerosis  734 Eosinophilic fasciitis  749 Relapsing polychondritis  757
Localized scleroderma  743 Polymyositis/dermatomyositis  751

in up to 20% of patients with systemic lupus.11 Periungual telangiectasia, sclero-

Lupus erythematosus
Lupus erythematosus is a complex disorder associated with numerous clinical
signs and symptoms and a wide range of laboratory abnormalities. It shows
a spectrum of varying prognosis, ranging from a benign, solely cutaneous
variant (localized discoid) through to a potentially fatal systemic illness.1–4
The range of subtypes is shown in Table 17.1.
Although the precise etiology is unknown, it is thought that interplay of
genetic factors, autoantibodies, immune complexes, hormones, and other fac-
tors is responsible for the development of the illness. There is evidence sug-
gesting that the incidence of the systemic variant is increasing, but due to
earlier diagnosis and more effective therapy, the mortality rate has signifi-
cantly diminished and the 10-year overall survival rate in adults now exceeds
90%.5 The presence of renal and/or neurological involvement, however,
remains a poor prognostic indicator.6
Pediatric systemic lupus erythematosus (SLE) is an aggressive illness with con-
siderable mortality, largely due to the incidence of renal disease. Even with corti-
costeroid and immunosuppressive therapy the death rate is as high as 15%.7
dactyly, and the presence of Raynaud's phenomenon may also signify potential
disease progression.10 Patients with DLE should not be made unduly worried
about the risk of developing systemic involvement, which is not high.
Discoid lupus erythematosus is persistent and affects twice as many females
as males. Although any age group may be involved, it is most common in the
third, fourth, and fifth decades, with a peak incidence in the late thirties.12
Presentation in childhood is rare.13–18 Lesions typically arise on sun-exposed
sites and patients frequently experience photosensitivity; there may be spring
and summer exacerbation.5 In the localized form, the head and neck are usu-
ally affected, but in the generalized variant, lesions may also be present on the
dorsal aspect of the arms, hands, and fingers and on the ‘V’ of the neck.
Nonexposed sites, including the trunk, upper limbs, and the palms and soles,
are also commonly involved.19
Facial plaques occur most often on the cheeks (Fig. 17.1). Other sites
affected include the bridge of the nose, the ears, the neck, and the scalp (Figs
17.2–17.6). The associated scarring of the scalp is followed by permanent

Clinical features
Discoid lupus erythematosus
Discoid lupus erythematosus (DLE), the commonest form, is subdivided into
localized and generalized variants. This is of prognostic importance because only
about 1% of patients with localized DLE develop systemic disease, but approxi-
mately 5% of those with the generalized form (in particular those with persistent
anemia, leukopenia, thrombocytopenia, false-positive Wassermann reaction, and
high-titer antinuclear factor) develop full-blown SLE.6,8–10 Discoid lesions develop

Table 17.1
Lupus erythematosus: subtypes

Discoid lupus erythematosus (localized)

Discoid lupus erythematosus (generalized)
Verrucous lupus erythematosus Fig. 17.1
Chilblain lupus erythematosus Discoid lupus
Chronic granulomatous disease with discoid lupus erythematosus-like erythematosus: typical
  dermatosis plaques are present on
Lupus erythematosus–erythema multiforme syndrome the cheek of a female.
Subacute cutaneous lupus erythematosus Note the erythema
Lupus erythematosus profundus and scale. This is a
Systemic lupus erythematosus characteristic site. From
Drug-induced lupus erythematosus the collection of the
C2 deficiency lupus erythematosus-like syndrome late N.P. Smith, MD, the
Neonatal lupus erythematosus Institute of Dermatology,
London, UK.
712 Idiopathic connective tissue disorders
Fig. 17.2
Discoid lupus erythematosus: close-up view showing erythema and scale. From the
collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
alopecia (Figs 17.7,17.8). Scalp involvement, which is more common in
those patients affected by the disease when they were young, is chronic, and
correlates with longstanding severe illness.20
Early lesions appear edematous and erythematous. An established plaque
of DLE, which may measure up to 10.0 cm across, is usually covered with
an adherent scale accompanied by epidermal atrophy, follicular dilatation,
and plugging (Figs 17.9, 17.10).5,19 If the scale is removed the horny plugs
are often seen attached to its undersurface (‘carpet tacks’ sign). Telangiectasia
is a common finding and lesions heal with scarring, which is often marked.
In dark- or black-skinned individuals the plaque may be hypo- or hyperpig-
mented and this may be particularly disfiguring (Figs 17.11–17.14).19
Fig. 17.3 Fig. 17.4
Discoid lupus erythematosus: there is scaling and Discoid lupus erythematosus: this severely affected
scarring on the ear lobe, a commonly affected site. patient shows healed ulceration with marked scarring
From the collection of the late N.P. Smith, MD, and disfigurement. By courtesy of the Institute of
the Institute of Dermatology, London, UK. Dermatology, London, UK.
Oral involvement occurs in 20–25% of patients with DLE, with the vermilion
border of the lower lip, alveolar processes, labial and buccal mucosae being par-
ticularly affected (Figs 17.15–17.17).21–26 Chronic lesions are typically erythema-
tous and atrophic with a scalloped white keratotic border and adjacent
telangiectasia.22 Erosions and ulcers are additional features.12 Lesions are some-
times indistinguishable from atrophic lichen planus. Involvement of the tongue
manifests as erythema, fissuring, and atrophy of the papillae.23 Chronic lupus
cheilitis is associated with cicatricial scarring and an increased risk of squamous
carcinoma.22 Perianal mucosal involvement has occasionally been documented.23
Discoid lupus erythematosus has been described in association with osteo-
poikilosis, α1-antitrypsin deficiency, polyarteritis nodosa, in a patient with scle-
roderma and chronic hepatitis C virus infection, and as a reaction to
tattoo.27–31
Verrucous (hypertrophic) discoid lupus erythematosus
Verrucous (hypertrophic) DLE presents as warty, hyperkeratotic papules and
plaques with a predilection for the face, scalp, mucous membranes of the lips,
and upper limbs (Figs 17.18, 17.19).5,32–34 It affects approximately 2% of
patients with chronic discoid disease.12 Although verrucous (hypertrophic)
hyperkeratotic skin changes have been observed in patients with SLE, such
cases are exceptional.34,35 Sometimes the palms and soles are affected and
occasionally the nails (Figs 17.20, 17.21). Rare manifestations include nodu-
lar keratoacanthoma-like, squamous cell carcinoma-like, and hypertrophic
lichen planus-like lesions on the arms and hands (Fig. 17.22).33,36 A variant
with associated necrosis of the subcutaneous tissue is known as lupus erythe-
matosus hypertrophicus et profundus.37
Systemic symptoms are usually absent in patients with localized DLE.38
In the generalized form in which cutaneous plaques may be quite wide-
spread, a small percentage may have Raynaud's phenomenon and arthral-
gia (Figs 17.23–17.25). Laboratory abnormalities are more common in the
generalized than in the localized variant.38 Anemia is not seen in localized
DLE, but is sometimes a feature of the generalized variant. Leukopenia, a
raised erythrocyte sedimentation rate (ESR), and hypergammaglobulinemia
Fig. 17.5
Discoid lupus erythematosus: in this chronic
lesion there is marked scarring. By courtesy of
R.A. Marsden, MD, St George's Hospital,
London, UK.
 Lupus erythematosus 713

Fig. 17.6 Fig. 17.7 Fig. 17.8

Discoid lupus erythematosus: dark-skinned races Discoid lupus erythematosus: hair loss is permanent. Discoid lupus erythematosus: there is alopecia with
are commonly affected. From the collection of the By courtesy of the Institute of Dermatology, very marked scarring. By courtesy of the Institute
late N.P. Smith, MD, the Institute of Dermatology, London, UK. of Dermatology, London, UK.
London, UK.

Fig. 17.9 Fig. 17.10

Discoid lupus erythematosus: close-up view of scale. Note the erythematous Discoid lupus
border. By courtesy of the Institute of Dermatology, London, UK. erythematosus: close-up
view showing follicular
plugging. By courtesy
can occur in both.8 Antinuclear factor (diffuse pattern), a positive of the Institute of
Wassermann reaction, and rheumatoid factor may also be features.8 Anti- Dermatology, London,
double-stranded DNA (dsDNA) antibodies are detected in a minority of UK.
patients with disseminated DLE, and these patients frequently transform to
the systemic disease; occasionally antibodies to single-stranded DNA Lupus erythematosus tumidus
(ssDNA) are present. Urinalysis and renal function tests are normal. Lupus erythematosus tumidus is a distinctive subset of cutaneous lupus clini-
Cutaneous squamous cell carcinoma and less often basal cell carcinoma cally presenting mainly in patients with DLE and rarely in patients with SLE.
may arise in patients with chronic lesions including the hypertrophic vari- It is characterized by erythematous papules, plaques or even nodules with an
ant.19,21,33,39–43 Squamous cell carcinoma occurs predominantly in males, par- urticarial appearance arising mainly on sun-exposed skin of the face, neck,
ticularly affects the scalp, and is sometimes associated with early and trunk. Scarring does not occur. This variant of lupus is discussed in more
metastases.6,44 detail in chapter 8.
714 Idiopathic connective tissue disorders
Fig. 17.11
Discoid lupus
erythematosus: foci of
hyperpigmentation can
be very disfiguring in
dark-skinned patients. By
courtesy of the Institute
of Dermatology, London,
UK.
Fig. 17.12
Discoid lupus erythematosus: close-up view. By courtesy of R.A. Marsden, MD,
St George's Hospital, London, UK.
Chilblain lupus erythematosus
Chilblain lupus erythematosus (CHLE), which accounts for approximately
11% of DLE cases, develops during the winter months or following expo-
sure to cold, wet, and damp conditions.45,46 Although CHLE appears most
frequently in sporadic patients,47 familial occurrence has recently been
reported.46,48,49 Patients with familial CHLE display mutations in the TREX1
gene located on chromosome 3p, encoding a DNA-specific 3′-5′ exonu-
clease 1.46,48,49 Autosomal dominant inheritance has been demonstrated in
these patients.46,48,49 While familial CHLE generally presents in early child-
hood, sporadic CHLE usually affects middle-aged females.45,46,48,50 Patients
develop itchy, painful, papuloerythematous or blue-purple plaques and
nodules on the fingers, heels, and soles of the feet; the hands, calves, knees,
knuckles, elbows, nose, and ears are less often affected (Fig. 17.26).6
Hyperkeratotic fissured lesions and ulcers are sometimes also present.50
CHLE may present with depigmentation mimicking vitiligo.51 Although
patients usually develop chilblains many years after the typical discoid rash,
lesions may develop simultaneously and sometimes the chilblains are the
Fig. 17.13
Discoid lupus erythematosus: marked hypopigmentation may be a distressing
complication. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 17.14
Discoid lupus
erythematosus: in
this patient, the arm
is severely affected.
By courtesy of R.A.
Marsden, MD, St
George's Hospital,
London, UK.
sole manifestation.50 Some patients with sporadic CHLE have an associated
cryofibrinogenemia or cold agglutinin.6 About 20% of patients with spo-
radic CHLE develop SLE, particularly those who develop discoid and perni-
otic lesions simultaneously and those with DLE-erythema multiforme-like
syndrome in addition to perniosis.6,45,47 None with the familial CHLE have
progressed to SLE.47
Lupus erythematosus-erythema multiforme-like
syndrome
The lupus erythematosus-erythema multiforme-like syndrome (Rowell's syn-
drome) is rare.52–58 Patients, mostly middle-aged women, develop recurrent
episodes of annular lesions on the limbs and, to a lesser extent, on the face,
neck, chest, and mouth, in addition to the features of any variant of lupus
erythematosus.6,52,59–61 Involvement of palms and soles is exceptional.62 Early
lesions are erythematous papules, which become annular and may vesiculate
at the edge. The condition usually heals without scarring, but in severe

Fig. 17.15
Discoid lupus erythematosus: there is gross ulcerative cheilitis. The upper lip has
been stained with gentian violet. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
Fig. 17.16
Discoid lupus erythematosus: typical scarred lesion on the buccal mucosa. By
courtesy of R.A. Marsden, St George's Hospital, London, UK.
Fig. 17.17
Discoid lupus erythematosus: oral involvement is sometimes difficult to distinguish
from lichen planus. By courtesy of the Institute of Dermatology, London, UK.
Lupus erythematosus 715
Fig. 17.18
Verrucous discoid lupus erythematosus: this lesion has a very warty appearance.
By courtesy of the Institute of Dermatology, London, UK.
Fig. 17.19
Verrucous discoid lupus erythematosus: extensive disfiguring warty plaque
involving the upper lip and angle of mouth. By courtesy of J. Newton Bishop, MD,
St James's University Hospital, Leeds, UK.
disease bullae may develop, become necrotic, and ulcerate. Patients with this
variant also have erythrocyanosis, chilblains, and Raynaud's phenomenon.
Their serum contains speckled antinuclear factor, rheumatoid factor, and
anti-Ro/La antibody.6,8,52,53 In rare cases, anti-Ro/La and rheumatoid factor
are negative.63 Association with antiphospholipid syndrome has exception-
ally been documented.64,65
Lupus erythematosus profundus
Lupus erythematosus profundus (panniculitis) is another uncommon variant
that may develop in association with either DLE or SLE. This is discussed in
detail in chapter 10.
DLE and chronic granulomatous disease
Occasionally, a DLE-like dermatosis develops in female carriers of X-linked
chronic granulomatous disease.66–70 Mothers of affected children may occa-
sionally show similar lesions, presenting with bluish-red, infiltrated, scaly pap-
ules on the face and hands, sometimes associated with photosensitivity.67
Additional features include recurrent aphthous-like ulcerative stomatitis and
perniosis.
716 Idiopathic connective tissue disorders

Fig. 17.20 Fig. 17.22

Verrucous discoid lupus Verrucous discoid lupus erythematosus: this example resembles a
erythematosus: note the keratoacanthoma. By courtesy of the Institute of Dermatology, London, UK.
gross hyperkeratosis. By
courtesy of J. Newton
Bishop, MD, St James's
University Hospital,
Leeds, UK.

Fig. 17.23
Generalized discoid lupus erythematosus: in this variant, lesions are widespread and
may involve the chest, shoulders, and upper limbs. Note the extensive erythema
and scaling. By courtesy of R.A. Marsden, St George's Hospital, London, UK.

Fig. 17.21
Verrucous discoid lupus
erythematosus: note
the hypertrophic cuticle,
pitting and onycholysis.
By courtesy of J. Newton
Bishop, MD, St James's
University Hospital,
Leeds, UK.

X-linked chronic granulomatous disease is inherited as a recessive trait,

and patients (usually boys) have severe and recurrent infections due to defec-
tive neutrophil bactericidal activity. Heterozygous female carriers display a
partial defect, indicated by diminished nitroblue tetrazolium reductions, but
are usually free from infections. An autosomal recessive variant in which dis-
coid lupus-like lesions may occur has also been documented.71 DLE-lesions
have been reported in both carriers and chronic granulomatous disease
patients; however, development of SLE in chronic granulomatous disease
patients is extremely rare.72–76 Subacute cutaneous lupus erythematosus-like Fig. 17.24
lesions and lupus tumidus may also occur.77,78 Discoid lupus erythematosus Generalized discoid lupus erythematosus: note the extensive erythema and scaling.
has also been described in non-X-linked hyper-IgM syndrome.79 By courtesy of R.A. Marsden, St George's Hospital, London, UK.

Fig. 17.25
Generalized discoid lupus erythematosus: in this patient, the chest is severely
affected. By courtesy of the Institute of Dermatology, London, UK.
Fig. 17.26
Chilblain lupus erythematosus: resolving perniosis involving the tips of the thumb and
ring and little fingers. By courtesy of R.A. Marsden, St George's Hospital, London, UK.
Subacute cutaneous lupus erythematosus
Subacute cutaneous lupus erythematosus (SCLE) accounts for 5–10% of
patients with lupus erythematosus.80–82 Approximately 50% have SLE as
defined by the revised American Rheumatology Association diagnostic crite-
ria (see below).83 SCLE predominates in Caucasians and is uncommon in
Blacks, Koreans and Chinese.84 Females are affected more often than males
(2.3:1) and the mean age at presentation is about 40 years.85 This variant of
lupus occurs very rarely in children.86–88 Nail dystrophy affecting the majority
of nails has been reported in a child with SCLE.88
The eruption, which is often widely distributed, consists of symmetrical,
nonscarring, and non-indurated erythematosquamous lesions (Fig. 17.27).
Unique presentation along the lines of Blaschko has also been reported.89
Absence of induration has been regarded as a useful clinical discrimination fea-
ture between SCLE and DLE.84 In addition, the absence of follicular plugging,
adherent scale, and dermal atrophy helps to distinguish the subacute lesion
from the discoid variant.81 Pruritus is very rare.90 Lesions may become papu-
losquamous (psoriasiform) or annular, the latter coalescing to produce polycy-
clic and gyrate configurations (Fig. 17.28).81,91,92 In some patients both patterns
are seen. Crusting and vesiculation are sometimes evident on the active border
Lupus erythematosus 717
Fig. 17.27
Subacute cutaneous lupus erythematosus: annular lesions, many healed with
pigmentary changes and delicate scale overlying an active lesion. From the
collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig. 17.28
Subacute cutaneous lupus erythematosus: coalescence of annular lesions has resulted
in this bizarre eruption. By courtesy of the Institute of Dermatology, London, UK.
of the annular lesions.85 Pityriasiform and erythema multiforme-like lesions
have also been described, as has occasional chronic leukoderma.81 Exceptionally,
the disease may present as generalized poikiloderma93,94 or erythroderma.95 In
addition, 15–30% of patients develop features of typical DLE, usually located
on the scalp or face.1,81,83,96 The malar erythema of SLE is also sometimes evi-
dent (15%). Subtle hypopigmentation, telangiectasia, nonscarring alopecia,
livedo reticularis, Raynaud's phenomenon, and mucous membrane ulcers are
additional features.81,85 Dystrophic calcification is exceptional.97 Cutaneous
leukocytoclastic vasculitis is seen in a minority of patients and appears to be
self-limited and not associated with a worsened prognosis.98
Photosensitivity is of major importance and lesions are therefore typically
seen on the face, neck, upper part of back and chest, shoulders, extensor
aspect of the arms, backs of hands, and fingers (Figs 17.29, 17.30).80,81,92
Patients with SCLE have an increased incidence of human leukocyte
antigen (HLA)-DR3 (75%), HLA-B8, and HLA-A1, and there is a signifi-
cant association with inherited homozygous C2 and C4 deficiency.81,83,84,99–102
HLA-DR2 is also present at a higher frequency, particularly in those with
papulosquamous rather than annular skin lesions.103 Antinuclear antibodies
are found in approximately 50% of patients, while anti-Ro (SS-A) ­antibodies
718 Idiopathic connective tissue disorders

Fig. 17.29 Fig. 17.30

Subacute cutaneous lupus erythematosus: in this patient, there is very extensive Subacute cutaneous lupus erythematosus: the lesions are intensely erythematous
involvement. By courtesy of Dr J.C. Pascual, Alicante, Spain. and there is marked scaling. By courtesy of Dr J.C. Pascual, Alicante, Spain.

are present in approximately 65%, particularly those with annular polycy-
clic lesions.6,82,86,91,102 Anti-La (SS-B) antibodies are also often evident.5
The course of SCLE tends to be relatively benign, but systemic manifestations
are quite common and may be severe.104 Severe extracutaneous disease appears to
be more common in men with papulosquamous SCLE.104 The type of cutaneous
lesion, however, has not always been proven to correlate with the severity of the
extracutaneous manifestations.105 Renal disease has been reported to be uncom-
mon but a recent study found its frequency to be as similar and equally severe as
in SLE.85,106 Rarely, patients develop other more serious manifestations of SLE.83
Patients with SCLE have an increased incidence of both rheumatoid arthritis
and Sjögren's syndrome.82,107,108 Those with SCLE and Sjögren's syndrome have
high titers of anti-Ro antibodies, a high incidence of cutaneous vasculitis, and an
increased risk of severe neuropsychiatric and pulmonary involvement.109 SCLE
has been documented in association with porphyria cutanea tarda, hepatitis B
virus infection, radiotherapy, squamous cell carcinoma of the head and neck
region, breast, hepatocellular, and lung carcinoma.110–115 An exceptional
­association with inclusion body myositis and interstitial myositis with mitochon-
drial changes has also been documented.115,116 A relationship with lichen planus
is exceptional.117 Clinically and histologically identical cases have been
­documented following therapy with hydrochlorothiazide, griseofulvin, antihista-
mines, terbinafine, calcium channel blockers, nifedipine, angiotensin-­converting
enzyme (ACE) inhibitors, proton pump inhibitors, interferon, phenytoin, bupro-
pion, ticlopidine, capecitabine, lansoprazole, leflunomide, fluorouracil, leuprore-
lin, efalizumab, acebutolol, tamoxifen, docetaxel, and statin.118–147
Systemic lupus erythematosus
In addition to the variable cutaneous manifestations, lesions may be found in
virtually any organ or system in the body in SLE.148–150 The guidelines of the
American Rheumatology Association are valuable in establishing the diagno-
sis: any patient who has experienced four or more of the criteria, either seri-
ally or concurrently, is considered to have SLE (Table 17.2).151,152 The
condition is characterized by a marked female predominance (9:1) and ­usually

Table 17.2
Systemic lupus erythematosus: diagnostic guidelines of the American Rheumatology Association
Criterion Definition
Malar rash Fixed erythema, flat or raised, over malar eminences tending to spare nasolabial folds
Discoid rash Erythematous, raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in old lesions
Photosensitivity Skin rash as result of unusual reaction to sunlight (observed by physician or recounted by patient)
Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by physician
Arthritis Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling or effusion
Serositis Pleurisy (convincing history of pleuritic pain or rub heard by physician or evidence of pleural effusion) Pericarditis (confirmed by ECG or
rub or evidence of pericardial effusion)
Renal disorder Persistent proteinuria (> 0.5 g/day or > 3 if quantification is not performed) Cellular casts (may be RBC, hemoglobin, granular, tubular or mixed)
Neurological Seizures (in absence of offending drugs or known metabolic derangements, e.g., uremia ketoacidosis or electrolyte imbalance)
disorder Psychosis (in absence of offending drugs or known metabolic derangements, e.g., uremia ketoacidosis or electrolyte imbalance)
Hematological Hemolytic anemia with reticulocytosis Leukopenia (< 4000/mm3 on two or more occasions) Lymphopenia (< 1500/mm3 on two or more
disorder occasions) Thrombocytopenia (< 1500/mm3 in absence of offending drug therapy)
Immunological Positive LE cell preparation Anti-DNA (antibody to native DNA in abnormal titer) Anti-SM (presence of antibody to SM nuclear antigen)
disorder False positive serologic test result for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum
immobilization or fluorescent treponemal antibody absorption test
Antinuclear Abnormal ANA titer by immunofluorescence or equivalent assay at any time and in absence of drugs known to be associated with
antibody drug-induced lupus syndrome

ANA, antinuclear antibody; LE, lupus erythematosus; RBC, red blood cell.
Reproduced with permission from Tan, E.M. et al. (1982) Arthritis and Rheumatism, 25, 1271–1277.
 Lupus erythematosus 719

presents in the third, fourth, and fifth decades. There is a high incidence ­Afro-Caribbeans, have lesions similar to those of DLE, apparently associated
among Afro-Caribbeans, with a maximum prevalence of 1/150 females in with a less severe disease and a lower frequency of renal involvement.3,10,92,148
Jamaica. In the United States the incidence is approximately 1/100.5 SCLE-like features are present in 10–15% of patients.153 It has been suggested
Cutaneous involvement occurs in 75–88% of patients.92 Lesions are highly that patients with SLE and SCLE lesions have a more favorable prognosis.154
polymorphic and may mimic many other dermatoses (Table 17.3). The ‘but- Alopecia is important, occurring in about 20% of patients, and may be
terfly rash’ is typical and is a slightly scaly, sometimes edematous, erythema scarring or nonscarring. The nonscarring lesions, which are more common,
that is particularly distributed on the bridge of the nose and on the cheeks often constitute a fairly diffuse hair loss occurring as a non-specific response
(Fig. 17.31). Photosensitivity is common, affecting more than 50% of to stress (telogen effluvium).92 Fractured frontal hairs are characteristic.19
patients, and erythematous or violaceous maculopapular eruptions may Raynaud's phenomenon occurs in 10–40% of patients.92 Purpura and ecchy-
develop, particularly in white patients, at other light-exposed areas such as moses are common and may be partly due to corticosteroid therapy, but throm-
the ‘V’ of the neck, and the forearms.92 Sensitivity is towards both ultraviolet bocytopenia and immune complex-mediated vasculitis also play a role in the
(UV) A and B light. Approximately 15% of patients, particularly pathogenesis. Vasculitis, which occurs in up to 30% of patients, may also result
in infarcts, ulcers, digital nodules, scars, and gangrene (Figs 17.32–17.34).92
Table 17.3 Livedo reticularis that particularly affects the arms and thighs and periarticular
Systemic lupus erythematosus: cutaneous manifestations
sites may be a presenting feature in up to 10% of patients, and the changes of
atrophie blanche have been documented occasionally (livedoid vasculitis) (Fig.
Malar erythema (butterfly rash)
Inflammatory periorbital edema
17.35).92 Livedo reticularis is often a feature of the ­anticardiolipin syndrome
Mucous membrane lesions
Oral and nasopharyngeal ulceration
Alopecia
–  fractured frontal hair
–  scarring and nonscarring hair loss
Raynaud's disease with or without skin changes
Cutaneous vasculitis
–  urticarial lesions
–  palpable purpura
–  digital nodules
–  cutaneous infarcts
–  leg ulcers
–  peripheral gangrene
–  thrombophlebitis
–  livedo reticularis
–  periungual erythema and telangiectasia
–  hemorrhagic bullous lesions
So-called bullous SLE
Lichen planus-like lesions
Perniotic lesions
Lupus profundus
Chilblain lesions
Sjögren's syndrome Fig. 17.32
Calcinosis cutis Systemic lupus
Rheumatoid nodules erythematosus:
Pigmentary changes erythematous vasculitic
lesion on the fingertip. By
Reproduced from Moschella, S.L. (1989) Journal of Dermatology, 16, 417–428, with courtesy of M.M. Black,
permission from Blackwell Publishing Ltd. MD, St Thomas' Hospital,
London, UK.

Fig. 17.31 Fig. 17.33

Systemic lupus erythematosus: characteristic ‘butterfly erythema’ on the cheeks Systemic lupus erythematosus: involvement of the palms is rare and may be
and nose. By courtesy of Dr J.C. Pascual, Alicante, Spain. vasculitic. By courtesy of the Institute of Dermatology, London, UK.
720 Idiopathic connective tissue disorders
Fig. 17.34
Systemic lupus erythematosus: erythematous nodules are present on the back of
the hand and on the fingers. By courtesy of Dr J.C. Pascual, Alicante, Spain.
Fig. 17.35
Systemic lupus
erythematosus: livedo
reticularis develops
as a consequence of
relative ischemia in the
watershed zones. There
are numerous causes,
particularly connective
tissue disease. By
courtesy of the Institute
of Dermatology, London,
UK.
and presenting lesions identical to those seen in Degos' disease (malignant atro-
phic papulosis) have been described occasionally.155,156 Vasculitic features cor-
relate with renal and central nervous system involvement.92 Urticaria is
frequently found.157
Erythromelalgia, a burning sensation accompanied by erythema following
exposure to heat, has also been noted.21 Localized and diffuse hyperpigmen-
tation and urticarial lesions, including urticarial vasculitis, are less commonly
found. Digital manifestations, in addition to infarction and ulceration, include
periungual and knuckle erythema, nail fold telangiectases, cuticular lesions,
and splinter hemorrhages. Telangiectases may also be seen on the fingertips
and palms.91 Some patients develop red lunulae.158,159 The associated ery-
thema multiforme-like and perniotic lesions are described above. Involvement
of the mucous membranes occurs in about 10% of patients: painless ulcer-
ation is most common, but other features include erythema, petechiae, ero-
sions, and hemorrhage. The central part of the hard palate, lips, and buccal
mucosa are particularly affected.24,156,160
Additional lesions that are occasionally seen include rheumatoid-like nod-
ules, dermal mucinosis, bullous variants, thrombotic thrombocytopenic
­ urpura, mixed cryoglobulinemia, and soft tissue calcifications.5,19,161,162
p
Vesicles and bullae in SLE may complicate extreme basal cell hydropic degen-
eration, represent coexpression of an autoimmune bullous dermatosis, or sig-
nify a specific dermatitis herpetiformis-like eruption (bullous dermatosis of
SLE). There is a recognized association with porphyria cutanea tarda.163
Approximately 5–10% of patients with SLE are antinuclear antibody neg-
ative. This seems to correlate with a specific subtype. Patients are usually
HLA-DR3 positive and have Sjögren's syndrome and an increased incidence
of pulmonary involvement, psychiatric manifestations, cutaneous vasculitis,
and hypergammaglobulinemic purpura.5
Non-specific symptoms are common and include chronic tiredness, weight
loss, fever, malaise, and weakness. Arthralgia and myalgia occur in 90% of
patients. The myalgia may be disabling, but objective muscle weakness is rare.164
Similarly, although arthralgia may be marked, there is usually little clinical evi-
dence of joint damage. Effusions are common.148 Approximately 25% of patients
have frank arthritis, either a migratory polyarthritis or a chronic progressive
polyarthritis with deformity. Patients sometimes develop avascular bone necro-
sis due either to the primary disease or to steroid therapy.148,164 Very rarely,
involvement of the tendons is associated with the development of contractures.
Lesions of the cardiovascular system manifest as cardiomegaly, pericardi-
tis, pericardial effusion and/or endocarditis (Libman-Sacks valvulitis).165 In
SLE, the mitral valve is predominantly affected, but patients with the lupus
anticoagulant syndrome appear to have a particular risk of developing aortic
valve disease.165,166 Conduction defects and congestive cardiac failure are
additional features.
Respiratory involvement may present as pleurisy, with or without effusion,
bacterial pneumonia or, very rarely, lupus pneumonitis.164 Pulmonary hyper-
tension has been estimated to be present in 0.5–14% of SLE patients, espe-
cially those associated with antiphospholipid antibodies.167
Involvement of the central nervous system is an important cause of mor-
bidity and mortality.148,164 It may affect up to 40% of patients.6 Encephalitis,
meningitis, vasculitis, and coagulation defects give rise to a wide range of
clinical manifestations, including convulsions, hemiplegias, chorea, and psy-
choses.19 Convulsions and coma are an indication of severe involvement and
portend a grave outcome. Peripheral neuritis affects up to 12% of patients;
ocular lesions, including conjunctivitis, fundal hemorrhages, and cotton wool
exudates, occur in 25%.19
Renal manifestations develop in approximately 45% of patients, and pro-
gressive renal involvement is an important cause of morbidity and mortality
(nephrotic syndrome and lupus glomerulonephritis). Evidence of active renal
disease includes the presence in the urine of more than five red blood cells/
high-power field.164 Proteinuria of greater than 1 g/24 hours, oval fat bodies,
granular, hyaline, and red blood cell casts may also be detected.19
Generalized lymphadenopathy is present in about 50% of the patients,
hepatomegaly in 20%, and splenomegaly in 10%.
Gastrointestinal manifestations are uncommon; the most important is
esophageal involvement leading to loss of peristalsis and dilatation reminis-
cent of that seen in scleroderma.164
Laboratory investigation commonly reveals anemia, leukopenia, lym-
phopenia, thrombocytopenia, and a raised ESR. False-positive reactions to
reagin and treponemal tests for syphilis are common, 10–20% of patients are
positive for the Coombs' test and rheumatoid factor, and 10–50% have circu-
lating anticoagulants.148
While lupus erythematosus (LE) cell preparation used to be the basic screening
test for SLE, it has now been superseded by testing for antinuclear factor. This and
other autoantibodies will be discussed further under pathogenesis. Serum comple-
ment levels are often low in patients with active disease (CH50 and C3); estima-
tions of C3 levels are of particular value in following disease activity.5,19
SLE is characterized by relapses, with remissions of variable duration
sometimes lasting a decade or more. There is still, however, significant mor-
tality. Causes of death include nephritis, infections, and central nervous sys-
tem involvement.
An association between SLE and inherited complement deficiency, involving
the early components of the classic pathway including C1r, C1s, C1q, C4, and
C2, has been described.168–170 Deficiency of C2 is inherited in an autosomal
recessive fashion; up to 60% of homozygotes develop lupus erythematosus
characterized by an erythematous, papulosquamous, SCLE-like photosensitive
dermatosis, a low incidence of renal involvement, and arthralgia. Additional
 Lupus erythematosus 721

features may include urticarial vasculitis, malar erythema and nail fold abnor-
malities.100 Discoid lesions are sometimes evident, and recently a patient with
C2 and C4 deficiency and LE panniculitis has been documented.12,171 Patients
are, however, often (but not invariably) negative for antinuclear factor and
manifest a negative lupus band test on unaffected skin. There is an association
with HLA-DR2, and over 60% of patients possess anti-Ro antibodies.80
Numerous drugs have been implicated in the induction of SLE including:
• isoniazid, hydralazine, procainamide, rifampicin, quinidine,
penicillamine, terbinafine, carbamazepine, phenytoin, sertraline,
valpromide, amiodarone, atenolol, sulfonamides, methimazole, COL-3,
hydrochlorothiazide, minocycline, spironolactone, captopril, methyldopa,
gold salts, penicillin, streptomycin, phenylbutazone, reserpine,
griseofulvin, clonidine, oral contraceptives, captopril, interleukin (IL)-2,
hydroxyurea, clobazam, clozapine, ciprofloxacin, cefuroxime, nafcillin,
celiprolol, hydralazine, para-amino salicylic acid, yohimbine, infliximab,
adalimumab, pegylated interferon alpha-2B, conjugated estrogens,
anti-tumor necrosis factor alpha (TNF-α), and etanercept.172–231
Transient skin and serological manifestations of SLE have been docu-
mented in two children with trichophyton mentagrophytes infection.211 The
disease has also been linked to hepatitis B vaccination and with exposure to Fig. 17.36
Neonatal lupus erythematosus: note the presence of erythematous, slightly
insecticides.232–235
scaly plaques on the cheeks, forehead, and scalp. By courtesy of the Institute of
Sjögren's syndrome coexists in approximately 10–20% of patients with Dermatology, London, UK.
SLE.91 SLE has also been described in association with scleroderma, morphea,
rheumatoid arthritis, eosinophilic fasciitis, dermatomyositis, lichen sclerosus,
pemphigus (including pemphigus vulgaris, foliaceous, and paraneoplastic
pemphigus), hypergammaglobulinemia of Waldenström, dermatitis herpeti-
formis, ulcerative colitis, alopecia areata, autoimmune thyroiditis, myasthe-
nia gravis, acanthosis nigricans, Sweet's syndrome, porphyria, gout,
sarcoidosis, psoriasis, lichen planus, and cutaneous T-cell lymphoma. It is
likely that many of these associations are chance associations except for those
diseases with an autoimmune basis.163, 236–260

Neonatal lupus erythematosus

Neonatal lupus erythematosus is very rare, occurring in approximately 1 in
20 000 live births261 and most commonly presents in female infants.261–263 It is
associated with maternal anti-Ro (SS-A) antibodies (95%) and/or anti-La (SS-B)
antibodies.262,263 Anti-U1-ribonucleoprotein (RNP) antibodies may also be
present.264–268 Anticardiolipin antibodies have been described in a single case.269
Transplacental transfer of anti-Ro and anti-La antibodies results in a SCLE-
like eruption consisting of erythematous annular scaly plaques that particu-
larly affect the periorbital region (‘owl-eye’ or ‘eye-mask’) and scalp, and to a
lesser extent, the trunk and extremities (Figs 17.36, 17.37).5 These cutaneous
lesions often appear after exposure to ultraviolet light. Photosensitivity in neo-
natal lupus erythematosus patients appears to show racial differences, being
more frequent in Caucasian and Americans than in Japanese infants.270 Crusted
lesions and cutis marmorata telangiectasia congenita are additional features in
some cases.271,272 Exceptionally, discoid lesions, panniculitis (lupus profundus),
multiple morphea, erosions, and alopecia may also occur.273–275 Atrophy and
scarring are very rare but residual hypopigmentation and telangiectasia are
present in about 25% of patients.276 Babies in subsequent pregnancies may
present manifestations of the disease277,278 and the overall recurrence rate for
neonatal lupus-associated cardiac disease is 17%.279
Neonatal lupus erythematosus is often associated with complete heart
block, and sometimes liver disease (cholestatic hepatitis), splenomegaly,
thrombocytopenia, leukopenia, and anemia are also evident.262,275 Circulating
autoantibodies to annexin A6 were detected in a single patient with neonatal
lupus erythematosus-related dilated cardiomyopathy.280 Multiple mucocuta-
neous and visceral hemangiomas have been reported in a single patient.281
The mortality associated with cardiac involvement is around 19%.277 Severe
hematological and liver involvement without evidence of cutaneous or car-
diac involvement has exceptionally been reported.282 By 6 months of age the
cutaneous, but not the cardiac manifestations, usually fade. The levels of
maternal autoantibodies in the infant decrease quickly during the first weeks
of life and generally become undetectable by the age of 1 year.283
The disease also occurs in identical and nonidentical twins.284 A single case
has been described in association with Turner's syndrome.285 Neonates who
survive until infancy have a fairly good prognosis, but there is an overall
Fig. 17.37
Neonatal lupus erythematosus: in this child, there is intense erythema affecting the
cheeks and nose and around the eyes.
­ ortality of about 10% due to heart disease.262 Mothers of affected infants
m
are commonly asymptomatic initially but they may have systemic lupus,
Sjögren's syndrome, leukocytoclastic vasculitis or an overlap syndrome.286
A number of mothers who present with no symptoms, often subsequently
develop evidence of connective tissue disease, particularly systemic lupus (in
about 20% of cases) and Sjögren's syndrome.262
Pathogenesis and histological features
Despite enormous research efforts, the precise etiology and pathogenesis are
unknown, but the condition is certainly multifactorial.287,288 Lupus erythemato-
sus is characterized by B-cell hyperactivity in association with defective sup-
pressor T-cell function. Patients develop a wide range of autoantibodies, many
of which result in immune complexes with resultant systemic manifestations
including vasculitis and glomerulonephritis. In addition to immunological fac-
tors, familial, genetic, and hormonal influences play a part. It is believed that in
lupus erythematosus there is a genetic predisposition; sex-associated and envi-
ronmental factors are necessary to promote the development of the disease.
Autoantibodies are important in the diagnosis of lupus erythematosus and
have a significant role in its pathogenesis, either by direct cytotoxic effects (such
as the lymphopenia induced by antilymphocyte antibodies) or by immune com-
plex deposition. Until the 1960s the presence of LE cells in a patient's blood
722 Idiopathic connective tissue disorders

was regarded as pathognomonic for lupus erythematosus. This was changed,

however, by the discovery of antinuclear factor (antinuclear antibody) with
direct immunofluorescent techniques. Antinuclear antibody is present in the
serum of 90–95% of patients with SLE, in 30% of patients with localized DLE,
and in 50% of patients with generalized DLE. It should also be noted that 10%
of the normal population have antinuclear antibody in the serum, albeit at low
concentration. Antinuclear antibody has at least four subtypes:
• A homogeneous or diffuse pattern is most commonly seen (Figs. 17.38,
17.39).
• Speckled fluorescence representing an antibody to saline-soluble nuclear
protein is present in patients with the lupus erythematosus-erythema
multiforme syndrome (Fig. 17.40).
• The nucleolar pattern (representing antinucleolar RNA antibody) is
occasionally evident in lupus erythematosus, although it is more common
in systemic sclerosis.
• The peripheral (outline) staining pattern reflects high titer anti-DNA
antibody and is a marker of active systemic disease.6,19
Patients with lupus erythematosus develop antibodies to a variety of nuclear
and cytoplasmic antigens; these autoantibodies, both singly and in combina-
tion, have varying associations, which may allow a prediction of (to some Fig. 17.39
Systemic lupus erythematosus: high-power view. By courtesy of G. Swana, MD,
extent, at least) the course of the disease in individual patients (Table 17.4).
St Thomas' Hospital, London, UK.
Antibodies to native (double-stranded) DNA (nDNA) are pathognomonic for

Fig. 17.38 Fig. 17.40

Systemic lupus erythematosus: homogeneous antinuclear antibody in rat liver. By Systemic lupus erythematosus: speckled antinuclear antibody – HEP II. By courtesy
courtesy of G. Swana, MD, St Thomas' Hospital, London, UK. of G. Swana, MD, St Thomas' Hospital, London, UK.

Table 17.4
Systemic lupus erythematosus: antibodies
Antigen Antibody Significance Comment
Nuclear constituents Anti-native DNA Highly specific for SLE associated with Found in NZB/NZW model
Antihistone hypocomplementemia and glomerulonephritis Found in high titer in drug-induced
Anti-single stranded DNA 30% of SLE patients lupus-like disease
90% of SLE patients, associated with May be detected in ANF-negative
glomerulonephritis SLE patients
Small nuclear ribonuclear Sm Highly specific for SLE 15% of SLE patients
protein nRNP May occur in SLE but also present in MCTD
La (SS-B) and PSS May be associated with low
Found in 10% of SLE incidence of renal disease
Small cytoplasmic Ro (SS-A) Found in 25% of SLE patients May be detected in ANF-negative
ribonuclear protein Found in SCLE SLE
Found in 50% of complement-deficient LE-like
syndromes
Found in all neonatal lupus

ANF, antinuclear factor; LE, lupus erythematosus; MCTD, mixed connective tissue disease; PSS, progressive systemic sclerosis; SCLE, subacute cutaneous lupus erythematosus;
SLE, systemic lupus erythematosus.
 Lupus erythematosus 723

Table 17.5
Diagnostic criteria for the antiphospholipid syndrome
Group Criteria
  I. Clinical conditions Thrombosis
venous:
recurrent deep vein thrombosis
axillary
retinal vein
arterial:
cerebrovascular accident
retinal artery
coronary
other:
pulmonary hypertension
livedo reticularis
neurological syndromes – transient
ischemic attack; progressive dementia
(repeated cerebrovascular stroke)
Recurrent fetal loss
Thrombocytopenia
Fig. 17.41
Systemic lupus erythematosus: anti-dsDNA (Crithidia luciliae). By courtesy of II. Laboratory* Positive anticardiolipin antibody assay; isotype
G. Swana, MD, St Thomas' Hospital, London, UK. IgG or IgM
Positive lupus antiocoagulant test
III. Other clinical Hemolytic anemia/positive direct Coombs' test
idiopathic (classic) SLE (Fig. 17.41).6,19 They are rarely seen in the drug-induced conditions Migraine
variant and are only very occasionally present in patients with DLE.2 The pres- Endocardial/valvular lesions
ence of anti-nDNA antibody in association with hypocomplementemia is indic- Transient visual loss
ative of active disease and is often accompanied by severe renal involvement. Chorea
Antihistone antibodies may be found in approximately 30% of patients IV. Histopathological 1. Thrombotic type (characterized by
with idiopathic SLE, but are particularly associated with the drug-induced classification dominating non-inflammatory bland
variant.289 The latter is caused by a wide variety of drugs, including hydrala- of lesions in occlusive or mural thrombosis and its
zine, procainamide hydrochloride, phenytoin, and isoniazid.14,290,291 Symptoms antiphospholipid consequences)
develop in up to 20% of patients taking procainamide and antinuclear anti- syndrome a. Large- and medium-sized arterial
bodies are present in 50%.291 Procainamide-induced SLE-like syndrome is and venous, cardiac (Libman-Sacks
characterized by the presence of leukocyte-specific antinuclear antibody.291 endocarditis), recent or organized
Clinical features include malaise, pneumonitis with pleural effusion, arthral- b. Microvascular (capillaries, arterioles and
small arteries)
gia, arthritis, and serositis; renal, central nervous system, and cutaneous
2. Microangiopathic type (characterized
lesions are less common and are usually mild. Although antinuclear antibod-
by dominating endothelial cell injury,
ies are often present, anti-DNA antibodies are not formed in most cases of subendothelial plasma insudation often
drug-induced lupus.164 Drug-induced lupus usually, but not invariably, under- associated with thrombotic necrotizing
goes remission on withdrawal of the drug.291 lesions) affecting capillaries, arterioles,
Antibodies to ssDNA occur in 90% of patients with classic SLE and in small arteries
approximately 20% of patients with disseminated DLE, and may also be 3. Ischemic type, secondary to vascular
found in other connective tissue diseases.10 Their presence in disseminated occlusion
DLE correlates with an increased risk of developing SLE.10 Patients with SLE 4. Tentatively associated pathology,
who are negative for antinuclear antibody may have anti-ssDNA antibodies in like accelerated atherosclerosis and
membranous glomerulopathy
their serum.6 Antibodies to the soluble nuclear antigen Sm are highly specific
5. Coincidental underlying disease related
for SLE.289 They may also be found in a group of patients with good prognosis
pathology
who are positive for antinuclear factor, but anti-nDNA-negative, and who 6.  Coincidental drug-induced pathology
have mild nonprogressive glomerulonephritis, hypocomplementemia, mild
central nervous system involvement, and conspicuous cutaneous eruptions. At least one finding from each of groups I and II must be present to constitute a
Antibodies to ribonucleoprotein are detected in 23% of patients with SLE, diagnosis.
Group III represents features occasionally present in these patients.
but are much more commonly associated with mixed connective tissue dis-
* Laboratory tests should be positive on two occasions 2 months apart.
ease: they may also be found in patients with progressive systemic sclerosis.289 Modified from ASCP check sample (TH 88-6), American Society of Clinical Pathologists,
Anti-La (SS-B) antibodies are detected in the serum of 10% of patients with 1989; with permission. Histopathological classification modified from Praprotnik, S.,
SLE. Anti-La antibodies, which are often present in Sjögren's syndrome, are Ferluga, D., Vizjak, A., et al. (2009) Clinic Rev Allerg Immunol, 36, 109-125.
almost invariably accompanied by anti-Ro (SS-A) antibodies.289 The latter are
particularly associated with SCLE, complement-deficient lupus erythemato-
sus, circulating IgG or IgM anticoagulant, and neonatal lupus erythematosus.
About 15–20% of patients with SLE have detectable antineutrophil cytoplas- SLE. It is due to the presence of circulating antiphospholipid antibodies which
mic antibodies (ANCA).292 inhibit coagulation in vitro, but more importantly are associated with a
The circulating anticoagulant (antiphospholipid or lupus anticoagulant) is greatly increased risk of thrombotic phenomena affecting both arteries and
associated with paradoxical thrombosis, spontaneous abortion, premature veins (Figs. 17.42, 17.43). About 50% of patients with SLE present with
labor, intrauterine death, labile hypertension, cutaneous necrosis, gangrene, antiphospholipid antibodies but only half of these will develop manifesta-
ecchymoses, purpura, leg ulcers, atrophie blanche, livedo reticularis, and tions of the disease.305 Presentation in the skin may also be with papules and
false-positive syphilis serology – the lupus anticoagulant syndrome (Table nodules or lesions resembling pyoderma gangrenosum.306,307 Interestingly,
17.5).289,293–304 The lupus anticoagulant syndrome is more accurately known patients with antiphospholipid antibodies and SLE appear to be more at risk
as the antiphospholipid syndrome because not all patients have associated of developing anetoderma.308–310 The incidence, however, is not high. Rarely,
724 Idiopathic connective tissue disorders

been substantiated.320 The antiphospholipid syndrome has also been docu-

mented in other autoimmune diseases including rheumatoid arthritis, hemo-
lytic anemia, thrombocytopenic purpura, ulcerative colitis, factor V Leiden
mutation, and mesothelioma.321,322 It may also complicate treatment with a
number of drugs including phenothiazines and procainamide, develop during
viral illnesses including acquired immunodeficiency syndrome (AIDS), and
can present with an underlying lymphoma.323,324 The antiphospholipid syn-
drome is futher discussed elsewhere.
Anti-Ro antibodies have been shown to bind to the epidermis in neonatal
and subacute lupus erythematosus, and to the conducting system and myocar-
dium in neonatal lupus erythematosus.262 They also bind to keratinocytes in
vitro and have been shown to react with the epidermis when infused into
human-skin-grafted mice.325,326 This – combined with the disappearance of the
cutaneous manifestations as maternal IgG is removed from the circulation –
suggests that in neonatal lupus erythematosus, anti-Ro antibodies are of major
pathogenetic significance. Ro antigens are present in the nuclei and cytoplasm
of keratinocytes and it has been demonstrated that UVB is capable of translo-
cating these antigens to the surface of cultured keratinocytes. Anti-Ro anti-
bodies in the sera bind to the antigens in keratinocytes and appear to be
Fig. 17.42 important in inducing antibody-dependent keratinocyte damage.327,328
Lupus anticoagulant Immune complexes have been shown to be important in the pathogenesis of
syndrome: extensive both vasculitis and glomerulonephritis in SLE; their presence may be inferred
gangrene with ulceration by the detection of immunoglobulin and complement in blood vessel walls in
affecting the nose and
skin biopsies (Fig. 17.44). High concentrations of anti-nDNA, anti-ssDNA,
cheek. By courtesy of
C. Stephens, MD, Poole
and anti-Ro (SS-A) antibodies have been detected in the renal cortex of patients
Hospital, Poole, UK. with lupus glomerulonephritis. The finding of large numbers of T lymphocytes
and macrophages with minimal or no B cells in the dermal infiltrate of skin
lesions suggests that cell-mediated immunity may be particularly important in
the pathogenesis of lesions at this site.327,329 Both delayed hypersensitivity and
antibody-dependent cellular cytotoxicity mechanisms have been proposed.323
There is a striking female predominance in SLE, suggesting that female sex
hormones are of pathogenetic significance.19 Interestingly, in the experimental
model of SLE in rabbits, females have a much more serious form of glomeru-
lonephritis than do their male counterparts and this difference can be negated
by castration or the administration of male sex hormones.323
There is, without question, a genetic predisposition to the development of
SLE.330 There are many examples of familial incidence, and immunoglobulin
abnormalities have often been documented in asymptomatic relatives; indeed,
as many as seven members in a single family have been recorded.164 Lupus ery-
thematosus has also been reported in identical twins.164 HLA typing has revealed
an increased incidence of HLA-A1, HLA-B8, HLA-B15, HLA-DR2, and
HLA-DR3 in SLE.12 It has been suggested that expression of the disease may be
inherited as an autosomal dominant trait. HLA-DR4 is associated with hydral-
azine-induced lupus erythematosus. The frequencies of HLA-DRw6 and HLA-

Fig. 17.43
Lupus anticoagulant
syndrome: the leg was
also involved. By courtesy
of C. Stephens, MD,
Poole Hospital, Poole, UK

patients develop reactive angioendotheliomatosis.311,312 Systemic involvement

includes deep venous thrombosis often complicated by pulmonary embolism,
arterial occlusion with resultant strokes, transient ischemic attacks, multi-
infarct dementia, myocardial infarction, and gangrene.289
The association of cutaneous thrombotic lesions, livedo racemosa, hyper-
tension, and cerebrovascular disease is known as Sneddon's syndrome.291,313–317
This presents mainly in young females and is exceptional in children.318
Antiphospholipid antibodies are present in around 41% of patients.319
How antiphospholipid antibody induces thrombosis is unknown. Theories Fig. 17.44
of inhibition of protein C (a natural vitamin K-dependent anticoagulant) Systemic lupus erythematosus: immunoperoxidase reaction demonstrating IgG
function and a suppressive effect on endothelial cell prostacyclin have not yet within a blood vessel wall.

B8 are increased in DLE.12 It has recently been demonstrated that patients with
polymorphic light eruption and HLA-DRB1*0301 have a higher risk of devel-
oping either subacute or discoid lupus erythematosus.331,332 The familial cluster-
ing of polymorphic light eruption in relatives of persons with lupus erythematosus
suggests that these diseases may share a similar pathogenesis.333
SCLE has been demonstrated to be associated with the TNF-308A
allele.334,335 Association between SCLE and single nucleotide polymorphism in
the TNF-alpha (TNF-α) gene promoter and gene that encodes C1qA chain of
C1q has been demonstrated.169,335 Transcription of TNF-α appears to be pho-
toregulated in subacute lupus.335 TNF-alpha, produced by keratinocytes, has
been localized within refratory lesions of SCLE, suggesting its potential role
in the pathogenesis of SCLE.336 Abnormal regulation of DNA metylation in
CD4+ T lymphocytes has recently been implicated in the pathogenesis of
SCLE.337 Triggering mechanisms in lupus erythematosus include UV light
(both naturally occurring and artificial), drugs and, possibly, viruses. Sunlight
commonly worsens the cutaneous manifestations and may exacerbate sys-
temic disease.164,338,339 Antibodies to UV DNA have been identified in patients
with SLE.340 These may be important in the pathogenesis of the photosensi-
tivity-induced lesions. Lesions are typically worse in spring and summer, and
cutaneous lesions can be induced artificially by UV irradiation. Dysregulation
of apoptosis has been suggested as an important mechanism in the pathogen-
esis of lupus erythematosus. A reduction of bcl-2 expression in epidermal
basal cells is associated with overexpression of FAS antigen and this appears
to correlate with the extent of apoptosis in the epidermis.341
Despite early enthusiasm for a viral etiology for lupus erythematosus,
extensive research has not provided convincing evidence. For many years
paramyxovirus-like inclusions within the cytoplasm of endothelial cells were
thought to represent evidence of a viral cause.342 They are now known to rep-
resent a non-specific membranous byproduct (tubuloreticular body) of organ-
elle degeneration. An association with parvovirus (erythrovirus) B19 has been
suggested.343 Two experimental virus-induced animal models – Aleutian mink
disease and New Zealand black–white hybrid mouse disease – have been
described.19 Recent investigations have shown that the latter is associated
with a primary stem cell defect. Bone marrow grafts can therefore transfer the
disease to previously irradiated normal recipients and induce tolerance
defects.344 Bone marrow cultures produce B cells with an increased capacity
for antibody synthesis.335 Murine lupus shows a striking similarity to its
human counterpart.
The lupus band test is particularly important in the diagnosis of lupus ery-
thematosus. It is also, to a lesser extent, of some value in assessing prognosis.
By either immunofluorescence or immunoperoxidase techniques, the pres-
ence of immunoglobulin and complement is sought at the epidermodermal
junction (Fig. 17.45). IgM is most commonly identified, although IgG, IgA,
and C3 are also frequently present.345 IgG deposits appear to be the most
Fig. 17.45
Systemic lupus erythematosus: positive band test (IgG). By courtesy of the
Department of Immunofluorescence, Institute of Dermatology, London, UK.
Lupus erythematosus 725
s­ pecific for lupus erythematosus. Other factors that may be identified include
properdin, C1q, and C4.346 Deposition of the membrane attack complex
(MAC) has also been shown to be a relatively sensitive and specific marker of
cutaneous lupus erythematosus.347,348 Although deposits are usually homoge-
neous, granular and thready (reticular) patterns are also recognized.345
Homogeneous bands are typical of chronic lesions, granular bands are seen in
uninvolved skin, and thready deposits are usually a feature of early lesions.348
Ultrastructurally, the immunoreactants are present in the sub-basal lamina
connective tissue and intimately associated with reduplicated lamina densa
(Fig. 17.46).12 The immunoglobulin deposition does not necessarily correlate
with the clinical or histological presence of cutaneous lesions and is therefore
unlikely to be of pathogenetic significance.
The lupus band test is positive in involved skin in approximately 50–94%
of patients with SLE, 60–80% of those with the discoid variant, 60% of
patients with SCLE, and 50% of infants with neonatal lupus erythemato-
sus.345,346,348–351 Lesional mucosa also shows immunoreactant deposition and
this can be of particular value in patients where histological distinction from
lichen planus proves impossible.23 It may also be positive in uninvolved skin
in up to 67% of patients with systemic disease.350 The prevalence of a positive
test in uninvolved skin depends upon the site, with the highest incidence in
skin from the shoulder (70%). Sun-exposed skin, such as the dorsal aspect of
the forearms, is more frequently positive (60–70%) than nonsun-exposed
skin (50–60%). However, the observation that 20% of specimens of sun-
exposed normal skin from healthy young adults show a positive lupus band
test indicates that nonsun-exposed skin is the substrate of choice.352
Positivity also depends upon the duration of the disease (lesions less than
3 months old are often negative) and the effect of previous steroid therapy.353
Much less often, positive immunofluorescence is seen in the uninvolved skin
of patients with DLE.354 The results must, however, be taken in the context of
the clinical information. A positive IgM lupus band test may be seen in unre-
lated conditions such as solar keratosis, polymorphous light eruption, rosa-
cea, lymphocytic infiltrate, and dermatomyositis, and as a consequence of UV
radiation.348,350 These latter conditions are usually associated with C3 deposi-
tion or a single immunoglobulin class, particularly IgM, in contrast to the
multiple immunoglobulin subclasses found in lupus erythematosus.348 In non-
lupus conditions the lupus band is usually fainter and patchy.354 With such a
significant false-positive rate, it is stressed that the results of a lupus band test
must be interpreted with considerable caution and always in the context of
the clinical information and histological features.
A characteristic particulate dust-like deposition of immunoglobulin (pre-
dominantly IgG) affecting the basal cells of the epidermis has been described
in patients with SCLE.326,355 Sometimes suprabasal epidermis, adnexal epithe-
lium, and the dermal cellular infiltrate show similar fluorescence.346,355 This
pattern of deposition correlates with the presence of Ro antibodies.350 It is
Fig. 17.46
Lupus band test: immunoelectron microscopy (frozen section) showing IgM
deposition below the lamina densa.
726 Idiopathic connective tissue disorders

also occasionally evident in SLE. In some cases speckled nuclear staining of

keratinocytes for IgG is seen in connective tissue diseases.356 In the setting of
SLE, this finding appears to be associated with a lower incidence of renal
disease.356
The histopathological features of the various subsets of lupus erythemato-
sus (with the exceptions of lupus erythematosus profundus and bullous der-
matosis of SLE) show considerable overlap and their distinction by microscopic
techniques is often difficult.357,358

Discoid lupus erythematosus

Discoid lupus erythematosus displays variable features, depending upon the
stage of the disease.12,351,352 The active lesion is characterized by hyperkerato-
sis and follicular dilatation with keratin plugging; occasionally focal parak-
eratosis is present (Figs 17.47–7.49). The epidermis is usually atrophic and
rather flattened, although sometimes there is acanthosis (Fig 17.50). The
most significant features seen at the dermoepidermal junction are:
• liquefactive degeneration of the basal layer of the epidermis (Fig. 17.51),
• basement membrane thickening (Fig. 17.52), which may be accentuated
by use of the periodic acid-Schiff (PAS) reaction.
Fig. 17.49
These two features may additionally affect follicular epithelium, and Discoid lupus erythematosus: there is marked follicular plugging.
­basement membrane thickening of the dermal blood vessels is also sometimes

Fig. 17.47
Discoid lupus erythematosus: this scanning view shows hyperkeratosis, follicular
plugging, an atrophic epidermis, and a perivascular and periadnexal chronic
inflammatory cell infiltrate. Fig. 17.50
Discoid lupus
erythematosus: there
is hyperkeratosis and
atrophy of the epidermis.

Fig. 17.48
Discoid lupus erythematosus: note the perifollicular lymphocytic infiltrate.
evident (Fig. 17.53). Liquefactive degeneration of the basal layer of the epi-
dermis is often accompanied by pigmentary incontinence (Fig. 17.54). In
some instances the epidermal changes are accompanied by cytoid body for-
mation, but this is not usually as conspicuous as in lichen planus (Fig. 17.55).
Amyloid formation may occasionally be seen.
The papillary dermis is edematous, and telangiectatic vessels are often
present (Fig. 17.56). Focal extravasations of red blood cells are sometimes
seen (Fig. 17.57). Characteristic of DLE is a perivascular and periappenda-
geal chronic inflammatory cell infiltrate of lymphocytes and variable num-
bers of histiocytes (Figs 17.58, 17.59). The most common cells are the T
lymphocytes, both helper and suppressor cells.329, 330 Neutrophil polymorphs
and plasma cells are not usually evident. However, the presence of neutro-
phils and leukocytoclasia has been described in the lupus-like lesions of a
patient with a lupus-like dermatosis with X-linked chronic granulomatous
disease.68 CD4+ cells predominate in DLE skin lesions.329 The majority of
these T lymphocytes are Ia+, indicating an activated state. Occasional CD4+
cells are present in the epidermis closely related to foci of basal keratinocyte
 Lupus erythematosus 727

Fig. 17.51 Fig. 17.54

Discoid lupus erythematosus: in this view there is hyperkeratosis, epidermal Discoid lupus erythematosus: note the pigmentary incontinence.
atrophy and basal cell hydropic degeneration.

Fig. 17.52 Fig. 17.55

Discoid lupus erythematosus: note the very marked thickening of the basement Discoid lupus erythematosus: several cytoid bodies are present in the papillary
membrane and pigmentary incontinence. dermis. Note the hydropic degeneration.

Fig. 17.53 Fig. 17.56

Discoid lupus erythematosus: there is marked blood vessel wall thickening with Discoid lupus erythematosus: note the telangiectatic vessels in the superficial
hyalinization. dermis.
728 Idiopathic connective tissue disorders
Fig. 17.57
Discoid lupus erythematosus: in addition to hyperkeratosis and epidermal atrophy
there is quite marked red cell extravasation.
Fig. 17.58
Discoid lupus erythematosus: blood vessels and hair follicles are surrounded by
a characteristic heavy lymphohistiocytic infiltrate.
Fig. 17.59
Discoid lupus erythematosus: the follicular epithelium shows basal cell hydropic
degeneration and there is a heavy lymphocytic infiltrate.
damage.329 Epidermal Langerhans cells are usually reduced in number.328 B
lymphocytes are generally present in only small numbers. The infiltrate is
typically sparse in the papillary dermis, but focal dense aggregates are char-
acteristically found in the reticular dermis and may sometimes extend into the
subcutaneous fat.
An increase in glycosaminoglycans (acid mucopolysaccharides) in the der-
mis is a common feature of the acute lesion (Fig 17.60); in tumid lupus this
is very marked (Figs 17.61, 17.62). Very rarely, dermal calcification has been
documented (Fig. 17.63).359 Exceptionally ‘fibrinoid’ change of the dermal
collagen is present (Fig. 17.64).
In the healing lesion of DLE there is hyperkeratosis and the epidermis may
be atrophic or, more commonly, slightly thickened. The basement membrane
region is characteristically markedly thickened. The dermis is fibrosed, some-
times to a degree that resembles lichen sclerosus (Fig. 17.65). In hair-bearing
sites, particularly the scalp, there may be very marked follicular plugging with
associated chronic inflammation, and in advanced disease there is often com-
plete loss of the pilosebaceous structures with replacement by collagenous
fibrous strands (Fig. 17.66).358 Sebaceous gland atrophy or loss occurs early
in scalp involvement and the chronic inflammatory changes are centered at
the level of the mid follicle.20 It has been suggested that this may represent a
focus of follicular stem cells and therefore chronic inflammation at this site
could readily result in permanent hair loss.
Fig. 17.60
Discoid lupus erythematosus: stromal mucin deposition, as seen in this field, is not
uncommon.
Fig. 17.61
Tumid discoid lupus erythematosus: in this rare variant, there is very marked mucin
deposition. By courtesy of J. Cohen, MD, Dermatopathology Laboratory, Tucson, USA.

Fig. 17.62
Tumid discoid lupus erythematosus: the mucin stains with Alcian blue, pH 2.5.
By courtesy of J. Cohen, MD, Dermatopathology Laboratory, Tucson, USA.
Rarely DLE may present as a dense superficial and deep perivascular and
periappendageal infiltrate in the absence of significant epidermal changes:
distinction from lymphocytic infiltrate of Jessner and polymorphous light
eruption is, therefore, histologically impossible.358
In hypertrophic lesions there is marked hyperkeratosis, hypergranulosis,
and irregular acanthosis with papillomatosis in addition to the features of
basal cell damage.12 Cytoid bodies are often conspicuous in the lower epider-
mis.358 Amyloid deposition has been reported as a frequent finding.360 The fea-
tures are commonly histologically indistinguishable from hypertrophic lichen
planus. The presence of intraepidermal elastic fibers, frequently associated
with transepidermal elimination of the elastotic material, has been reported in
hypertrophic lupus erythematosus.33,36 This is not a feature of lichen planus.
Resolving or evolving keratoacanthoma may sometimes be mimicked.36
Fig. 17.63 Fig. 17.64
Discoid lupus erythematosus: calcification is a Discoid lupus erythematosus: note the presence of
rare feature. In this example, there is striking fibrinoid necrosis. This is more usually a feature of
transepidermal elimination. the systemic variant.
Lupus erythematosus 729
Fig. 17.66
Discoid lupus erythematosus: note the complete absence of hair follicles in this
scalp specimen.
Biopsy from patients with lupus pernio reveals a cuffed perivascular lym-
phocytic infiltrate with edema, red cell extravasation, and variable vascular
fibrinoid change (Figs. 17.67–17.70). Some biopsies show frank lympho-
cytic vasculitis. The inflammatory infiltrate often extends into the deep der-
mis and subcutaneous adipose tissue. Interface epidermal changes, ranging
from focal vacuolar changes to a lichenoid tissue reaction, are often pres-
ent.2,15 Chronic inflammation around sweat glands is sometimes seen.9,16
Mucous membrane lesions are frequently difficult to distinguish from lichen
planus.22,23,358 They are characterized by hyperkeratosis, often accompanied by
parakeratosis. The epithelium may be atrophic or acanthotic. Hydropic degen-
eration of basal keratinocytes, sometimes associated with cytoid body forma-
tion, accompanies a dense lymphohistiocytic infiltrate in which plasma cells
are often numerous. The presence of a deep perivascular chronic inflammatory
Fig. 17.65
Discoid lupus erythematosus: in this example,
the presence of superficial dermal sclerosis is
reminiscent of lichen sclerosus.
730 Idiopathic connective tissue disorders

Fig. 17.67 Fig. 17.70

Chilblain lupus erythematosus: there is irregular acanthosis and a superficial Chilblain lupus erythematosus: there is a dense lymphocytic infiltrate.
lymphocytic infiltrate. Ectatic vessels are conspicuous.
cell infiltrate favors the diagnosis of DLE.359 Direct immunofluorescence is,
however, frequently necessary to establish the diagnosis.22,23

Lupus erythematosus profundus

The histological features of lupus erythematosus profundus are considered on
chapter 9.

Subacute cutaneous lupus erythematosus

Although the histological features of SCLE show considerable overlap with
those of DLE, there are diagnostic pointers.82,361,362 In SCLE, the hyperkera-
tosis tends to be mild, atrophy is more marked, and the epidermal ridge pat-
tern is often effaced (Fig. 17.71).362 Parakeratosis may sometimes be a
feature. Basement membrane thickening is minimal or absent, and hair fol-
licles are often unaffected or show only slight keratin plugging.361,362 In
DLE, the inflammatory cell infiltrate is denser, occupies the papillary and
reticular dermis, and often shows perifollicular accentuation. In SCLE, lym-
phocytic exocytosis may be conspicuous and satellite cell necrosis is not
uncommon (Fig. 17.72).362 Liquefactive degeneration of the basal layer of
the epidermis is usually present although often it is only mild (Figs 17.73,
Fig. 17.68 17.74). Sometimes, however, it is sufficiently marked that subepidermal
Chilblain lupus erythematosus: in this field, there is marked edema of the papillary vesiculation results.81,85 Homogenization of the papillary dermal collagen is
dermis.

Fig. 17.69 Fig. 17.71

Chilblain lupus erythematosus: there is focal basal cell hydropic degeneration, Subacute cutaneous lupus erythematosus: low-power view showing slight
and cytoid bodies are conspicuous. hyperkeratosis. A perivascular chronic inflammatory cell infiltrate is present.

Fig. 17.72
Subacute cutaneous lupus erythematosus: in this example, in addition to basal
cell hydropic degeneration, there is intercellular edema of the epidermis with
lymphocytic exocytosis.
Fig. 17.73
Subacute cutaneous lupus erythematosus: note the presence of numerous cytoid
bodies and focal satellite cell necrosis.
occasionally seen.362 Colloid body formation and pigmentary incontinence
are often inconspicuous, but sometimes they are a major feature.85 The
inflammatory cell infiltrate is typically mild, superficially located, and
perivascular in distribution. In some examples, however, it presents as a
lichenoid band.85,91,362
The histopathological features in cutaneous lesions of patients without
SCLE and antibodies to SS-A (Ro) are very similar to those seen in lesions of
patients with SCLE.363 These patients often have different clinical diseases
including Sjögren's syndrome and rheumatoid arthritis.
Systemic lupus erythematosus
The histological features of SLE are variable. The changes in early lesions,
which may be very mild and subtle, often comprise only slight epidermal
basal cell liquefactive degeneration, papillary dermal edema, and a mild
chronic inflammatory cell infiltrate and are seen, for example, in malar ery-
thema (Fig. 17.75).92,347 On other occasions the appearances are similar to
those of SCLE.
The histology of SLE is often indistinguishable from that of the discoid
variant (Fig. 17.76). Fibrinoid degeneration of the dermal collagen is, how-
ever, more common in SLE than in DLE. Dermal mucin deposition is often
Lupus erythematosus 731
Fig. 17.74
Subacute cutaneous lupus erythematosus: in this example, there is marked basal
cell hydropic degeneration and apoptosis. Only a patchy chronic inflammatory cell
infiltrate is present.
Fig. 17.75
Systemic lupus erythematosus: although the changes may be identical to the
discoid or subacute variants, sometimes the features are mild, as in this case. There
is focal basal cell hydropic degeneration, apoptosis, and telangiectasia.
seen between collagen bundles. In most cases, this feature is subtle, but mucin
deposition may be very prominent.364 A thick basal membrane is more com-
monly seen in lesions of DLE. As with DLE, the commonest cell type is the T
lymphocyte, but which subset predominates is uncertain. Both CD4+ and
CD4+ subset preponderance have been documented.328, 329 It may be that dif-
ferences in the age of the lesion, effects of treatment, and antibody specificity
can account for this apparent anomaly. CD4+ lymphocytes are present in
large numbers in the epidermis at sites of basal keratinocyte hydropic
degeneration.328
The histopathological features of the cutaneous lesions of the antiphos-
pholipid syndrome comprise both venous and arterial thrombosis in the
absence of any evidence of vasculitis (Figs 17.77–17.79). In early lesions,
endothelial cell damage may be marked and erythrocyte extravasation is
common. Older lesions are characterized by marked vascular proliferation,
commonly in a lobular distribution accompanied by hemosiderosis. Hobnail
reactive endothelial cells and eosinophilic hyaline globules are sometimes evi-
dent.323 A lymphocytic infiltrate accompanied by variable numbers of plasma
cells is often seen.323,365,366 In some patients, the clinical and histological fea-
tures of Degos' disease and anetoderma have been documented.366
732 Idiopathic connective tissue disorders

Fig. 17.76 Fig. 17.79

Systemic lupus erythematosus: in this example, the features resemble the discoid
variant. Note the hyperkeratosis, epidermal atrophy, follicular involvement, and
gross basal cell hydropic degeneration. A perivascular and perifollicular chronic
inflammatory cell infiltrate is present.
Fig. 17.77
Lupus anticoagulant syndrome: low-power view showing superficial blood vessels
occluded by small thrombi.
Fig. 17.78
Lupus anticoagulant syndrome: close-up view of occluded vessel – note the nuclear debris.
Lupus anticoagulant syndrome: the presence of fibrin is confirmed in this
phosphotungstic acid–hematoxylin stained section.
Renal lesions may be detected in 70–80% of patients. The histological fea-
tures are subdivided into six classes according to the International Society of
Nephrology/Renal Pathology Society 2003 classification of lupus nephritis,
representing an evolution of the previous WHO classification:367,368
• In class I lesions (minimal mesangial lupus nephritis) no abnormalities
can be detected by light microscopy. Mesangial deposition of immune
complexes can be identified by immunofluoresecence, electron
microscopy or both.
• Class II lesions (mesangial proliferative lupus nephritis) are characterised
by any degree of mesangial hypercellularity (defined as three or more
mesangial cells per mesangial area in a 3-micron thick section) associated
with mesangial immune deposits. Rare small immune deposits involving
peripheral capillary walls can occasionally be detected by
immunofluorescence or electron microscopy. Features not acceptable are
subendothelial deposits on light microscopy as well as any segmental or
global glomerular scars resulting from previous glomerular endocapillary
proliferation, necrosis or crescents. Immunofluorescence reveals
mesangial deposition of IgG and complement and mesangial electron-
dense deposits may be detected by electron microscopy. Mesangial lupus
glomerulonephritis is the mildest form of glomerular lesion and is present
in about 10% of patients with renal involvement.367
• Class III lesions (focal lupus nephritis) are distinguished by active or
inactive focal, segmental or global endo- or extracapillary
glomerulonephritis involving <50% of all glomeruli, associated with
focal subendothelial immune deposits, with or without mesangial
proliferation. Focal segmental proliferative glomerulonephritis is found
in about 30% of patients. In this variant, only scattered glomeruli are
affected (focal) and usually only a portion of the tuft is involved
(segmental).367 Lesions may be proliferative and necrotizing. Involved
glomeruli usually show mesangial and endothelial proliferation,
polymorph infiltration, fibrin deposition, and karyorrhexis; occasionally,
hematoxylin bodies are evident. Hematoxylin bodies are regarded as the
histological hallmark of SLE. They are round-to-oval structures, which
stain purple/red–pink/blue with hematoxylin and eosin. They stain
positively with the Feulgen reaction and are von Kossa negative.
Hematoxylin bodies are thought to be the in vivo counterpart of the LE
cell phenomenon. Although frequently sought they are often very difficult
to find. Electron microscopy typically reveals mesangial and
subendothelial electron-dense (immune complex) deposits. Clinically,
patients present with hematuria and proteinuria, although a proportion
may develop chronic renal failure.
• Class IV lesions (diffuse lupus nephritis) are characterised by active or
inactive focal, segmental or global endo- or extracapillary
glomerulonephritis involving ≥50% of all glomeruli, associated with
 Lupus erythematosus 733

diffuse subendothelial immune deposits, with or without mesangial Neonatal lupus erythematosus
proliferation. They can be further subclassified as diffuse segmental The histological features and immunofluorescence pattern of the cutaneous
(IV-S) and diffuse global (IV-G) lupus nephritis. Diffuse lupus lesions in neonatal disease are similar to those seen in SCLE.164,371 The most
glomerulonephritis occurs in about 50% of patients with SLE who have frequently documented findings include hydropic degeneration of basal kera-
the nephritic/nephrotic syndrome or hypertension.367 Almost all glomeruli tinocytes and adnexal epithelium, dermal edema as well as a superficial and
are affected and, in addition to mesangial and endothelial proliferation, occasionally deep perivascular and periadnexal lymphohistiocytic chronic
the epithelial cells may participate, with the formation of crescents. inflammatory cell infiltrate.343, 372 Eosinophils may be prominent in urticaria-
Careful examination of the periphery of the glomerular tuft often reveals like SCLE lesions.372
regularly thickened capillaries – ‘wire-loop’ lesions, thought to be specific
for SLE. Differential diagnosis
• Class V (lupus membranous glomerulonephritis) lesions show global or
Lupus erythematosus must be distinguished from other dermatoses that mani-
segmental subepithelial granular immune deposits with or without
fest basal cell liquefactive degeneration, particularly lichen planus and poikilo-
mesangial alterations. Scattered subendothelial immune deposits can also
derma. Lupus erythematosus lacks the wedge-shaped hypergranulosis and
be present. Class V lesions can be associated with both class III and class
sawtooth acanthosis of lichen planus. The inflammatory cell infiltrate is typi-
IV lesions. Lupus membranous glomerulonephritis is found in about
cally periappendageal, rather than adopting a bandlike distribution. Occasionally,
10% of patients with SLE and presents as proteinuria or the nephrotic
hypertrophic lupus erythematosus shows considerable overlap with lichen
syndrome.367 Histologically, there is uniform thickening of the glomerular
planus; in such instances a positive lupus band test resolves the problem.
capillaries without any significant inflammatory cell infiltration.
Poikiloderma, whether congenital or associated with dermatomyositis
Advanced glomerulosclerosis can be present. Ultrastructurally, the
(and rarely SLE) or as a manifestation of mycosis fungoides, is characterized
electron-dense deposits are found subepithelially.
by epidermal atrophy and marked basal cell liquefactive degeneration associ-
• Class VI lesions (advanced sclerosis lupus nephritis) are characterized by
ated with pigmentary incontinence. A patchy lymphohistiocytic infiltrate is
global sclerosis without residual activity in ≥90% of glomeruli, related to
evident in the upper dermis. Papillary dermal edema and telangiectases are
lupus nephritis. They can represent progression of class III, IV or V lesions.
typically present. Although there is obviously histological overlap, the very
In addition to glomerular lesions, patients with renal involvement may
different clinical manifestations should obviate any diagnostic difficulties.
manifest acute necrotizing vasculitis.
The presence of atypical lymphocytes will clearly distinguish the variant
The heart is involved in about 50% of patients with SLE. Acute lesions of
­associated with mycosis fungoides.
fibrinoid degeneration and hematoxylin bodies may be seen in the pericar-
The histological features of lupus erythematosus are sometimes difficult to dis-
dium, but it is more common to find obliteration of the pericardial sac by
tinguish from polymorphic light eruption, particularly when the latter is associ-
fibrous, sometimes gelatinous, adhesions. Fibrinoid necrosis of the myocar-
ated with a positive band test (see above). Polymorphic light eruption, which is
dial collagen is usually found in the connective tissue septa and occasionally
the most common photodermatosis, usually presents in young people, particu-
also affects the associated arteries. Libman-Sacks endocarditis is the best-
larly females, as recurrent, erythematous papules, vesicles and/or plaques follow-
known cardiac manifestation of SLE and is believed to occur in 30–60% of
ing exposure to ultraviolet light (Figs 17.80, 17.81).373 Lesions, which develop
the patients who come to autopsy.166 Small granular vegetations have been
after a latent period of hours to days, commonly subside completely within days
found on the surfaces of all valves, although the mitral and tricuspid are most
and heal without sequelae.362 Histologically, superficial dermal edema and a mild
often affected. The vegetations may spread to involve the chordae tendinae
to moderate superficial and deep perivascular lymphohistiocytic infiltrate are
and adjacent endocardium. Histologically, they consist of fibrin overlying
often seen.373 In early lesions helper-inducer T lymphocytes predominate and
degenerate collagen, with an associated chronic inflammatory cell infiltrate.
increased numbers of dermal Langerhans cells are present.374 With chronicity,
Infective endocarditis is an occasional, but important, complication. Increased
cytotoxic-suppressor T cells become more conspicuous. Basal cell hydropic
quantities of glycosaminoglycans are usually evident and sometimes hema-
degeneration is usually absent and epidermal atrophy is not a feature.
toxylin bodies are present.
The histological lesions of pulmonary involvement include interstitial
pneumonitis, fibrosing alveolitis, and infarction. In a large autopsy study of
patients with SLE, pleuropulmonary involvement has been detected in 97.8%
of patients, and included pleuritis (77.8%), bacterial infections (57.8%), pri-
mary and secondary alveolar hemorrhage (25.6%), distal airways alterations
(21.1%), opportunistic infections (14.4%), and thromboembolism (7.8%).369
Direct immunofluorescent examination of lung biopsies may reveal the pres-
ence of both immunoglobulin and complement.
Lymph nodes often show reactive hyperplasia; occasionally there are strik-
ing pathological features, which may be confused with a lymphomatous infil-
trate. These changes consist of a necrotizing lymphadenitis with prominent
hematoxylin bodies. Surviving follicles show reactive hyperplasia and conspic-
uous plasma cells and immunoblasts. The thymus may show prominent germi-
nal center formation, with an increase in the size and number of Hassall's
corpuscles. Perisplenitis (‘sugar icing’) of the splenic capsule is common and a
characteristic histological finding is concentric fibrosis (‘onion skinning’) of the
adventitia of the central (penicillary) arteries of the malpighian corpuscles.
Joint manifestations include fibrinoid degeneration within the synovium,
rheumatoid features, and arteritis. A variety of lesions may be seen in the
liver, including fatty change, focal hepatocyte necroses, and evidence of vas- Fig. 17.80
culitis. Central nervous system manifestations have an ischemic pathogenesis, Polymorphic light
eruption: patients present
most probably on an immune complex-mediated vasculitic basis. There is
with erythematous
some evidence to incriminate an antineuronal autoantibody. The cardiac papules and vesicles on
pathology of neonatal lupus erythematosus comprises fibrosis and calcifica- sun-exposed skin. By
tion of the atrioventricular node and, to a lesser extent, the sinoatrial node.370 courtesy of the Institute
Focal lymphocytic myocarditis and endocardial fibroelastosis may also be of Dermatology, London,
evident.262 UK.
734 Idiopathic connective tissue disorders

dermatomyositis, different sets of antibodies in the serum (anti-PM-Sci and

anti-U1RNP), and improved survival.16–18 Cardiopulmonary diseases have
predictive value for survival in juvenile systemic sclerosis.16,17
Systemic sclerosis has a high overall mortality, 5-year survival rates vary-
ing from 34% to 73%.1 It has been demonstrated that improvement of skin
thickening is associated with improved survival.19,20 Older patients and males
generally fare worst.

Limited cutaneous systemic sclerosis

Fig. 17.81
Polymorphic light eruption: the eruption is typically symmetrical and is usually
pruritic. By courtesy of the Institute of Dermatology, London, UK.
In the limited variant, the cutaneous manifestations, which often initially
affect the hands, include early edematous, sclerotic, and late atrophic stages.1
The edema is characteristically nonpitting, bilateral, and symmetrical. The
fingers are commonly described as having a sausage-like appearance (Fig.
17.82). The face, forearms, feet, and legs are sometimes affected. As the
edema subsides the skin becomes thickened and tight and is bound down to
the subcutaneous tissues. Typically, the fingers become tapered and, due to
ischemia, show pulp atrophy and absorption of the terminal phalanges, with
the fingertips often not protruding beyond the free margin of the nails (Figs
17.83–17.85). The latter may show longitudinal ridging and brittleness or
may even be shed. The affected skin has a very characteristic appearance,

Systemic sclerosis
Clinical features
Progressive systemic sclerosis includes two major variants:1–5
• In the more serious diffuse form, patients have widespread cutaneous
lesions proximal to the metacarpo- and metatarsophalangeal joints
(proximal scleroderma) in addition to involvement of the internal viscera,
particularly the kidneys, lungs, heart, esophagus, and intestinal tract. The
illness often has an acute onset with fatigue, weight loss, arthralgia, and
carpal tunnel syndrome. Tendon friction rubs are characteristic. Anti-
Scl-70 (anti-DNA topoisomerase) and RNA polymerase III antibodies are
often present and the outlook is generally poor.
• The other major variant is associated with limited peripheral cutaneous
sclerosis and an absence of severe systemic disease except for esophageal
involvement, small intestinal malabsorption, and pulmonary
hypertension; it usually has a better prognosis.2,6 This form is associated
with an anticentromere antibody.
Systemic sclerosis has also occasionally been recorded in the absence of Fig. 17.82
cutaneous manifestation (sine scleroderma variant) and overlap syndromes Systemic sclerosis: early stage showing characteristic swollen, sausage-shaped
have been described.7,8 Limited scleroderma also includes the CREST (calci- fingers. By courtesy of the Institute of Dermatology, London, UK.
nosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, telang-
iectasis) syndrome (Thibierge-Weissenbach syndrome, acrosclerosis) where
cutaneous disease expression is restricted to the fingers and toes (sclerodac-
tyly) and face (see below).9 Other generalized variants include sclerodermato-
myositis, mixed connective tissue disease, and the chemically induced
scleroderma-like syndromes.
Because of the variety of systems that can be affected in systemic sclerosis,
patients may be primarily under the care of dermatologists, rheumatologists,
nephrologists or other specialists, resulting in difficulties in determining the
exact incidence of the disease; it is estimated to be in the order of 20 new
cases per million of the population per year.10 In a large series, the diffuse and
limited forms were equally common.11 About 10% were classified as overlap
syndromes. The disease occurs more frequently in families and it is regarded
as the strongest risk factor identified for this condition.12 However, the abso-
lute risk for each family member is low.12 Systemic sclerosis is associated with
a marked female predominance (3–4:1); although any age group may be
affected, patients most often present in their fourth, fifth, and sixth decades.13,14
Young black females constitute a definite subset with a particularly high risk.
Occasional familial instances, usually in children, have also been docu-
mented.10 Juvenile systemic sclerosis represent about 3% of systemic sclerosis Fig. 17.83
patients.15 No sex predilection is seen before the age of 8 years.15 In contrast Systemic sclerosis: the fingers are erythematous and shiny and the skin appears
to adult-onset systemic sclerosis, juvenile systemic sclerosis is associated slightly bound down. By courtesy of R.A. Marsden, MD, St George's Hospital,
with higher incidence of overlap syndromes, especially with polymyositis/­ London, UK.

Fig. 17.84
Systemic sclerosis: the fingertips are tapered. By courtesy of R.A. Marsden, MD,
St George's Hospital, London, UK.
Fig. 17.85
Systemic sclerosis: note the marked atrophy of the fingertip. By courtesy of R.A.
Marsden, MD, St George's Hospital, London, UK.
being shiny, smooth and rather waxy. Patients often have markedly dimin-
ished mobility of their hands and feet, and flexion contractures are common
(Fig. 17.86). In advanced disease, many patients acquire a dramatically rigid,
expressionless face with beaked nose, thinned lips, and perioral furrowing
and wrinkling, and an inability to open the mouth fully (Figs 17.87, 17.88).21
Tightness of the lower eyelids may also be noticed and the forehead can
appear smooth and free of creases.2 Ulceration is a common complication,
particularly where taut skin is stretched over bony prominences susceptible to
trauma (Fig. 17.89).
Vascular changes are common and include peripheral gangrene, digital
autoamputation, and Raynaud's phenomenon.21 The last occurs so frequently
(in both limited and diffuse forms) that it is often taught that a patient who
has it must be presumed to have systemic sclerosis, until proven otherwise. In
limited cutaneous systemic sclerosis, Raynaud's phenomenon may precede
the onset of cutaneous lesions by many years in a large proportion of
patients.10 A useful diagnostic feature of systemic sclerosis is loss of many of
the nail fold capillaries and dilatation of the remainder. It has recently been
demonstrated that the nail fold capillaroscopy abnormalities correlate with
diffuse form of systemic sclerosis, severity of cutaneous involvement, number
of affected tracts, and the presence of anti-Scl-70 antibodies.22
Systemic sclerosis 735
Fig. 17.86
Systemic sclerosis: note the flexion contractures. The skin is bound down and
appears atrophic. There is periungual erythema. By courtesy of R.A. Marsden, MD,
St George's Hospital, London, UK.
Fig. 17.87
Systemic sclerosis: there is perioral scarring with atrophy. By courtesy of the
Institute of Dermatology, London, UK.
The cutaneous changes in CREST syndrome are located predominantly
distal to the metacarpophalangeal joints, although the dorsum of the hands
and mouth can sometimes also be affected. The inflammatory stage is persis-
tent in the CREST syndrome.
Raynaud's phenomenon, either alone or with swollen puffy fingers, is by
far the most common mode of presentation and telangiectases tend to be
much more numerous (often numbering hundreds) than in patients with dif-
fuse systemic sclerosis. They particularly affect the fingers and hands, face,
tongue, and mucous membranes (Figs 17.90–17.92). The telangiectasias
seen in this variant of scleroderma may be difficult to distinguish from those
seen in hereditary hemorrhagic telangiectasia.23 The esophageal dysfunction
is identical to that seen in the diffuse variant, but it tends to be more severe
and affects the majority of patients.
The value of the designation ‘CREST syndrome’ has, however, diminished
considerably since the discovery that many patients with limited cutaneous
disease fail to fulfill all of its criteria and the observation that ‘CREST’ mani-
festations may be seen in many patients with diffuse disease.8 For example,
there is a variant consisting of digital necrosis, Raynaud's phenomenon, and
anticentromere antibodies without sclerodactyly.24 The term should probably
be abandoned and all patients with limited distal disease classified as a single
736 Idiopathic connective tissue disorders

Fig. 17.88 Fig. 17.90

Systemic sclerosis: note Systemic sclerosis: telangiectasia as seen on these fingers is a common finding.
the thinned lips and By courtesy of S. Parker, MD, West Middlesex Hospital, London, UK.
characteristic radiating
furrows. By courtesy
of R.A. Marsden, MD,
St George's Hospital,
London, UK.

Fig. 17.91
Systemic sclerosis: numerous telangiectases are present. The hand is a commonly
affected site. By courtesy of the Institute of Dermatology, London, UK.

Fig. 17.89
Systemic sclerosis: ulceration is a particularly distressing complication. By courtesy
of the Institute of Dermatology, London, UK.

subtype. However, considering the frequency with which CREST syndrome

appears in the current literature, this is unlikely to happen, at least in the fore-
seeable future. It was originally thought that the limited variant was associ-
ated with a relatively benign outcome, but it is now known that if patients are
followed for sufficient time a significant proportion will develop severe pul-
monary hypertension with its sequelae. There is also an increased risk of
Sjögren's syndrome, biliary cirrhosis, discoid lupus erythematosus, and thy-
roid dysfunction, such as Hashimoto thyroiditis and Graves' disease.1,25–27
Sjögren's syndrome has been found in 14% of patients with systemic sclerosis
and was more common in the limited cutaneous variant of systemic sclero-
sis.28 More than one of the associated autoimmune conditions may coexist
with CREST syndrome.26 It has been suggested that patients with coexistent
primary biliary cirrhosis have a distinctive subset of the disease, which tends Fig. 17.92
to be milder and have a better prognosis.29 An exceptional case of antimito- Systemic sclerosis: extensive telangiectasia as seen in this patient is more often
chondrial antibody positive primary biliary cirrhosis developing after an a feature of the limited variant. By courtesy of S. Parker, MD, West Middlesex
acute myocardial infarction has been reported.30 Although clinically ­significant Hospital, London, UK.

primary biliary cirrhosis develops in 2.5% of systemic sclerosis patients, a
recent study has demonstrated the presence of antimitochondrial antibodies
in 15% of systemic sclerosis patients.31 Overlap syndrome between primary
biliary cirrhosis and autoimmune hepatitis has also been found in systemic
sclerosis.32 A multicenter French–Italian study has found coexistence of sys-
temic sclerosis and autoimmune disease in 21% of the patients, with Sjögren's
syndrome (12%) and thyroiditis (6%) being the most frequent associations.33
Systemic sclerosis patients with associated autoimmune conditions appear to
follow a milder course of the disease.33 Systemic sclerosis is associated with
rheumatoid arthritis in about 5% of the patients, and likely represents a dis-
tinctive disease subset associated with HLA-DR3, HLA-DR7, HLA-DR11,
and HLA-DRw53.34
Hyperpigmentation, from light brown to dark bronze reminiscent of
Addison's disease, is a frequent manifestation and is often associated with the
presence of small foci of hypopigmentation, giving a characteristic ‘salt and
pepper’ appearance. The pigmentary changes particularly affect the backs of
the hands and forearms, and the upper part of the chest and back. Sometimes
the degree of accompanying hypopigmentation is so marked that it resembles
vitiligo.35
The cutaneous changes are often associated with the development of calci-
nosis cutis, particularly in females.2,36,37 It is dystrophic in type and is due to
hydroxyapatite crystal deposition. Patients have no abnormalities of calcium
and phosphorus metabolism and their serum alkaline phosphatase levels are
normal. The sites of calcium deposition particularly include the metacarpo-
phalangeal joints of the thumbs and the fingertips, although the extensor
aspect of the forearms, the buttocks, the olecranon bursae, and the prepatel-
lar region may also be affected (Figs 17.93, 17.94). The deposits are often
exceedingly painful and commonly associated with ulceration and leakage of
white granular calcified debris. The combination of phalangeal reabsorption
and calcinosis cutis is said to be pathognomonic of systemic sclerosis.38
Calcinosis cutis has also been reported in patients with systemic sclerosis sine
scleroderma.39
Systemic sclerosis is sometimes associated with an erythema nodosum-like
panniculitis syndrome and patients may also develop livedo reticularis and
atrophie blanche affecting the lower limbs.40
CREST has been documented in association with familial lichen sclerosus,
chronic myelogenous leukemia, idiopathic myelofibrosis, and porphyria cuta-
nea tarda.41–43
Diffuse systemic sclerosis
In diffuse (progressive) systemic sclerosis, cutaneous lesions are particularly
common on the proximal extremities, thorax, and abdomen. The course
tends to be progressive and often there is a more severe superficial vascular
involvement.2 Skin thickening affecting the trunk indicates a poor prognosis
Fig. 17.93
Systemic sclerosis: there is a large calcified nodule on the fingertip. By courtesy of
R.A. Marsden, MD, St George's Hospital, London, UK.
Systemic sclerosis 737
Fig. 17.94
Systemic sclerosis:
radiograph demonstrating
a more widespread
example. By courtesy
of R.A. Marsden, MD,
St George's Hospital,
London, UK.
and correlates with extensive systemic involvement.10 Although the cutaneous
features cause considerable distress, the systemic manifestations are more
important in terms of severe morbidity and potential mortality. The early
investigation of a patient with systemic sclerosis should establish baseline val-
ues of respiratory, cardiac, and renal function so that progress may be accu-
rately monitored.
Clinical involvement of the lung is common and an important cause of
morbidity and mortality. It is thought to occur to a greater or lesser extent in
most patients.44 There are three major forms: interstitial pneumonitis, bron-
chiolitis, and pulmonary vascular disease.44
• Pulmonary interstitial involvement results in shortness of breath on
exertion and a nonproductive cough. Dyspnea is a feature in almost 60%
of unselected patients with diffuse scleroderma.45 Symptoms tend to be
particularly evident in patients who have associated Sjögren's
syndrome.44 Interstitial lung disease is the commonest cause of death in
systemic sclerosis. There is evidence suggesting an increased risk of
pulmonary fibrosis in patients with the haplotype HLA-DR3/-DRw52A
and anti-Scl-70 antibody.46,47
• Bronchiolitis is evident in approximately 13–25% of patients, but this is
usually asymptomatic.44
• Pulmonary hypertension, which may be a primary manifestation of
systemic sclerosis or develop secondary to interstitial fibrosis, is more
common in patients with the limited form of the disease.48,49 A study has
found that the postmenopausal state with or without the presence of
HLA-B35 is the main risk factor for the development of pulmonary
hypertension.50
Pulmonary radiographs typically show bilateral basal fibrosis, either as
diffuse mottling or linear infiltrates; cyst formation (‘honeycomb lung’) is a
not uncommon feature.
The cardiac, renal, peripheral nervous, gastrointestinal, and skeletal ­systems
are also involved:
• The majority of patients have subclinical primary cardiac involvement.51
Cardiac involvement may present as dyspnea on exertion, paroxysmal
nocturnal dyspnea, pericarditis, pericardial effusion, congestive heart
failure, arrhythmias, valvular abnormalities, myocardial hypertrophy or,
occasionally, atypical angina.51–53 Vasospasm of the small coronary
arteries and arterioles has been observed as an early cardiac
manifestation.51 Significant cardiac abnormalities including pericarditis
and effusion are common pathological findings, being present in more
than 50% of cases at autopsy.54 Usually, however, they are asymptomatic.
Occasionally, severe acute pericarditis may develop and rare instances of
fatal cardiac tamponade have been documented.52 Large pericardial
effusions correlate with acute renal failure and are a bad prognostic
indicator.54 Patchy myocardial scarring is common, and usually occurs
later in the course of systemic sclerosis.51 When severe, myocardial
fibrosis is associated with a poor outlook.55 It occurs independently of
738 Idiopathic connective tissue disorders
coronary artery disease and has been described in up to 70% of patients
in postmortem series.52 The major coronary arteries are patent and
normal (unless there is coexistent atherosclerosis), but the small vessels
and arterioles may undergo endothelial and intimal proliferative changes
with scarring, resulting in an increased risk of arrhythmia and the
consequent sudden death of the patient. A recent study has found
association between myocardial perfusion defects, skin thickness, digital
ulcers, and esophageal involvement.56
• Renal involvement presenting as ‘scleroderma renal crisis’ is an extremely
important complication with high mortality and occurs in approximately
10% of patients with systemic sclerosis.57 The use of ACE inhibitors has,
however, significantly diminished the mortality. It is defined as ‘the new
onset of accelerated arterial hypertension and/or rapidly progressive oliguric
renal failure’.57 Patients develop headache and blurred vision. Seizures are
sometimes a feature. The renal failure is commonly asymptomatic and
detectable only from abnormal renal function tests including proteinuria,
microscopic hematuria with casts, raised creatinine levels, and
hyperreninemia.57 Microangiopathic hemolytic anemia is sometimes
present, particularly in normotensive patients.58 Anti-RNA polymerase III
antibodies have been detected in about one-third of the patients with
‘scleroderma renal crisis’.59 A minority of patients with systemic sclerosis
develop renal pathology other then ‘scleroderma renal crisis’.60 ANCA-
related glomerulonephritis has occasionally been reported.61,62
• Peripheral neuropathy may lead to neuropathic ulceration.63 Intrauterine
fetal death has been described in pregnant women with the disease.64
Papular and nodular mucinosis has been documented as a presenting sign
of systemic sclerosis.65
• Clinically relevant gastrointestinal lesions occur in up to 50% of patients
with systemic sclerosis.66,67 Widening of the periodontal space, determined
radiographically, is characteristic. Patients frequently have symptoms
relating to esophageal involvement including heartburn, dysphagia, and
regurgitation. Gastrointestinal reflux is common and patients can develop
esophagitis, hemorrhage, stricture, Barrett's esophagus (gastric
metaplasia), and aspiration.66 Radiographs may show esophageal
dilatation and abnormalities of peristalsis. Epigastric fullness is a frequent
symptom, which might be related to restricted distension of the gastric
antrum.67 Gastric antral vascular ectasia appears to develop earlier in
those systemic sclerosis patients that display a rapidly progressive
cutaneous disease.68 Systemic sclerosis often involves the small intestine,
symptoms ranging from epigastric pain, nausea and vomiting, through to
the effects of pseudo-obstruction; a malabsorptive state due to stasis is an
important complication. Celiac disease can develop in patients with
systemic sclerosis.69 Colonic lesions may result in diarrhea or constipation.
Saccular diverticula along the mesenteric border of the colon are
characteristic; they sometimes also affect the small bowel.66
• Osteoarticular involvement, presenting with arthralgia or frank arthritis
is seen in the majority of patients.70 Joint lesions are usually mild and
affect the wrists, hands, knees, and ankles, although a more serious
rheumatoid arthritis-like variant has been documented.71 Osteoarthrosis
and psoriatic arthropathy-like manifestations have also been described.70
It is important in patients with significant joint manifestations that
overlap syndromes and mixed connective tissue disease are excluded.
Contractures and ankyloses resulting in immobility are important
complications and osteoporosis is common due to a combination of
immobilization and ischemia.
The diagnosis of systemic sclerosis may be readily apparent, but early dis-
ease, particularly the diffuse form, may clinically mimic a variety of other
diseases, for example, scleredema of Buschke. Late graft-versus-host disease
(GVHD) and chronic lesions of porphyria cutanea tarda are typically sclero-
dermatous.72 The American Rheumatology Association has guidelines for
classification, of which the major criterion is proximal scleroderma (Table
17.6).73 Minor criteria are:
• sclerodactyly,
• digital pitting scars on the fingertips or loss of substance of the distal
fingerpad,
• bilateral basal pulmonary fibrosis.
Table 17.6
American Rheumatology Association (ARA) guidelines for the classification
of scleroderma*
1. Proximal scleroderma is a single major criterion: sensitivity is 91% and
specificity is more than 90%.
2. Sclerodactyly, digital pitting scars of the fingertips or loss of substance
of the finger pad, and bibasilar pulmonary fibrosis contribute further
minor criteria in the absence of proximal scleroderma.
3. The major or two more minor criteria are present in 97% of definite
systemic sclerosis patients, but in only 2% of comparison patients
with systemic lupus erythematosus, polymyositis–dermatomyositis or
Raynaud's disease.
* Preliminary clinical criteria for systemic sclerosis exclude localized scleroderma and
pseudodermatous disorders. Reproduced with permission from Masi, A.T. et al and
the ARA Subcommittee for scleroderma (1980) Arthritis and Rheumatism, 23, 581–590.
If a patient has either the major or two minor criteria there is 97% sensi-
tivity for definite systemic sclerosis and 98% specificity. These criteria have
gained wide popularity, but have the disadvantage of excluding at least 10%
of cases where, despite a concrete diagnosis of systemic sclerosis, neither
major nor minor criteria are fulfilled. Unclassifiable and overlap syndromes
are also excluded. Other classifications have included two, three, and even
four subtypes based upon the extent of cutaneous sclerosis (Table 17.7).74
Limited cutaneous systemic sclerosis may therefore involve the hands, feet,
forearms, and face, or skin lesions can be absent, whereas in diffuse disease
the trunk skin is also involved. In a comparison of classification by two sub-
types (diffuse and limited) or three subtypes (diffuse, intermediate, and lim-
ited), the latter correlated best with antibody specificity and survival.75
A number of chemical-induced scleroderma-like syndromes have been
described:
• Workers in the vinyl chloride polymerization industry may develop
Raynaud's phenomenon, acral osteolysis, dermal thickening of the skin
of the arms, hands, face, and trunk, and pulmonary and hepatic
fibrosis.76–78 Examination of the capillaries of the nail folds reveals
abnormalities similar to those seen in systemic sclerosis.
• Bleomycin therapy may also be associated with sclerodermiform
infiltrated plaques and nodules that particularly affect the hands.79
Patients may develop hyperpigmentation, peripheral gangrene, and
pulmonary fibrosis.
• A high incidence of systemic sclerosis is found in those who work in
coalmines or who have excessive exposure to silica for other reasons.80
• A generalized morphea-like variant with Raynaud's phenomenon,
esophageal dysfunction, and pulmonary fibrosis has been described
following chronic exposure to industrial solvents.81
• A variety of autoimmune diseases have been documented following the
use of silicone breast implants. Systemic sclerosis appears to be the most
common.82
• Toxic oil and eosinophilia myalgia syndromes are discussed in the section
on eosinophilic fasciitis.
Systemic sclerosis is associated with increased risk of malignancies, which
develop in between 3.6% and 10.7% of patients.83 Population-based studies
have found most frequent association with breast cancer, lung cancer, and
hematological malignancies, such as non-Hodgkin's lymphoma.84–87 Increased
incidence of squamous cell carcinoma of the tongue has also been detected.88
Rare associations include basal cell carcinoma, melanoma, nasopharyngeal
carcinoma, and gastric MALT lymphoma.86,89,90
Pathogenesis and histological features
The etiology and precise pathogenesis are unknown. A complete understand-
ing must take into account vascular changes and abnormalities of collagen
deposition and distribution, in addition to the significance of the inflamma-
tory cells that characterize the early stages and their role in the control of
fibroblast growth and function.91 Systemic sclerosis has stimulated an enor-
mous research effort, which has resulted in an increased awareness of the
multiplicity of factors that may be involved, either singly or in concert, and

Table 17.7
Classifications of systemic sclerosis
Subsets of systemic sclerosis (SSc)
Diffuse cutaneous Onset of Raynaud's phenomenon within 1 year of
SS* onset of skin changes (puffy or hidebound)
Truncal and acral skin involvement
Presence of tendon friction rubs
Early and significant incidence of interstitial
–lung disease, oliguric renal failure, diffuse
gastrointestinal disease and myocardial
involvement
Absence of anticentromere antibodies
Nail fold capillary dilatation and capillary
destruction†
Antitopoisomerase antibodies (20–60% of patients)
Limited Raynaud's for years (occasionally decades)
cutaneous SSc Skin involvement limited to hands, face, feet, and
forearms (acral) or absent
A significance late incidence of pulmonary
hypertension, with or without interstitial lung
disease, trigeminal neuralgia, skin calcifications,
telangiectasia
A high incidence of anticentromere antibody
Dilated nail fold capillary loops, usually without
capillary dropout
Subsetting of SSc by early cutaneous involvement†
Digital Finger or toes, minimal non-extremity
involvements allowed: eyelid, neck and axillary
changes
Proximal Proximal extremity or face, but not trunk
extremity
Truncal Thorax or abdomen
Systemic sclerosis subsets according to skin sclerosis extent
ssSSc lcSSc icSSc dcSSc
ssSSc = sine scleroderma systemic sclerosis sclerotic
lcSSc = limited cutaneous systemic sclerosis skin
icSSc = intermediate cutaneous systemic sclerosis uninvolved
dcSSc = diffuse cutaneous systemic sclerosis skin
Skin sclerosis extent in four SSc subsets. LcSSc patients may present
minimal sclerotic lesion at eyelids, neck and axillae
*Experienced observers note some patients with dcSSc who do not develop organ
insufficiency and suggest the term chronic dcSSc for these patients.
†Nail fold capillary dilatation and destruction may also be seen in patients with
dermatomyositis, overlap syndromes and undifferentiated connective tissue disease.
These syndromes may be considered as part of the spectrum of scleroderma-
associated disorders.
‡ The subject is defined within 1 year from presentation.
Top panel reproduced with permission from Leroy, E.C. et al (1988) Journal of
Rheumatology, 15, 202–205; middle and lower panels reproduced with permission
from Valentini, R. (1994) Clinics in Dermatology, 12, 217–223.
Systemic sclerosis 739
has also greatly increased our knowledge of the basic processes involved in
the mechanisms of collagen synthesis and scarring. The two main areas of
investigation have revolved around:
• primary blood vessel endothelial cell damage and its sequelae,
• abnormalities of collagen and its synthesis.92,93
Inherent to both are the possible initiating and moderating roles of cell-
mediated and humoral immunity.
It has long been recognized that many of the features of systemic sclerosis
may have an ischemic basis.94 Alterations have been described in capillaries,
venules, and arteries and it has been suggested that the initial injury involves
capillary endothelial cells.95 The cause of this is unknown, although a circu-
lating specific cytotoxic substance reactive for endothelial cells has been iden-
tified.95,96 It has been suggested that this may represent a protease.97
Interestingly, specimens of early lesions and uninvolved skin have shown
ultrastructural evidence of endothelial cell damage combined with decreased
uptake of tritiated adenosine and diminished stores of immunodetectable von
Willebrand factor, suggesting that the vascular changes may well initiate the
connective tissue damage seen in this disease.98
Although immunoreactants (IgG and complement) have been detected in
the walls of renal glomerular capillaries by immunofluorescent techniques,
they have not been found in the cutaneous vasculature.98,99 If Raynaud's phe-
nomenon is induced in patients with systemic sclerosis, there is a concomitant
reduction in both renal and pulmonary blood flow, implying a circulating fac-
tor, as yet unidentified.
The dermal capillaries show a variety of ultrastructural changes. The earli-
est finding is separation of the endothelial cells; this may result in fluid ­leakage
and therefore be responsible, at least in part, for the edema that characterizes
the early stages.1 Evidence of more severe damage is manifest by the presence
of endothelial cell vacuolation, increased numbers of intermediate filaments,
reduction in pinocytotic vesicles and Weibel-Palade bodies, and abnormal
endothelial surface cytoplasmic blebs.98
Evidence of endothelial cell injury can be monitored clinically by estimating
plasma von Willebrand factor levels.93 Elevated levels of supranormal von
Willebrand factor multimers are typically seen in systemic sclerosis and may have
pathogenetic significance as they are known to bind to subendothelial ­tissues,
causing platelet aggregation and adhesion with resultant vascular ­proliferation
and thrombosis.93,100 ACE levels have been shown to be reduced in systemic scle-
rosis and this may also be of value in assessing the presence of endothelial cell
damage.93 Increased levels of the endothelial cell-derived ­peptide, endothelin,
which causes vasoconstriction, have been identified.82 Endothelin also has fibro-
blast mitogenic activity and stimulates the synthesis of collagen.101
The end stage appears as complete destruction of the capillary wall; the
nuclei are granular and homogeneous, cell membranes are disrupted, and
cytoplasmic contents are found in the capillary lumen and extravascular
spaces. Endothelial cell uptake of tritiated adenosine has been shown to be
reduced.98 Basement membrane thickening and reduplication is often present
and perivascular fibrosis is a common late accompaniment. The end result of
vascular damage can be demonstrated most easily by nail fold capillaroscopy.
It is likely that the dilatation of the residual vessels represents a compensatory
measure. Increased proliferation of the endothelial cells in these residual ves-
sels has been confirmed by tritiated thymidine uptake studies.91
Arterioles are also involved in the vasodestructive phenomenon, character-
ized by vessel wall thickening due to a combination of smooth muscle hyper-
plasia, fibrosis, and the deposition of excessive glycosaminoglycans. Arteries
show very marked intimal thickening, which is particularly well seen in the
renal arcuate vessels and is often referred to as ‘onion skinning’ due to the
concentric lamination. It develops as a consequence of myxoid change, cellu-
lar proliferation, and fibrosis.
Most of the inflammatory cells in the skin of patients with systemic sclero-
sis are CD4+ T cells.
A number of cytokines have been linked to the pathogenesis of systemic
sclerosis. Transforming growth factor beta (TGF-β) and IL-4 increase fibro-
blast proliferation and collagen synthesis and may be important in the induc-
tion of fibrosis in this disease. IL-17 is a cytokine secreted by T cells that
activates and induces proliferation of fibroblasts and activation of endothelial
cells. This cytokine has been demonstrated to be increased in the skin and
740 Idiopathic connective tissue disorders
blood of affected patients, particularly in the early stages of the disease. It
activates fibroblasts to secrete the proinflammatory cytokines IL-6 and -8 and to
increase surface expression of intercellular adhesion molecule-1 (ICAM-1).102–104
IL-17 also activates endothelial cells to secrete IL-6 and -1 and to express
ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1). IL-6 is also capa-
ble of inducing proliferation of fibroblasts and collagen synthesis. The com-
bined effects of IL-17 and other cytokines induced by it lead to damage to the
microcirculation and to fibrosis in the skin and internal organs. It has been
suggested that connective tissue growth factor, the production of which is
induced by TGF-β, may play an important role in the pathogenesis of fibro-
sis.105 It has recently been demonstrated that CD8+ effector T lymphocytes
are the source of increased IL-13 in the sera of patients with systemic sclero-
sis.106 IL-13 has well-known profibrotic activities by direct fibroblast stimula-
tion and, indirectly, by stimulation of TGF-β.107
The fibroblasts in systemic sclerosis are capable of assembling microfibrils
but these are unstable (probably due to an inherent defect of fibrillin 1, the
extracellular matrix protein) and this may also play a role in the pathogenesis
of the disease.108 Interestingly, duplication in the fibrillin-1 gene has been
implicated as the cause of tight skin,1 which is an animal model of systemic
sclerosis.108 Antibodies against fibrillin are raised in the sera of patients with
systemic sclerosis. Although this appears to be highly disease specific, it varies
amongst ethnic groups. Native Americans and Japanese patients have a high
frequency of anti-fibrillin-1 antibodies.109
Male cells have been found in multiple organs in women with systemic
sclerosis but not in healthy women.110 The migration of fetal cells into mater-
nal circulation and their survival in different organs is known as microchime-
rism. It is still not clear what role, if any, microchimerism plays in the
pathogenesis of systemic sclerosis.
The predominant histological feature of systemic sclerosis is scarring.
Intensive investigations have confirmed the presence of increased quantities
of collagen, but as yet the precise pathogenetic mechanism(s) remain uncer-
tain. Increased proline hydroxylase activity and increased uptake of labeled
proline, both indicators of active collagen synthesis, have been demonstrated
in patients with systemic sclerosis.111 There is typically an elevated level of
reducible aldimine cross-links, a feature of newly synthesized collagen.112
Raised serum concentration of the N-terminal propeptide of type III collagen
and increased urinary excretion of hydroxyproline have also been
documented.93
Cultures of fibroblasts from patients with systemic sclerosis synthesize
more collagen than do those from normal controls.113 Although diminished
levels of tissue collagenase have been reported, other workers have not con-
firmed this finding and its significance is therefore uncertain.114 The amino
acid composition of the collagen fibers is normal. Electron microscopy of
evolving lesions has revealed the presence of immature collagen fibrils, char-
acterized by a narrow caliber (30 nm), immature banding pattern, and dou-
ble-stranded beaded filaments.1 In the more mature lesion the collagen fibers
approach normal thickness (100 nm), but their distribution is highly disorga-
nized. Luse bodies are sometimes a feature.
Histological examination of active lesions often reveals increased numbers
of fibroblasts. It has been shown that fibroblasts from the lower dermis syn-
thesize more collagen than do those derived from the upper dermis, suggest-
ing two different populations in systemic sclerosis.115 The fibrosis, which is
due to the deposition of types I, III, V, and VI collagen, is accompanied by
excessive fibronectin.93,116
Recently, abundant type VII collagen has also been demonstrated within
the dermis of involved skin accompanied by elevated expression of TGF-β.116
The latter is known to upregulate the activity of the type VII collagen gene.
This finding is of potential importance as type VII collagen distribution is
normally restricted to the anchoring fibrils at the dermoepidermal junction.
Increased expression of types I and III collagen mRNA has been demonstrated
in cultured fibroblasts from patients with scleroderma.117,118 Systemic sclero-
sis is characterized by a normal concentration of collagen per unit weight. In
contrast, however, there is a greatly increased collagen content per unit sur-
face area.119
Collagen synthesis has a negative feedback control. Therefore, following
cleavage of the amino terminal of the procollagen molecule by the amino
­terminal peptidase, the released amino terminal inhibits collagen formation.
It has been shown by immunoelectron microscopic techniques that there is
retention of the amino peptide at the site of the collagen fibril.1
In addition to increased quantities of collagen, the skin of early lesions
of systemic sclerosis contains excessive quantities of glycosaminoglycans,
notably dermatan sulfate and chondroitin 4- and 6-sulfate.120 There is some
evidence to show that the increase in glycosaminoglycans may be due, at
least in part, to diminished degradation; their presence is associated with
water binding in vivo and presumably is therefore also responsible for
edema.
Systemic sclerosis is associated with abnormalities of both humoral and
cellular immunity.121 In contrast to SLE, anti-DNA antibodies are not usually
present. Almost all patients, however, do possess antinuclear antibodies; these
may be speckled, homogeneous or nucleolar in type (Fig. 17.95). The last are
found in 7–46% of patients, but are not specific, being found in a number of
other connective tissue diseases.8 They form a heterogeneous group reacting
against a variety of antigens including U3-RNP (fibrillarin), RNA polymerase I,
Th ribonucleoprotein, and PM-Scl, and have some prognostic significance
and subtype specificity (Table 17.8).8,10 Anti-U3 RNP antibodies are present
in 5–8% of systemic sclerosis, and are associated with African-American
race, male gender, higher incidence of skeletal muscle pathology, and
Fig. 17.95
Systemic sclerosis: antinucleolar antibody (HEP II). By courtesy of G. Swana, MD,
St Thomas' Hospital, London, UK.
Table 17.8
Systemic sclerosis: main autoantibody specificities giving a nucleolar pattern
of fluorescence
Frequency
Antigen in SSc (%) Clinical associations
Fibrillarin 8 Men with more lung and heart, less
(U3–RNP) joint involvement; dcSSc with
telangiectasia
RNA 4 DcSSc with high frequency of
polymerase I internal and musculoskeletal
involvements and shorter disease
duration at presentation
Th 4 LcSSc with reduced survival;
pulmonary hypertension, small
bowel involvement
PM-Scl 3 LcSSc in overlap with myositis;
higher frequency of renal
involvement
dcSSc, diffuse cutaneous SSc; lcSSc, limited cutaneous SSc; SSc, systemic sclerosis.
Reproduced with permission from Valentini, R. (1994) Clinics in Dermatology, 12,
217–223
 Systemic sclerosis 741

­ ulmonary arterial hypertension.122 Anti-U11/U12 RNP antibodies have been

p Histologically, the edema of the early stage produces a picture that is indis-
demonstrated in about 3% of systemic sclerosis, and have increased risk of tinguishable from scleredema of Buschke.146,147 In an established lesion the
pulmonary fibrosis and gastrointestinal involvement.123 Anti-Ku antibodies epidermis sometimes appears normal or there may be loss of the rete ridge
are detectable in 2.2% of systemic sclerosis and have been related to muscu- pattern. There is often increased pigmentation of the basal cells, and melano-
loskeletal abnormalities, such as myositis, arthritis and joint contractures, as phages are common in the superficial dermis. The characteristic change is
well as fingertip ulcers and telangiectasias.124 that of thickening of the dermis by broad, elongated, swollen collagen bun-
There are a number of subsets of antinuclear antibodies, which also have dles that often appear orientated parallel to the surface epithelium (Figs
clinical predictive value: 8,125–127 17.96, 17.97). The individual fiber borders are frequently indistinct, giving
• Anticentromere antibody (which is almost specific for systemic sclerosis) the collagen a rather homogenous appearance. The elastic fibers are usually
is particularly common in the limited cutaneous variant.128 It is usually unaffected. The fibrosis characteristically involves the subcutis and therefore
found in patients with less severe disease and a more favorable outcome.8
Calcinosis and telangiectasia may be conspicuous, but interstitial
pulmonary fibrosis is less likely.
• Scl-70 antibody (anti-DNA topoisomerase) is found in 20–60% of
patients with systemic sclerosis, particularly the diffuse variant.129 It is
also highly specific.8,130 Scl-70 antibody correlates with severe systemic
involvement including pulmonary interstitial fibrosis and a poor
prognosis.
• Anticentriole antibody occurs in both the limited and diffuse forms.
Although these antibodies are of great diagnostic importance they do not
appear to have any pathogenetic significance.
The presence of Ro (SS-A) and La (SS-B) antibodies suggests the coexis-
tence of Sjögren's syndrome.1 Autoantibodies against matrix metalloprotei-
nase-3 have been detected in about 50% of patients with systemic sclerosis.131
They are significantly higher in patients with diffuse cutaneous systemic scle-
rosis than those with limited cutaneous systemic sclerosis, and are signifi-
cantly correlated with skin fibrosis, lung fibrosis, and thickening of the renal
blood vessels.131
Antibodies to types I and IV collagen have been described, but it is not
clear whether they represent primary pathogenetic agents or are secondary
phenomena.132 More recently, antiendothelial cell antibodies have been
­documented in scleroderma.133 Circulating immune complexes have been Fig. 17.96
Systemic sclerosis:
reported, but are not a constant feature, and their significance, if any, is
scanning view of acral
unknown.98,134 skin showing dermal
Various T-cell abnormalities have been reported, most of which point fibrosis. The specimen
towards a diminished concentration of circulating T lymphocytes, particu- was a foot amputation
larly of the suppressor subset.93 An increased T helper:suppressor ratio has performed because
been described.135 Soluble cytotoxic T lymphocyte-associated molecule-4 of severe vascular
(sCTLA-4) has been found to be increased in patients with diffuse cutaneous involvement.
systemic sclerosis and elevated levels of sCTLA-4 appear to correlate with the
diseased severity and activity.136 Clonal expansion of T cells have been
detected in both blood (61%) and skin (45%) of patients with systemic scle-
rosis, which is significantly higher than in normal matched controls.137
Investigations have recently been directed towards the role of cytokines in
the development of the fibrosis in systemic sclerosis. Evidence suggests that
they are major regulators of fibroblast function and collagen synthesis. It has
been proposed that in systemic sclerosis there is excessive fibroblast stimula-
tory activity, due, for example, to fibroblast chemotactic factors including
fibronectin, collagen fragments, platelet-derived growth factor, epidermal
growth factor and C5a.1 Fibroblast growth stimulating factors, including
IL-1, -2, and -3, TGF-β, and platelet-derived growth factor, are also of major
importance.93,138,139
As yet no consistent strong class I or II major histocompatibility (MHC)
antigen associations have been discovered in systemic sclerosis.10,140 There
are, however, significant HLA associations with individual autoantibodies.
Therefore, PM-Scl antibody correlates with HLA-DR3 and Scl-70 antibody
with HLA-DR5.46,141
Susceptibility genes recently described to be associated with the develop-
ment of systemic sclerosis include STAT-4, IRF5, and BANK-1.142–144
A useful working hypothesis for the pathophysiology of systemic sclerosis
was suggested by Fleischmajer and Lebwohl.145 They proposed that following
vascular injury, possibly caused by an autoimmune mechanism, exposure of
type IV collagen or other substances leads to the recruitment of both B and T Fig. 17.97
lymphocytes in addition to monocytes and mast cells. Excess T-helper cells Systemic sclerosis: the
stimulate the production of autoantibodies by B cells, whereas the activated dermis is homogenized.
T cells, macrophages, and mast cells secrete a variety of cytokines, which in Note the compressed
turn promote collagenosis. eccrine ducts.
742 Idiopathic connective tissue disorders
Fig. 17.98
Systemic sclerosis: severe vascular involvement characterized by intimal fibrosis
and obliteration of the lumen. Note the surrounding chronic inflammation and
scarring.
fat cells are usually incorporated into the dermis.148 Atrophic skin append-
ages, particularly eccrine sweat glands, are a common feature.
The arteries, especially the digital vessels, typically show endothelial cell
swelling, intimal thickening, and medial hypertrophy. Later they may become
hyalinized (Fig. 17.98). In early lesions, endothelium-associated platelets are
significantly increased in number.98 Fibrin deposition is sometimes present and
occasionally complete occlusion results in digital ulceration and gangrene.
With chronicity there is a progressive reduction in the number of vessels,
­particularly in the more superficial dermis.98 Perineural fibrosis is sometimes a
feature and calcification is not uncommon (Figs 17.99, 17.100).
In early lesions there may be a chronic inflammatory cell infiltrate com-
prising lymphocytes, histiocytes, and a few plasma cells around blood vessels
and at the interface between the dermis and the subcutaneous fat.1,149 T-helper
cells predominate and increased numbers of dermal Langerhans cells have
been described.98 Mast cells, usually activated, are often present in increased
Fig. 17.99
Systemic sclerosis: there
is dramatic perineural
fibrosis.
Fig. 17.100
Systemic sclerosis: high-power view.
numbers.150 Palisaded neutrophilic and granulomatous dermatitis has been
reported in a single patient with limited systemic sclerosis.151 Deposition of
amyloid in the dermis and subcutis in a patient with CREST syndrome has
also been reported.152
It is usually not possible to distinguish localized scleroderma (morphea)
from systemic sclerosis on histological grounds, although the epidermis is
usually normal in the localized form and vascular changes are less severe. In
contrast, the inflammatory cell infiltrate is often heavier in the localized vari-
ant and commonly affects the reticular dermis.149
Examination of skeletal muscle may reveal focal scarring and a chronic
inflammatory cell infiltrate (Figs 17.101, 17.102).153 Features of muscle
degeneration (vacuolation, homogenization with eosinophilia, and loss of
cross-striations) and regeneration (basophilia and sarcolemmal nuclear pro-
liferation) similar to that seen in dermatomyositis may also be present. In the
sclerotic phase there is atrophy and fibrosis.
Macroscopic examination of the kidney often reveals multiple infarcts,
foci of hemorrhage and, occasionally, the features of renal cortical necrosis.64
The histological appearances are similar to those of malignant hypertension
and are characterized by the presence of fibrinoid necrosis, which ­particularly
affects the interlobular and arcuate arteries, and ischemic glomerulosclero-
sis; an inflammatory cell infiltrate is not a feature.59,154 Characteristic of
­systemic sclerosis is the presence of edema and mucoid change in the ­initima
Fig. 17.101
Systemic sclerosis: myositis characterized by a lymphohistiocytic infiltrate and focal
skeletal muscle regeneration.

Fig. 17.102
Systemic sclerosis: Note the focal cytoplasmic basophilia on the left side of
the field.
of the interlobular arteries. There is also increased cellularity, giving rise to a
characteristic ‘onion skin’ appearance with reduction in the lumen of the
vessel.
The histological features of sclerodermatous interstitial pneumonitis are
indistinguishable from those seen in idiopathic fibrosing alveolitis. Early
stages are characterized by intra-alveolar edema with reactive pneumocytes
and a variable infiltrate of macrophages, lymphocytes, and occasional neu-
trophils.46,155 Interstitial accumulations of lymphocytes and plasma cells are
evident, sometimes associated with focal lymphoid hyperplasia; in older
lesions, these are accompanied by the deposition of glycosaminoglycan-rich
new collagen. End-stage disease is characterized by the development of vari-
ably sized cysts lined by metaplastic bronchiolar epithelium and containing
abundant collagen and hyperplastic smooth muscle in their walls.156
The features of pulmonary hypertension are commonly present, particu-
larly in patients with the CREST variant. Muscular arterioles are predomi-
nantly affected, although in late stages venules may also be involved, and show
medial muscular hypertrophy and concentric myxoid-rich new collagen depo-
sition in the intima with variable reduction in the diameter of the lumen.156 In
late stages, muscular atrophy and medial elastosis may be evident. Focal lym-
phocytic/plasma cell endovasculitis has been documented, suggesting a possi-
ble autoimmune pathogenesis.156 Fibrosis of pulmonary veins and venules can
be similar to the changes observed in pulmonary veno-occlusive disease.157
Pulmonary hypertension correlates with the presence of anticentromere anti-
body. Bronchiolitis predominantly affects the terminal and respiratory bron-
chioles. In addition to chronic inflammation, bronchiolar squamous metaplasia
and variable scarring with luminal constriction may be seen.156
The most important gastrointestinal lesion is atrophy with fibrosis of the
esophageal smooth muscle; similar changes may also develop in the small and
large intestines. Vascular myointimal proliferation with luminal narrowing is
also usually evident.66 Reflux esophagitis may show erosions and areas of
ulceration in addition to chronic inflammatory changes. In contrast to con-
ventional diverticulae, those of systemic sclerosis are composed of all layers
of the bowel wall.
Early myocardial changes are characterized by necrosis of muscle fibers
accompanied by a chronic inflammatory cell and histiocytic infiltrate.58
Subsequent fibrosis affects the right and left ventricles with equal frequency.57
The major coronary arteries appear normal in systemic sclerosis, but arterio-
lar, endothelial, and intimal proliferation accompanied by mural scarring is
common.158
In active lesions, synovial biopsies show a heavy surface fibrin deposit.70
There is adjacent chronic synovitis with an admixture of lymphocytes and
plasma cells. Lymphoid follicles with germinal center formation as seen in
rheumatoid arthritis are not a feature. With chronicity, synovial scarring
supervenes.
Localized scleroderma 743
Localized scleroderma
Localized scleroderma (morphea) constitutes a group of diseases characterized
by thickening or sclerosis of the dermis with loss of subcutaneous fat, some-
times with involvement of the underlying skeletal muscle.1–6 There is predilec-
tion for children and young adults, with the peak incidence between 20 and 40
years, and females being more frequently affected.7–9 Rare congenital cases
have been documented.10–12 About 15% of cases develop before the age of 10
years.13 Localized scleroderma is not usually associated with severe systemic
symptoms or Raynaud's phenomenon, is often self-limited, and in general has
a good prognosis, although the linear variant in particular may be very dis-
abling and often disfiguring, especially in children.2 The linear and deep vari-
ants can be associated with arthralgias, synovitis, uveitis, and joint
contractures.14 A large study of patients with morphea has found mild internal
involvement consisting of abnormal lower sphincter pressure and peristaltic
failure in the esophagus and slightly impaired carbon monoxide diffusion in
the lung in up to 19% of patients.15 These abnormalities do not result in clini-
cal symptoms and do not affect prognosis adversely. A rare case has been doc-
umented in which morphea induced severe extrapulmonary thoracic
restriction.16 Extracutaneous involvement is present in about one-fifth of the
children, and includes articular, neurologic, vascular, ocular, gastrointestinal,
respiratory, cardiac, and renal manifestations, in decreasing order of fre-
quency.13 Although the plaques and, to a lesser extent, the linear lesions often
improve with time, the contractures and hemiatrophy are permanent.3 Imaging
studies frequently reveal muscle atrophy and leg length discrepancy.17 Localized
scleroderma may occur after trauma, laparoscopy, radiotherapy, tattooing,
and silicone implants.18–24 It has also been described in association with bro-
mocriptine, balicatib, valproic acid, and ibuprofen therapy.25–28 Localized
­scleroderma has also been reported following silica dust exposure.29
The precise relationship between localized scleroderma and systemic scle-
rosis is uncertain. Because of clinical and pathological overlap, some authors
believe that the two conditions represent extreme ends of a spectrum of con-
nective tissue damage in a manner similar to the relationship between discoid
and systemic lupus erythematosus. Indeed, patients rarely have both morphea
and progressive systemic sclerosis (the former usually preceding the latter);
this phenomenon occurs so infrequently, however, that most believe that the
relationship is purely coincidental.2 Alternatively, the features of these two
disorders may merely represent a common manifestation of tissue damage
caused by quite different mechanisms, analogous to the wide range of patho-
genetic factors which may result in the histological appearance of allergic
vasculitis.
Clinical features
Localized scleroderma includes a variety of conditions, which may arise inde-
pendently, but which frequently occur together:
• plaque-form (the most common variant),
• bullous morphea,
• guttate lesions,
• linear morphea including facial hemiatrophy,
• generalized morphea,
• subcutaneous scleroderma (morphea profunda),
• disabling pansclerotic morphea of children.2,30–32
Plaque-form and linear morphea
Plaque-form and linear morphea are more common in females (3:1) and, in
contrast to progressive systemic sclerosis, often occur in childhood.1 Linear
morphea develops before the end of the first decade in up to 20% of patients
and by the fourth decade in up to 75%. Localized plaques occur a little later
in life, although 75% of patients are between 20 and 50 years of age at
presentation.
Morphea usually develops slowly and the onset may manifest as ery-
thema and edema. An established lesion is typically circumscribed, ivory or
white in color, and densely sclerotic (Fig. 17.103).2 A characteristic feature
is the presence of a violaceous border, an indicator of disease activity (Figs
17.104, 17.105).2 As the lesion subsides, atrophy, loss of hair and
­sebaceous glands, and variable hypo- and hyperpigmentation become
744 Idiopathic connective tissue disorders

­evident (Fig. 17.106).30 Vesicles, bullae, purpura, and telangiectasia may

rarely be present, particularly in the generalized variant.1,33 Tense bullae,
due to subepidermal edema, are a rare manifestation that has been described
in morphea, including the profunda variant.34 They are thought to develop
as a consequence of both trauma and lymphatic obstruction. The latter is
suggested by the finding of lymphatic dilatation in 77% of biopsies from
patients with this variant of morphea.35 It has also been suggested that this
type of morphea may be related to release of major basic protein from
eosinophils.35
The plaque form of morphea usually consists of multiple, round or oval,
sometimes pruritic, 2–15-cm diameter lesions, which are usually bilateral and
asymmetrical in distribution (Fig. 17.107). Lesions occur (in decreasing order
of frequency) on the thorax and neck, the lower extremities, the upper extrem-
ities, and the face; the axillae, umbilical region, perineum, and perianal area
are usually spared (Fig. 17.108).
The so-called linear atrophoderma of Moulin, which presents with band-
like lesions following Blaschko's lines, is likely to represent a variant of linear
morphea.36
Linear morphea is usually solitary and unilateral in distribution. Lesions
Fig. 17.103
are found (in decreasing order of frequency) on the lower limbs, the upper
Morphea: characteristic white sclerotic plaque. By courtesy of the Institute of
Dermatology, London, UK.
limbs, the frontoparietal region (e.g., en coup de sabre), and the anterior

Fig. 17.104 Fig. 17.106

Morphea: in this example the violaceous border is apparent. From the collection of Morphea: atrophic lesions showing variable hypo- and hyperpigmentation.
the late N.P. Smith, MD, the Institute of Dermatology, London, UK. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 17.105 Fig. 17.107

Morphea: multiple lesions are present on the abdomen. From the collection of the Morphea: multiple asymmetrical lesions are present. Note the characteristic en
late N.P. Smith, MD, the Institute of Dermatology, London, UK. coup de sabre. By courtesy of D. McGibbon, MD, St Thomas' Hospital, London, UK.
 Localized scleroderma 745

Fig. 17.108 Fig. 17.110

Morphea: extensive lesions can be very disfiguring, as in this patient showing Linear morphea: en coup de sabre. By courtesy of the Institute of Dermatology,
bilateral breast involvement. By courtesy of the Institute of Dermatology, London, UK. London, UK.

Fig. 17.109 Fig. 17.111

Linear morphea: Linear morphea: severe
atrophic lesion on the facial hemiatrophy.
thigh. By courtesy of By courtesy of
R.A. Marsden, MD, D. McGibbon, MD,
St George's Hospital, St Thomas' Hospital,
London, UK. London, UK.

t­ horax (Fig. 17.109). Linear lesions may involve both the upper and lower
extremities simultaneously and, on occasion, plaque-type morphea is also
present.2 Although the clinical appearances of linear scleroderma are very
similar to those of the plaque form, lesions tend to show more pigmentary
change and the violaceous border is less conspicuous. Linear morphea may
affect the underlying skeletal muscle and even bone, giving rise to contrac-
tures and deformities. Calcification of skeletal muscle may exceptionally
occur.37 An association with melorheostosis has been described.38,39 Cases pre-
senting with hypertrichosis are also documented.39–41 Occasionally it follows
Blaschko's lines.42–47
Frontoparietal linear morphea presents as a densely sclerotic plaque
extending from the eyebrow onto the scalp and may be associated with alo-
pecia. Involvement of the cheek, nose, and upper lip has also been docu-
mented.30 Progression of the lesion results in the development of a groove
and hence the term ‘en coup de sabre’ (Fig. 17.110). Gingival recession has
occasionally been documented.48 Familial occurrence is exceptional and
bilateral lesions are rare.49–51 A further complication, particularly in children,
is the development of facial hemiatrophy (Romberg's disease) (Fig.
17.111).2,52 Exceptionally, central nervous system involvement may occur,53
with presentations such as intractable partial seizures and cerebral vasculitis. 54,55
Linear morphea has also been described in association with hereditary
­deficiency of C2.56
Guttate morphea
In guttate morphea lesions are multiple, small (2–10 mm), nonindurated,
and yellowish-white, and are limited by a delicate lilac border.1,30
Typically, there is no hyperkeratosis or follicular plugging. Coalescence
of lesions to form plaques is not uncommon. Guttate morphea most com-
monly presents on the upper back and shoulders, but the lower back,
chest, and abdomen may also be affected.1 There is much clinical (and
histological) overlap between the lesions of guttate morphea and lichen
sclerosus and it is worthy of note that the two disorders are frequently
seen together.2,57
746 Idiopathic connective tissue disorders
Generalized morphea
Generalized morphea, which most commonly affects the trunk and abdomen,
is characterized by widespread large lesions resembling plaque-type mor-
phea.1,58 These may merge and in many patients almost the entire skin surface
is involved. Extension to the subcutaneous fat and muscle sometimes results
in severe contractures and disabling and disfiguring deformities (Fig. 17.112).
Generalized morphea may occasionally prove fatal, for example, due to pneu-
monia. Rarely, systemic involvement supervenes.2 When generalized morphea
and systemic sclerosis coexist, the activity of the generalized morphea may be
independent of the lesions of systemic sclerosis.59 An association with por-
phyria cutanea tarda, eosinophilic fasciitis, and childhood sclerodermatomy-
ositis has been described.60–62 Occurrence with Felty's syndrome and after
antitetanus vaccination has also been reported.63,64 Unilateral generalized
morphea has been documented.65,66 A patient with this form of the disease
developed multiple acral adult myofibromas.67 Multiple squamous cell carci-
nomas of the skin developing in the background of generalized morphea are
an exceptional finding.68
Subcutaneous scleroderma
Subcutaneous scleroderma (morphea profunda, nodular scleroderma, keloi-
dal scleroderma) presents clinically as nodular or keloid-like lesions.30,34,69–75
Association with systemic sclerosis can be present.74,76 The abdomen, sacral
region, and the extremities are affected most commonly.2 Osteoma cutis can
rarely develop in subcutaneous scleroderma.77 Two cases of morphea pro-
funda, as well as an atrophic variant of morphea profunda mimicking local-
ized lipoatrophy, have been reported at the site of previous intramuscular
vaccination.78,79
Disabling pansclerotic morphea of children
Disabling pansclerotic morphea of children is a particularly aggressive and
mutilating variant, which involves fascia, muscle, and bone in addition to the
deep dermis and subcutaneous fat. It usually affects the scalp, face, trunk, and
extremities.1,80–82 An adult-onset variant of disabling pansclerotic morphea
has also been reported.83 Patients have tendencies for chronic nonhealing
ulceration, most commonly involving legs, followed by upper extremities,
trunk, and head.82 Patients may also have arthralgias, contractures that par-
ticularly affect the extensor surfaces of the extremities, and osteoporosis.30,80
This exceedingly severe variant of localized scleroderma is unremitting and
Fig. 17.112
Generalized morphea: a
very advanced extreme
example showing almost
complete involvement of
the skin, hair loss, and
contractures. By courtesy
of R.A. Marsden, MD,
St George's Hospital,
London, UK.
permanent, and is fortunately very rare. Some patients have had abnormal
respiratory function tests and diminished esophageal motility, suggesting
overlap with systemic sclerosis.80 Blood eosinophilia is also seen.80 A rare
complication of squamous cell carcinoma has been documented.84,85 A further
exceptional association is that of hypogammaglobulinemia.86
Associated conditions
Localized scleroderma has been associated with a variety of conditions includ-
ing arthralgia, carpal tunnel syndrome, unilateral Raynaud's phenomenon,
intermittent abdominal pain, and spina bifida.30,31 Concurrent lichen planus,
often in the company of lichen sclerosus, has also been documented.1 Other
associations include vitiligo, alopecia areata, granuloma annulare, pigmented
purpuric dermatosis, psoriasis vulgaris, cutaneous amyloid deposition, lupus
anticoagulant, DLE, SCLE, SLE, xanthomatosis, elastosis perforans serpigi-
nosa, B-cell lymphoma, human T-cell lymphoma/lymphotropic virus type 1
infection, chronic hepatitis B and C virus infection, posthepatitis C cirrhosis,
primary biliary cirrhosis, Rosai-Dorfman disease, sarcoidosis, necrotizing
vasculitis, and necrobiotic xanthogranuloma.1,2,87–112 A recent analysis of 245
patients with localized scleroderma has found concomitant rheumatic or
autoimmune disorder in 17.6%.113 Generalized morphea is the most frequent
subtype associated with autoimmune diseases, which are present in 45.9% of
patients with this form of the disease.113
Pathogenesis and histological features
The etiology and pathogenesis of localized scleroderma are unknown.
Theories of causation include trauma, hormonal influences, and familial
aspects.30,114,115 Thus localized scleroderma may present or worsen during
pregnancy, the menarche or the menopause. The condition has also been
described following chickenpox and measles.1,116 An infectious etiology has
received some support with the identification by immunohistochemistry, sil-
ver stains, and polymerase chain reaction (PCR) of Borrelia burgdorferi in
biopsies of lesional skin combined with the presence of elevated antibody lev-
els.117–124 Lymphoproliferative responses to this organism have also been
reported in patients with morphea.125 Most studies, however, have cast doubt
on the association between morphea and B. burgdorferi.126–135 It has also been
shown that false-positive tests for B. burgdorferi with indirect immunofluo-
rescence and even enzyme-linked immunosorbent assay (ELISA) are not
uncommon.136 It is therefore more likely that B. burgorferi is not etiologically
linked to localized morphea. A further possibility is that only certain subspe-
cies of Borrelia are capable of inducing the disease.137,138 However, this theory
has not been substantiated by different studies from the same country.138
The occasional simultaneous occurrence of localized scleroderma and sys-
temic sclerosis has led some authors to postulate a shared pathogenetic
mechanism.31,139 In both conditions increased serum levels of procollagen
type I carboxyterminal propeptide have been reported.140 Similarly, the pres-
ence of localized scleroderma in both discoid and systemic lupus erythema-
tosus and dermatomyositis has been cited as additional evidence for an
immunological basis.1,141–143 It is also of interest that the clinical appearances
and histology of late GVHD are very similar to those of scleroderma.
Increased expression of connective tissue growth factor has been detected in
sclerotic fibroblasts of nodular scleroderma by immunohistochemistry and
in situ hybridization.76
Antinuclear antibodies may be detected in approximately 70% of patients
with morphea.144 Homogeneous, nucleolar, and speckled patterns have all been
recognized, but the first is the most common variant.145 Rheumatoid factor,
anti-dsDNA, anticentromere, and anti-Scl-70 antibodies have also been docu-
mented but are rare.58 Anti-ssDNA antibodies are present in 38–75% of
patients, are frequently of the IgM subclass, and are found more often in linear
and generalized morphea than in the plaque form.58,146 Antihistone antibodies
have been reported in up to 50% of cases.147 Most antibodies are more com-
monly seen in patients with active or widespread disease.143 Antinuclear anti-
bodies are frequent in children with localized scleroderma and often have
specificity for denatured DNA and for high mobility group proteins.148 Anti
Cu/Zn superoxide dismutase antibodies are present in the serum of 89% of
patients with localized scleroderma, and 100% of patients with the generalized
variant.149 Anti-DNA topoisomerase IIα antibodies have been detected in 76%

of patients with localized scleroderma, and 85% of patients with the general-
ized variant.150 Increased serum levels of ICAM-1 have also been reported,
­particularly in patients with prominent involvement.151 Peripheral eosinophilia
is sometimes a feature, particularly in the pansclerotic morpheic variant.1,80
Direct immunofluorescence studies have demonstrated immunoglobulin
(usually IgM) and complement at the basement membrane region and around
the dermal vasculature in about 35% of patients.1 Generalized morphea is
more often positive than the plaque and linear variants. Immunohistochemical
studies of established lesions reveal increase in the number of factor XIIIa+
cells and decrease in the number of CD34+ cells.152–154
The histological features of localized scleroderma involve both the dermis
and subcutaneous fat; a deep incisional biopsy is therefore indicated if sclero-
derma is suspected.58,146 Biopsies from early lesions often show very subtle
histological findings and are frequently non-specific. The histological diagno-
sis may be more difficult to establish in biopsies of lesions from guttate mor-
phea as the changes tend to be more focal and superficial. In an established
indurated plaque, the epidermis is usually normal or occasionally flattened.
Mucin deposition is not usually a feature but may be occasionally present.
Abundant mucin throughout the reticular dermis has been described excep-
tionally in nodular morphea.47,155 The papillary dermis either appears unaf-
fected or shows a rather homogenized change (Fig. 17.113). The most
striking features are seen in the reticular dermis, where the collagen bundles
are swollen, intensely eosinophilic, and orientated parallel to the surface (Figs
17.114–17.116). There is also involvement of the septa of the subcutaneous
fat; this is associated with atrophy of the adipocytes and subsequent fibrosis,
resulting in an apparent increase in thickness of the dermis.1 Hair follicles and
sebaceous glands may be atrophic or absent and the eccrine ducts often
appear compressed within the densely sclerotic dermis. Due to fibrous replace-
ment of the subcutaneous fat, the eccrine glands appear to be situated abnor-
mally high within the dermis rather than at the dermosubcuticular interface.
In rare cases only the superficial reticular dermis is affected.156
An important feature of localized scleroderma, especially in the early stages,
is a dense, chronic inflammatory cell infiltrate of lymphocytes, histiocytes, and
plasma cells; some authors believe this to be the initial feature (Fig. 17.117).58
The infiltrate may surround blood vessels and appendages and tends to be
Fig. 17.113 Fig. 17.114
Morphea: the dermis is thickened by dense collagen Morphea: the collagen fibers are eosinophilic and
bundles. Note the heavy perivascular infiltrate. swollen.
Localized scleroderma 747
particularly conspicuous in the dermis in addition to the ­subcutaneous fat
(Fig. 17.118). In the linear and generalized variants in ­particular, the inflam-
matory changes may affect the underlying skeletal muscle.
In the late stages, dermal sclerosis is still evident, but the dermis appears
thinned due to concomitant atrophy.2 Vascular changes similar to those
described for systemic sclerosis may be evident and consist of thickening of
the walls of small blood vessels. Vasculitis is not a feature. Calcinosis cutis is
occasionally seen and neuritis similar to that seen in indeterminate leprosy
has also been documented.157,158
In lesions of deep morphea the infiltrate is much more prominent and is
located predominantly in the junction between the dermis and subcutaneous
tissue with extension into the subcutaneous tissue. The infiltrate and the scle-
rotic collagen have a more nodular distribution.
Several patterns have been described in bullous morphea.35,159,160 The most
common is that of prominent superficial edema with prominent lymphatic
dilatation.35 A further pattern is one identical to that seen in lichen sclero-
sus.160 It is worth remembering that autoimmune blistering diseases such as
epidermolysis bullosa acquisita may occur concomitantly with morphea, and
immunofluorescence may be indicated in cases in which a subepidermal blis-
ter is present.159
In addition to the features described above, generalized morphea and dis-
abling pansclerotic morphea of childhood may show a lymphocytic and hya-
line panniculitis with lymphoid follicle formation reminiscent of lupus
profundus.58,80 Eccrine squamous syringometaplasia and syringomatous
hyperplasia have been described in linear scleroderma.161
Differential diagnosis
The lesions of localized scleroderma may be histologically indistinguishable
from those of systemic sclerosis, but the inflammatory cell infiltrate tends to
be more pronounced in the former, at least in the early stages. Also, involve-
ment of the papillary dermis may be a feature in some cases of localized
scleroderma.162
Other diseases that enter the differential diagnosis include late porphyria
cutanea tarda and chronic GVHD. Adequate clinical information will resolve
Fig. 17.115
Morphea: the changes are highlighted with this
Masson's trichrome stained section. In this example,
the papillary dermis is involved.
748 Idiopathic connective tissue disorders
Fig. 17.116 Fig. 17.117
Morphea: this is a chronic lesion. There is loss of Morphea: a perivascular chronic inflammatory cell
elastic tissue (van Gieson). infiltrate is usually present, particularly in early lesions.
most diagnostic dilemmas, but where doubt exists, the presence of ­PAS-positive
thickened dermal vessels is indicative of porphyria, whereas epidermal
lichenoid features with cytoid body formation strongly support the diagnosis
of chronic GVHD.
The relationship between localized scleroderma, particularly the guttate
variety, and lichen sclerosus has been the source of considerable controversy.
However, basal cell liquefactive degeneration with a lichenoid inflammatory
cell infiltrate is not a feature of morphea, and sclerosis of the reticular dermis
and subcutaneous fat with atrophy or loss of appendage structures is not seen
in lichen sclerosus (Fig. 17.119).57
Marked dermal sclerosis may also be a feature of atrophie blanche and
chronic radiation dermatitis. Vascular changes, including thromboses, purpura,
and hemosiderosis, however, are conspicuous in the former, while bizarre fibro-
blasts, elastosis, and endarteritis obliterans are characteristic of the latter.
Fig. 17.119
Morphea: intense papillary dermal edema is present, producing a lichen sclerosus-
like appearance.
Fig. 17.118
Morphea: the infiltrate often involves the
subcutaneous fat.
Phenylketonuria has also been reported to show sclerodermatous
features.2
Histological distinction between morphea and late lesions of acroder-
matitis enteropathica may be difficult and occasionally impossible.163
Close clinicopathological correlation allows distinction between these
entities.
Atrophoderma of Pasini and Pierini
Clinical features
Atrophoderma is a rare, primary dermal atrophic process of uncertain nature.
Since its first description by Pasini in 1923 there has been controversy as to
whether it represents a distinct entity sui generis or whether it is a variant of
localized scleroderma (morphea).1–5 It presents usually in the second or third
decade with a mean age of onset of 30 years and shows a predilection for
females (5:1).6 A congenital variant of atrophoderma of Pasini and Pierini has
also been described.7
The typical lesion is a gray–brown or violaceous, atrophic, round to oval,
depressed macule with a ‘cliff-drop’ border (Fig. 17.120).3 The distribution
is usually bilateral and symmetrical.6 Widespread unilateral involvement is
rare.8 While previous studies demonstrated the lower back as the most com-
monly affected site,6 recent analysis of 16 patients revealed predominance of
lesions on lower extremities (62.5%), followed by upper extremities and
trunk.9 Lesions may also be found on the chest, arms, and abdomen. A case
with a zosteriform distribution has been documented.10 The lesions are
­frequently hypopigmented.9
Atrophoderma of Pasini and Pierini may coexist with lichen sclerosus and
morphea, and progression to systemic sclerosis has been documented.10–14 In
contrast to localized scleroderma, it lacks the violaceous border, is primarily
atrophic rather than indurated, and tends to great chronicity, lesions often
being present for decades rather than resolving after a few years, as is often a
feature of morphea.3
An entity described as atrophoderma elastolytica discreta clinically simu-
lates atrophoderma of Pasini and Pierini but the histopathological changes
are those of anetoderma.15

Fig. 17.120
Atrophoderma: lesions
present as depressed
atrophic plaques with a
typical cliff-drop border.
By courtesy of the
Institute of Dermatology,
London, UK.
Pathogenesis and histological features
It is still controversial whether this disease represents a variant of morphea. A
large study of 139 patients suggested that the disease represents an atrophic
abortive variant of morphea in which the sclerotic phase fails to develop.16 A
study of lesional skin of two patients showed a decrease in the total amount
of disaccharide and a normal or decreased amount of DeltaDi-4S(DS), the
main disaccharide unit of dermatan sulfate.17 This is in contrast with findings
in patients with morphea in which there is increase in the total amount of
disaccharide and increase in DeltaDi-4S(DS). This finding suggests that the
two diseases are different. However, a further study of lesional and normal
skin revealed an increase in the amount of dermatan sulfate in lesional skin as
is a feature of morphea.18 The identification in the serum of antibodies to
Borrelia burgdorferi in 20–53% of patients, combined with occasional reports
of culture of the organism from lesional material, raises the possibility of a
causal relationship.6
Histologically, atrophoderma often shows very subtle features. The epider-
mis may be atrophic or normal and is often hyperpigmented. Within the
superficial dermis is a perivascular and interstitial chronic inflammatory cell
infiltrate consisting of lymphocytes and histiocytes. The lymphocytes are T
cells and the helper-inducer subset predominates.19,20 Rarely, plasma cells may
be conspicuous. In early lesions the collagen bundles are homogenized and
swollen but, with progression, sclerosis often supervenes in the deeper reticu-
lar dermis.10,21 The appendage structures are usually normal. The elastic fibers
commonly show no change, but diminution and fragmentation have been
documented.6,9 The late stages of atrophoderma are indistinguishable from
localized scleroderma.
Eosinophilic fasciitis
Clinical features
The precise nosological status of eosinophilic fasciitis (Schulman's syndrome)
is uncertain: some authors regard it as a variant of morphea (morphea pro-
funda) but others consider it an entity in its own right.1–4 For the purpose of
this text it is classified separately.
Eosinophilic fasciitis occurs equally in males and females, and most
patients are in their third to sixth decades.1 Female predominance has been
demonstrated in some studies.5,6 Pediatric disease has, however, also been
documented.7–10 White Caucasians are predominantly affected.11
Eosinophilic fasciitis 749
The clinical features of painful, tender swelling, stiffness, and sclerodermi-
form induration affect (in decreasing order of frequency) the forearms, upper
arms and lower legs, thighs, hands, trunk, neck, and feet.1,11 The face and fin-
gers are only rarely affected. Localized involvement of a limb has rarely been
documented.12 Unilateral presentation is rare.13 Early cutaneous manifesta-
tions include pitting edema, peau d'orange or a cobblestone appearance.1,14
At least 50% of patients relate the onset of their illness to an episode of stren-
uous physical activity.15–18 Patients have a variety of non-specific features
including malaise, weakness, fever, and weight loss.1 Raynaud's phenomenon
is typically absent and the nail fold capillaries are normal – points of distinc-
tion from systemic sclerosis.19 Pediatric disease commonly progresses to scle-
rodermiform cutaneous scarring.7,16,20 Blood eosinophilia and
hypergammaglobulinemia have been reported.4,21 Hypogammaglobulinemia
is exceptional.22
Extracutaneous involvement is becoming increasingly recognized.23
Patients may develop arthralgia and synovitis. Inflammatory arthritis (pre-
dominantly involving the hands, wrists, and knees) and carpal tunnel syn-
drome occur in about 25% of patients.1,16,19,20,24 Contractures develop in up to
75% of patients and particularly affect the shoulders, elbows, wrists, hands,
and knees.11,25 Subclinical myositis is common.1 Posterior ischemic optic neu-
ropathy has also been described.26 Clinically significant systemic features are
rare, but have included esophageal dysmotility, pericardial and pleural effu-
sions, and lung and kidney involvement.1,27,28
A number of other associations have recently been documented including
aplastic anemia, polycythemia rubra vera, thrombocytopenia, hemolytic ane-
mia, monoclonal gammopathy, abnormal circulating T-cell clone, peripheral
T-cell lymphoma, leukemia, lymphoma, multiple myeloma, alogenic stem cell
transplantation, chronic graft-versus-host disease, combined immunodefi-
ciency, Hashimoto's disease, idiopathic hypercalcemia, psoriasis, IgA neph-
ropathy, primary biliary cirrhosis, eosinophilic colitis, serositis, miliary
tuberculosis, SLE, myelodysplasia, acquired ichthyosis, absence of the spleen,
vitiligo-like changes and peripheral neuropathy, local irradiation for breast
cancer, toxic thyroid adenoma, metastatic choroidal melanoma, and meta-
static colorectal carcinoma.1,15,29–61 The association with serious hematologi-
cal abnormalities has led to the suggestion that all patients with the disease
should have a bone marrow examination to exclude myelodysplasia.62 An
exceptional familial case in association with breast cancer has been
documented.63
Laboratory investigations reveal a raised ESR, peripheral blood eosino-
philia, and hypergammaglobulinemia (usually IgG).15 Antinuclear antibodies
(speckled and homogeneous), rheumatoid factor and, rarely, anti-nDNA anti-
bodies may be present.11,16 Serum aldolase levels appear to be a useful indica-
tor of disease activity.64 Cytoplasmic antineutrophilic cytoplasmic antibodies
(c-ANCA) have been demonstrated in a patient with recurrent eosinophilic
fasciitis.65
Characteristically, eosinophilic fasciitis responds well to corticosteroid
therapy – a diagnostic pointer. Spontaneous resolution occurs in some
patients. Progression to scleroderma and coexistence with lesions of localized
morphea may sometimes occur.7,66–69
Pathogenesis and histological features
The etiology and pathogenesis of eosinophilic fasciitis are unknown. The clin-
ical findings of hypergammaglobulinemia, occasional antinuclear antibodies,
and positive immunofluorescence suggests a humoral immune mechanism.1
Even in those instances when eosinophilic fasciitis has followed strenuous
physical activity, it is unlikely that trauma, on its own, is responsible. There
are occasional reports of possible drug toxicity following, for example, anti-
tuberculous therapy, phenytoin, subcutaneous heparin and fosinopril, sim-
vastatin, atorvastatin, and an eosinophilic fasciitis-like picture sometimes
constitutes part of the eosinophilia–myalgia syndrome (see below).19,70–73 The
disease has also followed exposure to trichloroethylene, radiotherapy, subcu-
taneous injection of phytonadione, and after the initiation of dialysis.74–77
Borrelia burgdorferi has been associated with some cases of eosinophilic
fasciitis (Fig. 17.121).78–80 However, positive serology for Borrelia bugdorferi
in patients with eosinophilic fasciitis without direct confirmation of the pres-
ence of the organism by polymerase chain reaction has been regarded insuf-
ficient for establishing a pathogenetic link.81
750 Idiopathic connective tissue disorders

Fig. 17.121 Fig. 17.122

Eosinophilic fasciitis: a spirochete is present in the center of the field (Dieterle Eosinophilic fasciitis: the fascia is thickened and there is marked fibrin deposition.
stain) (arrow).

In some patients, elevation of serum IL-2, -5, and -10, transforming growth
factor β1, tissue inhibitor of metalloproteinase-1, manganese superoxide dis-
mutase, interferon gamma (IFN-γ), and leukemia inhibitory factor has been
documented.10,82–84 The increase in IL-5 and -10 possibly leads to eosinophilia
and immune globulin overexpression.82 Eosinophils have been shown to stim-
ulate DNA synthesis and matrix production in dermal fibroblasts, leading to
increased collagen deposition.85
Immunofluorescence has revealed deposition of IgM at the dermoepider-
mal junction, immunoglobulin and complement around blood vessels in the
deep dermis, and IgG and complement in the deep fascia and skeletal
muscle.11,16,86
The pathology of eosinophilic fasciitis predominantly affects the deep sub-
cutaneous fat and fascia and therefore a substantial incisional biopsy is neces-
sary for diagnosis. The epidermis, papillary dermis, and superficial adnexal
structures are usually unaffected.11 A mild chronic inflammatory cell infiltrate
consisting of lymphocytes, plasma cells, histiocytes, and variable numbers of
eosinophils may be present in the deeper reticular dermis, which is also often
fibrosed with atrophy of sweat glands.86 Immunophenotyping of mononuclar
inflammatory cell infiltrate demonstrated predominancy of macrophages and
CD8+ lymphocytes.87 Occasionally, the dermal changes are indistinguishable Fig. 17.123
Eosinophilic fasciitis: high-power view.
from morphea.16
The most dramatic changes are found in the superficial fascia, which is
markedly thickened, fibrosed, and sclerotic, and in the acute stages may show
focal fibrinoid necrosis and/or myxoid degenerative changes due to excessive
glycosaminoglycan deposition (Figs 17.122, 17.123).1,86 A chronic inflam-
matory cell infiltrate is present within the fascia in both a diffuse distribution
and centered around blood vessels (Fig 17.124).67 Primary vascular lesions,
however, are not a feature. Tissue eosinophilia is focal and often transitory.
Its absence in no way precludes the diagnosis. Lymphoid follicles, sometimes
with germinal centers, are also occasionally evident.86 The inflammatory
changes usually extend into the septa of the subcutaneous fat and fibrosis
may result in fat entrapment.15 There may also be superficial infiltration by
inflammatory cells into the underlying skeletal muscle, which occasionally
shows focal necrosis, degeneration, and foci of regeneration.1,86,88

Differential diagnosis
While there is obvious overlap with morphea, the diffuse nature of the indu-
ration clinically, the high peripheral eosinophilia, and history of preceding
strenuous exercise, combined with the usually less severe dermal changes and
preservation of the skin appendages on histology, commonly serve to distin-
guish the two disorders.
Sclerodermoid and eosinophilic fasciitis-like syndromes have been Fig. 17.124
described as features of the toxic oil and L-tryptophan-related eosinophilia– Eosinophilic fasciitis: the infiltrate consists of lymphocytes with only one or two
myalgia syndromes.89–94 eosinophils.
 Polymyositis/dermatomyositis 751

• The toxic oil syndrome arose as a consequence of contaminated Table 17.10

rapeseed oil and presented in Spain in 1981.94,95 Patients developed Variants of polymyositis
myopathy, peripheral neuropathy, and arthralgia in addition to Type Variant
morphea-like skin induration affecting the face, trunk, and extremities.94 I Polymyositis
Xerostomia was common and Raynaud's phenomenon was not
II Dermatomyositis
infrequent.
• The eosinophilia–myalgia syndrome is due to contaminated (Peak E) III Type I or II plus malignancy
commercial L-tryptophan. Patients develop a wide variety of clinical and IV Childhood polymyositis or dermatomyositis
laboratory abnormalities involving the skin, muscles, nerves, fascia, and
V Overlap syndromes
lungs.91 Acute cutaneous involvement is most commonly seen as a
non-specific erythematous macular eruption affecting the trunk and After Bohan, A. and Peter, J.B. (1975) Parts 1 and 2. New England Journal of Medicine,
extremities.91 Chronic lesions include edema of the extremities followed 292, 344–347, 403–407.
by the development of sclerodermiform and/or eosinophilic fasciitis-like
features.89
Variable histological features have been documented, presumably reflect- dermatomyositis or dermatomyositis sine myositis has been the source of
ing different stages of evolution. In some patients the most conspicuous much controversy.10–15 In addition to a prolonged follow-up, adequate elec-
changes have included fibrosis involving the papillary dermis, periappenda- tromyographic studies and muscle biopsy are mandatory before accepting
geal connective tissue sheath and subcutaneous fat.90 An inflammatory cell that the patient has only cutaneous lesions.15,16 Only 5% or less of cases of
infiltrate composed of lymphocytes, histiocytes, plasma cells, and variable dermatomyositis can be classified as the amyopathic variant after long-term
numbers of eosinophils is present in the dermis, subcutaneous fat, and fas- follow-up.14 For the diagnosis of amyopathic dermatomyositis to be made,
cia.91,92 Mast cells are sometimes conspicuous.92 Late stages are characterized it has been suggested that there should be absence of clinical or laboratory
by hyaline sclerosis involving the dermis through to the subcutaneous fat.92 signs of muscle disease for at least 2 years after the onset of skin disease.17
Additional features that have been documented include dermal edema with The clinical cutaneous signs of amyopathic dermatomyositis are identical to
lymphangiectasia and heavy mucin deposition in both the dermis and fascia.90 those seen in classic dermatomyositis. Patients with amyopathic dermato-
The histological features overlap between morphea/systemic sclerosis and myositis, like those with dermatomyositis/polymyositis, are at increased
eosinophilic fasciitis. risk of developing severe interstitial fibrosis of the lung and associated
malignancies.16
Polymyositis/dermatomyositis Dermatomyositis/polymyositis is associated with severe morbidity and
high mortality, the latter particularly reflecting cardiac and pulmonary
Clinical features involvement.
The cutaneous features are usually quite distinctive.18 Commonly, the
Polymyositis is a rare inflammatory disorder of muscle, the etiology of which
patient presents with periorbital edema and a reddish–violet discoloration,
is unknown.1,2 If certain cutaneous lesions are also present, the term ‘dermat-
often termed heliotrope erythema (heliotrope flower) (Figs 17.125, 17.126).
omyositis’ is applied. The overall incidence is approximately five new hospi-
The upper eyelids are most often affected and the eruption is typically sym-
tal cases per million of the population per year.1 As many diseases may include
metrical.19 This is usually associated with a lupus-like erythema, which
features of muscle weakness and elevated muscle enzyme activities, strict cri-
involves the rest of the face and spreads to the neck, upper trunk, and ­extensor
teria must be applied to the diagnosis of these two diseases (Table 17.9).
surfaces of the limbs and dorsal aspects of the hands and fingers (Fig. 17.127).
Either of these conditions may be confidently diagnosed if a patient fulfills the
It is associated with a slight scale. Exceptionally, generalized ­subcutaneous
first four criteria (polymyositis) or three of the four plus the typical rash
edema may develop.20
(dermatomyositis).3,4
Other cutaneous features include erythematous papules over the
Five variants of the disease are recognized (Table 17.10). With respect to
metacarpo­phalangeal joints (Gottron's sign), periungual erythema,
type V, dermatomyositis most commonly coexists with scleroderma (sclero-
telangiectasia, and splinter hemorrhages ( Figs 17.128 , 17.129 ).
dermatomyositis), but it may also develop in association with SLE, rheuma-
toid arthritis, and Sjögren's syndrome.4,5 To diagnose an overlap syndrome
the appropriate diagnostic criteria must be fulfilled for each disease and not
just a few common manifestations. Overlap syndromes occur more frequently
in polymyositis than in dermatomyositis and show a marked female predomi-
nance (9:1).6,7
Dermatomyositis not uncommonly presents solely with cutaneous mani-
festations. The quoted frequency of this type of presentation is variable and
it is not that rare for the skin eruption to precede the onset of muscle
involvement by more than 2 years.8,9 The proposed concept of amyopathic

Table 17.9
Diagnostic criteria for polymyositis/dermatomyositis
Symmetrical weakness of proximal limb muscles and anterior neck flexors
plus esophageal and respiratory muscle involvement
Positive muscle biopsy features
Elevated skeletal muscle enzymes
Appropriate electromyographic features
A typical rash
Fig. 17.125
After Bohan, A. and Peter, J.B. (1975) Parts 1 and 2. New England Journal of Medicine,
Dermatomyositis: note the characteristic red–mauve discoloration around the eyes.
292, 344–347, 403–407. There is also spread onto the cheeks. From the collection of the late N.P. Smith, MD,
the Institute of Dermatology, London, UK.
752 Idiopathic connective tissue disorders
Fig. 17.126
Dermatomyositis: the upper eyelids are particularly affected. From the collection of
the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig. 17.127
Dermatomyositis: note the erythema and slight scale on this patient's chest. By
courtesy of the Institute of Dermatology, London, UK.
Gottron's papules are typically found on the knuckles, but knees, elbows,
and malleoli may also be affected.21 The toes are characteristically
spared. The nail fold capillaries may be enlarged, dilated, and distorted.
Avascular areas are also often present.18 Cuticular overgrowth is some-
times evident, and occasionally there is a cutaneous vasculitis presenting
as digital ulceration, periungual infarcts, and mouth ulcers, though more
often in the childhood variant.18 With time, the skin may become more
atrophic and show the features of poikiloderma, which particularly
affects the extensor surfaces and upper back, but may be more wide-
spread ( Fig. 17.130 ). 6,7 Scalp involvement, which presents with scaling
and erythema, is not uncommon and is frequently pruritic.18
Photosensitivity has occasionally been reported. 6,19 Other rare or unusual
features include gingival telangiectases, follicular papules resembling
pityriasis rubra pilaris, erythroderma, erythema confined to seborrheic
areas, dermographism, lesions resembling malignant atrophic papulosis
(Degos' disease), a vesicobullous rash, a pustular eruption, Sweet-like
dermatosis, granuloma annulare, cutaneous amyloidosis, localized muci-
nosis, panniculitis, and lipodystrophy. 21–45 Gingival telangiectases have
also been found in association with anti-Jo-1 antibody.46 Some patients
present with a centripetal flagellate erythema affecting the trunk and
proximal extremities.47 Subepidermal blistering may occur and this has
Fig. 17.128
Dermatomyositis: characteristic purple papules on the knuckles (Gottron's sign).
By courtesy of Dr J.C. Pascual, Alicante, Spain.
Fig. 17.129
Dermatomyositis: Gottron's papules, periungual erythema and telangiectatic
capillary loops. By courtesy of Dr J.C. Pascual, Alicante, Spain.
been linked to internal malignancy.26,48,49 A rare case with acute onset
vesiculobullous lesions and massive mucosal necrosis of the intestine has
been documented. 50 Bullous pemphigoid may also rarely be associated
with dermatomyositis. 51 Eruptive dermatofibromas have been reported
in a single patient with dermatomyositis who was treated with predniso-
lone and methotrexate.52
Symmetrical proximal (limb girdle) muscle weakness is the most common
presenting feature of polymyositis.6 The legs are almost always the initial site
of involvement. The patient experiences difficulty in getting out of a chair,
walking up the stairs, combing his hair or raising his head from a pillow.
Interestingly, the facial muscles are almost never involved.53 Although the
muscles may be painful, this is not usually severe, and tenderness is not often
present. Muscle atrophy develops later in the course of the disease when
fibrosis and troublesome contractures may supervene.
Esophageal involvement manifests as dysphagia, which correlates with the
presence of an associated malignancy.4 Symptoms may also indicate pre-
esophageal involvement due to cricopharyngeal striated muscle weakness.6
Sequelae include nasal regurgitation and aspiration pneumonitis, the latter
being associated with a high mortality. A change in voice is a not uncommon
manifestation. Juvenile dermatomyositis has also been associated with isch-
emic ulcerative colitis and celiac disease.54,55

Fig. 17.130
Dermatomyositis: in this
patient with longstanding
disease, atrophy and
variable pigmentary
changes (poikiloderma)
are present on the
dorsum of the hand.
By courtesy of the
Institute of Dermatology,
London, UK.
Electromyographic features in polymyositis/dermatomyositis are said to
be pathognomonic and include the triad of short, low amplitude, polyphasic
potentials, increased spontaneous activity including fibrillation potentials
with positive sharp waves at rest, irritability, and bizarre high-frequency
repetitive discharges.53,56
The serum usually contains raised levels of creatine kinase, aldolase, lac-
tate dehydrogenase, and transaminases; as not all these may be elevated in
any one patient it is usually recommended that all are estimated routinely.6
Sequential muscle enzyme studies are particularly useful for monitoring prog-
ress and response to treatment.
Involvement of cardiac muscle is not uncommon and patients may have
tachycardia, sinus bradycardia, electrocardiographic abnormalities (e.g.,
bundle branch block), congestive heart failure, and cardiomegaly.57,58
Restrictive cardiomyopathy has also been described in a patient with
dermatomyositis.59
Pulmonary involvement, as determined by the radiological changes of
interstitial fibrosis and/or clinical evidence of impaired respiratory function,
may occur in as many as 40% of patients with polymyositis/ dermatomyosi-
tis.6 Patients are also at increased risk for development of pulmonary hyper-
tension.60 Pneumomediastinum and interstitial pneumonia are rare
complications.61,62 Pulmonary hemosiderosis is an exceptional finding in juve-
nile dermatomyositis.63 An important recently described association is that
between the anti-Jo-1 antibody, pulmonary fibrosis, and dermatomyositis.64–69
More than 50% of patients with anti-Jo-1 antibody have interstitial lung dis-
ease.65 Patients with this variant are not at risk of an increased incidence of
internal malignancy. Additional features of this variant may include Raynaud's
phenomenon, arthritis and tenosynovitis. Spread to the thoracic muscles can
result in severe respiratory difficulties; terminal bronchopneumonia is there-
fore an important cause of death.70
Cutaneous vasculitis is characteristic of the childhood variant, which may
involve the viscera; it has also been described in adult patients and may be
associated with an increased risk of malignancy. Digital ulcers, periungual
infarcts, and oral ulcers are associated manifestations.6 Deep cutaneous and
subcutaneous ulcers, not associated with vasculitis, have rarely been reported
in adult-onset dermatomyositis, and are likely to be related to obliterative
(micro)vasculopathy.71 Calcification of the skin, soft tissues, and muscle is
rare except in the childhood variant where it may be widespread and of help
diagnostically.72–74 Skin calcification has been demonstrated to correlate with
autoantibodies to a 140-kD protein.74
Polymyositis/dermatomyositis 753
Arthralgia is not uncommon, but frank arthritis is rare except in the over-
lap group of patients.4 Destructive arthropathy has been reported in a patient
with amyopathic dermatomyositis associated with anti-Jo-1 and anticyclic
citrullinated peptide antibodies.75 Aseptic bursitis of the olecranon has been
reported in a single patient.76
Laboratory investigations may reveal non-specific findings of a raised
ESR, hypergammaglobulinemia, and a false-positive Wassermann reaction.
Antinuclear factor may be found in a small percentage of patients with poly-
myositis/dermatomyositis. Anti-RNP and -SM antibodies are only seen in
‘overlap’ patients. In addition to anti-Jo-1 antibody, additional newly
described antibodies include PM-1, Ku, Mi-1, -2 and -3, and Pa-1.77 The sig-
nificance of these (except anti-Jo-1) is uncertain.78
Often stressed in polymyositis/dermatomyositis is the association with an
increased risk of developing malignancy.79 Although there has been a great
range in reported incidences from small studies, varying from 15% to 60% of
cases, recent investigations have suggested that the risk is less.56,80–85
Polymyositis/dermatomyositis has been described in association with the fol-
lowing malignancies: breast cancer, neuroendocrine carcinoma of the lung,
small cell lung cancer, hepatocellular carcinoma, neuroendocrine carcinoma
of the liver, duodenal carcinoid, gallbladder carcinoma, carcinoma of the
bladder, prostate cancer, renal cell carcinoma, clear cell ovarian carcinoma,
fallopian tube cancer, carcinosarcoma of the uterus, nasopharyngeal carci-
noma, esophageal cancer, Klatskin tumor (hilar cholangiocarcinoma), thy-
roid cancer, thymic carcinoma, cancer of the colon, primary gastric melanoma,
metastatic melanoma, diffuse large B-cell lymphoma, primary cutaneous
B-cell lymphoma-leg type, follicular lymphoma, lymphoplasmocytoid lym-
phoma, acute myeloid leukemia, and Kaposi's sarcoma.86–120 Among the
reported associations, breast, stomach, and ovarian tumors are most often
cited. In a recent study analyzing patients with dermatomyositis in China,
nasopharyngeal cancer was the most frequent association, followed by lung
cancer.121 Patients should have a very thorough physical examination com-
bined with routine laboratory investigations, chest X-ray, CT scan of the
abdomen and pelvis, and (in female patients) mammography. Underlying
malignancy should be suspected in patients who do not respond to therapy or
those who develop frequent episodes of myositis.81,122 A recent study suggests
that patients requiring more extensive search for malignancy should include
those with constitutional symptoms, with rapid onset of dermatomyositis or
polymyositis, without Raynaud's phenomenon, with a high ESR, and with a
very high creatine kinase level.85
There appears to be an increased risk of thyroid disease, particularly hypo-
thyroidism, especially in patients with interstitial lung disease.56 Juvenile der-
matomyositis, which has an annual incidence of about one new case per
million of the population per year, shows a female predominance (2:1) and
presents most often in the first decade.72 In addition to the features described
above there is a high incidence of vasculopathic manifestations including gas-
trointestinal ulceration with hemorrhage, which may be fatal.1 Multiorgan
involvement is common. The condition is often preceded by an infection.123
The prognosis is usually good, with up to 70% of children making a full
recovery.123 In severely affected patients, widespread cutaneous involvement
may be complicated by extensive scarring and diffuse calcification.124
Scleroderma/polymyositis overlap (sclerodermatomyositis) is the most
common overlap syndrome. Although the myositis component is usually
identical to that seen in dermatomyositis/polymyositis, the heliotrope ery-
thema and Gottron's papules are usually absent.125 The sclerodermatous cuta-
neous manifestations tend to be restricted to the peripheries. This overlap
syndrome is associated with the Ku antibody and a case has been reported in
association with Graves' disease and thrombocytopenic purpura.126
Autoimmune idiopathic thrombocytopenia with anti-Ku antibody has also
been associated with dermatomyositis.127
Pathogenesis and histological features
While the etiology and pathogenesis of polymyositis/dermatomyositis are
unknown, it has been proposed that environmental factors (e.g., drugs, toxins
or viruses) acting in association with a genetic predisposition result in a pri-
marily immune-mediated disorder.56 There is evidence to suggest that both
humoral and cell-mediated components are important.
754 Idiopathic connective tissue disorders

Antinuclear factor is commonly present. Antimyosin and antimyoglobin ­ emphigus foliaceus, Duchenne muscular dystrophy carrier status, familial
p
antibodies have been described, but their significance is uncertain. It is not polyposis colli, ulcerative colitis, hemophagocytic syndrome, organic solvent,
clear whether they precede or follow the onset of the myositis, and their pres- and silicone gel-filled breast implants.166–175
ence does not explain the cutaneous manifestations. However, antimyosin Direct immunofluorescence of lesional skin reveals granular deposits of
antibodies accompany any inflammatory myositis and are therefore probably immunoglobulin (IgG, IgA, and IgM) and complement at the dermoepidermal
a consequence of muscle necrosis. junction in about 35% of patients.176,177 Site selection is of importance, positiv-
A further set of antibodies directed against nuclear antigens have been ity being most frequent with nail bed biopsies.176 A more recent study has dem-
described in 35–40% of patients with dermatomyositis/polymyositis:128 onstrated C5b–9 deposition in blood vessel walls and along the dermoepidermal
• PM-1 (PM-Scl) antibody correlates closely with polymyositis and junction in conjunction with a negative lupus band test.178,179 This finding has
polymyositis/scleroderma overlap. high specificity (93.5%) and sensitivity (78.5%). Epidermal keratinocytes may
• Ku antibody is a marker for sclerodermatomyositis. also be positive for C5b–9 and IgG.179 The finding of C5b–9 in the wall of small
• PA-1 antibody correlates with polymyositis, arthritis, and fibrosing alveolitis. blood vessels suggests that a complement-mediated microvascular injury may
• Mi-2 correlates with dermatomyositis.6,56,128 be of some importance in the pathogenesis of dermatomyositis.
The presence of antibodies to the RNP antigens, U1 and U2, although not The pathogenesis of childhood dermatomyositis has a predominantly isch-
specific, is certainly highly suggestive of dermatomyositis/systemic sclerosis emic basis (see below).123
overlap syndrome.125,129,130 Antisignal recognition particle (SRP) antibodies are The cutaneous findings are variable. The erythematous eruption shows
uncommon, but are usually associated with severe disease.126 Although these slight hyperkeratosis and epidermal atrophy, with effacement of the ridge pat-
antinuclear autoantibodies are of diagnostic value, they have not yet been tern (Fig. 17.131).123 Basal cell liquefactive degeneration is typical and cytoid
shown to be of pathogenetic significance. Anti-p155-kD protein antibody has bodies are sometimes present (Fig. 17.132). Basement membrane thickening
been detected in 22% of patients with polymyositis/dermatomyositis and 75% is occasionally prominent. There is upper dermal edema and melanophages
of patients with cancer-associated dermatomyositis.131 Anti-CADM-140 anti- may be evident. Rarely, the edema results in subepidermal vesiculation.180
body is more frequent in patients with amyopathic dermatomyositis and
­correlates with interstitial lung disease in Japanese patients.132,133
Dermatomyositis and polymyositis may develop in patients with other
known autoimmune disorders, including autoimmune thyroid disease and
insulin-dependent diabetes mellitus.56,134 The precise role of humoral immu-
nity in dermatomyositis is unclear, but it is thought to be particularly related
to the capillary loss and ischemic damage.135
Cell-mediated immunity is important in the development of experimental
models of polymyositis. Lymphocytes taken from animals with allergic myo-
sitis (based upon sequential injections of heterologous muscle with Freund's
adjuvant) prove cytotoxic to skeletal muscle fibers in culture and may undergo
lymphoblastic transformation. Parallels do exist in the human disease, but
whether these represent initiating factors or develop as a consequence of mus-
cle damage is unknown.1 A variety of cellular immune abnormalities have
been documented, including the presence of activated mononuclear cells
within skeletal muscle, abnormal trafficking of mononuclears to skeletal
muscle, decreased autologous mixed lymphocyte responses, and mitotic and
proliferative responses to autologous muscle.56,136,137
There is some evidence to suggest an inherited predisposition with an
increased incidence of HLA-B8 and HLA-DR3 in both dermatomyositis and
polymyositis, particularly in patients who have anti-Jo-1 antibodies.56,138
Fig. 17.131
There are rare instances of familial disease.56 Dermatomyositis: there is hyperkeratosis and epidermal atrophy. Note the mild
A number of animal experimental models have shed some light on the telangiectasia.
­possible pathogenesis of human myositis.56 Injection of muscle extracts into a
number of animals results in a mild, nonpersistent myositis.56
Several viruses – including Coxsackie B virus, simian acquired immunodefi-
ciency retrovirus, and murine encephalomyocarditis virus – have been shown
to induce a chronic myositis-like disease. Virus strain and host genetic factors
appear to be of particular importance.56 Although uncertain, it has been sug-
gested that some cases of dermatomyositis, particularly the juvenile variant,
may represent an abnormal immunological response to a viral infection.70
Picornaviruses, including the coxsackievirus group, have been particularly
implicated.1 The anti-Jo-1 antibody (an antiaminoacyl-tRNA synthetase) reacts
with histidyl-transfer RNA synthetase.135 This enzyme has been shown to be
capable of interacting with the RNA of a number of picornaviruses in addition
to its normal substrate tRNA.56 It has been suggested that the development of
the autoantibody may occur as a consequence of this aberrant interaction.56
It is interesting to note that an illness similar to dermatomyositis may be
induced by a number of infectious organisms including leishmania, parvovi-
rus (erythrovirus) B19, human immunodeficiency virus, and toxoplasma.139–143
Tuberculous myofasciitis has developed in a dermatomyositis patient.144
Dermatomyositis/polymyositis has been reported as an adverse reaction to a
number of drugs, such as hydroxyurea, cyclophosphamide, etoposide, ­fluvastatin,
simvastatin, pravastatin, omeprazole, minocycline, carbimazole, ­terbinafine, Fig. 17.132
and interferon beta-1a.145–165 Furthermore, polymyositis/­dermatomyositis has Dermatomyositis: there is atrophy with effacement of the ridge pattern. In this
also been found in association with hepatitis B vaccination, psoriasis, example cytoid bodies are conspicuous. Note the pigmentary incontinence.
 Polymyositis/dermatomyositis 755

Fig. 17.133 Fig. 17.134

Dermatomyositis: focal, mild basal cell hydropic degeneration is seen on the right. Gottron's papule: note the hyperkeratosis, hypergranulosis, and irregular acanthosis
A chronic inflammatory cell infiltrate is present. simulating lichen planus. There is basal cell hydropic degeneration and cytoid bodies
are present in the superficial dermis. By courtesy of D. Whittemore, DO, MD
Anderson Cancer Center, Houston, Texas, USA.

A light chronic inflammatory cell infiltrate is usually present (Fig. 17.133). It

is commonly restricted to the superficial dermis and is not associated with the
cutaneous adnexae. The infiltrate consists of activated T lymphocytes and
macrophages with occasional dermal Langerhans cells.181 Helper T cells pre-
dominate. In some instances the presence of marked hyperkeratosis, follicular
plugging, dermal edema, and increased quantities of basement membrane-like
material results in considerable histological overlap with lupus erythematosus,
and clinicopathological correlation is essential. A recent study found the most
consistent histological parameters in dermatomyositis to be vacuolar changes
of basal keratinocytes, dermal mucin accumulation, and a mild to moderate
dermal mononuclear inflammatory cell infiltrate.182 Dermal sclerosis may
occasionally be present.183
Increased quantities of Alcian blue-positive glycosaminoglycans are fre-
quently present within the dermis.180 Sometimes there are foci of calcification
and panniculitis is occasionally evident.
The poikilodermatous lesions show hyperkeratosis, mild epidermal atro-
phy with loss of the epidermal ridge pattern, and basal cell liquefactive
degeneration.123 Additional features may include marked pigmentary incon-
tinence, cytoid body formation, and a patchy lymphocytic inflammatory
cell infiltrate. The dermis is edematous, often contains increased mucin, and Fig. 17.135
characteristically shows conspicuous dilated vascular channels. Nuclear Dermatomyositis: note the perivascular chronic inflammatory cell infiltrate.
atypia of the infiltrate as seen in poikilodermatous mycosis fungoides is not
a feature.
Gottron's papules are characterized by hyperkeratosis, mild papillomato-
sis, acanthosis or, less often, epidermal atrophy and the features of interface
dermatitis as described above (Fig. 17.134).184,185 The histology of the cen-
tripetal flagellate erythema shows the changes of interface dermatitis.47
Ultrastructural studies contribute little to our understanding of dermato-
myositis. Tubuloreticular inclusions as described in SLE have been documented
in endothelial cell and pericyte cytoplasm, but their significance is
uncertain.186
In the juvenile variant, the cutaneous features are similar to those described
above with the proviso that fibrosis is sometimes evident, calcification is more
common and occlusive vascular disease (as characterized by fibrous intimal
proliferation with fibrin thrombi) is often present.123,124
Skeletal muscle changes include both degenerative and regenerative fea-
tures in addition to a focal chronic inflammatory cell infiltrate (Figs 17.135,
17.136).123 The latter is composed predominantly of lymphocytes, but histio-
cytes, eosinophils, and plasma cells may also be evident.187 The lymphocytes
consist of substantial numbers of B cells, particularly in association with blood
vessels, in addition to T-cells, which are predominantly found in and around
the altered muscle fibers.188 As in cutaneous lesions, T-helper cells predomi- Fig. 17.136
nate. Up to 25% of muscle biopsies may, however, show no evidence of Dermatomyositis: the infiltrate consists predominantly of lymphocytes.
756 Idiopathic connective tissue disorders
Fig. 17.137
Dermatomyositis: the central fiber is intensely swollen, eosinophilic, and
fragmented; there is a loss of striations.
Fig. 17.138
Dermatomyositis: the fiber in the upper midfield is swollen, eosinophilic,
vacuolated, and in places granular; beneath is a regenerating basophilic cell.
i­nflammation.4 The degenerative fibers are swollen and intensely eosinophilic
and may show loss of striations (Fig. 17.137). Some fibers are vacuolated, but
others appear granular or fragmented (Fig. 17.138). Proliferation and central-
ization of muscle nuclei is common, as is sarcoplasmic basophilia – features of
regeneration (Fig. 17.139). Histological changes identical to inclusion body
myositis, namely rimmed vacuoles, have also recently been reported in patients
with dermatomyositis.189,190
If material from a longstanding ‘burned out’ lesion is biopsied, the muscle
fibers are atrophic and there is endomysial fibrosis. Perifascicular atrophy – the
presence of one or two rows of atrophic fibers at the edge of a fascicle – is said
to be characteristic of dermatomyositis.191 The muscle pathology in dermato-
myositis and polymyositis is said to differ.56 In dermatomyositis the inflamma-
tory cell infiltrate tends to be septal or perivascular whereas in polymyositis it is
intrafascicular. Muscle necrosis in dermatomyositis tends to involve small groups
of fibers, while in polymyositis the affected fibers tend to be single and sparse.
Denervation neuropathic features are also occasionally present, presum-
ably due to involvement by the inflammatory process of small intramuscular
nerve fibers.123 Steroid atrophy of type II muscle fibers may be seen in biopsies
from treated patients.
In childhood dermatomyositis, vascular changes affecting the capillaries,
venules, and arterioles are common.192 The inflammatory component, which
Fig. 17.139
Dermatomyositis: the lower fiber is basophilic and shows excessive nuclei –
features of regeneration. Note the centralization of nuclei in the upper fiber.
is usually quite sparse, consists of lymphocytes, monocytes, and plasma cells
centered predominantly on the vasculature in the perifascicular connective
tissue.193 Muscle changes are variable and range from perifascicular atrophy
in milder disease through to focal necroses and infarction in the more seri-
ously affected patients, in whom fibrosis may also be a feature.193 The vascu-
lar lesions include endothelial cell swelling and necrosis with or without
occlusion, non-necrotizing lymphocytic vasculitis, and loss of the peripheral
fascicular capillary bed.193
Immunofluorescence of muscle biopsies in childhood dermatomyositis
commonly shows vascular intramural IgM and C3.193
Mixed connective tissue disease
Clinical features
As originally defined by Sharp et al., mixed connective tissue disease (MCTD)
represents a clinical condition in which patients have an overlap of signs and
symptoms of systemic sclerosis, systemic lupus erythematosus, and polymyo-
sitis/dermatomyositis.1,2
Although the concept of mixed connective tissue disease as a distinctive
entity separated from other connective tissue diseases has been controversial,
the disease has characteristic and reproducible clinical and serological fea-
tures.3,4 Some patients present with manifestations that are not entirely diag-
nostic and may progress over time to develop typical features of MCTD or
other connective tissue diseases, particularly SLE. These patients are desig-
nated as having an unclassified or undifferentiated connective tissue disease.5
MCTD is characterized by a marked female predominance (16:1) and
shows no racial predilection.6,7 Presentation is usually in the second and third
decades, but children may also be affected.1,8–10 Clinical features include
­arthralgias and nondeforming arthritis, swollen hands with tapered or
­sausage-shaped fingers, Raynaud's phenomenon, abnormal esophageal motil-
ity, myositis, lymphadenopathy, fever, hepatomegaly, serositis, and splenomeg-
aly.1,11 Patients were initially thought not to show features of renal, pulmonary
or neuropsychiatric involvement or vasculitis. In addition, their sera invariably
contained high titers of antibody to a saline extractable nuclear antigen
(ENA), U1-RNP, and speckled antinuclear antibody. Precipitating antibody
to SM soluble nuclear antigen was absent. The disease responded to
­corticosteroid therapy and had a favorable outcome.
In the light of data from subsequent experience, the above, rather simplis-
tic, overview has had to be modified.6,12 Although a variety of diagnostic cri-
teria have been proposed, that of Alarcón-Segovia and Cardiel has been
chosen, largely because of their simplicity.13 They suggest that if the criteria
used are restricted to certain key clinical manifestations then MCTD may be
accurately diagnosed (Table 17.11).7

Table 17.11
Diagnostic criteria for mixed connective tissue disease
Serologic
high anti-RNP titer (> 1:1600 by hemagglutination or an equivalent by
another method)
Clinical
edema of the hands
synovitis
myositis (biopsy proven or elevated CPK)
Raynaud's phenomenon (two or three phases)
acrosclerosis
Diagnosis of MCTD requires
positive serology plus three or more of the clinical criteria
CPK, creatinine phosphokinase; MCTD, mixed connective tissue disease; RNP,
ribonucleoprotein. Reproduced with permission from Alarcón-Segovia, D. (1994)
Clinics in Dermatology, 12, 309–316.
Essential to the diagnosis is the presence of high titer anti-ENA antibodies
(anti-U1-RNP). The U1-RNP is an RNA-protein complex, composed of U1
snRNA and several proteins, of which U1-70K proteins are specific for the
complex.14 In MCTD, antibodies against the U1-70K proteins are the most
prominent, and those directed against the apoptotic form of U1-70K appear to
be particularly useful as serological markers of MCTD.15 Anti-ENA antibodies
are also present in the sera of patients with SLE. In MCTD, however, the anti-
body–antigen interaction is sensitive to ribonuclease and trypsin and resistant
to deoxyribonuclease, the antigen in fact being ribonucleoprotein (U1-RNP).16
In SLE, the antibody activity is resistant to ribonuclease and deoxyribonu-
clease, but sensitive to trypsin, and the antigen is SM. Anti-ENA antibodies are
not seen in systemic sclerosis or dermatomyositis. Patients with MCTD do not
usually develop antibodies to native DNA.17 The presence of anti-Ro (SS-A)
antibodies appears to identify a subgroup of patients frequently presenting
with malar rash and photosensitivity.18 Nucleoporin p62 antibodies have been
reported in a single patient with MCTD and were suggested to signify poor
prognosis in patients with connective tissue disorders.19 Patients with active
MCTD have significantly higher serum levels of antiendothelial cell antibodies
than those with inactive MCTD, making antiendothelial cell antibodies a
­useful marker of clinical disease activity.20 Exceptionally, antineutrophil
­cytoplasmic antibodies against proteinase-3 have been detected in MCTD,
and contributed to the development of systemic atherosclerosis.21
In addition to hand and finger changes and Raynaud's phenomenon,
patients may develop alopecia, areas of hypo- and hyperpigmentation, and
sclerodermiform nail fold capillaropathy. Cutaneous lesions of DLE, SCLE,
and SLE also occur.22 Occasionally, the cutaneous lesions of dermatomyositis
are evident. Livedoid vasculitis with ulcers has also been documented and
was associated with poor prognosis in the single patient described.23 Other
less common manifestations include alopecia and oral ulcers.24 Sicca symp-
toms are present in up to one-third of patients.25
Systemic features that are more commonly documented in MCTD include
deforming polyarthritis, which particularly affects the hands and feet (often
in association with rheumatoid factor), juxta-articular and peritendinous
nodules, and calcification involving the forearms, wrists, hands, and feet.6,26
A distinctive mutilating arthropathy giving rise to a ‘main en lorgnette’
appearance is said to be characteristic.16
It is now known that if patients are followed for a sufficiently long period
there is a much greater risk of visceral lesions than was previously realized.22
The majority develop asymptomatic respiratory involvement. Pulmonary
hypertension with a poor prognosis is, however, not rare27,28 and represents
the most severe clinical manifestation of MCTD.29 The presence of anti-β2-
glycoprotein I antibodies has been demonstrated to correlate with develop-
ment of pulmonary hypertension in patients with MCTD.30 Pulmonary
veno-occlusive disease has also been implicated in the pathogenesis of pulmo-
nary hypertension in MCTD.31 Up to 10% of patients develop renal disease
(albeit usually mild) and a significant proportion of patients develop neurop-
sychiatric and cerebral manifestations, including trigeminal neuropathy and
migrainous headaches.32 The mixed nature of the clinical manifestations later
becomes less obvious with evolution towards a single disease process, usually
Relapsing polychondritis 757
systemic sclerosis. It is generally considered that, although mortality is low in
MCTD, there is a much greater morbidity due to internal involvement than
was originally appreciated.
MCTD has also been associated with Hashimoto's thyroiditis, thymic car-
cinoma, sarcoidosis, vitamin D deficiency, retinal vasculopathy, acute coro-
nary syndrome, Kikuchi-Fujimoto disease, mixed-type autoimmune hemolytic
anemia, autoimmune thrombocytopenia, thrombotic thrombocytopenic pur-
pura, panniculitis, hypertrophic obstructive cardiomyopathy, esophageal
motor dysfunction, interstitial lung disease, mucous membrane pemphigoid,
and sensorineural hearing loss, MPO-ANCA-positive polyangitis, cutaneous
polyarteritis nodosa, human T-lymphotropic virus type 1 carrier status, aseptic
meningitis, ANCA-positive glomerulonephritis, and nephrotic syndrome.33–54
Pathogenesis and histological features
The etiology and pathogenesis of MCTD are unknown. MCTD has, however,
apparently followed vinyl chloride exposure.32 Immunoglobulin (Gm) allo-
type association and an increased frequency of HLA-DR4 in patients with
polyarthritis have been documented.16,55 Patients are frequently lymphopenic
with diminished circulating T cells and increased B cells.16
The histological features of the varying cutaneous manifestations have
been described in the appropriate sections (Figs 17.140, 17.141). Biopsies
from cutaneous lesions with no typical features may show histological fea-
tures similar to those of subacute lupus.56
Direct immunofluorescence may reveal epithelial speckled nuclear positiv-
ity, presumably representing in vivo binding of anti-U1-RNP antibodies.57
Relapsing polychondritis
Clinical features
Relapsing polychondritis is a rare disorder characterized by recurrent episodes of
inflammation of cartilaginous tissue throughout the body and its subsequent
degeneration and replacement by fibrous tissue (Fig. 17.142).1,2 The ears (93%),
nose (56%), larynx, and trachea (30%) are predominantly affected.3–7 Skin mani-
festations are the presenting features in approximately 50% of cases.6 There is a
slight male predominance and the median age at diagnosis in one large study was
46.6 years.8 Presentation in children is exceptional.9,10 Pediatric and adult-onset
relapsing polychondritis patients share similar clinical features.10 However, chil-
dren have a family history of autoimmune diseases more often than adults.
However, they infrequently present with associated autoimmune conditions.10
Clinical criteria for diagnosis have been established. Three of these, together with
biopsy confirmation of chondritis, are required for diagnosis (Table 17.12).5
Although it particularly affects Caucasians, cases have been recorded in
Asians, blacks, Hispanics, and the Japanese.3 The sex incidence is equal. Most
patients present in the fourth decade.4 There is no evidence of a hereditary
predisposition.6 Clinical signs may be subtle and can resemble those seen in
Behçet's disease or inflammatory bowel disease; the diagnosis is often diffi-
cult.2,11 Familial cases are exceptional.12
Auricular chondritis is the commonest lesion and is frequently bilateral.3
Patients present with painful, tender, erythematous, sometimes blue–black,
and swollen ears.6 Chronicity leads to distortion and flabbiness. Arthritis
(seronegative) particularly affects the sternoclavicular, costochondral, and
sternomanubrial joints.3 One or more joints may be affected and lesions are
often migratory.6 Painful nasal chondritis may result in epistaxis, and saddle
nose is an occasional complication. Nasal involvement is seen in over 50% of
patients.8 Oral aphthosis was present in 11% of patients in a large series.2 In
6% of patients, oral and genital aphthae were seen.2 When the disease initially
presents, inflammation of a single site may be confused with erysipelas.13
Ocular lesions include conjunctivitis, corneal ulceration, iridocyclitis, epis-
cleritis, proptosis, cataract, chorioretinitis, scleromalacia perforans, scleritis,
retinal detachment, blindness, edema of the eyelids and muscle palsies, and
optic neuropathy.3,6,8,14–17 Chronic conjunctivitis due to obliterative micoran-
giopathy has been reported in a single patient with relapsing polychondritis.18
Central nervous system complications comprise aseptic meningitis and menin-
goencephalitis, encephalitis lethargica, Lewy bodies-like dementia is a rare
complication.17,19–23 Trigeminal neuralgia has also been reported.24
758 Idiopathic connective tissue disorders
Fig. 17.140 Fig.17.141
Mixed connective tissue disease: morphea-like Mixed connective tissue disease: high-power view
features. There is dense dermal sclerosis with showing dermal sclerosis.
extension into the subcutaneous fat.
Table 17.12
Diagnostic criteria for relapsing polychondritis
Recurrent articular chondritis
Cochlear and vestibular damage
Ocular involvement
Nasal involvement
Tracheal/pharyngeal involvement
Nonerosive polyarthritis
Respiratory lesions may affect the larynx, trachea, and major bronchi
with obstructive symptoms, stenosis, collapse, pneumothorax, pneumoperi-
toneum, and bronchopneumonia.3,7,8,25 Exceptionally, airway involvement
may be the only manifestation of the disease.26 Cardiovascular lesions
include valvular incompetence, conduction defects including complete heart
block, cystic medial necrosis of the aorta, aortitis, aortic valve regurgita-
tion, vasculitis and pericarditis, and pericardial effusions.3,8,17,27–30
Involvement of the heart valves occurs in up to 10% of patients and sys-
temic vasculitis, reminiscent of polyarteritis nodosa, has been described.31
Ear involvement includes external ear chondritis, otitis media, vertigo, and
deafness.32
Dermatological manifestations are present in 35–50% and may even pre-
cede the development of relapsing polychondritis in about 12% of cases.2
Skin lesions have included leukocytoclastic vasculitis, hypocomplementemic
urticarial vasculitis, cutaneous polyarteritis nodosa, erythema elevatum diuti-
num, livedo reticularis, alopecia, retarded nail growth, erythematous nod-
ules, erythema annulare centrifugum, erythema multiforme-like lesions,
urticarial plaques, erythema nodosum, thrombosis, pyoderma gangrenosum-
like lesions, Sweet's syndrome, postinflammatory hyperpigmentation, and
psoriasis.2,3,6,33–43 Exceptional associations with normolipemic plane xan-
thomatosis and with panniculitis showing septal and lobular involvement
accompanied by vasculitis have been documented.44,45
Significant disease associations that may be present in up to 30% of
patients include leukocytoclastic vasculitis, systemic vasculitis (Takayasu and
temporal arteritis, Wegener's granulomatosis), Hashimoto's thyroiditis,
Fig. 17.142
Relapsing polychondritis: the ear shows considerable
erythema and swelling. By courtesy of R.A. Marsden,
MD, St George's Hospital, London, UK.
arthritis, Sjögren's syndrome, dermatomyositis, MCTD, SLE, inflammatory
bowel disease (both ulcerative colitis and Crohn's disease), and myeloprolif-
erative disorders.2,6,32,46–54 Rare associations of relapsing polychondritis
include ankylosing spondylitis, Behçet's disease, HIV, splenic abscess, chronic
hepatitis C, mixed cryoglobulinemia, sarcoidosis, common variable immuno-
deficiency, familial Mediterranean fever, and amyloidosis.55–62
An increased ESR and anemia are the commonest significant laboratory mani-
festations. Increased urinary glycosaminoglycans have also been documented.63
Relapsing polychondritis has a significant mortality. The 5-year survival rate
is approximately 74%.32 Infection, respiratory failure, systemic vasculitis, large
vessel aneurysm rupture, and renal failure are the commonest causes of
death.1,32
A number of patients have been reported to have myelodysplastic syn-
drome associated with relapsing polychondritis.41,64–68 This is of interest since
myelodysplastic syndrome is known to be associated with autoimmune dis-
ease.69,70 In a large study of 200 patients, 11% had myelodysplastic syn-
drome.2 Other malignancies occurring with relapsing polychondritis include
splenic non-Hodgkin's lymphoma, chronic lymphocytic leukemia, chronic
myelomonocytic leukemia, and Kaposi's sarcoma.71–74 Association with epi-
thelial malignancies is less frequent.75
Relapsing polychondritis has been associated with the luteinizing hor-
mone-releasing hormone (LH-RH) analogue goserelin. As the disease may
worsen during pregnancy and during chorionic gonadotropin therapy, it is
suggested that hormones may be a precipitating factor.76
Pathogenesis and histological features
The precise etiology of relapsing polychondritis is poorly understood. Several
studies have suggested an immunological mechanism.6 The association with
autoimmune diseases in many patients lends support to this thesis. Antibodies
(predominantly IgG) to type II collagen, which accounts for over 50% of the
proteins in cartilage, have been detected in a proportion of patients in titers of
1:10 to 1:320.37,46,77,78 The antibodies are directed against both native and dena-
tured protein.46 Using ELISA, one study showed that 50% of patients have anti-
bodies against type II collagen.79 In this same study, 4% of control subjects and
15% of rheumatoid arthritis patients also had antibodies in their sera. Those
 Relapsing polychondritis 759

patients who have the autoantibody show evidence of active disease, whereas
those without it are either in remission or being treated.46 Rats immunized with
type II collagen develop auricular chondritis. Cartilage from these same ani-
mals had positive immunofluorescence for IgG and C3.80 In a single patient,
T-cell clones were found to be specific for the collagen II peptide 261–273.81
An association between the disease and HLA-DR4 has been reported but
there is no predominance of any DR4 subtype.82
Antifetal cartilage antibodies have been detected by indirect immunofluo-
rescence studies.78 Documentation of transplacental transfer of these antibod-
ies with neonatal involvement suggests that they are of pathogenetic
significance. One group of authors suggested that matrilin-1, a cartilage
matrix protein, is the target of autoreactivity.83,84 Another group found
autoantibodies to matrilin-1 in 13% of patients and antibody titers correlated
with symptomatology.85 Rats immunized with matrilin-1 develop nasorespi-
ratory abnormalities (but not ear or joint changes).86 Cartilage oligometric
matrix protein has also been suggested as a potential autoantigen.87
Circulating immune complexes have also been demonstrated in relapsing
polychondritis, together with deposits of immunoglobulin and complement
in inflamed cartilage, adding further support to a possible immune mecha-
nism in this disease.3,38,46 Granular deposits of immunoglobulin and comple- Fig. 17.143
Relapsing polychondritis: in this early lesion, the degenerate cartilage shows
ment (C3) have been described at the chondrofibrous junction in two
intense eosinophilia.
patients.87 The presence of antineutrophil cytoplasmic antibody (ANCA) has
been reported.88 Elevated serum levels of macrophage migration inhibitory
factor have also been documented.89 Increased serum levels of proinflamma-
tory cytokines, namely macrophage inflammatory protein 1β, monocyte
chemoattractant protein 1, and interleukin-8 have also been demonstrated in
patients with relapsing polychondritis.90
There is some evidence suggesting that cell-mediated immunity may also
be of importance in the pathogenesis. Patients display positive lymphoblast
transformation and macrophage migration inhibition to cartilage glycosamin-
oglycans.1 Responses correlate with episodes of disease activity. Dysregulation
of NKT cells has also been detected in relapsing polychondritis.91
Histological examination of the skin is unremarkable. The dermis contains
a mild focal lymphohistiocytic infiltrate. Examination of the fibrocartilagi-
nous tissues, however, shows degenerative and inflammatory changes affect-
ing the marginal chondrocytes, with loss of basophilia and poor Alcian blue
staining of the cartilaginous tissue (Figs 17.143, 17.144). The inflammatory
cell infiltrate, which includes lymphocytes, plasma cells, histiocytes, and occa-
sional polymorphs, infiltrates the degenerate cartilage. Eventually, there is
replacement by granulation and fibrous tissue.3 Atypical lymphoid infiltrates
mimicking a lymphoma have rarely been described.92

Differential diagnosis
Chondrodermatitis nodularis helicis differs by the presence of characteristic lay-
ering of fibrin, granulation tissue, and cartilage with degenerative changes. Fig. 17.144
Clinically, chondrodermatitis helicis presents as a focal, punched-out ulcer. This Relapsing polychondritis: a mild chronic inflammatory cell infiltrate is present in the
differs from the diffuse involvement of the ear seen in relapsing polychondritis. perichondrium.
 Infectious diseases of the skin
18
Chapter

See
www.expertconsult.com
for references and
Wayne Grayson additional material

Viral infections  761 Diseases caused by Bartonella Algal infections  850

species  803
Common wart  761
Cat scratch disease  803
Plantar warts  763 Trench fever  803
Bartonellosis  804
Plane warts  766 Bacillary angiomatosis  804
Condyloma acuminatum  767 Lyme disease  806
Bowenoid papulosis  769 Endemic (nonvenereal)
Epidermodysplasia verruciformis  769 treponematoses  808
Endemic syphilis  808
Herpes simplex virus infections  771 Yaws  809
Pinta  811
Varicella and herpes zoster  776
Cytomegalovirus infections  779 Tuberculosis  811
Exanthem subitum  780 Tuberculids  818
Eruptive pseudoangiomatosis  780 Cutaneous complications of Bacille
Calmette-Guérin vaccination  819
Diseases caused by orthopox viruses  781
Nontuberculous environmental
Milker's nodule  783 mycobacterial infections  820
Ecthyma contagiosum  783 Leprosy  825
Molluscum contagiosum  785 Rhinoscleroma  831
Protothecosis  850
Fungal infections  851
Tinea capitis  852
Infections caused by Microsporum canis and
Microsporum audouinii  852
Kerion  852
Endothrix infections  853
Favus  853
Black piedra  854
White piedra  854
Tinea corporis  855
Tinea pedis and tinea cruris  856
Nodular granulomatous
perifolliculitis  858
Diseases caused by Malassezia
species  858
Tinea versicolor  858
Malassezia (Pityrosporum) folliculitis  859

Hand, foot, and mouth disease  787 Nocardiosis  834 Tinea nigra  861
Viral hemorrhagic fevers  788 Botryomycosis  835 Candidiasis  861
Virus-associated trichodysplasia Malakoplakia  836 Aspergillosis, fusariosis and
spinulosa  789 pseudallescheriosis  863
Actinomycosis  837
Whipple's disease  838 Blastomycosis  865
Bacterial infections  790
Erythrasma  839 Paracoccidioidomycosis  868
Impetigo  790
Trichomycosis  840 Coccidioidomycosis  869
Staphylococcal scalded skin
syndrome  791 Pitted keratolysis  840 Cryptococcosis  871
Erysipelas and cellulitis  794 Cutaneous diphtheria  841 Zygomycosis  874
Necrotizing fasciitis  796 Sago palm disease  841 Chromoblastomycosis  876
Infective folliculitis  797 Tularemia  842 Mycetoma  877
Folliculitis keloidalis nuchae  799 Infections caused by Rickettsiae  842 Phaeohyphomycosis  879
Pseudofolliculitis  799 Alternariosis  881
Protozoal infections  844
Meningococcal septicemia  799 Histoplasmosis  881
Leishmaniasis  844
Gonorrhea  800 Penicilliosis  883
Amebiasis cutis  848
Plague  800 Sporotrichosis  883
Infections caused by free-living
Cutaneous anthrax  801 amebae  848 Lobomycosis  885
Brucellosis  802 Toxoplasmosis  849 Pneumocystosis  886
 Common wart 761

Diseases caused by Nematode infestation  891 Cestode infestation  894

Mesomycetozoea  887
Onchocerciasis  891 Cysticercosis  894
Rhinosporidiosis  887
Cutaneous larva migrans  893 Echinococcosis  894

Arthropod infestations  888

Trematode infestation  893
Scabies  888
Schistosomiasis  893
Tungiasis  890

Viral infections

Common wart
The common wart (verruca vulgaris) is caused by infection with human
papillomavirus (HPV) (Fig. 18.1). HPV is a DNA virus of the papovavi-
rus family. The number of known HPV genotypes currently stands at more
than 100, classified according to the extent of their DNA homology (DNA
hybridization) (Table 18.1).1–4 In order for an HPV type to be regarded
as ‘new’, sequences in selected genomic regions must exhibit more than
10% divergence compared to any of the known HPV types.4 Monoclonal
­antibodies to intact viruses have been produced and can ­demonstrate
­individual types of HPV; antibodies to viral components are only group
specific (Fig. 18.2). In recent years, advances in molecular pathology
have resulted in improved and more specific methods of HPV ­detection,
­including in situ polymerase chain reaction (PCR) and nonisotopic in situ
hybridization (NISH).5
Papillomaviruses, which are small, nonenveloped, and show icosahedral
symmetry, contain circular double-stranded DNA composed of approxi- A
mately 8000 base pairs.4,6 The viral particle, which has a diameter of approx-
imately 55 nm, contains 72 capsomeres.1,2,4,6 The HPV genome is divided
into three functional regions: a late region, an early region, and a noncod-
ing 1000 base pair upstream regulatory region (URR). The URR is located
immediately upstream of the E6 open reading frame (ORF) and contains
sequences regulating expression of all ORFs, including promoter elements
and transcriptional enhancer sequences. In excess of 20 messenger RNAs
are expressed, usually in a differentiation-specific and cell-specific manner.4
Genes in the early region (E1, E2, E4, E5, E6, E7) are responsible for tran-
scription, replication, and cellular transformation. The E4 ORF is highly
expressed in differentiated HPV-infected epithelial cells. Some forms of E4
encode a protein capable of disrupting the cytokeratin network, resulting
in the phenomenon of koilocytosis.4 The E4 ORF represents a region of
maximal divergence between different HPV types.7 Each viral genotype is
most often detected in lesions at specific anatomical sites or shows distinct
­histological characteristics.2,8–10
HPV infection in man results in a variety of lesions including ­verruca
vulgaris, filiform warts, verruca plana, plantar warts, anogenital warts, B
and bowenoid papulosis.6 Mucosal lesions include oral warts and con-
dylomata, focal epithelial hyperplasia or Heck's disease, nasal and con- Fig. 18.1
junctival papillomas, laryngeal papillomatosis, and cervical lesions.4,6 In Viral warts: (A) these are exceedingly common and may affect any site; (B) lesions
addition to its role in cervical cancer, HPV is increasingly recognized are frequently multiple. (A) By courtesy of the Institute of Dermatology, London,
as an important cause of a number of neoplasms including Bowen's UK; (B) By courtesy of J.C. Pascual, MD, Alicante, Spain.
disease and malignant lesions of the anus, external genitalia, and else-
where.2 Of equal importance is the recognition that HPV infection may
be asymptomatic or result in a carrier status. A recent study showed Clinical features
that cutaneous HPV infections commonly persist on healthy skin Common warts are caused by HPV types 1, 2, 4, 7, and 26–29.2,6 In immuno-
over several years, and that persistence does not appear to be associated suppressed patients, HPV subtypes 75, 76, and 77 may be pathogenetic.12
with age, sex, a history of warts, immunosuppressive therapy, or HPV A case with extensive, recalcitrant verrucae linked to infection with HPV type
type.11 57 has been reported.13 Rarely, HPV subtypes associated with genital warts
762 Infectious diseases of the skin

Table 18.1
Variants of human wart virus infection

HPV type Associated clinical lesions

1 Deep plantar warts, common warts
2 Common warts, flat warts
3 Flat warts
4 Common warts, plantar warts
5 Epidermodysplasia verruciformis (EV)
6 Genital warts, laryngeal papilloma
7 Butcher warts
8 EV
9 EV, keratoacanthoma
10 Flat warts
11 Laryngeal papillomas, genital warts
12 EV
Fig. 18.2
13 Focal epithelial hyperplasia Verruca vulgaris: note the positive labeling of the nuclei in this section stained with
14, 15 EV a peroxidase-labeled antiserum to papilloma virus.
16 Genital warts, bowenoid papulosis, cervical dysplasia,
cervical carcinoma, digital, squamous cell carcinoma, as an erroneous clinical or histological diagnosis of condylomata acuminata
nongenital Bowen's disease could lead to allegations of sexual abuse.16
17 EV Warts are very common lesions, particularly in children.17 Adults are also
frequently affected. In a survey of 2180 adults, 3.5% had warts.18 Butchers
18 Genital warts, bowenoid papulosis, cervical dysplasia,
and slaughterhouse workers have an increased risk.19,20 Common warts may
cervical carcinoma
occur anywhere on the skin and in people of any age, but are most common
19–25 EV, keratoacanthoma on the backs of the hands and the fingers and on the knees of young ­children,
26–29 Common warts, flat warts where they appear as firm keratotic papules 1–10 mm across (Figs 18.3,
18.4).17 Koebnerization is common (hence kissing lesions on fingers).6
30 Laryngeal carcinoma, genital warts
31–32 Genital warts, bowenoid papulosis, cervical dysplasia,
cervical carcinoma
33 Cervical carcinoma
34 Bowenoid papulosis, Bowen's disease Fig. 18.3
35 Cervical dysplasia, cervical carcinoma Verruca vulgaris: there is
a raised, discrete scaly
36 EV plaque on the dorsal
37 EV, keratoacanthoma aspect of the hand. From
the collection of the
38 EV late N.P. Smith, MD, the
39 Bowenoid papulosis, cervical carcinoma Institute of Dermatology,
London, UK.
41 Flat warts
42 Genital warts, bowenoid papulosis, cervical dysplasia,
cervical carcinoma
43, 44 Genital warts, laryngeal papillomas
46, 47 EV
48 Bowenoid papulosis, Bowen's disease
49, 50 EV
51–54 Genital warts, bowenoid papulosis, cervical dysplasia,
cervical carcinoma
55 Genital warts, laryngeal papillomas

Reproduced with permission from Melton, J.L. and Rasmussen, J.E. (1991)
Dermatologic Clinics, 9, 219–233.

such as 6 and 11 have been found in common warts in children.14 HPV-16,

a common genital HPV type with oncogenic potential, was detected in 6.6%
of lesions in a recent series of 45 immunocompetent patients with nongenital
cutaneous warts.15 Conversely, verrucae vulgaris may sometimes occur on the
vulva. HPV type 2 has been detected in such cases. It is important to note that
these ‘nonvenereal’ genital lesions may occur in girls less than 5 years of age,
Fig. 18.4
Verruca vulgaris: verrucae are most commonly seen on the hands and fingers. From
the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

In other sites they may appear more filiform and less firm (Fig. 18.5). The
latter are particularly seen on the lips, nostrils, and eyelids.3 Giant periungual
lesions have been described.21 Warts may also present as a cutaneous horn.
They persist for a few months up to several years and often regress spontane-
ously, particularly in children.
Chronically immunosuppressed patients (e.g,. following renal trans-
plantation) often have a large number of warts (Fig. 18.6).22,23 Chronicity
is associated with increasing numbers of lesions. Epidermodysplasia
­verruciformis-like lesions due to HPV-5 have also been described in
­HIV-positive patients and following renal transplantation.24 Numerous
warts may be seen in other immunosuppressed patients (e.g., with
­lymphoma, leukemia, Hodgkin's lymphoma, and HIV infection).6,25–27 In
patients with AIDS, warts may regress following highly active ­antiretroviral
therapy (HAART).28
Fig. 18.5
Filiform wart: this variant
occurs most often on
the face and around the
axillae. From the collection
of the late N.P. Smith, MD,
the Institute of
Dermatology, London, UK.
Fig. 18.6
Verruca vulgaris: presentation with such large numbers of lesions raises the possibility
of immunosuppression. By courtesy of the Institute of Dermatology, London, UK.
Plantar warts 763
Pathogenesis and histological features
In situ hybridization studies of HPV lesions have shown that viral DNA syn-
thesis in the epidermis occurs in the superficial prickle cell layer and full virus
assembly with capsid production occurs in the granular cell layer.6 HPV DNA
has been demonstrated in apparently normal skin up to 15 mm from a virus-
associated lesion.29 The requirement for growth in very well-differentiated
epithelia may explain the difficulty of culturing HPV and why host destruc-
tion of the lesions may be protracted. Immune mechanisms are ­presumed to be
less effective against organisms or altered cells that are situated ­superficially
with no direct blood supply.
Regression of HPV lesions is usually spontaneous, but may not occur for
several years.30 Cell-mediated immunity seems to be important in effecting
the regression since lymphocytes are seen infiltrating the wart epithelium at
this stage. Other features of regression include liquefactive basal cell degen-
eration, epidermal degeneration, and vascular thrombosis.30,31 Recently, Toll-
like receptors (TLRs) have been identified as important role players in viral
recognition and the initiation of an antiviral host immune response. TLR3,
TLR9, IFN-β and TNF-α appear to play an important role in the skin's innate
immune response to HPV infection.32 Langerhans cells and Langerhans-
like dendritic cells may exert direct antiviral activity. This is facilitated via
the expression of TLRs such as TLR3, which may in turn trigger the release
of IFN-inducible chemokines, including CXCL9, a monokine induced by
IFN-γ.33
Following regression of the wart(s), an individual is usually immune to
further HPV infection. Patients with a deficiency in cell-mediated immunity –
whether primary or acquired, iatrogenic or virally induced (HIV/AIDS) – are
particularly susceptible to the development of warts, which tend not to invo-
lute spontaneously and can be a particularly refractory therapeutic problem.
Transmission of HPV is by inoculation of infected desquamated cells
through close contact at points of minor trauma; hence common warts are
seen most often on the hands. Periungual warts are particularly associated
with nail biting and plantar warts are especially related to prolonged immer-
sion in water.18
Common warts show filiform acanthosis with vertical tiers of parakerato-
sis over the tips of the exophytic component (Fig. 18.7). There is also marked
orthokeratosis. A downward extension of the acanthosis produces a curvi-
linear deep margin and curved distortion of the adjacent rete ridges in the
uninvolved epidermis. There is a prominent granular cell layer within which
are enlarged clumps of irregular basophilic keratohyalin (Fig. 18.8).3 These
are seen best in the concavities between the papillomatotic epithelial papil-
lae. Large cells with prominent vacuolated cytoplasm and a small pyknotic
nucleus are seen in the upper layers of the epidermis (koilocytes) (Fig. 18.9).
Koilocytes are, however, more frequently observed in genital warts (see
below). Connective tissue and tortuous small blood vessels may invade the fil-
iform projections (Fig. 18.10). In some cases, involvement of the s­uperficial
portion of the hair follicles by HPV results in focal changes identical to a
trichilemmoma or an inverted follicular keratosis.34 However, not all of these
lesions are induced by HPV as has been suggested.35
Ordinary common warts are only exceptionally associated with in situ
or invasive squamous cell carcinoma.36,37 HPV-16 has been associated with
periungual Bowen's disease and squamous carcinoma.38–40 The role of HPV
in cutaneous neoplasia is discussed further in Chapter 22. Recent molecular
studies have implicated cutaneous HPV infection as a carcinogenic cofactor in
association with solar ultraviolet radiation in the evolution of ­nonmelanoma
skin cancer.41
Plantar warts
Clinical features
Plantar warts occur on the sole of the foot; they are only slightly elevated
and appear as a horny plug surrounded by a ring of hyperkeratotic skin (Fig.
18.11). Often they are covered with black dots representing thrombosed
capillaries (Fig. 18.12).1 They are most common in children and are fre-
quently seen over pressure points. Most plantar warts are caused by HPV-1
and are painful; however, HPV-4 may produce a confluent or mosaic pattern
764 Infectious diseases of the skin

A B

Fig. 18.7
Verruca vulgaris: (A) note the hyperkeratosis and papillomatosis; (B) there is often marked parakeratosis typically arranged as a vertical tier. Koilocytes are conspicuous.

Fig. 18.8 Fig. 18.10

Verruca vulgaris: large vacuolated cells with enlarged and irregular keratohyalin Verruca vulgaris: the core of the papillary projection contains conspicuous dilated
granules are characteristic. capillary loops.

of ­similar small warts (‘mosaic plantar warts’) and these are painless (Fig.
18.13).2,3 They may also be seen on the palms and in the periungual region.
There have been reports from Japan of unusual plantar warts produced by
HPV-60.4–6
The lesions may be nodular, ridged or pigmented. A cystic variant has also
been described.4–10 The cystic variant has the features of an epidermoid cyst
and may rarely be multiple.11 Most are associated with HPV-60 but an asso-
ciation with HPV-57 has also been reported.12–14 Epidermoid cysts induced by
HPV may also be seen outside acral locations.15,16 Pigmented warts are caused
by HPV-4, 60 or 6517 and may contain fibrillar intracytoplasmic inclusion
bodies.18 A case of a large plantar wart caused by HPV-66 has been docu-
mented.19 A further subtype of HPV associated with palmoplantar warts is
HPV-63.8,20
Plantar warts usually regress within a few months in children, but may
persist longer in adults. Rarely, chronic plantar warts may be associated
with the development of verrucous carcinoma (carcinoma cuniculatum) (see
Ch. 22).21,22

Histological features
Fig. 18.9 Plantar warts are almost entirely endophytic, with a central parakeratotic plug
Verruca vulgaris: high-power view of koilocytes. surrounded by multiple deep extensions of acanthotic ­epidermis (Fig. 18.14).
 Plantar warts 765

Fig. 18.11 Fig. 18.13

Plantar wart: the lesion Mosaic warts: here there are a large number of small warts. They are particularly
is flat and shows very resistant to therapy. By courtesy of the Institute of Dermatology, London, UK.
marked hyperkeratosis.
By courtesy of
R.A. Marsden, MD,
St George's Hospital,
London, UK.

Fig. 18.14
Plantar wart: typical depressed, crateriform lesion containing a parakeratotic plug.

Fig. 18.12
Plantar wart: vascular thromboses as seen in these two lesions are common
manifestations of involution. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.

The depth and complexity of these downgrowths have been likened to an

anthill, giving rise to the term ‘myrmecia’. Vacuolation is more prominent in
the plantar wart and, in the active growing phase, large eosinophilic (and to
a lesser extent basophilic) cytoplasmic inclusions are present, which repre-
sent disordered growth of giant keratohyalin granules (Fig. 18.15). The large
eosinophilic cytoplasmic inclusions are usually seen in infections caused by
HPV-1 and to a lesser extent in those caused by HPV-60 and 65.7 In warts
induced by HPV-4, the infected keratinocytes show prominent cytoplasmic
vacuolar change with almost no keratohyalin granules. Intranuclear inclu-
sions may also be evident (Fig. 18.16). HPV can be demonstrated in the
nuclei of these cells by electron microscopy (Fig. 18.17). Melanin granules
are discernible within the cytoplasm of HPV-60-induced pigmented plantar Fig. 18.15
warts. Plantar wart: these eosinophilic keratohyalin granules are characteristic.
766 Infectious diseases of the skin
Fig. 18.16
Plantar wart: note the conspicuous intranuclear eosinophilic inclusions.
Fig. 18.17
Plantar wart: this honeycomb arrangement of HPV is characteristic. By courtesy of
I. Chrystie, FIMLS, St Thomas' Hospital, London, UK
Regressive changes are the same as those described in common warts
and consist of thrombosis of superficial blood vessels, necrosis, and a mixed
inflammatory cell infiltrate.23 A recently described multiplexed PCR-based
assay may have merit in both HPV genotyping and in monitoring treatment
efficacy.24
Plane warts
Clinical features
Plane warts (verrucae plana), usually caused by HPV-2, 3 or 10, are flat,
smooth, and a few millimeters in diameter with typically little change in color
from the adjacent skin, although they may appear gray-yellow or pale brown
(Fig. 18.18).1–3 HPV-5 is rarely implicated in HIV-infected patients.4 Plane
warts may also result from HPV types 26–29 and 41 infection.5 They affect
the face, backs of the hands, and the shins. There may be only a few present,
but occasionally they are very numerous and become confluent in areas of
scratching (koebnerization).6 Plane warts are common in children and may
be seen in women, but are not usually found in males after puberty except
in association with HIV infection. They may regress spontaneously after a
Fig. 18.18
Plane wart: note the typical flat, flesh-colored papules, which have extended in a
linear distribution due to scratching (Koebner phenomenon). By courtesy of
B Al-Mahmoud, MD, Qatar, Oman.
Fig. 18.19
Plane wart: there is hyperkeratosis and slight regular acanthosis; papillomatosis is
only mild. Note the prominent cytoplasmic vacuolation.
few weeks or months, or may persist for years. Signs of regression include
pruritus, an erythematous, edematous appearance, depigmented haloes, and
an eruption of multiple tiny plane warts.2,6,7 Cell-mediated immunity plays
a key role in the spontaneous regression of plane warts in immunocompe-
tent individuals.8 Multiple plane warts may evolve as a cutaneous manifesta-
tion of immune reconstitution inflammatory syndrome (IRIS) in HIV-infected
patients receiving highly active antiretroviral therapy.9 Exacerbation of lesions
has been reported following facial laser resurfacing.10
Histological features
Plane warts are acanthotic and show orthokeratosis with an open pattern remi-
niscent of ‘chicken wire’ (‘basket weave’ hyperkeratosis). Parakeratosis is not a
feature and there is little papillary configuration to the acanthosis (Fig. 18.19).
Keratinocytes of the upper part of the stratum spinosum show striking cytoplasmic
vacuolation with margination of the keratohyalin ­granules and tonofilaments.4
Regression is characterized by keratinocyte necrosis (­apoptosis), individual cell
keratinization, parakeratosis, lymphocytic ­exocytosis with ­spongiosis, and a
superficial perivascular chronic ­inflammatory cell ­infiltrate.2,11–13 The lympho-
cytes encountered in regressing lesions have been found to express the ­cytotoxic
granule granzyme-B.14 Extravasation of erythrocytes may be a feature and
edema of the papillary dermis is frequently present.15
 Condyloma acuminatum 767

Condyloma acuminatum
Clinical features
Condylomata acuminata are particularly caused by HPV types 2, 6, 11, 16,
18, 30–33, 35, 39, 41–45, 51–56, and 59 and develop as a consequence of the
trauma accompanying sexual intercourse.1–13 HPV-6 and 11 alone account
for more than 90% of these lesions, with HPV-6 present in about two-thirds
of cases and the remaining one-third caused by HPV-11.4,5 The incubation
period is variable (usually between 2 and 3 months).14 Condylomata acumi-
nata occur on the glans penis and prepuce or shaft as soft, fleshy, sometimes
filiform plaques and may extend into the meatus (Figs 18.20, 18.21). On
the shaft they are less exophytic. Vulval lesions may be bulky and macer-
ated, and may extend into the introitus (Fig. 18.22). Similar fleshy and fili-
form soft masses occur perianally, more often in males (Figs 18.23, 18.24).
Fig. 18.20
Condyloma acuminatum:
note the typical filiform
appearance. By courtesy
of the Department of
Genitourinary Medicine,
St Thomas' Hospital,
London, UK.
Anal squamous carcinoma has also been shown to contain HPV-6, 16, and
18 in a significant proportion of cases (Fig. 18.25).6 The rate of local recur-
rence is about 30%.15 The lesions are uncommon in children (when they
may be a sign of sexual abuse) and are seen most often in young adults
­(second and third decades), frequently in association with other genital
infections.4,9,16 Childhood condylomata regress spontaneously in more than
50% of cases.17
It is important to note that a significant proportion of genital HPV
infections are asymptomatic.3,18 The female partners of male patients with
condyloma acuminata have been shown to have an increased risk of cervi-
cal HPV infection and intraepithelial neoplasia (SIL/CIN).19 Cervical neo-
plasia associated with pre-existent condylomata acuminata has also been
related to a background of immunosuppression, at least in some patients.20
The worldwide HPV prevalence in cervical carcinomas is reported to be
99.7%.21 HPV-16, 18, 31–33, 35, 39, 42, and 51–54 are most commonly
associated with cancers of the cervix, vulva, and penis.7–9,22,23 According to
a recent study, patients with condylomata acuminata are at increased risk
for developing not only carcinomas of the vulva, vagina, penis, and anus,
but also certain nonanogenital squamous cell carcinomas.24 It is antici-
pated that routine vaccination with a quadrivalent vaccine against HPV
types 6, 11, 16, and 18 will lead to a significant reduction in the burden
of vulval and cervical carcinomas, genital warts, and genital intraepithelial
neoplasia.25
A large, exuberant, and locally destructive variant of condyloma (Buschke-
Löwenstein tumor) may rarely be encountered (Fig. 18.26).26,27 This is associ-
ated with HPV types 6, 11 or 16. It is likely that this giant variant represents
a variant of verrucous carcinoma but the issue has been controversial
(see Ch. 22).26–30 Juvenile laryngeal papillomas containing HPV-6 and 11 can
be seen in children born to mothers with condylomata acuminata.3 They may
show malignant progression if irradiated.
Malignant transformation of condyloma acuminatum is uncommon but
it is seen more often than in other lesions associated with HPV except for
­epidermodysplasia verruciformis.

Fig. 18.21 Fig. 18.22 Fig. 18.23

Condyloma acuminatum: there are multiple lesions
on the shaft of the penis and scrotum. By courtesy of
the Department of Genitourinary Medicine,
St Thomas' Hospital, London, UK.
Condyloma acuminatum: in this patient there is very
widespread involvement of the vulva and perineum.
This patient is likely to have cervical HPV infection.
By courtesy of R.A. Marsden, MD, St George's
Hospital London, UK.
Condyloma acuminatum: multiple perianal lesions are
present. By courtesy of N.C. Dlova, MD, Nelson R.
Mandela School of Medicine, University of KwaZulu-
Natal, South Africa.
768 Infectious diseases of the skin
Fig. 18.24
Condyloma acuminatum:
there is very extensive
involvement of the
perineum. From the
collection of the late N.P.
Smith, MD, the Institute of
Dermatology, London, UK.
A
Fig. 18.25
(A, B) Condyloma acuminatum: in addition to multiple condylomata, there was
histological evidence of in situ squamous cell carcinoma. By courtesy of P. Ngheim,
MD, Dana Farber Cancer Institute and Harvard Medical School, Boston, USA.
Fig. 18.26
Buschke-Löwenstein tumor: there is massive infiltration of the buttocks and
perineum with numerous sinuses. HPV type 6 was identified by DNA in situ
hybridization and Southern blot analysis. By courtesy of A. Grassegger, MD,
University of Innsbruk, Austria.
Histological features
Condylomata acuminata are characterized by marked acanthosis with a
solid or trabecular pattern and a broad rounded exophytic growth (Fig.
18.27). There is a sharp, fairly regular, deep margin. The surface of the
lesion is hyperkeratotic and parakeratotic. Superficial vacuolated keratino-
cytes (koilocytes) are characteristic (Fig. 18.28) and coarse keratohyaline
granules may be present. The vacuolated epithelium is often most marked
in the declivities. Condylomata that are treated with podophyllin prior to
removal demonstrate marked epidermal pallor and increased mitoses and
necrotic keratinocytes in the lower half of the epidermis.31 These changes
may lead to a misdiagnosis of malignancy. Giant condyloma acuminatum
(anogenital verrucous carcinoma, Buschke-Löwenstein tumor) occurs most
frequently on the genitalia, and is larger and more cauliflower-like.26–28 It
shows some tendency to endophytic growth, but without any suggestion
of frank infiltration. It can recur locally, but ­metastasizes very rarely. Most
experts regard this lesion as a variant of verrucous carcinoma. Anal condy-
lomata may develop bowenoid features, and ­occasionally invasive tumor
supervenes.6–8
Fig. 18.27
Condyloma acuminatum: note the keratotic acanthotic epidermis with rounded
lateral borders. Koilocytes are present in the declivities of the papillomatous
epithelium.
 Epidermodysplasia verruciformis 769

Histological features
A bowenoid papulosis lesion consists of a well-circumscribed area of acan-
thosis producing a raised plaque or dome, which is hyperkeratotic and
sometimes shows superficial epithelial vacuolation.20,21 The ­keratinocytes
may show nuclear hyperchromatism and pleomorphism. There is variable
dyskeratosis.
These histological features of atypia, associated with numerous mitoses,
including atypical forms, are similar to those of true Bowen's disease. The
distinction rests in the circumscribed elevated plaquelike pattern, the age of
the patient, and the size and multiplicity of lesions.

Epidermodysplasia verruciformis
Clinical features
Epidermodysplasia verruciformis (EV) is a rare inherited condition characterized
by selective susceptibility to skin infection with certain HPV types, defects in cell-
mediated immunity, and an increased risk for the development of cutaneous malig-
Fig. 18.28 nancies, especially squamous cell carcinomas.1,2 Affected individuals present with
Condyloma acuminatum: note the parakeratosis and vacuolation of the superficial a wide range of HPV subtypes including 3, 5, 8–10, 12, 14, 15, 17, 19–25, 28, 29,
keratinocytes. 36–38, 46, 47, 49, 50, 51, and 59.1,3–5 The more common flat warts, caused by

Bowenoid papulosis
Clinical features
Bowenoid papulosis (koilocytosis with intraepithelial neoplasia) is a clinico-
pathological entity that bears marked histological similarity to koilocytosis,
SIL/CIN, and Bowen's disease. Although the term is no longer used by The
International Society for Study of Vulval Disease (ISSVD), many clinicians
believe that it represents a distinctive clinicopathological entity and we have
decided to describe it in this chapter. Clinically, it is quite different from geni-
tal Bowen's disease in that multiple small papules develop over a short time
scale in young people. Prognosis is uncertain; many patients do not show evi-
dence of progression, but a small proportion may develop invasive tumor and,
on occasion, this may have metastatic potential. It is usually associated with
HPV-16 or 18, but occasionally HPV types 31–35, 39, 42, 49, and 51–54 are
detected.1–6 Although uncommon, some cases may be associated with mixed
infection by different HPV types.6,7 A unique HIV-associated case with geni-
Fig. 18.29
tal and extragenital (lip) lesions caused by two separate HPV types (HPV-16
Epidermodysplasia
and HPV-32, respectively) has been described.8 E6 and E7 viral oncoproteins verruciformis: (A)
of high-risk HPV types induce overexpression of p16 and human telomerase innumerable small flat
reverse transcriptase.9 warts are present; (B)
Bowenoid papulosis most often presents as multiple reddish-brown, some- the dorsum of the hand
times lichenoid, discrete papules, but occasionally these become a conflu- is a commonly affected
ent plaque. Papules, on average 4 mm in diameter, are found on the penis, site. By courtesy of the
vulva, perianal region, and perineum. Extragenital sites of occurrence include A Institute of Dermatology,
the face, neck, and fingers.10–12 An isolated case of oral bowenoid papulosis London, UK.
in an HIV-infected male has been reported.13 Bowenoid papulosis manifests
in young, sexually active adults in contrast to true Bowen's disease, which
occurs in an older age group. Genital Bowen's disease is, however, also often
associated with HPV-16.14 The occurrence in childhood should raise suspi-
cion of sexual abuse.3 Genital bowenoid papulosis has been associated with
periungual bowenoid dysplasia.15
Spontaneous regression is uncommon.16 As progression to frank inva-
sive carcinoma in bowenoid papulosis is rare, these lesions are best managed
­conservatively. However, bowenoid papulosis may be resistant to treat-
ment and may be characterized by a prolonged course in immunosuppressed
patients.2 Bowenoid papulosis has also been associated with oral warts and
lingual carcinoma.4 It has recently been shown that patients with bowenoid
papulosis and HPV infection may be primarily immunosuppressed due to
diminished T-helper cell levels (non-HIV-associated).2,14 The condition may
also occur in organ transplant recipients.17 Penile bowenoid papulosis is
associated with a high risk of the ­consort developing cervical dysplasia.18,19
Consequently, female patients and consorts should regularly have cervical B
smears.
770 Infectious diseases of the skin

Fig. 18.30 Fig. 18.32

Epidermodysplasia verruciformis: these plane warts are due to HPV-3 and HPV-10 Epidermodysplasia verruciformis: these scaly macules on the chest and axilla
infection. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK. resemble pityriasis versicolor.

lupus erythematosus, Hodgkin's lymphoma, and HIV infection and in rare

patients following renal transplantation or peripheral blood stem cell trans-
plantation.13–17 An EV-like eruption has been documented in association with
idiopathic CD4 lymphopenia and even with CD8 lymphopenia.18,19
EV therefore represents an unusual condition in which HPV infection,
inherited predisposition (possibly a defect in cell-mediated immunity), and
exposure to the sun all play a role (co-carcinogens).1,2,11

Pathogenesis and histological features

Fig. 18.31
Epidermodysplasia verruciformis: note the numerous flat warts on the dorsum
of the hand. From the collection of the late N.P. Smith, MD, the Institute of
Dermatology, London, UK.
The pathogenesis of epidermodysplasia verruciformis is not yet fully under-
stood. The EV-related HPV may be present in the general population, but the
characteristic lesions only occur in predisposed individuals (Fig. 18.33).1,11 It
has recently been established that invalidating mutations in either of two adja-
cent novel genes termed EVER1 and EVER2 are responsible for most cases
of EV.20 This susceptibility locus for EV has been mapped to the long arm of
chromosome 17 (17q25).20,21 The EVER1 and EVER2 transmembrane proteins
encoded by these genes are located in the endoplasmic reticulum.22 One group
of investigators has shown that the proteins form a complex that interacts with
zinc transporter 1 (ZnT-1), resulting in altered intracellular zinc ­distribution in
keratinocytes.23 It has been proposed that EVER proteins in keratinocytes may
serve as restriction factors for EV-specific HPV types.22 There have, however,
been reports of cases lacking EVER1 and EVER2 mutations.24,25

HPV-3 and HPV-10, may also occur in these patients but have an extensive distri-
bution pattern; they may form plaques and can be persistent.6 These are seen most
often on the arms, legs, face, and the dorsum of the hands (Figs 18.29–18.31).4
The specific EV ­subtypes of HPV cause reddish, or pigmented or depigmented,
scaly flat macular plane warts, mainly on the trunk, but also on the face, neck, and
arms.2 Clinically they resemble pityriasis versicolor (Fig. 18.32). Some patients,
especially those who are dark-skinned, may present with seborrheic keratosis-like
changes.7,8 Spiny hyperkeratosis of the fingers is a rare manifestation.9
Susceptibility to EV is usually inherited in an autosomal recessive manner
although X-linked recessive inheritance has been reported in one family.10 The
lesions persist throughout life, and after some years (usually more than 20) they
may show nuclear atypia resembling Bowen's disease, and frank carcinoma
sometimes develops. Basal cell carcinoma can also occur.11 The tumors develop
particularly on sun-exposed skin and are most often associated with HPV-5 or
8.4,12 Patients who develop invasive squamous carcinoma in association with
EV do so at a younger age than those who develop this tumor not in association
with EV (27 years compared with 67 years in one study).1,12 Such tumors, which
are often multiple, are usually associated with a good prognosis unless they are
treated with radiotherapy when they may be associated with ­metastatic dis- Fig. 18.33
ease, which has a high mortality.3 EV-like disease has been reported in patients Epidermodysplasia verruciformis: electron micrograph showing the characteristic
with a background of immunosuppression in such conditions as systemic lattice structure.

There appears to be a specific abnormal T-cell response to HPV-infected
keratinocytes. The immune defect most often associated is a reduction in the
number and function of T-helper cells, but patients with EV do not show general
immunodeficiency or susceptibility to other infections. There have nevertheless
been rare reports of EV in association with common ­variable immunodefi-
ciency syndrome.26 EV is not usually seen in patients with ­iatrogenic immuno-
suppression. Humoral immunity is characteristically normal, although a case
with isolated IgM deficiency has been documented.27 EV has been described in
association with severe immunodeficiency, lymphoma, and disseminated mol-
luscum contagiosum infection.28 EV has also been reported in a patient with
malignant thymoma.29 EV-associated HPVs have been detected in the amniotic
fluid, placenta, and cervical scrapes of a pregnant patient with EV, thereby sug-
gesting that vertical transmission of EV HPVs may play a role.30
Histologically, EV is characterized by hyperkeratosis, hypergranulosis,
and acanthosis (Figs 18.34, 18.35). The keratinocytes are vacuolated and
show a striking blue-gray pallor on staining with hematoxylin and eosin.
They are arranged in clusters or columns, the pallor being most conspicuous
in the superficial granular cell layer. Identical focal changes may be occasion-
ally seen in samples removed for other reasons in patients without the disease.
As the lesions progress to atypicality, the nuclei of the keratinocytes become
larger and hyperchromatic, and cellular maturation is more disorderly.3,31 The
dysplastic changes may also affect appendigeal epithelium, particularly that
of sweat ducts. The atypia eventually amounts to carcinoma in situ and in
30–50% of patients the lesions progress to ­invasive carcinoma. Cutaneous
neoplasia in EV is largely associated with HPV-5 and 8. The E6 oncoprotein of
HPV-5 inhibits transa­ctivation of SMAD3, which is an important ­component
A
B A first-episode infection – i.e., in someone who is seronegative (first-episode
Fig. 18.34
Epidermodysplasia verruciformis: (A) there is hyperkeratosis and acanthosis;
(B) note the characteristic, swollen, paler-staining cells showing nuclear vacuolation.
Herpes simplex virus infections 771
Fig. 18.35
Epidermodysplasia verruciformis: the superficial keratinocytes are swollen and have
basophilic cytoplasm.
of the TGF-β1 signaling pathway.32 Most ­carcinomas are squamous in type,
but some show features reminiscent of sweat gland differentiation. The sweat
ducts may show markedly disordered growth and atypia. These stages in the
progression to frank carcinoma only occur on sun-exposed skin. In contrast
to cervical cancer where the viral genome is integrated into the host DNA, in
EV it remains extrachromosomal (episomal). Ultraviolet-B radiation has been
shown to modulate the noncoding region promotor activity of HPV-5 and 8
in infected keratinocytes.33
Differential diagnosis
Swollen keratinocytes, as described above as a diagnostic feature of EV, have
been recorded as a manifestation of immunosuppression, particularly HIV
infection.34 Focal histological features of EV have rarely been documented
as an incidental finding in a variety of benign skin lesions in the absence
of ­clinical evidence of underlying EV, including an intradermal nevus, a
pigmented seborrheic keratosis, and an acantholytic acanthoma. The term
‘EV acanthoma’ has been proposed for these isolated, incidental cutaneous
lesions.35
Herpes simplex virus infections
Herpes simplex virus (HSV) has two subtypes: HSV-1 and HSV-2.1 There is
considerable homology between the two genomes, about 50% of sequences
being highly conserved.2 Humans are the natural hosts for HSV-1 and
HSV-2 and therefore also represent the viral reservoir.3 Herpes viruses are
­double-stranded DNA viruses with a complex capsid and glycoprotein
­envelope (Fig. 18.36).
Clinical features
HSV-1 usually causes herpes labialis (90%), whereas HSV-2 most often causes
herpes genitalis. Although HSV-2 previously accounted for approximately
90% of herpes genitalis cases, more recent epidemiological evidence reflects
an increase in the proportion of cases attributable to HSV-1 (22–29%) and a
diminished number of HSV-2 positive cases (68–71%).4,5 In some European
cohort studies, HSV-1 infection has been a more common cause of genital
herpes than HSV-2 infection. This trend may be attributable to the practice of
oral sex.4 Both HSV-1 and HSV-2 are transmitted through mucosal surfaces
or traumatized skin by exposure to contaminated secretions.3,6–8
primary infection) or who has serum antibodies to the heterologous HSV type
(first-episode, nonprimary infection) – may be associated with ­constitutional
symptoms of fever and malaise.9,10 These symptoms are often worse in women
with genital herpes, perhaps because of the wider area of ­epithelium involved
772 Infectious diseases of the skin

Fig. 18.36
Herpes virus: all members
of the herpes virus
group have identical
ultrastructural morphology.
Note the outer membrane
surrounding the virus
core. The herpes virus
is an icosahedron with
162 capsomeres on its
surface. By courtesy of
I. Chrystie, FIMLS, St
Thomas' Hospital, London, Fig. 18.38
UK. Herpes simplex: this patient shows a particularly severe infection. By courtesy of
the Institute of Dermatology, London, UK.

and the greater viral load. The lesions may be found in the mouth, pharynx,
lips, penis, vulva, vagina, or cervix (Figs 18.37–18.41). HSV infections are
also being seen more frequently in perianal and anorectal sites. Involvement
of a finger in the form of a herpetic whitlow is most often seen in healthcare
workers, especially dental practitioners (Fig. 18.42).11 Primary HSV-1 infec-
tion, however, is asymptomatic in about 90% of patients, and primary HSV-2
in about 75%.12 It is important to remember that infection is for life. Herpes
compunctorum is a rare form of HSV infection acquired as a result of tattoo-
ing.13 HSV may also be transmitted during close contact sports such as wres-
tling and rugby (herpes gladiatorum).14
At the original inoculation site there is no detectable change for 3–5
days. The lesions that develop vary with site, but all are associated with the
development of small grouped vesicles, often on an erythematous base. On
mucosal surfaces the vesicles rupture early and are superseded by grayish-
yellow plaques or ulcers. In skin, grouped vesicles are seen on an erythema-
tous base and then evolve into grouped pustules, which rupture and result
in a crusted ulcer.15,16 The lesions are typically painful and sting or itch. The
distribution of the lesions is characteristically wider than the initial site of
inoculation, involving the area of innervation by the sensory nerve to that
site. Occasionally, a separate area of lesions may develop away from the ini-
tial inoculation site, after transmission along a different branch of the same
Fig. 18.39
Herpes simplex 2: vulval
involvement showing
erythema and crusted
vesicles. By courtesy of
R.A. Marsden, St George's
Hospital, London, UK.

Fig. 18.37
Herpes simplex 1: primary infection showing grouped vesicles on an erythematous
base. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
nerve. These initial cutaneous lesions only develop after involvement of the
nerve and the ganglion and subsequent return of the virus to the epithelium.3
The lesions may then extend peripherally to involve adjacent skin or mucosa.
This first episode of infection lasts for around 15 days. The epithelial lesions
then resolve completely, but the virus persists, becoming latent within the
ganglia of the corresponding sensory nerve.17
Recurrent HSV lesions are usually less florid than the first infection and
are not usually associated with general symptoms. They may be precipitated
by sunlight, fever, menstruation, pregnancy, HIV infection, emotional stress
or local trauma.12 The incidence of recurrent orofacial herpes varies from
16% to 45%, while that of recurrent genital herpetic infection varies from
about 50% to 65% of patients.3 Repeated recurrence is usual with genital
HSV-2 and common with orofacial HSV-1, but with gradually decreasing
­frequency. ‘Reinfection’ with the heterologous type resembles a less severe
first-episode primary infection.

Fig. 18.40
Herpes simplex 2: in this patient there is very severe ulceration. By courtesy of J.C.
Pascual, MD, Alicante, Spain.
Fig. 18.41
Herpes simplex 2: there is intense erythema and multiple ulcers are present on both
the glans and the shaft. By courtesy of C. Furlonge, MD, Port of Spain, Trinidad.
Fig. 18.42
Herpetic whitlow: intact vesicles may be seen on the proximal phalanx. The medical
and dental professions are at particular risk from this mode of spread. By courtesy
of R.A. Marsden, MD, St George's Hospital, London, UK.
Herpes simplex virus infections 773
Fig. 18.43
Eczema herpeticum: this
variant usually presents
in atopic children.
By courtesy of J.C. Salas,
MD, Azteca, Monterrey,
Mexico.
Antibodies to HSV-1 are found in about 70–90% of adults, suggesting
very wide contact with the virus, with a subclinical infection or an unrecog-
nized oropharyngitis in childhood.8 Worldwide, an estimated 16% of people
aged 15–49 years are infected with HSV-2.18 The seroprevalence of HSV-2
infection varies geographically.18,19 The seroprevalence in Asian countries
ranges from 10% to 30%, whereas more than 80% of female commer-
cial sex workers in parts of sub-Saharan Africa are infected.20 The United
States saw a 30% rise in the prevalence of HSV-2 infection between the
late 1970s and the early 1990s.18 Although HSV-1 occurs most commonly
above the waist and HSV-2 below, these are preferential rather than obliga-
tory sites. It has been noted that 10–15% of first-episode genital herpes
is associated with pharyngeal lesions, emphasizing not only the frequency
of ­orogenital contact, but that both viruses can affect either orofacial or
­genital epithelia.
Occasionally, a first-episode primary infection in an atopic patient may
result in extensive vesicular crops, so-called Kaposi's varicelliform erup-
tion (eczema herpeticum) (Figs 18.43, 18.44).21 These lesions pustulate,
ulcerate, and crust, as in the usual herpetic infection, but involve more or
less the whole skin surface. Systemic symptoms may be severe, with fever
and dehydration. The condition may occasionally prove fatal. Recurrent
attacks may occur, but they are usually short and less severe. This man-
ifestation of herpetic infection may also complicate Darier's disease,
Hailey-Hailey disease, Grover's disease, pemphigus foliaceus, and other
bullous dermatoses.22 Historically, a similar clinical picture was occasion-
ally caused by vaccinia virus (eczema vaccinatum) as a complication of
vaccination against smallpox. Histologically, the lesions of Kaposi's vari-
celliform eruption are the same as those of the more localized form of
herpetic infection. Disseminated disease may be seen in the immunosup-
pressed (Fig. 18.45).
HSV infection in pregnancy may be associated with both severe maternal
illness and fetal involvement via transplacental spread.20,23 Congenital infec-
tion is rare, but neonatal herpes simplex infection is seen in 10% of babies
born to women with an active herpetic lesion after the thirty-second week
of pregnancy.20,24 Congenital HSV infection forms part of the TORCH com-
plex.25 Lesions in congenital herpes infection can be extensively bullous, with
severe erythroderma and loss of body fluid through exudation. The reported
mortality rate in infants with disseminated infection is approximately 57%.26
Neonatal infection usually presents as a relatively mild oropharyngitis and
many are probably undiagnosed.
774 Infectious diseases of the skin

The most characteristic feature in the pathogenesis of herpetic infections

is the early involvement of sensory nerves within which the virus, without its
lipid/glycoprotein envelope, is transported to the ganglia.30 Further replica-
tion (associated with cell lysis) occurs within the ganglia and the complete
virus then migrates to the skin around the site of inoculation via the periph-
eral sensory nerves. This process of viral migration also occurs at times of
recurrence. The state of the virus during the latent periods, which may last
for many months or years, is not clear. It may continue as a more or less
intact virus, but in virtually suspended animation without cell death, or it
may ­persist as episomes or be incorporated into the cell genome. Immune
mechanisms are responsible for both latency and reactivation of the virus.30
Although immune defects (particularly of cell-mediated immunity and
including HIV infection) are associated with a high incidence of severe and
extensive herpetic infections, a state of raised immunity (either humoral
or cellular) does not preclude recurrent lesions; indeed, recurrent lesions
are usually associated with very high titers of IgG antibody. It is thought
that humoral immunity may impede neuronal extension and reduce the
likelihood of encephalitis, but cell-mediated immunity is effective in lim-
iting the local cutaneous extension of the lesions and accelerates healing.
Fig. 18.44 Low levels of interferon-gamma (IFN-γ) may contribute to reactivation of
Eczema herpeticum: this infections.31
can be a very serious Histologically, the early change of HSV infection is increasing edema of
condition and affect the
the keratinocytes, which progresses to so-called ballooning degeneration.32
whole body. By courtesy
Some adjacent keratinocytes fuse so that they appear large and multinu­
of R.A. Marsden, MD,
St George's Hospital, cleate. A number of cells show acantholysis, while others rupture as a result
London, UK. of extreme balloon degeneration (reticular degeneration). The result of
­acantholysis and balloon degeneration is an irregular intraepidermal ­vesicle
­containing groups of keratinocytes, many of which may be multinucleate
(Figs 18.46–18.50). The nuclei of keratinocytes may contain basophilic
and/or pale ground-glass inclusions. As a vesicle expands it involves the
full thickness of the epidermis and may not be so clearly intraepidermal.
HSV infection of the hair follicle epithelium can result in herpes folliculitis.33
Involvement of hair follicles is, in fact, very common in most infections.
In cases with very prominent superficial secondary changes, the distinctive
findings of the infection are sometimes only evident in the infundibular por-
tion of the hair follicle.
The underlying dermis is usually intensely infiltrated by mixed inflammatory
cells. The infiltrate shows perineural ­accentuation and occasionally a super-
ficial leukocytoclastic vasculitis is present (Fig. 18.51).32 Dermal nerve twigs
may exhibit a perineural inflammatory ­infiltrate ­composed of lymphocytes
and neutrophils, sometimes associated with ­intraneural involvement. Schwann
cell hypertrophy and frank neuronal necrosis are occasionally encountered.34
Infection is sometimes associated with a ­prominent lymphoid infiltrate with
frequent CD30-positive cells resulting in a pseudolymphoma.35

Fig. 18.45
Disseminated herpes infection: widespread lesions may be seen in immuno­
suppressed patients. By courtesy of the Institute of Dermatology, London, UK.

Pathogenesis and histological features

The double-stranded DNA of herpes virus is enclosed in an icosahedral ­protein
shell (capsid) which in turn is invested by a complex envelope of lipid and gly-
coproteins. The latter are important in the attachment and penetration of cells.
The complete virus measures about 150–1200 nm in diameter.12 Viral replica-
tion occurs within the nucleus where a basophilic Feulgen-positive inclusion
body, including viral DNA, may be found as well as an eosinophilic inclusion
body, which represents a focal deficiency of viral DNA, a so-called ‘scar’ of
viral infection.2 Heparan sulfate moieties act as receptors to which HSV-1
and HSV-2 bind.27,28 HSV-1 encodes a complement-interacting glycoprotein
(gC) and an IgG Fc binding glycoprotein (gE). These glycoproteins mediate
immune evasion.29 Glycoproteins C and D (gC and gD) play an important
role in the attachment of HSV-1 to host cell surface ­heparan ­sulfate receptors, Fig. 18.46
whereas glycoprotein B (gB) is responsible for HSV-2 ­cellular attachment, Herpes simplex: intraepidermal vesicle in which there is intracellular edema
entry, and cell-to-cell spread.27,28 (ballooning degeneration) and acantholysis.
 Herpes simplex virus infections 775

Fig. 18.47
Herpes simplex: scanning view of intact intraepidermal blister.

Fig. 18.50
Herpes simplex: high-
power view of blister.

The features of an ulcerated herpetic lesion are not diagnostic unless the
epithelial margins retain the characteristic features of intracellular edema,
multinucleate epithelial cells, and inclusion bodies. Careful scrutiny of the
surface exudate may nevertheless reveal isolated degenerate epithelial cells
whose nuclei contain ghost outlines of herpetic viral inclusions. This should
prompt examination of the adjacent intact epidermis for more characteristic
features of HSV infection.36 The viable multinucleate cells are the diagnos-
tic feature of the Tzanck test, a Giemsa-stained smear of vesicle contents.
Biopsies of anogenital HSV-related ulcers in HIV-infected patients may show
evidence of concomitant cytomegalovirus infection.36,37 In the past, labora-
tory diagnosis of herpes infection was confirmed by growth in tissue cul-
ture, electron microscopy, immunofluorescent demonstration of viral-specific
protein or viral DNA hybridization.38 Nowadays, the diagnosis of HSV-1 or
Fig. 18.48 HSV-2 infection can also be confirmed by PCR or immunohistochemistry
Herpes simplex: the roof shows acantholysis and scattered characteristic (Fig. 18.52).39
intranuclear inclusions.

A B

Fig. 18.49
(A, B) Herpes simplex: note the numerous multinucleate giant cells and conspicuous pale-staining inclusions (B).
776 Infectious diseases of the skin
Fig. 18.51
Herpes simplex: multiple vessels show intense fibrinoid necrosis.
Fig. 18.52
Herpes simplex: positive immunohistochemistry.
Varicella and herpes zoster
Clinical features
Varicella-zoster virus (VZV), also referred to as herpes varicella virus, is
­similar morphologically to herpes simplex virus (HSV), and is the causative
agent of varicella and zoster.1–3
Varicella, or chickenpox, which is highly contagious, is most often an
infection of children and is characterized by a disseminated vesicular erup-
tion in crops. The major route of dissemination is by airborne droplets from
the respiratory tract.4,5 In the immunocompetent, spread via the cutaneous
lesions seems to be of little importance. Varicella is endemic in the temperate
climates and manifests predominantly in winter and spring.4,5
The incubation period is around 2 weeks and is followed by a rash, which is
most pronounced on the trunk. The rash starts as red macules 2–4 mm across,
which progress rapidly to fragile vesicles said to resemble ‘dew drops on rose
petals’; these become pustular and rapidly show crusting (Fig. 18.53). Lesions in
varying stages are present at any one time. There is often considerable pruritus and
the associated scratching may result in secondary infection with Staphylococcus
aureus or Streptococcus pyogenes.5 Mucosal lesions are frequently also present.
Systemic effects in children are mild whereas they are almost invariably severe
in adults, neonates, and immunocompromised patients.
Fig. 18.53
Varicella (chickenpox):
(A) note the widespread
distribution of vesicles
on the face, upper
chest, arms, and legs;
(B) close-up view. (A) By
courtesy of R.A. Marsden,
MD, St George's Hospital,
London, UK; (B) by
A courtesy of the Institute of
Dermatology, London, UK.
B
Complications include pneumonitis, meningitis, encephalitis, myelitis, and
purpura fulminans. In the last, symmetrical hemorrhagic and necrotic lesions
are seen on the legs following typical chickenpox, and the condition is asso-
ciated with disseminated intravascular coagulation. Acquired deficiencies in
protein S or protein C has been implicated in the pathogenesis of varicella-
associated purpura fulminans.6,7 Less common complications include orchitis,
hepatitis, glomerulonephritis, arthritis, myocarditis, and rhabdomyolysis.4,8,9
Necrotizing fasciitis is a potentially life-threatening complication of child-
hood varicella.10
Varicella occurring in pregnancy may have serious consequences for
both mother and fetus.11 Varicella pneumonia may lead to maternal death.
Congenital varicella syndrome occurs in approximately 2% of neonates
born to mothers who acquire chickenpox during the first two trimesters.
Manifestations of this syndrome include dermatomal cutaneous lesions, ocu-
lar involvement, neurological complications, and skeletal abnormalities.5,11
Generalized neonatal varicella, which carries a mortality of around 20% if
untreated, is the result of a maternal varicella rash appearing in a mother
without antibodies between the last 4 or 5 days of pregnancy and the first
2 days following delivery of the baby.5,11
 Varicella and herpes zoster 777

A B

Fig. 18.54
(A, B) Herpes zoster (shingles): intact vesicles in a characteristic dermatomal distribution. From the collection of the late N.P. Smith, MD, the Institute of Dermatology,
London, UK.

Herpes zoster, or shingles, occurs particularly in adults, usually the

elderly, and most often presents as a girdle-like vesicular eruption in the tho-
racic or lumbar region, or with facial lesions as a result of trigeminal nerve
­involvement (Figs 18.54, 18.55).3,4,12 It is analogous to a recurrent episode
of herpes simplex where the virus remains latent in the ganglia of sensory
nerves. It is, however, worth noting that although rare, coinfection with VZV
and HSV has been reported.13 Herpes zoster is thought to develop as a con-
sequence of partial immunity.4 The eruption is preceded by paresthesia or
pain in the dermatome supplied by a sensory nerve. This is followed, usually
after 2–4 days, by the development of an edematous erythematous plaque
on which groups of vesicles arise. As in chickenpox, these rapidly become
pustules, which may coalesce to form bullae, occasionally hemorrhagic
(Fig. 18.56). The areas become crusted and this may very occasionally be
­followed by scarring and keloid formation. The lesions are usually painful and
this may persist for months or years as postherpetic neuralgia. Involvement of

Fig. 18.56
Herpes zoster (shingles): older lesion in which the rash has a hemorrhagic
component. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

the ophthalmic division of the trigeminal nerve (herpes zoster ophthalmicus)

Fig. 18.55
Herpes zoster (shingles):
there is intense erythema,
intact vesicles, and crusted
lesions. By courtesy
of R.A. Marsden, MD,
St George's Hospital,
London, UK.
is an important manifestation in the elderly, which can have serious compli-
cations (Fig. 18.57).12 Involvement of the mucocutaneous division of the sev-
enth cranial nerve or the eighth cranial nerve leads to Ramsay Hunt syndrome,
which is characterized by lesions in the auricular canal, facial paralysis, and
auditory and vestibular symptoms.12 Rarely, noncontiguous multidermato-
mal cutaneous involvement (zoster multiplex) may occur.14 Although uncom-
mon, herpes zoster may occur in children who have received varicella vaccine,
a live attenuated virus. Cervical and sacral dermatomes are most commonly
affected in these children and potential complications include secondary bac-
terial infection, scarring, and depigmentation.15
Reactivation of latent VZV may be associated with a deficiency in cell-
mediated immunity, as immunity to chickenpox per se is normally lifelong.
Patients with Hodgkin's lymphoma, non-Hodgkin's lymphoma or systemic
lupus erythematosus, and those treated with irradiation or chemotherapy, are
particularly at risk and often develop a more serious illness.4,5 In more severe
cell-mediated immunodeficiency the zoster may become widely disseminated
and sometimes proves fatal. Disseminated cutaneous lesions most often
present as vesicles, pustules, hemorrhagic bullae, ulcers, and black eschars
although occasionally patients may develop verrucous, hyperkeratotic lesions
(Fig. 18.58).16 Visceral involvement is most often seen in the lung, liver, and
778 Infectious diseases of the skin

Herpes zoster is a well-recognized cutaneous manifestation of the immune

­reconstitution inflammatory syndrome occurring in HIV-infected patients
(including c­ hildren) receiving highly active antiretroviral therapy.22,23

Pathogenesis and histological features

Although inhalation of viral particles is the usual route of infection, direct
cutaneous inoculation may occur. Initial contact is followed by viremia
before the cutaneous lesions develop. During the viremic stage VZV is trans-
ported to the skin by T cells. Cell-free viral replication takes place in the
skin and facilitates person-to-person spread. Even when the resolution of
the lesions is clinically complete, the virus may remain latent in the ganglia
of sensory nerves.24 IgG, IgM, and IgA antibodies develop soon after the
vesicles; some IgG antibody is detectable thereafter throughout life, but the
other antibodies disappear. It has been noted that cell-mediated immunity is
depressed during an episode of chickenpox and for at least the first few days
of zoster.
VZV has the ability to interfere with the expression of major histocom-
patibility complex (MHC) class I and class II proteins required for CD4 and
CD8 T-cell recognition, leading to delayed clearance of virus-infected cells.25
Fig. 18.57 VZV glycoprotein E (gE) is essential for viral replication and also plays a
Herpes zoster (shingles): role in spread of the virus from cell to cell, secondary envelopment, and viral
ophthalmic involvement entry.26,27 Open reading frame 66 (ORF66) of VZV encodes a protein kinase
is particularly seen in
which modulates apoptosis and interferon pathways, down-regulates MHC
the elderly. By courtesy
class I protein expression on cell surfaces, and facilitates tropism of VZV
of R.A. Marsden, MD,
St George's Hospital, for T cells.28 These are just some of many aspects of the complex pathogen-
London, UK. esis and immunobiology of VZV infection.3,25,29,30 A more detailed account
is beyond the remit of this text, and the reader is thus referred to reference
numbers 3, 25, 29, and 30.
Histologically, the cutaneous lesions of VZV, whether in varicella or zoster
form, are generally indistinguishable from those of herpes simplex although it
has been suggested that inflammation is more profound in the latter. Follicular
epithelial involvement may also serve as a further point of distinction (see
below).31 The intraepidermal blisters associated with intracellular edema and
multinucleate epithelial cells with inclusion bodies are characteristic. The der-
mal infiltrate and fibrinopurulent exudate are seen regularly, but are not diag-
nostic. There is often more intraepidermal and dermal hemorrhage than in
herpes simplex infection.
The wart-like cutaneous lesions encountered in patients with AIDS show
hyperkeratosis, verruciform acanthosis, and virally induced cytopathic alter-
ations, often with minimal or absent cytolysis of the infected epidermal
keratinocytes, and little by way of a dermal inflammatory infiltrate.17,19,20
Immunosuppressed individuals with VZV infection may have a protracted
clinical course during which biopsies reveal a lichenoid inflammatory reac-
tion pattern rather than cytolysis of keratinocytes.32
Biopsies from early herpes zoster lesions may exhibit VZV-infected cells
Fig. 18.58
Herpes zoster:
in the hair follicles, suggesting that VZV spreads from dorsal root ganglia
disseminated lesions or trigeminal ganglia to an area of skin innervated by myelinated nerves, the
may be seen in latter terminating at the level of the follicular isthmus.31,33 Exclusive involve-
immunosuppressed ment of folliculosebaceous units in this manner may predate the evolution
patients. By courtesy of of more characteristic vesicular lesions, and serves as a point of distinction
N.C. Dlova, MD, Nelson R. from recurrent herpes simplex. In the latter, there is axonal transport of
Mandela School of the virus from sensory ganglia to the skin via terminal nonmyelinated nerve
Medicine, University of twigs.31 Very rarely, VZV infection may manifest with dermal vasculitis in
KwaZulu-Natal, South the absence of associated epidermal involvement.34 Another rare occurrence
Africa.
is exclusive involvement of epithelium of the eccrine apparatus (herpetic
syringitis), manifesting with isolated nodular skin lesions in the absence of
epidermal viropathic changes.35 A number of cutaneous reactions have been
brain.4 Cerebral disease most often presents as progressive leukoencephalitis. described at the sites of healed herpes zoster scars. These include pseudo-
A nonimmune individual may contract chickenpox from a person with herpes lymphomatous cutaneous lymphoid hyperplasia, granulomatous vasculitis,
zoster. Herpes zoster occurs in as many as 40–50% of patients in the first year granulomatous folliculitis, granuloma annulare, lichen planus, reactive per-
following bone marrow transplantation, but the lesions increasingly resemble forating collagenosis, lichen sclerosus, and cutaneous Rosai-Dorfman dis-
varicella as the time after transplantation increases. This suggests that T cells ease.36,37 Active lesions may also harbor a pseudolymphomatous dermal
specific for VZV are less well represented as time goes by. lymphoid infiltrate.38
VZV infection in patients with AIDS may present with unusual mani- As with HSV, the presence of multinucleate cells is valuable in the Tzanck
festations, including verrucous skin lesions resembling viral warts and dis- test. In shingles, the spinal ganglia may show necrosis with inflammation, and
seminated varicella in the absence of skin lesions.17–20 Verrucous VZV intranuclear inclusions are sometimes evident.39 Otherwise, diagnosis is usu-
infection, however, has also been reported in a renal transplant recipient.21 ally based on clinical criteria, but can be confirmed by electron microscopy,

Fig. 18.59
Herpes zoster: positive immunohistochemistry.
immunofluorescence of blister contents, growth in tissue culture, PCR, in situ
hybridization or immunohistochemistry (Fig. 18.59).5,20,40 Serological tests
are less useful than rapid antigen-detection methods and are only of value
later, when a rising titer can be demonstrated.5
Cytomegalovirus infections
Clinical features
Antibody studies suggest that most people have been exposed to cytomega-
lovirus (CMV).1 Generally, an asymptomatic infection ensues. CMV infec-
tion, however, may result in clinical features under a variety of circumstances.
These include neonatal lesions, an infectious mononucleosis-like disease in
adults, or a manifestation of disseminated disease in immunocompromised
patients.2,3 A recent in-depth review of the literature revealed that severe
­visceral CMV infection in apparently immunocompetent individuals might
not be as uncommon as previously considered.4 Clinical lesions in the skin,
however, are distinctly uncommon.
CMV is the most frequently transmitted viral infection in utero.5,6 The
incidence of reported infection ranges from 0.2% to 2.2% of live births.7,8
Less than 10% of affected infants and neonates will actually develop clini-
cal lesions.5,9 Clinical manifestations have been grouped with other neonatal
infections under the rubric ‘TORCH syndrome’ which includes toxoplas-
mosis, other infections (e.g., syphilis), rubella, cytomegalovirus, and herpes
simplex.10
Affected newborn babies and neonates may develop a wide range of lesions
including jaundice, hepatosplenomegaly, microcephaly, sensorineural deaf-
ness, chorioretinitis, pneumonia, direct hyperbilirubinemia, thrombocytope-
nia with petechiae, purpura, and ‘blueberry muffin’ lesions.2 The last consist
of blue-red or violaceous papules and nodules and represent foci of dermal
erythropoiesis.11 The mortality in this syndrome is of the order of 20–30%.5
Other reported pediatric manifestations of CMV infections include sclere-
dema, the Gianotti-Crosti syndrome, perineal ulceration, the juvenile variant
of papular-purpuric gloves and socks syndrome, acute hemorrhagic edema of
infancy, and the fetal inflammatory response syndrome (FIRS).12–18
Adults, particularly females, most often in the third decade, may develop
a heterophil agglutinin-negative infectious mononucleosis-like syndrome in
which a short-lived rubelliform eruption has been described.2,19,20 Patients
are also at risk of developing an ampicillin-related allergic dermatosis
(cf., i­nfectious mononucleosis).2,20–22
CMV infection may also be a feature of immunosuppression.3,23–25
Generalized CMV infection is a not uncommon finding at autopsy in
AIDS patients. CMV is frequently detected in association with toxoplas-
mosis and Pneumocystis jiroveci (formerly Pneumocystis carinii) infection,
and has also been described in patients with concomitant cutaneous ­herpes
Cytomegalovirus infections 779
­simplex, bacillary angiomatosis, Mycobacterium avium complex, and even
mucormycosis.26–30 CMV infection is said to occur in 20–60% of organ
transplant recipients, with cutaneous manifestations occurring in 10–20%
of patients with systemic infection.24 Skin lesions in AIDS- and non-AIDS-
associated immunocompromised patients do not appear to differ clinically
or histologically.25
Reported cutaneous manifestations include ulcers on the genitalia, anus,
perineum, buttocks and thighs, purpuric eruptions, petechiae, erythema
nodosum, cutaneous vasculitis, hyperpigmented nodules and plaques, lesions
resembling prurigo nodularis, erythema multiforme (including the persistent
form of the latter), nodular auricular lesions, epidermolysis, urticaria, pus-
tules, vesiculobullous lesions and a generalized, pruritic erythematous macu-
lopapular eruption.23–25,31–45 Cutaneous CMV infection has also been detected
in a patient with febrile ulceronecrotic Mucha-Habermann disease.46 There
are isolated reports of CMV infection in association with eruptive pseudoan-
giomatosis and reactive perforating collagenosis.47,48 A possible link to sclero-
derma has also been suggested.49,50 In one study, graft-versus-host disease-like
histological changes were observed in biopsies of clinically normal skin from
allogeneic bone marrow transplant recipients who had peaks of CMV antigen
in the blood within 100 days of transplantation.51
Pathogenesis and histological features
In addition to maternally derived infections, there is also some evidence to
suggest a venereal mode of spread.52 In the immunocompromised patient,
CMV infections represent an acquired phenomenon or reactivation of a
latent focus.40 In immunosuppressed transplant recipients, infection occurs
predominantly after the first month post-transplantation and is the result of
either primary infection, reinfection or reactivation of latent disease.42 A high
­antigen-specific T-cell response to CMV is responsible for ­chemokine-­mediated
endothelial cell damage.53
The histological hallmark is the presence of large, often purple-staining,
intranuclear inclusions surrounded by a clear halo (Figs 18.60, 18.61).
Smaller basophilic, periodic acid-Schiff (PAS)-positive intracytoplasmic
inclusions may also be evident. These have been described within enlarged
endothelial cells of dermal blood vessels, sometimes accompanied by the fea-
tures of leukocytoclastic vasculitis.21,25,34,35 Inclusions may sometimes be iden-
tified in dermal fibrocytes, macrophages, and eccrine ductal epithelial cells,
the last rarely associated with syringosquamous metaplasia.25,54,55 They have
also been identified within the endothelial cells of blood vessels and histio-
cytes in the inflammatory bed deep to cutaneous ulcers (Figs 18.60, 18.61).31
Cutaneous nerve involvement (CMV neuritis) has been reported in perineal
Fig. 18.60
Cytomegalovirus: this
specimen comes from
a patient with HIV/AIDS.
Note the hemorrhage and
intense inflammatory cell
infiltrate.
780 Infectious diseases of the skin
Fig. 18.61
Cytomegalovirus: high-power view showing the typical eosinophilic intranuclear
inclusions.
Fig. 18.62
Cytomegalovirus: positive immunohistochemistry.
ulcers.56 In ­histological specimens from immunocompromised hosts, care
should be taken to rule out CMV infection in association with other infective
disorders, such as herpes simplex virus infection or bacillary angiomatosis.
Vesiculobullous lesions are characterized by spongiosis and reticular degen-
eration, accompanied by epidermal multinucleate giant cells which may ­contain
viral inclusion bodies.26 The diagnosis of CMV infection can be confirmed by
immunohistochemistry, in situ hybridization or PCR (Fig. 18.62).57
Exanthem subitum
Clinical features
Exanthem subitum (roseola infantum) is a benign disease of infancy usually
caused by infection with human herpesvirus 6 (HHV-6).1,2 Infection with
human herpesvirus 7 (HHV-7), a closely related β-herpesvirus, however, may
also manifest as exanthem subitum.3,4 Usual clinical features include fever
and a cutaneous eruption that resembles rubella or measles.3,5 A case with
vesicular lesions has been reported.6
A similar rash caused by HHV-6 infection has been reported in leuke-
mic patients and bone marrow transplant recipients; a possible link to graft-
versus-host disease has also been suggested.7–9 HHV-7 is also recognized
as an important pathogen in transplant recipients.3,8 Other reported clini-
cal associations and cutaneous manifestations of HHV-6 infection include
­papular-purpuric ‘gloves and socks’ syndrome, erythema elevatum diutinum,
an infectious mononucleosis-like syndrome, the Gianotti-Crosti syndrome,
drug hypersensitivity syndrome, and more recently, pityriasis rosea.10–16
HHV-6 DNA has also been detected in lesions of Langerhans cell histio-
cytosis.17 HHV-7 has been implicated in pityriasis rosea and drug-induced
­hypersensitivity syndrome.16,18
Histological features
The histopathological findings in exanthem subitum are rather non-specific
and include papillary dermal edema and a superficial perivascular mononu-
clear inflammatory cell infiltrate. Rare cases with a vesicular presentation
may show mononuclear inflammatory cell exocytosis into the epidermis, with
microscopic intraepidermal spongiotic vesiculation. Intranuclear inclusions
(as seen in herpes simplex virus infection or varicella-zoster virus ­infection) are
absent. The diagnosis can be confirmed by immunofluorescence ­microscopy,
using an antibody to HHV-6.6
Eruptive pseudoangiomatosis
Clinical features
In 1969, Cherry et al. reported a series of four infants who developed an
eruption of small hemangioma-like papules, which blanched on pressure. The
lesions had an abrupt onset and apparently evolved in association with an
acute echovirus infection, resolving spontaneously within a few days.1 This
uncommon condition was later referred to as eruptive pseudoangiomatosis
(EPA), and was initially regarded as an exanthem unique to infants and chil-
dren.2,3 A recent review of the literature, however, revealed that more than
half of all cases recorded thus far have occurred in adults, often as small
outbreaks, in the Mediterranean region during the summer months.4–6 The
condition is similar to or synonymous with the entity referred to in Japan
as erythema punctatum Higuchi, which has been linked to mosquito bites.6,7
In children the eruption is frequently preceded by an upper respiratory tract
infection or, less commonly, gastroenteritis.3,5 Prodromal constitutional symp-
toms such as malaise, fever, headache, vomiting or diarrhea are encountered
more frequently in pediatric patients than in adults.5 Rare cases have occurred
in iatrogenically immunosuppressed individuals.4,8
The acute eruption comprises numerous small, asymptomatic, bright red
angiomatoid papules. The individual lesions, which measure between 2 mm
and 5 mm in diameter, are surrounded by a distinctive pale halo and charac-
teristically blanch on pressure.9,10 The face, trunk, and limbs are sites of pre-
dilection. Spontaneous resolution usually takes place within 3 to 10 days.3
Relapse, however, has been reported in around 70% of cases in some series.6
Exceptionally, EPA may persist for months.3
Pathogenesis and histological features
Although there is often strong circumstantial evidence to suggest that the erup-
tion is precipitated by a viral infection, further investigation seldom leads to
the identification of a specific pathogen.3,6 Isolated cases, however, have been
linked to cytomegalovirus infection and infection with Epstein-Barr virus.11,12
Some cases have occurred following arthropod bites, especially those of mos-
quitos.6,13 A vector-borne infectious agent therefore seems probable in a sub-
set of patients.4 Since there is no true vascular proliferation, the authors who
initially described the condition proposed that the cutaneous lesions were the
result of either a direct viral effect on vascular endothelial cells or binding
of antigen–antibody complexes to the endothelium.1 The latter is unlikely as
there is no evidence of vasculitis. The surrounding white ring observed clini-
cally around each lesion has been ascribed to vasoconstriction peripheral to
the central zone of vasodilatation.9 It seems likely that EPA represents an
unusual reaction pattern in response to a number of different viruses.2
The histopathological picture predominantly shows dilated blood vessels in
the papillary dermis and upper reticular dermis. These vessels are lined by plump
endothelial cells, which usually assume a hobnail-like appearance.2,10,14,15 A sparse
perivascular lymphoid infiltrate is sometimes evident.8,9,12,15 Importantly, there is
no increase in dermal vascular density.9,10
 Diseases caused by orthopox viruses 781

Differential diagnosis
Although eruptive pyogenic granulomas, bacillary angiomatosis, bartonello-
sis and multiple glomeruloid hemangiomas may enter the clinical differential
diagnosis, each of the aforementioned conditions has distinctive histology
and is associated with a true angiomatous dermal vascular proliferation.
Furthermore, the individual lesions are not surrounded by a peripheral white
halo.
Hobnail hemangioma (targetoid hemosiderotic hemangioma) is charac-
terized clinically by a perilesional halo and histologically by hobnail-like
vascular endothelial cells. Unlike EPA, however, lesions are usually single,
the surrounding halo is pigmented rather than pale, and there is a true der-
mal vascular proliferation. Telangiectases lack protrusion of plump endothe-
lial cells into the dilated vessel lumina. Spider angiomas comprise centrally
located dilated dermal arterioles with thin branches; they too are devoid of
the prominent endothelium observed in EPA.1

A
Diseases caused by orthopox viruses
Clinical features
The orthopox viruses are DNA in type and cause variola, vaccinia, cowpox,
and monkeypox.

Variola
Variola, or smallpox, has not been diagnosed endemically since 1977 and
until recently appeared to be of historical interest only.1–4 In recent years,
however, there has been renewed interest in smallpox as a potential agent in
bioterrorism.5–7 It was endemic in parts of Africa, South America, and Asia,
with only occasional cases seen in Europe and North America. Transmission
of the virus, which is capable of retaining viability in dried exudate, is by
inhalation. The disease typically has an incubation period of 12 days, fol-
lowed by a prodromal phase of high fever, headache, and vomiting and 3–4
days later by a transient erythematous and petechial rash. This is in turn fol-
lowed by the characteristic eruptive lesions (Fig. 18.63). These lesions are
most common on the face and limbs. They begin as papules, which become
vesicular and then pustular and crusted. Healing is usually associated with a
pitted scar. Mortality varied from 2% to 50%, depending on the severity of
the infection. Although death was previously attributed to secondary bacte-
rial sepsis, it has since come to light that it was probably the direct result of
the cytopathic effects of the smallpox virus itself.8 It has been suggested that
the scarring observed in survivors of the disease might have been the result of
destruction of sebaceous glands, although other mechanisms have also been
proposed.9
Vaccinia
Vaccinia virus is closely related antigenically to variola virus, but is probably
derived from cowpox virus. It was used for immunization against variola and
no doubt was effective because of its similar antigenicity. This skin inocula-
tion results in a single vesicle, which becomes pustular and crusts, like variola
(Fig. 18.64). It also heals similarly, leaving a scar. Since it was accepted that
variola had been eradicated in the wild, for many years vaccination was no
longer thought necessary except in laboratory workers at special risk. Public
fear of smallpox as a potential biological weapon or bioterrorism agent in the
United States of America, however, has led to the reintroduction of a small-
pox vaccination campaign in that country.7 The vaccination procedure is not
without risk. Generalized vaccinia was occasionally seen and the vaccine was
responsible for some cases of Kaposi's varicelliform eruption (eczema vacci-
natum). Vaccinia necrosum and encephalitis were also rare complications.10
Occasional cases of generalized vaccinia following smallpox vaccination have
been recorded recently.11
Cowpox
Despite the name, the reservoir for cowpox virus is not cattle, but wild ani-
mals such as hedgehogs and badgers. Cattle and man are both infected acci-
dentally, although man may acquire the disease from cows. Cats, and more
recently rats, have been identified as additional sources of infection.12–19
Fig. 18.63
Variola (smallpox): (A)
in contrast to those
of chickenpox, the
lesions are larger and
less superficial; (B)
note the widespread
hyperpigmented scars
in healed lesions. (A) By
courtesy of H.P. Lambert,
MD, St George's Hospital,
London, UK; (B) By
courtesy of R.A. Marsden,
B St George's Hospital,
London, UK.
Although this rare zoonotic disease generally results in a self-limiting infec-
tion, more severe illness may occur in immunocompromised individuals and
those with eczema.20 The incubation period after inoculation is usually 5–7 days;
a papule then develops, which rapidly becomes pustular. The pustule is sur-
rounded by a zone of erythema and edema. Eschars or necrotic ulcers may be
seen.16,21,22 The lesions are often multiple and can occur on the hands, arms or
face (Figs 18.65, 18.66).23 A severe generalized or varicelliform eruption in
association with atopy has been reported.24,25 Sporotrichoid spread has been
documented.26 Lymphangitis, lymphadenitis, and fever are almost invariably
present. Healing and recovery occur in 3–4 weeks. A fatal case of a cowpox-
like illness has been recorded.27 One reported case developed facial cellulitis
and necrotizing lymphadenitis with abscess formation after inoculation of the
virus in the nasal respiratory epithelium.28
Monkeypox
Monkeypox is an uncommon zoonosis attributable to monkeypox virus, a
member of the orthopox virus group.29–31 The first recorded cases occurred
in the Democratic Republic of Congo (formerly Zaire) in 1970.29,32 Although
sporadic cases are encountered in remote villages in the tropical rain for-
ests of West and Central Africa, an outbreak of the disease occurred in the
state of Wisconsin in the United States of America in 2003, spreading to
782 Infectious diseases of the skin

Fig. 18.64
Vaccinia: due to the
eradication of smallpox, Fig. 18.66
routine vaccination is no Cowpox: note the edema and surrounding erythema. By courtesy of M.S. Lewis
longer performed. Note Jones, MD, Wrexham Maelor Hospital, Wrexham, UK.
the eschar, edema, and
intense erythema.
By courtesy of the
Institute of Dermatology,
London, UK.
Pathogenesis and histological features
Orthopox viruses are large and have a discrete DNA compartment (nucleoid)
and a complex capsid and lipoprotein coat containing characteristic tubu-
lar structures. They are brick-shaped and their outer tubular structures are
irregularly arranged. These viruses are all transmitted by inoculation except
variola, which usually gains entry by inhalation. The virus is able to resist
dehydration outside the host and therefore inhalation or inoculation of dust
or inoculation from shared facilities is quite possible, as well as direct inocu-
lation from an active lesion. Evidence has shown that these viruses secrete
interleukin (IL)-18 binding proteins, resulting in viral dissemination or per-
sistent infection.40 Variola virus encodes CrmB, a tumor necrosis factor recep-
tor homologue, which serves as a specific binding protein for a number of
chemokines that mediate recruitment of inflammatory cells to the skin and
mucosae, sites of viral entry, and viral replication. Binding of chemokines
is potentiated via the C-terminal domain of CrmB, referred to as smallpox
virus-encoded chemokine receptor (SECRET).41 In primate animal models,
multiorgan failure ensues in the presence of a high viral burden in the affected
tissues. A hemorrhagic diathesis and depletion of T-cell dependent zones in
lymphoid tissues may also be encountered. A cytokine storm arises due to
elaboration of cytokines such as IL-6 and IFN-γ.42 The vaccinia virus is able
to evade the host immune response by impairing dendritic cell maturation,
with subsequent inhibition of T-cell activation.43
Fig. 18.65 After inoculation the viruses proliferate within keratinocytes and basal
Cowpox: characteristic cells. This leads to severe intracellular edema with resultant ballooning degen-
umbilicated, ulcerated
eration and consequent reticular degeneration due to cell rupture, giving rise
nodules. Lesions are often
multiple. By courtesy of
to multilocular vesicles and subsequent infiltration by polymorphs. In variola,
M.S. Lewis Jones, MD, vaccinia, and monkeypox there is often extensive epidermal necrosis. Variable
Wrexham Maelor Hospital, degrees of hyperkeratosis and acanthosis are present. Cytoplasmic eosinophilic
Wrexham, UK. inclusion bodies may be seen in the keratinocytes of all four diseases. The
small inclusions of variola are called Guarnieri bodies. They are surrounded
by a clear halo and are located close to the nucleus (Fig. 18.67). Similar bod-
neighboring states.29,30,32–37 This outbreak was traced to a shipment of exotic ies are seen in vaccinia and monkeypox. Those of ­cowpox, ­however, are
animals from West Africa.31,36,37 Patients appeared to have come into direct slightly larger, but are still predominantly seen in the cytoplasm.44 A ­dermal
contact with ill prairie dogs that were being kept or sold as pets. It was estab- chronic inflammatory cell infiltrate consisting of lymphocytes is usually pres-
lished that these animals had been exposed to infected rodents imported from ent. CD30-positive cells may be very prominent and confusion with a CD30-
Ghana.31,37 Person-to-person spread may also occur.32 Prior smallpox vacci- positive lymphoproliferative disorder is possible if close attention is not paid
nation may confer some protection against monkeypox infection.29,35,38 The to the epidermal changes and the presence of inclusions.
condition presents with fever, rigors, and a skin rash, sometimes accompa- Diagnosis is based upon clinical information, but confirmation can be
nied by lymphadenopathy.30,34 The cutaneous lesions progress from papules obtained by electron microscopy, isolation of the viruses in tissue culture or,
to vesicopustules to resolving eschars.30 Encephalitis may also occur, and more recently, with the aid of PCR or in situ hybridization studies.22,30,35,45–47
fatalities have been recorded.29,35,39 Monkeypox may be confused clinically Variola virus is detectable in formalin-fixed, paraffin-embedded tissue after
with chickenpox.34 decades of prolonged archival storage.48

Fig. 18.67
Variola (smallpox): high-power view showing Guarneri bodies (arrowed). By courtesy
of D. Wear MD, the Armed Forces Institute of Pathology, Washington, DC, USA.,
Milker's nodule
Clinical features
Milker's nodule (or paravaccinia) is caused by a parapox virus, distinct from
that which causes cowpox.1,2 It occurs as a localized lesion on the udders
of cows and causes little systemic disturbance. It may be recurrent in the
same herd. It is usually acquired by man by inoculation, but since the virus
is viable in a dried state, indirect fomite infection is possible. Small out-
breaks involving several patients have been recorded.2 The incubation period
is around 5 days; some two to five red papules then develop, which gradu-
ally become bluish tender nodules.2 The overlying epidermis is at first tense
and shiny, but becomes opaque and gray (Fig. 18.68). The center of the
lesion is crusted and slightly depressed. The surrounding skin often shows
lymphangitis, but despite this the lesion has the appearance of a tumor and
is well circumscribed. There are few systemic symptoms, but there may be
an associated short-lived papulovesicular eruption on the upper limbs and
occasionally on the legs. The main nodular lesions resolve, without scarring,
in 4–6 weeks.
Fig. 18.68
Milker's nodule: the blister roof has an opaque appearance and there is surrounding
erythema. By courtesy of the Institute of Dermatology, London, UK.
Ecthyma contagiosum 783
Histological features
Milker's nodule virus measures 160–260 nm and is ellipsoid in shape.2 It is
characterized by spirally arranged tubules. The histological features are indis-
tinguishable from those seen in orf infection (see below).3,4 A CD30-positive
atypical dermal lymphoid infiltrate may sometimes be encountered and con-
fusion with a CD30-positive lymphoproliferative disease is possible.5 In the
latter, the CD30-positive cells are usually in clumps while in Milker's nod-
ule the CD30-positive cells are scattered between other inflammatory cells.
This is, however, not entirely consistent and in some cases clusters of CD30-
positive cells may be seen.
Ecthyma contagiosum
Clinical features
Ecthyma contagiosum (orf, contagious pustular dermatosis) is caused by an
epitheliotropic DNA parapoxvirus morphologically identical to that caus-
ing milker's nodule. The infection is endemic in sheep in which it causes
crusted pustules of the lips and perioral area (Fig. 18.69).1–4 This underlies
the accurate descriptive term of ‘scabby mouth’ used by Australian farm-
ers. It is transmitted by inoculation from sheep to sheep, though it is said
that the virus can persist in pastures. It is particularly likely to arise when
the pasture is dry and results in minor abrasions of the labial mucosa of the
sheep. Transmission to man, most often males and usually sheep-­handlers,
is usually by direct inoculation from infected lesions, but it may also result
from contact with contaminated objects such as fences and shears.5 Orf
may also be seen in goats.3,4,6 In one English study, 23% of individuals
employed or living on a sheep farm reported having had the condition.7
Nonoccupational acquisition of the infection has been described following
a sacrificial feast.8
After an incubation period of 5–6 days, the lesion (usually a solitary, small,
firm, red-blue papule) develops. It is most common on the hand or forearm
(Figs 18.70, 18.71).9 Less commonly, lesions may occur on the facial and
perianal regions.10–12 The papule becomes a flat-topped hemorrhagic blister
or pustule, later crusting over its depressed center. By this stage it may be
2–5 cm in diameter. Clinically, it may be mistaken for a pyogenic granuloma
or keratoacanthoma.6 The lesions are surrounded by a zone of erythema,
which may be associated with itching and tenderness. The main lesion usu-
ally resolves without scarring in 3 weeks, although on rare occasions digital
deformity may occur.13 Lymphangitis, lymphadenitis, and mild fever occasion-
ally develop.1 In addition, some patients develop a transient maculopapular
eruption on the trunk or erythema multiforme-like lesions on the limbs.6,9,13
Fig. 18.69
Orf: the scabby mouth. By courtesy of B.J. Leppard, MD, Royal South Hants
Hospital, Southampton, UK.
784 Infectious diseases of the skin

Fig. 18.70
Orf: in this example there is a markedly hemorrhagic component. By courtesy of
M.M. Black, MD, Institute of Dermatology, London, UK.

Fig. 18.72
Orf: (A) the lesion is pedunculated and there is massive superficial dermal edema;
(B) the keratinocytes show ballooning degeneration.

Fig. 18.71
Orf: older lesion with a typical depressed center. By courtesy of A. Qureshi, MD,
Harvard Medical School, Boston, USA.

Other potential complications include erysipelas, Pseudomonas aeruginosa

­infection, a papulovesicular eruption, and a bullous pemphigoid-like bullous
eruption.13,14 Ocular involvement may be a rare manifestation.15 Giant lesions
are sometimes encountered.12,13,16,17 Giant orf lesions were reported recently
in an organ transplant recipient.16

Histological features
The histological features are quite characteristic. The overall appearance of
the lesion is that of a symmetrical nodule. There is a parakeratotic crust and
acanthosis with thin epidermal strands extending quite deeply into the adja-
cent dermis.18 Viral cytopathic changes including cytoplasmic and nuclear
vacuolation are usually conspicuous.19 Reticular degeneration with intraepi-
dermal vesiculation is often evident (Fig. 18.72).
If the biopsy is taken from an early lesion, typical 3–5 μm intracytoplasmic
eosinophilic inclusions may be seen (Fig. 18.73).19 Sometimes intranuclear
inclusions may also be evident.5 They can be rendered more conspicuous with
Lendrum's phloxine tartazine (Fig. 18.74). Similar inclusions may also be
seen in the cytoplasm of the endothelial cells lining blood vessels, among the
underlying heavy chronic inflammatory cell infiltrate. The latter comprises
lymphocytes and histiocytes although neutrophils and occasional eosinophils Fig. 18.73
may be evident. The dermis is often very edematous, and characteristic of orf Orf: in the center of the field is an eosinophilic intracytoplasmic inclusion.

Fig. 18.74
Orf: the inclusions may be highlighted by Lendrum's phloxine tartazine.
(and milker's nodule) is the presence of massive capillary proliferation and
dilatation.10,19 This is attributable to the production of virus-encoded homo-
logues of ovine vascular endothelial growth factor.3,20 In addition, orf virus
encodes a homologue of interleukin-10, which appears to impair dendritic
cell function and monocyte proliferation.21,22 A prominent, CD30-positive
reactive dermal lymphoid infiltrate may occur.23
The immunobullous (bullous pemphigoid-like) lesions are subepidermal
in location and contain a mixed inflammatory cell infiltrate, which includes
polymorphonuclear leukocytes and eosinophils. A recent study of two cases
showed that orf virus DNA was absent from the blistering lesions, while direct
immunofluorescence microscopy revealed linear deposition of IgG and com-
plement C3 along the dermoepidermal junction in perilesional skin. Although
the precise autoantigen has yet to be identified, the condition appears to be
distinct from true bullous pemphigoid and other immunobullous conditions
such as epidermolysis bullosa acquisita.14
The diagnosis of orf may be confirmed immunocytochemically or by PCR,
including real-time PCR.24–27 The Tzanck test has also been used as a diag-
nostic aid.9 Ultrastructural studies reveal that the orf virus is best visualized
in negatively stained preparations (Fig. 18.75).6
Fig. 18.75
Orf: on electron micrographic examination the parapoxvirus has a cylindrical
appearance and a typical criss-crossed internal structure. By courtesy of I. Chrystie,
FIMLS, St Thomas' Hospital, London, UK.
Molluscum contagiosum 785
Molluscum contagiosum
Clinical features
Molluscum contagiosum is a self-limiting epidermal papular condition caused
by a poxvirus of the Molluscipox virus genus (Fig. 18.76).1,2 The genome
encodes 163 proteins of which 103 are closely related to variola virus.3 It
occurs on the face, trunk, and limbs of young children, who are infected by
direct cutaneous contact or inoculation from fomites, and in young adults on
genitalia and surrounding skin after transmission by sexual contact.2,4 The
palms and soles are usually unaffected, but rare cases have been reported.5,6
Although the condition is worldwide it is more prevalent in tropical regions.1
The earlier literature indicated that lesions were particularly common in Fiji
and Papua New Guinea where 1 child in 10 had or had had the condition;
most infected children were under 5 years of age.7,8 More recent studies from
India and the United States have shown that around 80% of children with
molluscum contagiosum are younger than 8–10 years of age.9,10 There have
been rare reports of congenital infection.11
It has been suggested that molluscum contagiosum may be more common
in people with atopic dermatitis.5 In the USA and UK the incidence in adults
attending STD clinics is in the range of 1 for every 40–60 cases of gonorrhea.
Transmission can also occur between wrestlers, between doctor and patient,
and through joint use of equipment and bathing facilities. The use of public
swimming pools appears of particular significance in children.12 The disease
has an increased incidence in patients with impaired immunity. In the latter,
lesions tend to be more extensive, generalized, and persistent.5 Although man
was initially thought to be the only host to the virus, there have been isolated
reports of molluscum contagiosum in animals such as certain bird species, the
chimpanzee, and possibly the red kangaroo.2
The incubation period ranges from 2 to 7 weeks but may be as long as
6  months.13 Individual lesions are smooth, shiny, pearly, firm, umbilicated
papules up to 5 mm across or occasionally larger (Figs 18.77–18.79). Mucous
membrane involvement is seen occasionally.14 The lesions are usually quite
characteristic in appearance, but may be confused occasionally with a fibrous
histiocytoma, intradermal melanocytic nevus, keratoacanthoma, syringoma,
basal cell carcinoma, common wart, and even cutaneous cryptococcosis. They
are often multiple, especially in patients with immune deficiency. Although
uncommon, giant lesions may also occur, especially in immunocompromised
patients.15–17 HIV-infected individuals can manifest with exclusive involvement
of facial and perioral skin.18 Molluscum contagiosum may be a ­cutaneous
manifestation of the immune reconstitution inflammatory syndrome in
­HIV-infected patients receiving highly active antiretroviral therapy.19,20
Fig. 18.76
Molluscum contagiosum: electron micrographic examination shows that the
molluscum virus body is composed of virions, which are indistinguishable from
those in the other poxviruses. By courtesy of I. Chrystie, FIMLS, St Thomas'
Hospital, London, UK.
786 Infectious diseases of the skin

Symptoms of itching, tenderness, and pain are uncommon, but approxi-

mately 10% of patients develop an eczematous dermatitis around the mol-
luscum papule. The papule itself may become secondarily infected and then
resemble a furuncle. The individual lesion usually persists for 2 months, but
sometimes lasts much longer. Since the patient may have numerous lesions at
different stages of development, molluscum contagiosum can be present for
years in some patients. Pitted scarring sometimes occurs in atopic individu-
als.21 Systemic lesions have not been described.5

Histological features
In molluscum contagiosum intracellular edema with reticular degeneration
and vesiculation are not features, in contrast to those caused by the other
pox viruses. The characteristic feature is the presence of lobulated, endo-
phytic hyperplasia, producing a circumscribed intradermal pseudotumor
(Fig. 18.80). The keratinocytes contain a very large intracytoplasmic inclu-
sion, which compresses the nucleus against the cell membrane. Although
initially eosinophilic in size, the inclusion gradually develops a marked baso-
philia (Fig. 18.81). The latter can be recognized in a cytological ­preparation
Fig. 18.77
Molluscum contagiosum: multiple umbilicated lesions are present. From the
collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Fig. 18.80
Molluscum contagiosum: characteristic scanning view showing the central
umbilication and epidermal hyperplasia.

Fig. 18.78
Molluscum contagiosum: central umbilication is a diagnostic clinical marker. From
the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Fig. 18.81
Molluscum contagiosum:
the intracytoplasmic
Fig. 18.79 inclusions almost
Molluscum contagiosum: this often develops as a result of sexual contact in young completely fill the cell and
adults. By courtesy of R.A. Marsden, St George's Hospital, London, UK. compress the nucleus.

Fig. 18.82
Molluscum contagiosum:
note the tinctorial change
in this section stained
with Lendrum's phloxine
tartrazine.
from the surface of the lesion; this may serve as a quick diagnostic test. Their
­presence may be rendered more conspicuous by the use of Lendrum's ­phloxine
tartrazine reaction (Fig. 18.82).
Usually there is no dermal infiltrate, but when it does occur, allegedly in
response to virus or inclusion bodies entering the dermis, the lymphocytic
infiltrate is so intense that lymphoma may enter the differential diagnosis if
the characteristic inclusion bodies are not obvious (Figs 18.83, 18.84). This
dermal lymphoid infiltrate may harbor large, atypical CD30-positive lym-
phoid cells, potentially mimicking a CD30-positive cutaneous lymphoprolif-
erative disorder.22 This is particularly seen in regressing lesions containing few
inclusion bodies, and the histologic diagnosis may be very difficult.
The presence of metaplastic bone formation in otherwise typical lesions
of molluscum contagiosum has been reported.16,23 Molluscum contagio-
sum has also been noted in association with epidermal cysts, melanocytic
nevi, ­melanoma, sebaceous hyperplasia, soft fibromas, lupus erythematosus,
­leukemia cutis, and eosinophilic cellulitis.16,24–27
Fig. 18.83
Molluscum contagiosum: rupture of an epidermal nodule has released inclusions
into the dermis with a resultant intense chronic inflammatory cell response.
Hand, foot, and mouth disease 787
Fig. 18.84
Molluscum contagiosum: there is an intense lymphohistiocytic infiltrate. Numerous
infected keratinocytes are present.
Hand, foot, and mouth disease
Clinical features
This is a viral illness caused most often by coxsackievirus A16 and less often
by enterovirus 71.1–11 It usually affects young children, shows ­seasonal varia-
tion (being more common in summer and autumn), and presents as small
­epidemics. A ­number of outbreaks have been documented in the East, ­especially
Taiwan.1,3–6,9,10 Outbreaks have also occurred in Malaysia, Singapore, and
India.7,8,11,12 Children in their first four years of life are most susceptible.4,9,11
Other viruses implicated include echovirus 19, and very rarely, echovirus 4.13,14
Recently, molecular phylogenetic analysis has shown that two distinct geno-
groups of coxsackievirus A16 exist, namely, A and B.15 Phylogenetic ­evidence
has also revealed that intertypic recombination between enterovirus 71 and
­coxsackievirus A16 may play a role in the emergence of subgenotypes of
­enterovirus 71.16
Hand, foot, and mouth disease has an incubation period of 3–7 days.
Following a prodrome of headache, fever, malaise, abdominal pain, and some-
times diarrhea, patients develop oral ulcers and blisters, most commonly on
the inner cheeks and lips, accompanied by small erythematous papules, which
soon evolve into grayish vesicles on the soles, palms, and ventral surfaces and
sides of the fingers and toes (Figs 18.85–18.88).1 Lesions are less commonly
found on the perineum, buttocks, trunk, and extremities. The eruption is self-
limiting. Complications only occur in approximately 6% of cases attributable
to coxsackievirus A16, notably aseptic meningitis.3
Hand, foot, and mouth disease due to enterovirus 71 is a more serious
illness, with complications occurring in approximately one-third of patients.
These include central nervous system lesions predominantly affecting the
­cerebellum. Encephalitis, aseptic meningitis, and a poliomyelitis-like condition
can also occur.1,3,9–12 Concomitant infections may sometimes be seen.12 A mor-
tality rate of around 8% has been recorded. Death is usually attributable to
cardiopulmonary decompensation and acute pulmonary edema.3 The mecha-
nism of pulmonary edema is unclear, since it does not appear to be the direct
result of viral myocarditis in most cases; it has been ­postulated that increased
pulmonary vascular permeability secondary to brainstem lesions or a systemic
inflammatory response to encephalitis may play a role.5,17 In one outbreak in
Singapore, however, most fatalities were the result of interstitial pneumonitis,
either alone or in association with myocarditis or encephalitis.12
Pathogenesis and histological features
The virus is transmitted by direct contact with nasal and pharyngeal secretions,
feces, and blood. Histologically, the blister is intraepidermal and ­develops as
a consequence of marked inter- and intracellular edema (Figs 18.89, 18.90).
788 Infectious diseases of the skin

Fig, 18.85 Fig. 18.88

Hand, foot, and mouth disease: multiple oral ulcers are present. By courtesy of the Hand, foot, and mouth disease: there are numerous erosions on the sole of the
Institute of Dermatology, London, UK. foot. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 18.86 Fig. 18.89

Hand, foot, and mouth disease: there are numerous erosions with surrounding Hand, foot, and mouth disease: this low-power view of the finger shows gross
erythema. By courtesy of E. Wilson Jones, MD, Institute of Dermatology, London, UK. reticular degeneration with intraepidermal vesiculation. Degenerative changes
have resulted in epidermodermal separation. By courtesy of E. Wilson Jones, MD,
Institute of Dermatology, London, UK.

There may be associated papillary dermal edema. Viral ­inclusions and giant
cells are not a feature. Enterovirus 71 may induce apoptosis of infected host
cells via a virus-encoded protein.18
A real-time reverse transcriptase PCR method that allows for the dif-
ferentiation of enterovirus 71 from coxsackievirus A16 was described
recently.19

Viral hemorrhagic fevers

Fig. 18.87
Hand, foot, and mouth disease: note the small vesicles with surrounding erythema.
By courtesy of E. Wilson Jones, MD, Institute of Dermatology, London, UK.
Clinical features
The hemorrhagic fever (HF) viruses are a special group of highly infectious
viruses transmitted to humans by arthropods (mosquitoes, ticks) or rodents,
resulting in systemic illness and a generalized bleeding diathesis.1–4 The viral
etiologic agents may be grouped according to family:
• Flaviviridae, which are responsible for infections such as yellow fever,
dengue fever, Omsk HF, and Kyasanur Forest disease,
• Bunyaviridae, which cause Rift Valley fever, Crimean–Congo HF, and
hantavirus infections (e.g., hemorrhagic fever with renal syndrome),

Fig. 18.90
Hand, foot, and mouth disease: the epithelium shows necrosis and dyskeratosis.
A chronic inflammatory infiltrate is evident. By courtesy of E. Wilson Jones, MD,
Institute of Dermatology, London, UK.
• Arenaviridae, which are responsible for Lassa fever, Argentine HF,
Bolivian HF, Venezuelan HF, Brazilian HF, etcetera,
• Filoviridae, which cause Marburg virus disease and Ebola virus HF.1–3
There is marked diversity in the severity of illness and the mortality within
this group of diseases; dengue fever, for example, has a mortality of around
5% whereas the purported mortality associated with Ebola is 50–90%.4 Most
viral HFs manifest as an acute febrile illness, often with myalgias. Conjunctival
injection and periorbital edema may occur.2,4 Although some earlier classifica-
tions of viral HF included chikungunya (caused by chikungunya fever virus, a
member of the Togaviridae), hemorrhagic manifestations are relatively rare and
the disease has thus been omitted from more recent HF classifications.1,2,5
A detailed discussion of all of the conditions listed above is not possible,
and the reader is referred to references 1 and 2 for excellent overviews on the
subject. The further discussion here will focus on the potential mucocutane-
ous manifestations of viral HFs.
A conspicuous, diffuse, nonpruritic maculopapular skin rash is typically
encountered in filovirus infections such as Marburg virus disease and Ebola
HF. Desquamation may take place during the recovery phase in nonfatal
cases.3 A similar although less prominent eruption may be seen on the trunk
and limbs of patients with Rift Valley fever.2 Dengue HF is frequently associ-
ated with a morbilliform rash, often with islands of spared skin.3,6 Omsk HF,
Kyasanur Forest disease, Argentine HF, and Bolivian HF are associated with a
papulovesicular eruption involving the palate.3 Around 30% of patients with
dengue HF have mucosal involvement, most often of the conjunctiva.6
Thrombocytopenia is a characteristic sequel in the majority of viral HFs
and manifests as petechial hemorrhages on the skin and in relation to the
mucous membranes. Ecchymoses may develop in severe infections and are
usually located over pressure points. There may also be bleeding from veni-
puncture sites. Disseminated intravascular coagulation (DIC) is known to
complicate the clinical course of some infections, especially Rift Valley fever.2–4
Jaundice is a typical feature of yellow fever but may also be encountered in
Rift Valley fever, Crimean–Congo HF, and the filoviral HFs.2,4
Although Sindbis fever is not strictly one of the viral HFs, this relatively
mild, self-limiting togavirus infection may rarely be associated with hemor-
rhagic skin lesions, and has been included here for the sake of completeness.7
In usual cases of Sindbis fever the exanthem is papular or vesicular, occurring
in crops lasting up to 10 days. Lesions tend to be concentrated over the but-
tocks, legs, palms, and soles.8
Pathogenesis and histological features
Although the precise pathogenesis of all viral HFs has yet to be fully elucidated,
the general trend is to target dendritic reticulum cells, monocytes, lympho-
cytes, hepatocytes, and vascular endothelial cells. The profound pathophysio-
logical effects are mediated via the release of a host of ­inflammatory cytokines
Virus-associated trichodysplasia spinulosa 789
from these infected cells, resulting in increased vascular permeability, shock,
tissue necrosis, hemorrhage, and coagulopathy.1,9 Many of these viruses are
capable of suppressing innate and adaptive immune responses in the infected
host, leading to rapid local and systemic dissemination.1,10
The dermatopathological manifestations of this group of infections are
poorly documented, largely because of the infectious and hemorrhagic risks
associated with biopsy. In most cases the findings are relatively non-specific.
Consequently, skin biopsy is of questionable diagnostic or prognostic value
The cutaneous histological features of dengue HF are perhaps the best stud-
ied among the HFs.11–13 In general, HF cases with a maculopapular erup-
tion show mild lymphocytic vasculitis, with a mild perivascular mononuclear
inflammatory cell infiltrate, endothelial swelling, and minor perivascular
erythrocytic extravasation.2,4,11–14 Viral antigens may be demonstrated by
immunohistochemistry if specific antibodies are employed.14 Extensive der-
mal hemorrhage is seen in ecchymotic lesions. Intravascular fibrin-platelet
thrombi characterize cases complicated by DIC.
Differential diagnosis
It is important to remember that the HF viruses are not the only infective agents
that may be associated with pyrexia and hemorrhage. Other viruses such as
smallpox virus and herpes simplex also may produce a hemorrhagic fever pic-
ture (e.g., hemorrhagic smallpox). Additional infective agents that may cause
hemorrhagic fever are rickettsiae (e.g., Rickettsia rickettsii), chlamydiae (e.g.,
Chlamydia psittaci), bacteria (e.g., Neisseria meningitidis, Yersinia pestis),
fungi (e.g., Aspergillus), spirochetes (e.g., Leptospira icterohaemorrhagiae,
Borrelia recurrentis) and protozoa (e.g., Plasmodium falciparum).8
Virus-associated trichodysplasia spinulosa
Virus-associated trichodysplasia spinulosa (VATS) also known as viral-
­associated trichodysplasia is a rare, recently recognized, and novel viral infec-
tion of the hair follicle in immunocompromised patients.1–3 It is mainly seen
in solid organ transplant patients, mainly renal transplant, but may also occur
in patients with chemotherapy-associated immunosuppression.4 It is likely
that VATS is the same entity as pilomatrix dysplasia and cyclosporin-induced
folliculodystrophy.3,5,6 Both conditions were attributed to cyclosporin therapy
but the clinical and histologic features are remarkably similar.
Clinical features
Virus-associated trichodysplasia spinulosa is characterized by multiple small,
skin-colored to erythematous spiky follicular papules which are asymptom-
atic or mildly pruritic and have predilection for the face and ears.1–3 Lesions
can also occur on the trunk and limbs, although they tend to be more sparse
in these locations, and may coalesce. Focal alopecia can occur. When the
immunosuppression is reduced the condition improves or regresses.
Pathogenesis and histological features
Virus-associated trichodysplasia spinulosa is induced by viral infection of
the hair follicle. Electron microscopy studies have demonstrated intranuclear
viral particles of variable size, from 30 to 46 nm with features that suggest a
polyoma virus.1–4 Cultures so far have been unsuccessful.
Histologically, anagen hair follicles appear distended with dilatation and
hyperkeratosis of the infundibula and abnormal maturation with marked inner
root sheath differentiation.3 The process has been described ‘as if the hair fol-
licles were entirely devoted to producing inner root sheath’.2 Prominent cells
with eosinophilic cytoplasm and numerous trichohyaline granules are seen. The
outer root sheath persists beyond the isthmus and the bulbs are abnormal, lack-
ing fully formed papillae. Often there are only few matrical-cells as they are
replaced by large numbers of cells with eosinophilic cytoplasm. There is usually
no transition between the inner root sheath and a fully cornified hair shaft.
Differential diagnosis
The differential diagnosis includes keratosis pilaris and lichen spinulosus.
Keratosis pilaris mainly involves the proximal limbs, rarely involves the face,
and it has very subtle microscopic features, mainly hyperkeratosis and plug-
ging of the infundibula. Lichen spinulosus mainly occurs in children, has pre-
dilection for the proximal limbs, neck and buttocks, and it is characterized
histologically by hyperkeratosis in the infundibular part of the hair follicles.
790 Infectious diseases of the skin

Bacterial infections
Impetigo
The skin has a normal commensal population of bacteria in which
Staphylococcus epidermidis predominates.1 Other resident Gram-positive
bacteria include Micrococcus spp. and Corynebacterium spp.2 The free fatty
acids and other lipids derived from the stratum corneum and sebum have an
antibacterial role, yet 10–20% of the normal population are cutaneous car-
riers of S. aureus and approximately 10% are pharyngeal carriers of group
A β-hemolytic streptococci (Streptococcus pyogenes).1,3 This ‘carrier’ state
may precede infective lesions in the host or may be the origin of infections in
others. S. aureus and S. pyogenes are the most common agents in superficial
bacterial infections of the skin, but even organisms of low virulence, such as
S. epidermidis, can become pathogenic with a sufficiently large inoculum or
in an immunocompromised host.1 S. aureus toxin production is also respon-
sible for bullous impetigo, the staphylococcal scalded skin syndrome, and the
toxic shock syndrome.4,5
A
Clinical features
Impetigo is the most superficial pyogenic (pyoderma) bacterial skin infection
and is highly infectious. It is exceedingly common and occurs most often in
childhood, but may be seen in the elderly and in patients with immunodefi-
ciency states. It is typically subdivided into nonbullous (simple) impetigo and
bullous impetigo and follows the contamination of minor skin abrasions and
insect bites by S. aureus or S. pyogenes.6,7
In simple impetigo the lesions present as small superficial vesicles, which
rapidly burst and are replaced by a characteristic, adherent, thick yellow-
ish dirty crust with a margin of erythema (Figs 18.91–18.94). The mouth,
nose, and extremities are particularly affected. Regional lymphadenopathy
is sometimes present. Simple impetigo may occur in endemic or epidemic
form and often spreads to involve siblings and schoolmates. It is seen more
often in warm, humid conditions.8,9 S. aureus is the more frequent cause in
North America, whereas S. pyogenes is the more important etiological agent
of impetigo in developing countries.10 In some cases, however, the two bac-
teria appear to coexist. Streptococcal impetigo may occasionally ­progress to
­cellulitis or precede acute glomerulonephritis, erythema nodosum or ­erythema B
multiforme.
Fig. 18.92
(A, B) Impetigo: note that the vesicles are covered by a golden crust. These perioral
lesions are at a characteristic site. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.

Bullous impetigo is primarily a staphylococcal-mediated disease ­exclusively

due to phage group II S. aureus.8 Superficial blisters up to 2 cm across are
the initial features (Fig. 18.95). The contents are at first clear, but rapidly
become cloudy and then develop a thin seropurulent crust; erythema is not
marked. The lesions do not usually involve mucosae. There may be mild con-
stitutional symptoms, and the lesions resolve in 2–3 weeks.
Ecthyma is probably a variant of impetigo and occurs predominantly
on the lower limbs of children, but may occur in adults and at other sites
(Figs 18.96, 18.97).11,12 It presents with thick crusting, overlying punched-
out ulceration, and resultant scarring. S. pyogenes is the usual cause. It is
more common in tropical climates, where it occurs in all age groups. Minor
trauma or scabies infestation may determine the site of the lesions. It is pos-
sible that vasculitis and necrosis induced by bacterial toxins determine the
different presentation.
Ecthyma gangrenosum is usually a complication of Pseudomonas
aeruginosa septicemia that occurs in immunodeficient patients, particu-
Fig. 18.91
larly those with a neutropenia.13,14 It has also been reported in association
Impetigo: note the crusted
lesions on this patient's with hypogammaglobulinemia.15 There have been rare reports of ecthyma
forehead and cheeks. By gangrenosum occurring in the absence of neutropenia or septicemia.16–18
courtesy of R.A. Marsden, The condition has also been reported following toxic epidermal necrol-
MD, St George's Hospital, ysis.19 Lesions, which may be single or multiple, begin as painless ery-
London, UK. thematous macules that become indurated, bullous or pustular.13 Annular

Fig. 18.93
Impetigo: in this patient
numerous vesicles are
evident. By courtesy
of R.A. Marsden, MD,
St George's Hospital,
London, UK.
Fig. 18.94
Impetigo: note the crusted healing lesions on the back. By courtesy of J Dayrit, MD,
Manila, The Philippines.
lesions have been described.20 The lesions soon become gangrenous and
covered by a characteristic gray-black eschar and erythematous halo.
Lesions are especially seen on the gluteal and perineal regions and on the
limbs.13 The mortality is high, particularly in those with multiple lesions.
Organisms other than P. aeruginosa have been implicated in the evolution
of the disease.21
Pathogenesis and histological features
The carrier state or inoculation by a contaminated object is a necessary
precondition to superficial infection of the skin. The organisms become
attached to the traumatized area, binding strongly to fibronectin and
­possibly type IV collagen and laminin, which are abundant in the exudate.1,8
The innate ­virulence of the organisms and the host defense capability deter-
mine the ­subsequent progress of the infection, but this is facilitated if the
­bacteria ­produce coagulase, hyaluronidase or lipases.1 The form of S. aureus
­responsible for bullous impetigo is of serotype II and mainly of phage type
Staphylococcal scalded skin syndrome 791
Fig. 18.95
Bullous impetigo: there is a large raw erosion and a healed lesion distally. By courtesy
of the Institute of Dermatology, London, UK.
71 and ­produces exfoliative toxins A and B; the latter are also involved
in the staphylococcal scalded skin syndrome (see below).4,5,22,23 Impetigo
may be caused by ­community-acquired infection with methicillin-resistant
S. aureus.10,24
An early lesion of impetigo is characterized by a split in the epidermis just
beneath the stratum granulosum (Fig. 18.98). The resultant vesicle becomes
filled with neutrophils, Gram-positive cocci, and occasional acantholytic cells
(Fig. 18.99). The underlying dermis contains a mixed neutrophil and lym-
phocyte infiltrate. Neutrophils may be seen in the spongiotic stratum spino-
sum beneath the vesicle in the process of migrating from the dermis as a
chemotactic response to the causative bacteria. In conditions of impaired neu-
trophil function, impetigo may be common and more extensive.1
In echthyma, there is a sharply circumscribed area of ulceration with a
heavy neutrophil infiltrate and overlying adherent crust (Fig. 18.100).
Ecthyma gangrenosum is characterized by epidermal necrosis with hemor-
rhage and dermal infarction, usually accompanied by a mixed inflammatory
cell infiltrate of lymphocytes, histiocytes, and neutrophils.13 Less commonly,
a dearth of inflammatory cells is noted.13,25 Gram-negative bacilli may be seen
in the dermis and involving the media and adventitia of venules.13 Vasculitis
and thrombosis may be present.
Differential diagnosis
The diagnosis is usually made on clinical grounds and supported by culture
of the causative organisms. Rarely, a biopsy is necessary.
The lesion may be confused histologically with a superficial variant of
­pemphigus, particularly as the latter can become secondarily infected and
there may be one or two acantholytic cells in impetigo. Antibodies in a
­pemphigus-like pattern may be demonstrated in bullous impetigo and distinc-
tion from ­pemphigus foliaceus may therefore be a problem.5,26,27 Generally,
the ­presence of numerous neutrophils and the recognition of Gram-positive
cocci is ­sufficiently characteristic to confirm impetigo, as ­acantholytic cells
are very scanty. Distinction from subcorneal pustular dermatosis and ­pustular
­psoriasis may be considered histologically, but the lack of ­acanthosis, although
not conclusive, should point towards impetigo.
Staphylococcal scalded skin syndrome
Clinical features
Staphylococcal scalded skin syndrome (SSSS) is so named because of the pres-
ence of staphylococcal toxin and the resemblance of the established lesion
to a scald. It may present in epidemic form as well as sporadically. It occurs
almost entirely in neonates and young children, who develop first a macular
792 Infectious diseases of the skin

A B
Fig. 18.96
Ecthyma: (A) characteristic lesions in varying stages of
evolution; (B) a punched-out ulcer is shown in close-up.
By courtesy of M.M. Black, MD, Institute of Dermatology,
London, UK.

Fig. 18.97
Ecthyma: multiple lesions
are present. By courtesy
of N.C. Dlova, MD,
Nelson R. Mandela School
of Medicine, University
of KwaZulu-Natal, South
Africa.

scarlatiniform eruption in association with a staphylococcal infection. This

is often associated with fever, irritability, and skin tenderness.1–4 The erup-
tion then spreads from its usual original sites on the face, axillae, and groins
to involve large areas of the skin surface. Conjunctivitis is often also present.
Mucous membranes, however, are not affected. At the same time, the skin
becomes edematous and the surface fragile so that it can be sheared off in thin
wrinkled sheets, likened to peeling wet wallpaper, leaving a glistening red sur- B
face, and the child becomes sick and feverish (Fig. 18.101). SSSS is therefore
associated with a positive Nikolsky sign.1,5 Fig. 18.98
Following blistering, desquamation occurs and the skin often returns Bullous impetigo: (A) the site of cleavage is immediately below the granular cell
to normal by 2–3 weeks.6 Scarring is not usually a feature. The associated layer; (B) Gram-positive cocci are present.
 Staphylococcal scalded skin syndrome 793

Fig. 18.99 Fig. 18.101

Bullous impetigo: in addition to neutrophils, occasional acantholytic cells may be Staphylococcal scalded skin syndrome: note the very extensive blistering.
present causing diagnostic confusion with pemphigus foliaceus. By courtesy of A. du Vivier, MD, King's College Hospital, London, UK.

Fig. 18.102
Staphylococcal scalded skin syndrome: note the widespread denuded areas at
the edge of which the epithelium is being shed. This case developed in a patient
following wound infection after a coronary artery bypass. By courtesy of S. Parker,
MD, West Middlesex Hospital, London, UK.

source of infection may be an upper respiratory tract infection, conjunctivitis

or umbilical sepsis, or it may be more occult, such as in the middle ear, in the
pharynx or at the site of minor surgery. The condition is rarely seen at other
ages, such as the first day after birth or even at birth, indicating an infection
acquired in labor or in utero, and it may be seen in older children.7 More than
50 adult cases have been reported, although many of these patients were either
immunocompromised (including HIV infection) or in renal failure with a possi-
ble inability to excrete the toxin. The condition does occur rarely in previously
healthy adults or those with relatively minor conditions (Fig. 18.102).1,8–17
The disease in neonates (Ritter's disease) is usually self-limiting with rapid
B resolution of the skin blisters and complete recovery. However, there is a mor-
tality of 2–4% due to progression of the staphylococcal infection or the com-
Fig. 18.100 plications of exfoliation. In the adult this rare condition has shown a mortality
(A, B) Ecthyma: there is a sharply delineated ulcer. Artifact is an important of over 50%.1,15 Recovery is facilitated by antistaphylococcal ­antibiotics and
differential diagnosis. attention to fluid balance.
794 Infectious diseases of the skin

An abortive form, the scarlatiniform variant (staphylococcal scarlet fever)

in which the initial erythroderma evolves into the desquamative phase in the
absence of blistering, has been described.4,6 This may be particularly ­associated
with occult bone and joint infections or contaminated wounds.6

Pathogenesis and histological features

In SSSS the organism is of group II and usually phage type 71, but phage types
3A, 3B, 3C, and 55 have also been found.4,12 These bacteria all produce an
epidermolytic toxin (formerly referred to as exfoliatin) of which there are two
antigenic types: exfoliative toxin A (ETA) and exfoliative toxin B (ETB).18–21
ETA is associated with a chromosomal gene while ETB is plasmid encoded.4,22
They have indistinguishable activity and manifest exquisite pathological sen-
sitivity by inducing blistering only at the level of the superficial epidermis.19,20
The effect of the toxins is determined by their site of production:
• Toxins produced by the appropriate staphylococcal infection of mucosae
or surgical wounds enter the circulation (toxemia) and produce a
generalized change in the skin, the SSSS. The intensity is determined by
the rapidity with which the toxins are metabolized and excreted renally
and by the presence of antibodies against the toxins.23
Fig. 18.104
• If the same staphylococcus infects the skin directly, local release of toxin Staphylococcal scalded skin syndrome: there is quite marked acantholysis in this
results in bullous impetigo. example.
Staphylococcal strains also produce toxic shock syndrome toxin (TSST-1)
and a variety of enterotoxins (A–E). These are more frequently associated
with staphylococcal scarlet fever and the toxic shock syndrome.19,24 Differential diagnosis
The toxin in both SSSS and bullous impetigo causes a split in the epidermis
The main clinical differential diagnosis is from toxic epidermal necrolysis
at the level of the granular layer (Fig. 18.103). Ultrastructurally, the level of
(TEN), a severe variant of erythema multiforme usually due to a drug reac-
separation is in the midgranular layer.25 It is associated with separation of the
tion. This, however, is uncommon in children. In TEN the skin changes are
cell membranes at the desmosomes, and the interdesmosomal regions appear
very widespread and mucosal involvement is common, whereas SSSS extends
less dense.26 The cells on either side of the cleft appear normal. It has been
from the face and flexures and does not involve mucosae. The contrasting
shown that the epidermolytic toxins (ETA and/or ETB) act as serine proteases
histology of the two conditions can be used with a frozen section technique
and bind desmoglein 1, a desmosomal adhesion molecule.20,21 The cleavage
to give a rapid diagnosis:4,5
and subsequent inactivation thereof induces blistering.21,24
• TEN is characterized by a subepidermal blister with a necrotic epidermal
Histologically, the clefts through the granular layer of the epidermis in
roof and a moderately intense lymphocytic infiltrate in the dermis.
SSSS are associated with only a scanty inflammatory infiltrate in the epider-
• SSSS is characterized by separation through the granular cell layer.
mis or dermis and there may be some dermal edema and dilatation of the
Alternatively, a Tzanck smear can be used, which reveals necrotic kerati-
superficial vascular plexus. The adjacent epidermis does not show necrosis.
nocytes with inflammatory cells in TEN and viable acantholytic keratinocytes
Acantholysis is variably present (Fig. 18.104).
without inflammatory cells in SSSS.

Erysipelas and cellulitis

Fig. 18.103
Staphylococcal scalded
skin syndrome:
vesiculation occurs at the
level of the granular cell
layer.
Clinical features
Erysipelas
Erysipelas is classically a S. pyogenes (group A β-hemolytic streptococcal)
infection of the skin of the face, characterized by a sharply outlined edema-
tous, erythematous, tender, and painful plaque (Fig. 18.105). The outer mar-
gin is elevated and contrasts with the adjacent normal skin. Towards the edge
of the lesion there may be vesicles and hemorrhagic bullae. Other sites com-
monly affected include the feet and hands. Although S. pyogenes is the most
common organism, it is not always possible to culture it, and other strepto-
cocci (group C or G) or S. aureus may occasionally be isolated.1–4
The classical presentation of erysipelas is most often on the face, but it
has been suggested recently that the features of this condition are chang-
ing because it is becoming more common and is predominantly affecting the
lower limbs.4 A seasonal variation in incidence is not uniformly found.
The superficial infection of erysipelas is associated with a fever and mal-
aise. It is similar in its presentation, etiology and associated symptoms to
cellulitis, a spreading infection affecting deeper tissues. This lesion is again
clearly demarcated, hot, red, and painful, but without the elevated margin
of erysipelas. An associated lymphangitis and lymphadenitis are common.
The lesions may progress to pustulation, ulceration, and necrosis; the last
may involve underlying fascia and muscle, resulting in necrotizing fasciitis.5
Osteoarticular complications such as bursitis, arthritis, tendinitis, and osteitis
have been reported.6

Cellulitis
Cellulitis is similar to erysipelas, but tends to involve the deeper tissues and
is seen most often on the legs, where it complicates tinea pedis or chronic
­lymphedema (Fig. 18.106).7,8 Other potential risk factors include diabe-
tes mellitus, leukemia, postsaphenous venectomy, and peripheral vascular
­disease. Patients with dry skin may also be susceptible.9 Cellulitis is char-
acterized by an expanding area of erythema. Involvement of lymphatics in
both erysipelas and cellulitis is characteristic, resulting in the edema which
is sometimes associated with vesiculation (Fig. 18.107); infective damage
to ­lymphatics in ­cellulitis may be the reason this condition can become
recurrent.
The term hemorrhagic cellulitis has been applied to an uncommon
clinical syndrome caused by Gram-positive or Gram-negative organisms
of noncutaneous origin. Patients manifest with the abrupt onset of pain-
ful erythema on the lower extremities, followed by dermal hemorrhage
and sloughing of the overlying epidermis.10 There is usually a satisfac-
tory response to a combination of antibiotics and corticosteroid therapy.
Virulent marine bacteria such as Vibrio vulnificus may result in this form
of bullous and hemorrhagic ­cellulitis; the disease carries an estimated mor-
tality of 15%.11
Pathogenesis and histological features
Minor trauma to the skin is important in the development of both erysipe-
las and cellulitis, but peripheral vascular disease, diabetes, lymphedema, and
alcohol abuse are additional predisposing factors.
In both erysipelas and cellulitis, S. pyogenes is the most common organ-
ism and the lesions are initiated by inoculation of minor abrasions or splits in
the epidermis.12 Proliferation of the organisms is associated with the produc-
tion of enzymes (streptolysins, deoxyribonuclease B, hyaluronidase) which
may be detected in rising titers and may therefore be useful diagnostically.13
These enzymes are also important in facilitating the extension of the bacte-
ria in the skin. Lymphatic involvement with obstruction is common, result-
ing in edema, and is associated with lymphangitis and lymphadenitis. In the
Fig. 18.105 Fig. 18.106
Erysipelas: characteristic sharply demarcated Cellulitis: note the widespread erythema. The lower leg
erythematous and edematous plaque. By courtesy of is a characteristic site. By courtesy of R.A. Marsden,
J.C. Pascual, MD, Alicante, Spain. MD, St George's Hospital, London, UK.
Erysipelas and cellulitis 795
more aggressive forms of cellulitis it is likely that other organisms (certainly
S. aureus and some anaerobes) may be causative or synergistic.14 A syner-
gistic role for Staphylococcus aureus (especially methicillin-resistant strains)
and S. pyogenes has been implicated in the development of bullous erysipe-
las.15 Group G streptococci predominated over group A β-hemolytic strepto-
cocci in a recent Finish series of 90 patients with acute cellulitis.16 There have
been rare reports of severe cellulitis due to organisms such as S. pneumoniae,
Haemophilus influenza, and Nocardia otitidiscaviarum.17–19 In those forms of
cellulitis in which necrosis is a more prominent feature bacterial toxins are an
important mechanism.
Histologically, the conspicuous features of erysipelas and cellulitis are der-
mal edema and lymphatic dilatation. There is also a diffuse, heavy neutrophil
infiltration with a limited localization around blood vessels. Vascular and
lymphatic dilatation and red cell extravasation are variable features. In later
stages some lymphocytes and histiocytes are also seen and granulation tis-
sue may be present deep to the zone of subepidermal edema. When clinical
vesicles or bullae are noted, there is a corresponding severe papillary edema
merging with subepidermal vesiculation.20
In hemorrhagic cellulitis the bacterial lipopolysaccharide-induced or bac-
terial mitogen-induced release of tumor necrosis factor alpha (TNF-α) is
thought to result in injury to endothelial cells and epidermal keratinocytes.
DNA fragmentation and cell lysis may be the consequence of neutrophil
degranulation and anti-DNase activation.10 Digestion of vascular basement
membrane as a result of V. vulnificus metalloprotease production leads to the
formation of hemorrhagic bullae.21 Histologically, there is necrosis of epider-
mal keratinocytes, necrotizing vasculitis affecting dermal blood vessels, and
large numbers of bacteria.22
It is important to remember that not all cases of cellulitis are bacte-
rial in origin; deep fungal infections such as cryptococcosis and aspergil-
lus may ­present with cellulitis in immunocompromised hosts.23 Appropriate
­histochemical stains and the referral of additional specimens for microbio-
logical ­examination should facilitate correct identification of the etiological
agent.
Fig. 18.107
Cellulitis: marked edema has resulted in vesiculation.
By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
796 Infectious diseases of the skin
Necrotizing fasciitis
Clinical features
Necrotizing fasciitis (NF) is an uncommon, rapidly progressive, and poten-
tially fatal bacterial infection of the subcutaneous soft tissues. In recent years
there has been a dramatic resurgence in the number of reported cases.1–3 NF
may evolve following a surgical procedure (e.g., esthetic liposuction, caesar-
ean section, laparoscopic appendicectomy, excision of a skin lesion or even
cardiac catheterization), minor trauma, seemingly insignificant scratches, in
the presence of a chronic wound, or even in apparently intact skin.4–9 NF
occurs predominantly in middle-aged individuals, although the pediatric pop-
ulation may also be affected.1,10–14 Patients with underlying diabetes mellitus
and iatrogenic immunosuppression are particularly susceptible.10,15–19 NF is
a well-recognized complication of childhood varicella.13,14,20 Many reported
cases have developed after intramuscular injection of nonsteroidal antiinflam-
matory drugs, which may in turn mask the symptoms of evolving NF.10,21–24
Rare cases have occurred following the bite of a spider.25 NF may be a rare
complication of fistulating Crohn's disease.26 Reported mortality ranges from
9.4% to 53%.2,3,10,13,18,19 An increased fatality rate may be encountered in the
elderly and in those with worsening symptoms and signs within the first 48
hours of hospital admission.15
Although group A β-hemolytic streptococci (so-called ‘flesh-eating’ bacte-
ria) were first recognized as a prime etiological agent, a number of other aero-
bic and even anaerobic pathogens have been implicated.1,27,28 It has become
increasingly apparent that NF very often is a polymicrobial condition. In
some series, Staphylococcus aureus is the most frequently cultured organ-
ism.28,29 Less often, other streptococci have been identified; these include
group B and group G β-hemolytic streptococci, Streptococcus pneumoniae
and anaerobic streptococci (Peptostreptococcus spp.).22,28,30–32 Other bacte-
ria implicated include marine organisms (Vibrio vulnificus, V. parahaemo-
lyticus, Photobacterium damsela), members of the family Enterobacteriaceae,
Serratia marcescens, Pseudomonas spp., Clostridium spp. and Bacteroides
spp.11,17,28,33–41 Meleney's postoperative progressive synergistic gangrene
(Meleney's gangrene) is synonymous with polymicrobial NF arising as a com-
plication of surgical trauma.42 The latter condition may be clinically indistin-
guishable from postsurgical cutaneous amebiasis.42,43
The clinical presentation may be fulminant, acute or subacute.10 NF com-
mences as an ill-defined area of erythema, accompanied by tenderness, swell-
ing, and increased temperature.44 It is, therefore, not uncommon for evolving
NF to be mistaken for cellulitis or an insignificant wound infection, especially
when the hallmark cutaneous necrosis is not established. This may result in
a potentially life-threatening delay in diagnosis and aggressive surgical deb-
ridement.45 The clinical features of established NF include severe pain, indu-
rated edema, skin necrosis, cyanosis, bullae (which may be hemorrhagic,
especially in cases caused by Vibrio spp.), crepitation, muscle weakness, and
malodorous exudates (Fig. 18.108).19,23,35,44 Anesthesia may be a late sign.44
Patients often have other systemic manifestations of severe sepsis, including
hypotension, tachycardia, tachypnea, oliguria, and mental confusion.23,46 In
NF caused by streptococcal species, the latter signs are usually attributable
to streptococcal toxic shock syndrome.21 Radiographs may reveal gas in the
affected soft tissues.46 NF occurs mainly on the extremities, although almost
any site may be affected, including the abdominal wall, chest wall, eyelids
and periorbital region, and the head and neck region.15,47–50 Periumbilical NF
may occur in newborn infants.12,14 The Waterhouse-Friderichsen syndrome is
a potential complication of NF.51
Fournier's gangrene is a clinical variant of NF which involves the penis,
scrotum, perineum, and abdominal wall in men and (less often) the vulva in
women.52–55 An obliterative endarteritic process affecting the small branches
of the superficial branch of the internal pudendal artery may play a key
pathogenetic role.56 Because of a response to corticosteroids, Fournier's gan-
grene may be perceived as a localized vasculitis.57 In addition to the usual
risk factors such as diabetes mellitus or immunosuppression, rare associa-
tions include vasectomy or unhygienic ritual circumcision.54 The reported
mortality of this polymicrobial synergistic necrotizing infection is in the
order of 16–20%.52,54,58 Extent of infection is a significant predictor of ­clinical
outcome.58
Fig. 18.108
Necrotizing fasciitis: this
example has resulted in
exposure of muscle and
tendons. By courtesy
of R.A. Marsden, MD,
St George's Hospital,
London, UK.
Pathogenesis and histological features
Necrotizing fasciitis due to invasive group A β-hemolytic streptococcal infec-
tion is associated predominantly with M types 1 and 3, which produce either
pyrogenic exotoxin A or B, or both.27 Tissue invasion is facilitated by CD44-
mediated cell signaling with subsequent manipulation of the host cytoskel-
eton.59,60 Superantigens and Th1 cytokines appear to play a critical role in
severe group A invasive streptococcal infections.61 Streptococcal cysteine pro-
tease SpeB inactivates the antimicrobial peptide cathelicidin LL-37 at the bac-
terial surface.62 Impaired recruitment of polymorphonuclear leukocytes to the
site of the infection has been linked to the streptococcal peptidase ScpC which
degrades IL-8.63 Protein S deficiency may be responsible for the necrosis.64
Staphylococcus aureus may potentiate the β-hemolytic streptococcal infec-
tion in NF.43
An adequately sized specimen including subcutaneous soft tissue is essential
for diagnosis. The histological appearances are those of a severe necrotizing
process with edema, necrosis, and inflammation involving skin and subcuta-
neous tissue, including fascial planes (Figs 18.109, 18.110).65 Deep biopsies
or debridement specimens containing underlying skeletal muscle may exhibit
concomitant myonecrosis.1 Vascular thrombosis is encountered at all levels,
and secondary vasculitic alterations are not uncommon. Hyaline necrosis of
sweat glands has been described.65 The presence of large numbers of bacteria
often results in diffuse basophilia of the tissue on low-power examination.
A Gram or Brown-Hopps' stain confirms the latter (Fig. 18.111).
Although the histological picture is sufficiently distinctive to facilitate
a diagnosis of NF, microbiological examination (including aerobic and
anaerobic tissue culture) is of paramount importance in the identification
of the specific infective etiological agent(s). Intraoperative frozen section
has a ­particularly useful role to play, not only in early diagnosis but also
in ­assessing the viability of surgical margins at the time of debridement.66
PCR detection of streptococcal pyrogenic exotoxin B may be useful in
confirming group A streptococcal infection when cultures are negative or
unavailable.67
Differential diagnosis
Necrotizing (gangrenous) cellulitis has a similar etiopathogenesis to NF but
shows no extension of the necrotizing inflammatory process into subcutane-
ous tissue planes. This diagnosis should be made with caution and only when
 Infective folliculitis 797

Fig. 18.109 Fig. 18.111

Necrotizing fasciitis: there is intense acute inflammation of the dermis and Necrotizing fasciitis: innumerable Gram-positive cocci are present.
subcutaneous fat.

there is a complete absence of subcutaneous involvement in a specimen that

is of sufficient depth. NF is invariably associated with necrotizing inflamma-
tion of the dermis. Furthermore, necrotizing cellulitis may be a harbinger of
impending NF.
Tissue autolysis with bacterial overgrowth may closely mimic NF, espe-
cially if tissue is obtained from a patient with a relatively minor cutaneous
infection and the specimen was not placed in the appropriate formalin fixa-
tive prior to submission to the laboratory.
NF is distinguished from pyoderma gangrenosum and Sweet's syndrome
by the absence of true tissue necrosis and demonstrable bacterial organisms
by culture or appropriate stains in the latter two conditions. Although there
is frequent dermal infiltration by polymorphonuclear leukocytes in pyoderma
gangrenosum and invariable neutrophilic dermatosis in Sweet's syndrome,
the acute inflammatory changes in both conditions are centered on the dermis
rather than the subcutis. Vasculitic alterations may occur in both pyoderma
gangrenosum and NF but are usually absent in Sweet's syndrome.

Infective folliculitis
A
Clinical features
Infection of hair follicles is probably the commonest form of skin infection.
It is usually due to S. aureus (impetigo of Bockhart) and, although disfig-
uring, is self-limiting.1–7 Pustular folliculitis usually implies infection of the
ostium and upper part of the follicle. It presents as numerous small red and
­tender pustules, which discharge pus and quickly resolve without scarring
(Fig. 18.112). Staphylococcal carriers tend to have recurrent infections.8
The role of community-acquired methicillin-resistant S. aureus in cutaneous
­infections, including folliculitis, has been emphasized in the recent literature.9
Pseudomonas aeruginosa is a well-recognized cause of epidemics of fol-
liculitis associated with swimming pools, whirlpools or spa baths.10–12 These
shared facilities can be infected by Pseudomonas if they became alkaline and
if the chlorine content drops. Nevertheless, moisture and occlusion are neces-
sary to affect normal skin. For this reason lesions of this type are found only
under the area covered by bathing costumes. Other Gram-negative bacteria
such as Klebsiella spp., Escherichia coli, Enterobacter spp., and Proteus spp.
have been implicated in the pathogenesis of folliculitis in patients receiving
B long-term antibiotic therapy for treatment of acne or rosacea.13 Extensive
folliculitis may be an early manifestation of HIV infection.1 Micrococcus
Fig. 18.110 spp., which are considered to be commensal organisms, may be a cause of
(A, B) Necrotizing fasciitis: there is an almost pure neutrophil infiltrate with f­olliculitis in patients with HIV infection.14 Folliculitis due to Acinetobacter
necrosis. baumanii has been reported in a patient with AIDS.15
798 Infectious diseases of the skin
Fig. 18.112
Folliculitis: characteristic small pustules with surrounding erythema. By courtesy of
R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 18.113
Furuncle: early lesion characterized by edema and erythema. By courtesy of the
Institute of Dermatology, London, UK.
A furuncle or boil is a more exuberant form of suppurative folliculitis. It
is common in young adults and usually affects the skin of the face, neck, but-
tocks, and axillae (Figs 18.113–18.115).1 Lesions can be up to 2 cm across
and the inflammation is not confined within the follicle, but is associated with
much surrounding erythema and often systemic symptoms. After discharge of
the pustular necrotic core the lesion heals rapidly, but with scarring. A deep fol-
liculitis due to S. aureus may affect the beard area; this form is termed sycosis
or folliculitis barbae.
A carbuncle is a variant of a furuncle with multiple tracks and routes of
discharge. It is most commonly seen in older men and may be associated with
systemic symptoms.1,5
Acute paronychia is comparable to a folliculitis in that it is a painful suppu-
rative infection of the nail fold, most commonly caused by S. aureus; it heals
rapidly on release of the pus (Fig. 18.116). A rare scarring alopecia in which
S. aureus has been implicated is termed folliculitis decalvans.16 Although the
scalp is predominantly affected, lesions may also be found in the axillae and
pubic region (Fig. 18.117).
Fig. 18.114
Furuncle: multiple
erythematous nodules
in the axilla, which is a
commonly affected site.
The lesions are exquisitely
painful. By courtesy
of R.A. Marsden, MD,
St George's Hospital,
London, UK.
Fig. 18.115
Furuncle: note the large swelling on the thigh. This patient was HIV positive.
By courtesy of C. Furlonge, MD, Port of Spain, Trinidad.
Pathogenesis and histological features
Many cases of superficial suppurative folliculitis are associated with S. aureus.
The infection is not due to a break in the epithelium, but growth occurs with
the ostium of the follicle and may progress more deeply around the hair shaft.
There is an associated accumulation of neutrophils, forming an abscess asso-
ciated with spongiosis and infiltration of the adjacent follicular epithelium.
The superficial suppurative folliculitis may discharge through the ostium
and rapidly resolve. Alternatively, it may progress more deeply and rupture
through the follicular epithelium; the abscess then extends into perifollicular
dermis and surrounds the whole follicle. The follicular epithelium and hair
shaft with pus then form the purulent necrotic core of the furuncle or boil.
Healing is preceded by a lymphohistiocytic or even granulomatous phase and
is followed by scarring and loss of hair in the involved area. A carbuncle is
 Meningococcal septicemia 799

c­ ommonly in black than in white men. Although it was initially thought

not to develop in females, rare cases have been reported.1–3 It presents in the
early stages with inflamed papules and pustules, but no consistent organisms
are found. Patients may complain of itching, burning or pain and advanced
lesions may be foul smelling.1 Each lesion is complicated by dense scarring,
producing a keloid-like appearance. Scarring alopecia is a complication.2 The
condition has recently been reported in Caucasian organ transplant recipi-
ents on cyclosporin therapy.4 Isolated cases occurring in association with
keratosis follicularis spinulosa decalvans have been documented in recent
publications.5,6

Pathogenesis and histological features

The pathogenesis is unknown. Any bacteria identified probably represent a
secondary phenomenon. It is doubtful whether poor hygiene is a factor. There
may be an element of pseudofolliculitis (see below) since the condition is
common in Afro-Caribbeans and Africans and is worsened by close shaving
of the neck.1,7–9 The use of pomades and wearing tight collars is said to exac-
erbate the condition.1 The term acne keloidalis is a misnomer, as the disorder
has nothing to do with acne vulgaris or its variants.
The follicle, which may contain pus extending through the epithelium, is
Fig. 18.116 initially surrounded by a lymphocytic and neutrophil infiltrate; later there are
Acute paronychia:
large numbers of plasma cells. The perifollicular inflammation is maximal at
pus and erythema are
present. By courtesy the level of the isthmus and lower infundibulum.2,10 The condition is more often
of E.E. Gluckman, MD, seen at a later stage, however, when there is marked fibrosis accompanying
King's College Hospital, free, broken hair shafts, many of which are surrounded by a foreign body giant
London, UK. cell reaction. Hyalinization as seen in a true keloid is only very occasionally a
­feature. Complete loss of the sebaceous glands is a frequent occurrence.2,10

Fig. 18.117
Folliculitis decalvans: there is severe scarring with alopecia. Erosions, crusting,
and pustules are seen at the hairline. By courtesy of M.M. Black, MD, Institute of
Dermatology, London, UK.
associated with more persistent suppuration, much more fibrosis and granu-
lation tissue. Panton-Valentine leukocidin-producing strains of S. aureus have
been linked to the evolution of deep-seated, often multiple furuncles.17
Although most of the suppurative forms of folliculitis are due to S. aureus,
other causal conditions include dermatophytosis, herpes simplex, and ­syphilis;
the features of these infections are described under the appropriate headings
elsewhere in this chapter.
Folliculitis keloidalis nuchae
Clinical features
This deep and scarring folliculitis and perifolliculitis (sometimes known
as acne keloidalis or acne keloidalis nuchae) occurs on the back of the
neck (lower occipital/nuchal region) of postpubertal males. It occurs more
Pseudofolliculitis
Clinical features
Pseudofolliculitis (pseudofolliculitis barbae) presents with an acneiform pap-
ular and pustular eruption on the beard area. Comedones are not a feature. It
develops as a consequence of the reentry of a terminal hair shaft through the
epidermis and occurs most often in males with curly hair, but is also seen in
women in the pubic region following cosmetic shaving.1–4 Pseudofolliculitis
occurs predominantly in patients of African, African-American, and Hispanic
origin.2 The pathogenesis appears to be multifactorial, and seems to relate
to the shape of the hair follicle, the hair cuticle, and the direction of hair
growth.2 The penetration is facilitated by the sharp ends produced on hairs
by shaving and the curliness of the hair bringing the cut end back into con-
tact with the skin surface.4 Alternatively, the penetration may occur laterally
through the superficial part of the follicular infundibulum following partial
retraction of the hair after close shaving. A single-nucleotide polymorphism
in the keratin K6hf gene has been implicated in the pathogenesis of pseudo-
folliculitis.5 A hypertrophic form of the disease has been described in renal
transplant recipients.6
Histological features
The process is not a true folliculitis, and is not usually associated with infec-
tion. The reentry of the hair shaft provokes a foreign body granulomatous
reaction with accompanying fibrosis. The inflammation is predominantly his-
tiocytic with occasional multinucleate giant cells. Secondary infection may
result in superimposed suppuration. Resolution occurs rapidly, with slight
scarring, once the hair shaft is removed.
Meningococcal septicemia
Clinical features
Meningococcal septicemia is due to the Gram-positive diplococcus Neisseria
meningitidis.1–4 In its acute form this is a very serious condition with a high
mortality, which affects children in seasonal epidemics. It is spread via drop-
let inhalation from upper respiratory tract infections. Meningitis is the most
frequently encountered manifestation of meningococcal infection. Children
with acute meningococcal septicemia develop widespread purpura that shows
800 Infectious diseases of the skin
a predilection for the trunk and limbs. Ecchymoses may also be a feature. In
the more chronic variant (chronic meningococcemia), patients present with
vasculitis-like lesions, particularly nodules, and palpable purpura.5
Pathogenesis and histological features
The histological features are essentially those of a leukocytoclastic vasculitis.6
Superimposed DIC may also be present. The hemorrhagic skin lesions and
vascular thromboses are attributable to upregulation of tissue factor lead-
ing to coagulation, and by inhibition of fibrinolysis by plasminogen activator
inhibitor.7 Impairment of the protein C anticoagulation pathway also plays
an important role.8
Diplococci may be demonstrable in Gram-stained sections, especially
in biopsies obtained from purpuric lesions.6 Culture or Gram staining
of aspirates or biopsies of skin lesions may facilitate early diagnosis. 9
Diagnosis can also be confirmed on skin biopsy with the aid of a PCR-
based method.10
Gonorrhea
Clinical features
This common venereal disease is due to infection with the Gram-negative
intracellular diplococcus Neisseria gonorrhoeae, which especially affects
the mucous membranes. In males this results particularly in purulent ure-
thritis, although gonococcal proctitis and oropharyngitis may also be seen.
Females most often develop endocervicitis. Urethritis and proctitis can also
be features.1
Systemic gonococcal infection most commonly affects the skin, but may
also result in arthritis and less often endocarditis or meningitis.1–3 Patients
present with small numbers of erythematous macules that progress to
painful papular, petechial or pustular lesions that particularly affect the
distal limbs (Fig. 18.118).2,4 They measure from 1 to 2 mm up to 2 cm
in diameter. Lesions may appear frankly vasculitic.5 Cutaneous lesions
can be a presenting feature of disseminated infection during pregnancy.3,6
Rarely, however, patients present with primary cutaneous (genital and
extragenital) involvement.2,4 Cellulitis, pustules, ulcers, and furuncle-like
lesions have been documented.7,8 Pyogenic granuloma-like lesions of the
penile shaft have also been described.9 Primary digital gonorrhea has been
recorded.7
Pathogenesis and histological features
Disseminated lesions show variable epidermal changes ranging from edema
accompanied by a neutrophil infiltrate with purpura, to vesiculation,
Fig. 18.118
Gonococcemia: pustules are commonly found on the hands and feet. By courtesy
of R.N. Thin, MD, St Thomas' Hospital, London, UK.
­ ustulation, and eventually necrosis.4 In the dermis the histological features
p
are essentially those of a neutrophil-mediated acute vasculitis, often accom-
panied by thrombosis.10 Very occasionally Gram-negative diplococci may be
identified.
Plague
Clinical features
Plague is an acute, febrile infectious disease caused by Yersinia pestis, a non-
motile, bipolar Gram-negative aerobic bacillus and one of the most deadly
pathogens known to man.1–5 The disease has a high incidence in South
Africa, Madagascar, the Far East, and parts of India. Foci of plague have
also been reported from southwestern states of the USA and in parts of South
America.1,2,6–8 Rodents act as the reservoir, and the infection is usually trans-
mitted to humans via the bite of a flea; aerosol spread may also occur, leading
to pneumonic plague.1,3–5 Y. pestis is well recognized as a potential bioweapon
and bioterrorism agent.5 There are three distinct clinicopathological forms
of the disease: bubonic plague, primary pneumonic plague, and primary
­septicemic plague.1–4
Bubonic plague
Bubonic plague accounts for the vast majority of cases. After a short incuba-
tion period of approximately 2–4 days, the disease manifests abruptly with
pyrexia, chills, tachycardia, and tachypnea, and the formation of a so-called
bubo – a painful, pathologically enlarged unilateral group of infected lymph
nodes, usually in the groin or axilla (Fig. 18.119).1 Cervical and axillary
buboes are more common in children than in adults.7 Septicemia and second-
ary pneumonic plague may follow in untreated cases. Minor (‘ambulatory’)
forms of bubonic plague also exist.1
Primary pneumonic and primary septicemic plague
Primary pneumonic plague is acquired by inhalation of the organisms,
whereas primary septicemic plague tends to occur after the bite of an infected
flea on the head and neck region. Untreated, both of these forms of plague
carry a mortality of around 90%.2
Cutaneous manifestations
Cutaneous manifestations of Y. pestis infection are seen predominantly in
bubonic plague. A small vesicle, pustule, papule or necrotic lesion may
develop at the site of the flea bite. The skin overlying the bubo is ery-
thematous and edematous and may undergo hemorrhage and necrosis,
Fig. 18.119
Bubonic plague: note the
inguinal lymphadenopathy
(bubo). By courtesy
of J. Frean, MD, and
the late M. Isaäcson,
MD, University of
Witwatersrand,
Johannesburg, South
Africa.
 Cutaneous anthrax 801

resulting in the formation of fistulae.1,2 Roseolar, scarlatiniform, vesico-

pustular, and erythema multiforme-like eruptions may occur elsewhere
on the body.1 Petechial hemorrhages and ecchymoses characterize severe
cases. Cutaneous ulceration and necrosis may ensue, hence the term ‘black
death’.2

Histological features
The lymph nodes comprising the buboes show severe acute hemorrhagic
lymphadenitis in the presence of large amphophilic or ‘ground-glass’ aggre-
gates of bacilli. Their characteristic ‘safety-pin’ appearance is discernible on
sections stained with the Gram's or Giemsa methods.1,2 Extranodal extension
results in ulceration of the overlying skin. Subsequent septicemic illness may
be complicated by DIC. In the skin the latter manifests with intradermal hem-
orrhage, thrombotic vascular occlusion, and multiple cutaneous infarcts.2 The
diagnosis may be confirmed by microscopy, culture, immunofluorescence,
enzyme-linked immunosorbent assay or PCR.1–4,7 An immunohistochemical
method for detection of the organism in formalin-fixed, paraffin-embedded
tissue has been described.9
Fig. 18.121
Cutaneous anthrax Anthrax: multiple lesions on the forearm. By courtesy of J. Frean, MD, and the late
M. Isaäcson, MD, University of Witwatersrand, Johannesburg, South Africa.

Clinical features
Anthrax is a zoonotic infection caused by Bacillus anthracis, an encapsu-
lated, spore-forming, Gram-positive bacillus.1,2 Although the condition is
relatively uncommon in humans, epidemic outbreaks still occur in tropical
and subtropical regions of the world (including Africa and South America),
southern Europe, the Middle East, and India.1–5 Anthrax is very rarely seen
in developed countries.6–8 Cutaneous anthrax accounts for more than 95%
of cases; pulmonary and gastrointestinal forms account for the remainder,
and are associated with a high mortality.1 The condition is usually acquired
after contact with infected animals (herbivores) or contaminated animal
products.4 It has also been described in rural Turkish children who were sub-
jected to the ritual smearing of cow's blood on their foreheads.9 Under ideal
conditions, spores may survive in the soil or in animal products for many
years.1 Recently there has been renewed interest in the organism as an agent
of bioterrorism.8,10
Cutaneous anthrax occurs after inoculation of B. anthracis into abraded
skin. An erythematous macule or papule develops after an incubation period
of 2–3 weeks. This later evolves into a pruritic vesicle. A characteristic black
eschar develops after breakdown of the blister (Figs 18.120, 18.121).1 There
is often pronounced edema of the surrounding skin, sometimes accompanied
by the formation of bullae.1 Lymphadenitis is ­sometimes seen. Septicemia may
arise in untreated cases; this carries a mortality of 10–20%.1,2 A rare form of
the disease termed malignant edema presents with severe, rapidly spreading
edema, lymphangitis, lymphadenitis, and ­systemic symptoms. Hemorrhagic
and necrotic vesicles may evolve in these cases.1
Pathogenesis and histological features
B. anthracis is associated with potent virulence factors, namely a poly-D
­glutamic acid capsule and a plasmid-encoded protein exotoxin consisting of
three components: edema factor, protective antigenic factor, and lethal fac-
tor.2,11 Edema factor leads to increased vascular permeability via the produc-
tion or release of inflammatory mediators, including neurokinins, prostanoids
and histamine.12
The histological picture is dominated by massive subepidermal edema
(Fig. 18.122).6,13 Intraepidermal edema results in coalescent intercellular
vacuoles.1 The epidermis is often attenuated. The dermis is expanded by a

Fig. 18.120 Fig. 18.122

Anthrax: cutaneous disease is the commonest manifestation in humans. This black Anthrax: there is massive subepidermal edema with subepidermal vesiculation.
crusted lesion is typical. By courtesy of J. Frean, MD, and the late M. Isaäcson, MD, Reproduced with permission from Mallon E, McKee PH. Extraordinary case report:
University of Witwatersrand, Johannesburg, South Africa. cutaneous anthrax. American Journal of Dermatopathology. 1977; 19: 79–82.
802 Infectious diseases of the skin
dense ­inflammatory infiltrate consisting of large numbers of polymorpho-
nuclear leukocytes, admixed with lymphocytes and histiocytes. The ­process
often extends into subcutaneous fat.6 Vasodilatation may be prominent.
Hemorrhage and fibrin deposition occur in the deep dermis and subcutis
(Fig. 18.123). Thrombotic vascular occlusion and fibrinoid necrosis of blood
­vessel walls may be encountered in the deep dermis and subcutaneous fat (Fig.
18.124). Gram stain will reveal considerable numbers of large Gram-positive
bacilli in the superficial dermis (Fig. 18.125).6 The diagnosis is confirmed by
culture. Serological investigations are also available. Immunohistochemical
methods of detection may be employed on tissue specimens.2
Brucellosis
Clinical features
Brucellosis is a zoonotic infection by Brucella spp. such as B. meliten-
sis, B. abortus, B. canis, and B. suis.1–3 The organism is a Gram-negative
bacillus and infection is acquired either by ingesting contaminated,
Fig. 18.123
Anthrax: marked fibrin deposition is evident. Reproduced with permission from
Mallon E, McKee PH. Extraordinary case report: cutaneous anthrax. American
Journal of Dermatopathology. 1977; 19: 79–82.
Fig. 18.124
Anthrax: thrombosed vessels are present. Reproduced with permission from
Mallon E, McKee PH. Extraordinary case report: cutaneous anthrax. American
Journal of Dermatopathology. 1977; 19: 79–82.
Fig. 18.125
Anthrax: numerous elongated Gram-positive bacilli are present. Reproduced with
permission from Mallon E, McKee PH. Extraordinary case report: cutaneous
anthrax. American Journal of Dermatopathology. 1977; 19: 79–82.
unpasteurized milk/milk products, or by handling infected animal prod-
ucts (contact brucellosis). Human-to-human transmission does not occur.
Brucellosis results in either an acute febrile illness or a chronic systemic
disease ­characterized by fever, malaise, sweats, arthralgia, myalgia, and/
or ­hepatosplenomegaly.1–3 The mortality is low and most patients recover
within 3 months.3
Cutaneous manifestations occur in approximately 6% or less of cases;
however, this figure approached 14% in a recent series from Turkey.4–7
A number of cutaneous manifestations have been recorded, including a
disseminated papulonodular eruption, a diffuse maculopapular rash,
­erythema nodosum-like subcutaneous nodules, purpura, leukocytoclastic
vasculitis, erythema multiforme, urticaria-like papules and plaques, multi-
ple abscesses, cutaneous ulcers, ecchymoses and (rarely) livedo reticularis,
palmar erythema or a even a large mass mimicking a soft tissue tumor.3–6,8–12
Vasculitic skin lesions may form part of an infection-induced systemic
thrombotic microangiopathy mimicking Henoch-Schönlein purpura.13,14
There is a single case report of Brucella-associated Stevens-Johnson syn-
drome.15 Contact brucellosis manifests with erythema or pruritus, usually
on the forearm or hand. In some cases this may progress to a follicular,
vesicular or pustular eruption.3 A rare case of contiguous skin involve-
ment secondary to underlying Brucella chronic osteomyelitis was recorded
recently.16 A factitious case of brucellosis caused by autoinoculation has
also been reported; the patient developed bacteremia and ulcerating
­cutaneous abscesses.17
Histological features
The histological features vary according to the type of cutaneous lesion
biopsied. Biopsies obtained from the erythematous papular lesions show
a perivascular and periadnexal infiltrate of lymphocytes and histiocytes,
sometimes accompanied by epithelioid histiocytes and multinucleated
giant cells.4 Erythrocyte extravasation is sometimes seen, and inflamma-
tory cells may infiltrate the overlying epidermis.8 Erythema nodosum-like
nodules are characterized by a perivascular lymphohistiocytic infiltrate
centered on the deep dermis and superficial subcutis.4,9 There is associ-
ated vascular endothelial swelling and luminal thrombosis, sometimes
with foci of necrosis. Accompanying granulomatous inflammation is not
uncommon.8 Erythema multiforme lesions and leukocytoclastic vascu-
litic lesions exhibit the usual histological changes associated with these
conditions.
Brucella organisms are rarely visualized in histological material. The diag-
nosis is therefore confirmed by culture, serology or PCR.1,3,4,8,18
 Diseases caused by Bartonella species 803

Diseases caused by Bartonella species

Cat scratch disease
Clinical features
Cat scratch disease is a not uncommon, usually self-limiting illness which,
as its name implies, usually follows (after 3–5 days) a scratch or bite by a
cat (usually a kitten).1–7 On rare occasions, it has been reported following
a similar injury caused by a dog or even by a monkey.4 It occurs equally in
males and females, most often during the first two decades. Cat scratch dis-
ease shows seasonal variation, occurring usually in autumn and winter.1 The
causative agent is Bartonella henselae (formerly Rochalimaea henselae), a
weakly Gram-negative bacillus measuring 1–2 μm in length.5,6 The condition
was first described in 1950, yet the nature of the infective etiological agent
remained elusive until recently.6 In the past, a variety of infectious agents had
been suggested as responsible for cat scratch disease, including mycobacteria,
Chlamydia, herpes-like viruses and, more recently, Afipia felis.5,8 The cat rep-
resents the primary reservoir for the bacillus in addition to being its principal
Fig. 18.126
vector.9 Although transmission among cats is via the cat flea, the latter does
Cat scratch disease: an irregular ill-defined focus of necrobiosis is surrounded by a
not appear to play a direct role in transmission to humans.5,6 nodular lymphocytic infiltrate.
The primary skin lesion – a macule, papule, vesicle, pustule or nodule –
develops most commonly on the arm or hand, followed by the head, leg, con-
junctiva, trunk or neck, in decreasing order of frequency. Sometimes more
than one member of a family may be affected. The cutaneous lesions measure
1–5 mm or more in diameter and may sometimes resemble an insect bite.1
Other rare cutaneous manifestations include a nonpruritic macular or
maculopapular rash, erythema nodosum, urticaria, erythema marginatum,
erythema annulare, and thrombocytopenic purpura. A case with cutaneous
lesions resembling those of Sweet's syndrome has been reported.10 Fever and
malaise are occasional symptoms. Less common additional features include
headache, nausea, vomiting, arthralgia, and splenomegaly.
Patients invariably develop lymphadenopathy in the drainage region, usu-
ally within 1–3 weeks of the initial lesion. The enlarged nodes are tender
and often persistent, with lymphadenopathy lasting up to 2 months or more.
Suppuration is not uncommon. Conjunctival or eyelid lesions may be asso-
ciated with preauricular lymphadenopathy (Parinaud's syndrome).11 The
only consistently abnormal laboratory function test is a moderately raised
erythrocyte sedimentation rate (ESR). Purported cases of disseminated cat
scratch disease occurring as a manifestation of the acquired immunodefi-
ciency ­syndrome (AIDS) probably represent examples of advanced bacillary
angiomatosis (see below).12,13
Atypical manifestations of cat scratch disease may occur in as many as
25% of cases.5 These include nonthrombocytopenic purpura and bone, liver,
spleen, pulmonary, endocardial, and/or neurological involvement, presum- Fig. 18.127
ably due to bacteremia.1,5 A vasculitic pathogenesis has also been proposed.16 Cat scratch disease: close-up view of the necrobiosis in Figure 18.126.
Central nervous system lesions have significant morbidity and include coma,
encephalitis, convulsions, pareses, cerebellar signs, and abnormal tendon
jerks.14,15 Hepatosplenic infection results in peliosis.5,6
centers and associated with karyorrhexis. A peripheral rim of epithelioid cells
and occasional giant cells is characteristic. These features are not in them-
Histological features selves diagnostic because they may be seen in a variety of conditions including
The histopathological features are those of dermal necrobiosis.16 The necrobi- lymphogranuloma venereum, yersiniosis, and fungal infections.2
otic foci are round, triangular or stellate and are surrounded by a palisade of Previously, the diagnosis of cat scratch disease was confirmed by a posi-
histiocytes with occasional multinucleate giant cells (Figs 18.126, 18.127). tive delayed hypersensitivity reaction to the cat scratch disease antigen.1 Since
Around the periphery of the histiocytic zone is a lymphocytic infiltrate in B. henselae is difficult to culture, serology and PCR have been advocated as
which eosinophils may be conspicuous. Nuclear debris may sometimes be more reliable diagnostic modalities.5,6,23
prominent. The bacteria may often be identified using the Warthin-Starry
reaction or the Brown-Hopps modified Gram stain within histiocytes or lying Trench fever
free.17–20 Bacteria may also be detected immunocytochemically.1,21 In the adja-
cent dermis the blood vessels are surrounded by an infiltrate consisting of Clinical features
lymphocytes, plasma cells, and histiocytes. A granulomatous reaction has Although a major epidemic of trench fever was documented during the First
been described but this is an uncommon phenomenon.22 World War, more recent outbreaks of this condition have been described
In early lesions the lymph nodes show subcapsular foci of necrosis associ- among homeless people, in whom there is a high seroprevalence of this bac-
ated with a neutrophil polymorph infiltrate. An established infection is char- teremic illness.1,2 Outbreaks have also occurred in overpopulated Central
acterized by extensive necrotic lesions often involving the follicular germinal African refugee camps.3 Trench fever is caused by Bartonella quintana; human
804 Infectious diseases of the skin
body lice (Pediculus humanus var. corporis) are the known vectors.1,2 It is
possible that head lice (P. humanus var. capitis) might also play a role in the
transmission of the disease.4 B. quintana may also cause chronic ­bacteremia,
endocarditis, and bacillary angiomatosis (see below).5
Patients present with non-specific symptoms and signs including head-
ache, malaise, pyrexia, rigors, tachycardia, myalgia, arthralgia, and injected
conjunctivae. An erythematous macular or papular skin rash may occur. The
rash is often seen on the trunk and usually lasts no more than a day or two.6
The disease is rarely fatal, except in some debilitated patients. Relapsing
­illness sometimes occurs, and the organism may remain latent in the host for
a ­number of years following the acute infection.6
Histological features
The histopathological features in the skin are non-specific. There is a perivas-
cular lymphocytic infiltrate, without evidence of vascular thrombosis.6
Organisms are not usually demonstrable in routinely stained skin biopsy
specimens. Dermal vascular proliferation and neutrophilic infiltration (as
seen in bacillary angiomatosis) are not features of trench fever. The diagnosis
is confirmed by serology, culture or PCR.7
Bartonellosis
Clinical features
Bartonellosis (Carrión's disease) is a biphasic disease caused by Bartonella
bacilliformis, an organism that is closely related to B. henselae and
B. ­quintana.1–3 The initial stage of infection (hematic phase) is referred to
as Oroya fever. Patients are acutely ill with pyrexia, rigors, myalgia, and
a severe hemolytic anemia. The last is attributable to infection of the cir-
culating erythrocytes and can be confirmed with the aid of a blood smear.
Later, the disease enters an eruptive phase characterized by the evolution of
numerous papular, nodular or verrucous vascular skin lesions, referred to as
­verruga peruana (Peruvian wart, cutaneous verrucous disease).2,4 These occur
predominantly on the face and extremities (Fig. 18.128). Atypical cases may
present with verrucous skin lesions as the sole manifestation.2 Most lesions
resolve spontaneously.3 Genital lesions and nasal mucosal involvement have
been recorded.5
The condition is endemic in the higher altitude regions of Peru, where it
was first decribed in the nineteenth century. Carrión's disease also occurs in
Ecuador and Colombia.6 Outbreaks have been recorded in nonendemic parts
of Peru, with a fatality rate of under 1%.7 It has also been suggested that the
Fig. 18.128
Verruga peruana: widespread papules are present. By courtesy of F. von Lichtenberg,
MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
condition may be underreported in some endemic areas due to the existence
of mild infection by less virulent strains of B. bacilliformis.2,7 The sand fly,
Lutzomyia (Phlebotomus) verrucarum is the suspected vector.6
Pathogenesis and histological features
There is infection of endothelial cells and circulating erythrocytes following
introduction of B. bacilliformis via the bite of the suspected vector. In the
cutaneous verruga peruana lesions, organisms are detectable in the extracel-
lular spaces, where they induce angiogenesis by producing putative microbial-
encoded or microbial-induced angiogenic factors.1,8 Recent in vitro studies
have shown that B. bacilliformis exercises a mitogenic effect on human vascu-
lar endothelial cells. GroEL produced by the organism regulates endothelial
cell growth.9,10 Others have observed that infection leads to the produc-
tion of angiopoietin-2 by endothelial cells, and the production of vascular
endothelial growth factor (VEGF) by epidermal cells.11 The dermal angioma-
tous proliferation appears to occur in concert with the reactivation of latent
B. bacilliformis organisms.1
Histopathological examination of the verrucous lesions reveals an exu-
berant intradermal capillary proliferation lined by swollen endothelial cells,
often accompanied by a neutrophilic infiltrate. Some of the superficial and
peripheral vessels may be dilated, whereas deep dermal or subcutaneous
nodules tend to have a more compact vascular and endothelial cell prolif-
eration.3,12 Occasional cases harbor a cytologically atypical endothelial pro-
liferation, resulting in potential confusion with malignant vascular tumors.13
There is a background mixed inflammatory cell infiltrate of variable intensity
comprising neutrophils, histiocytes, lymphocytes, and plasma cells. Careful
examination of the endothelial cells in early lesions may reveal characteristic
intracytoplasmic aggregates of B. bacilliformis, referred to as Rocha-Lima
inclusions.3 These may be highlighted with the aid of a Giemsa preparation.
Ultrastructurally, the endothelial inclusions represent degraded bacteria and
extracellular matrix components contained within cell surface invaginations.3
Bacteria are conspicuously absent from late lesions.
Differential diagnosis
Verruga peruana should be distinguished from Kaposi's sarcoma, bacillary
angiomatosis, pyogenic granuloma, and true epithelioid vascular neoplasms
(such as epithelioid hemangioma and epithelioid hemangioendothelioma).
Bacillary angiomatosis
Clinical features
Bacillary angiomatosis is a vasoproliferative lesion that may be readily con-
fused with pyogenic granuloma or Kaposi's sarcoma and is seen predomi-
nantly (but not exclusively) in the skin.1–4 Lesions have also been described
in the bones, soft tissues, liver, lymph nodes, and spleen. Patients may have
systemic manifestations including fever, malaise, hepatosplenomegaly, and
lymphadenopathy.5 Although it was originally thought to be a disease specific
to AIDS, it has also been described in other immunocompromised states, and
even in apparently normal individuals.2,6–9 Patients present with widespread,
numerous (sometimes hundreds) of blood-red, smooth-surfaced, superfi-
cial papules and skin-colored or dusky subcutaneous nodules (Figs 18.129,
18.130).2 The condition may be caused either by Bartonella henselae (the
organism responsible for cat scratch disease) or less frequently by B. quintana
(the cause of trench fever).6
Pathogenesis and histological features
Bartonella henselae infection is acquired via a cat bite or scratch, or cat flea
bites, whereas B. quintana infection is transmitted by body lice. Patients with
bacillary angiomatosis, however, seldom seem able to corroborate this history.
A PCR-based study from Johannesburg revealed a 10% rate of Bartonella
bacteremia among 188 attendees at an HIV clinic, only one of whom exhib-
ited clinical features of bacillary angiomatosis.10 Vascular endothelial cells are
the prime target of the organisms following initial intracellular colonization of
erythrocytes.11 The VirB type IV secretion system of Bartonella plays a crucial
role in not only establishing intraerythrocytic infection but also in mediating
 Diseases caused by Bartonella species 805

the organism's interaction with endothelial cells.12 Angiogenesis is potentiated

by a combination of mechanisms, including inhibition of a­poptosis, release
of chemokines such as interleukin-8, and activation of hypoxia-inducible
factor-1 (HIF-1).11,13–15
Histology reveals lobules of capillaries with prominent, often cuboi-
dal vascular endothelial cells, sometimes surrounding ectatic vessels among
which are dispersed neutrophil polymorphs showing leukocytoclasis and pur-
plish granules of bacilli, which can be identified best by the Warthin-Starry
reaction (Figs 18.131–18.134).4,6 Giemsa may also be used to identify the
organisms but since both the former and the latter stains are difficult to inter-
pret and often to perform, a PCR method has been developed (see below).
Sometimes solid endothelial cell proliferation is evident. Atypia and mitoses
may be present.4 Superficial lesions have a polypoid configuration and there
may be an associated epidermal collarette reminiscent of a pyogenic granu-
loma.3,16 Ulceration is seen occasionally. Associated pseudoepitheliomatous
epidermal hyperplasia has been described.17
Although collagen dissection by spindled endothelial cells is encoun-
tered at the periphery of some lesions, hemosiderin deposition and ­hyaline
globules as seen in Kaposi's sarcoma are not evident.16,18,19 Late, ­involuting
Fig. 18.129
Bacillary angiomatosis: numerous papules and nodules are present. By courtesy
of N.C. Dlova, MD, Nelson R. Mandela School of Medicine, University of KwaZulu-
Natal, South Africa.

Fig. 18.131
Bacillary angiomatosis: there is a dense nodular capillary proliferative lesion; note
the ectatic vessels.
A

Fig. 18.130
(A, B) Bacillary angiomatosis: the bright red coloration is characteristic. By courtesy Fig. 18.132
of N.C. Dlova, MD, Nelson R. Mandela School of Medicine, University of KwaZulu- Bacillary angiomatosis: the endothelial cells are swollen. Conspicuous neutrophils
Natal, South Africa. are evident.
806 Infectious diseases of the skin

lesions show extensive fibrosis of the vascularized dermis, and little by way
of a ­polymorphonuclear leukocytic infiltrate with karyorrhexis.2,16 Such
cases require a high index of suspicion, as the bacteria may be ­difficult to
­demonstrate. Since most patients with this condition are immunocompro-
mised HIV-infected individuals, it is prudent to examine sections ­carefully
for additional opportunistic pathogens, such as cytomegalovirus or
mycobacteria.16,20,21
The endothelial cells can be labeled with antibodies to factor VIII-related
antigen, CD31 and CD34. Histologically, liver and splenic involvement is
seen as peliosis.5 Typical bacteria are, however, also present. The recognition
and distinction of this infection from Kaposi's sarcoma and other vasopro-
liferative lesions is of great importance, particularly as it readily responds to
antibiotic therapy.3
Ultrastructurally, the organisms appear as aggregates of bacilli within the
dermis. The bacteria have trilaminar walls.

Differential diagnosis
A
Bacillary angiomatosis must be distinguished from verruga peruana, pyogenic
granuloma, epithelioid hemangioma, and Kaposi's sarcoma. Pyogenic granuloma
is not associated with Bartonella infection.22 The pyogenic granuloma-like vari-
ant of Kaposi's sarcoma in particular may be confused with bacillary angiom-
atosis.23,24 Although rare, bacillary angiomatosis and concurrent Kaposi's
sarcoma has been described.25 PCR or immunohistochemistry for detection
of HHV-8 is a useful means of differentiating Kaposi's sarcoma from bacil-
lary angiomatosis; the former is invariably associated with HHV-8 whereas
the latter has been found to be HHV-8 negative.24,26 Furthermore, PCR may
be employed to confirm the presence of Bartonella spp. in suspected cases of
bacillary angiomatosis since these organisms are difficult to culture.27

B feri (B. burgdorferi sensu lato), of which there are three main ­pathogenic geno-
Fig. 18.133
(A, B) Bacillary angiomatosis: lymphocytes and histiocytes are also present. Note
the purple colony of bacteria in the center of the field (B).
Lyme disease
Clinical features
Lyme disease is a generalized infection due to the spirochete Borrelia burgdor-
species in humans: B. burgdorferi sensu stricto, B. garinii, and B. afzelii.1–5
Two more recently described species in Europe are B. valaisiana and B. spiel-
manii.6 The Centers for Disease Control and Prevention (CDC) reported a
40% increase in the annual incidence of this emerging zoonosis in the United
States between 2001 and 2002; more than 40  000 cases were documented dur-
ing this period.7 A more recent CDC survey revealed that more than 64 000
cases were reported in that country during the period 2003 to 2005.8 This
trend has also been observed in parts of the United Kingdom and Europe.9–11
The disease affects most organ systems of the body.1–3 Lyme disease has
been divided into three stages, I–III: 12

Stage I
The skin lesion of the primary stage (erythema chronicum migrans, erythema
migrans) consists initially of a small erythematous papule at the site of an
insect bite and expands centrifugally as a flat ring (Fig. 18.135). It devel-
ops on average 1–3 weeks after the bite.13,14 Occasionally target lesions are
described.15 Necrotic lesions are rare.16 With extension, the macules may
develop a bluish or violet hue. If untreated, the ring may spread to a diameter
of 50 cm before clearing. Although lesions are usually asymptomatic, patients
may complain of pruritus, burning or rarely pain.17 The lower extremity and
trunk are most often affected.
Approximately 50% of patients have secondary lesions, which are smaller.
The palms, soles, and mucous membranes are usually unaffected.18 Erythema
chronicum migrans may occasionally recur.17 Other cutaneous manifestations
that have been described in the early stage of Lyme disease include granuloma
annulare, papular urticaria, and Henoch-Schönlein purpura.18 Age at presen-
tation is exceedingly variable, ranging from 15 months to 80 years. The sex
Fig. 18.134 incidence is equal and lesions present most often from May to September.18
Bacillary angiomatosis: the organisms are easily identified with the Warthin-Starry Systemic symptoms (due to a spirochetemia) tend to occur early in the
stain. disease and include chills, fever, general malaise and lethargy, arthralgia,

Fig. 18.135
Lyme disease: this annular, erythematous lesion developed (several weeks later)
around the site of a tick bite. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
myalgia, headache, and neck stiffness. Physical examination may reveal
lymphadenopathy, splenomegaly, hepatitis, and orchitis.13,19 B. garinii and
B. afzelii are the pathogens most often implicated in cases of Lyme disease
reported from Europe, and some authors have described differences in the
clinical presentation of erythema chronicum migrans caused by these two
organisms. Erythemas associated with B. garinii tend to evolve more rapidly,
are often larger and homogeneous, are more often located on the trunk than
the extremities, and are more frequently associated with systemic symptoms
when compared with B. afzelii erythemas, which are usually annular.20,21
Patients with B. garinii infection also tend to be older and there is a shorter
incubation period.21
Lymphocytoma cutis (borrelial lymphocytoma), a B-cell response, may pres-
ent in the acute stage and most often affects the lower ear lobes and ­nipples.13
It is, however, more often a feature of the third stage of the illness.14,19
Stage II
Stage II disease primarily affects the cardiovascular and nervous system
(meningopolyradiculitis; Garin-Bujadoux-Bannwarth syndrome).1,19,22,23
It may involve both the peripheral and central nervous systems, and tends to
present 1–2 months after the primary infection; symptoms include mening-
ism, nerve palsies (especially Bell's palsy), and cerebral symptoms, including
­personality changes, drowsiness or stupor.12,24 There have been isolated reports
of orbital myositis, neurosensory hearing loss, parkinsonism, and spontane-
ous brain hemorrhage.25–28 Cardiac involvement presents as ­myocarditis and
conduction defects.12,22,29
Stage III
Arthritis, which characterizes the third stage, presents as a recurrent, asym-
metrical, and oligoarticular process involving the large joints (especially
the knee) or as a migratory polyarthritis lasting up to a week in any one
­particular joint.19 Cutaneous lesions and peripheral nervous system involve-
ment are also frequently encountered in the third stage. The typical skin
lesions of late Lyme disease are acrodermatitis chronica atrophicans, which
characteristically ­presents as a red or violet discoloration of swollen periph-
eral skin, and lymphadenosis benigna cutis.14,17,19 Lesions are often bilateral.
Patients may also develop sclerodermatous changes. Lichen sclerosus et atro-
phicus-like lesions have also been described.12,19 In the late atrophic stages of
acrodermatitis chronica atrophicans, the skin may resemble crumpled tissue
paper.30 Nodular or bandlike juxta-articular fibrous nodules are not uncom-
mon, and may regress with appropriate antibiotic therapy.31 Acrodermatitis
Lyme disease 807
chronica atrophicans occurs mainly in Europe, where B. afzelii is the over-
whelmingly predominant etiologic genospecies.5 B. afzelii is not endemic in
North America, thereby accounting for the striking geographic distribution
of the condition.5
There have been rare reports suggesting a possible association between
B. burgdorferi infection and anetoderma.32,33 A case with acquired cutis
laxa has also been described.34 The conflicting role of B. burgdorferi in the
pathogenesis of morphea and lichen sclerosus et atrophicus is discussed
elsewhere.35–37
Reinfection may occur in a small but significant proportion of patients
following treatment with antibiotics. This usually manifests as a recurrent
episode of erythema migrans at a different cutaneous site from the pre-
vious lesion.38,39 A recent Swedish study showed that women were more
susceptible to reinfection than men, ascribing this phenomenon to gen-
der differences in immune reactivity, especially in the postmenopausal age
group.39
Pathogenesis and histological features
Erythema chronicum migrans was first described in association with tick
bites; cases were subsequently reported following mosquito bites and
thorn pricks, or without preceding trauma.29 In a proportion of cases an
encephalitis was noted and the disease was termed ‘tick-borne meningopo-
lyneuritis’. In the 1970s several cases were reported in the United States,
and because of a clustering effect near Lyme, Connecticut, the term Lyme
disease was coined (these cases had a high proportion of arthritis).40 The
Ixodes tick has been known to be the vector for some time, but the actual
etiological agent, a spirochete, was only identified in the 1980s after spiro-
chetes were found in Ixodes dammini ticks in an endemic disease area.12,41,42
In Europe, Ixodes ricinus has been incriminated.19,29 It has a worldwide
distribution.19
Patients recovering from the disease have been shown to have antibod-
ies to the spirochetes in their serum.17 Spirochetes have also been identi-
fied from biopsy sites, and cultured from or detected by PCR performed on
specimens of blood, cerebrospinal fluid, synovial fluid, and skin.4,19,29,43,44
Immunosuppression does not appear to alter clinical presentation, treatment
response or anti-B. burgdorferi antibody production.45
Borreliae have developed strategies to inactivate host immune defenses
via a variety of mechanisms, including recently described complement reg-
ulator-acquiring surface proteins (CRASPs), which confer complement resis-
tance. Borrelial CRASPs are capable of binding FHL-1/reconectin and factor
H, which are two major regulators of the alternative complement path-
way.46,47 The selective up-regulation of host matrix metalloproteinase-9 by
B. ­burgdorferi in skin lesions of erythema chronicum migrans may play a role
in the local spread of the organism and its dissemination to other organs.48 In
the early stage of Lyme disease, B. burgdorferi antigens induce a strong host
immune response in which the production of cytokines such as IFN-γ, TNF-α
and transforming growth factor beta-1 (TGF-β1) predominates.49,50 By con-
trast, chronic neuroborreliosis is associated with a lack of TNF-α and TGF-β1
responses.50 Studies performed on lesional skin have revealed high levels of
the T-cell-active chemokines CXCL9 and CXCL10 in erythema chronicum
migrans and acrodermatitis chronica atrophicans. Borrelial lymphocytoma,
on the other hand, is associated with high levels of CXCL13, a B-cell-active
chemokine.51
The central component of the initial lesion shows the typical appearance
of an insect bite reaction. Histology reveals a polymorphic inflammatory cell
infiltrate including polymorphs, eosinophils, histiocytes, lymphocytes, and
mast cells.19 Vascular proliferation and dermal necrosis may additionally be
present. A biopsy from the periphery is non-specific, showing a perivascu-
lar and interstitial infiltrate of lymphocytes, mast cells, and plasma cells in
both the superficial and deep dermis (Figs 18.136, 18.137). Identification
of spirochetes by a silver stain is diagnostic.52 An immunohistochemical
method for demonstrating the etiologic agent has been described.19 PCR
may also be used to detect the organisms in formalin-fixed, paraffin-embed-
ded tissue specimens.53 A recent study concluded that focus floating micros-
copy was more sensitive than PCR in detecting Borrelia spirochetes in the
808 Infectious diseases of the skin
Fig. 18.136
Lyme disease: the epidermis is normal; a chronic inflammatory cell infiltrate
surrounds the vessel in both the superficial and deep dermis.
lesional tissue of erythema chronicum migrans, borrelial lymphocytomas,
and acrodermatitis chronica atrophicans.54 Clonal or pseudoclonal IgH gene
rearrangements have been documented in DNA extracted from erythema
migrans cutaneous lesions. Care should therefore be exercised when inter-
preting PCR results in such cases; some authors have advocated duplicate or
triplicate testing.55
The borrelial lymphocytoma consists of a dense (polyclonal) dermal infil-
trate composed of lymphocytes, plasma cells with macrophages, and scattered
eosinophils. Although it has been suggested that germinal center formation,
when present, helps to exclude a cutaneous B-cell lymphoma, this is not nec-
essarily true; cutaneous lymphomas of marginal zone type typically display
germinal centers.17,19,56 The association between B. burgdorferi infection and
cutaneous B-cell lymphoma is discussed elsewhere.56,57
Acrodermatitis chronica atrophicans is characterized by vascular dilata-
tion in the mid and upper dermis accompanied by a dense infiltrate of lym-
phocytes, plasma cells, macrophages, and mast cells.19 Scattered groups of
‘vacuoles’ may be seen in the dermis; this phenomenon is thought to be attrib-
utable to lymphedema.30 The epidermis, which is usually hyperkeratotic, may
be acanthotic or atrophic with loss of ridge pattern.12 In some patients the
appearances are reminiscent of lichen sclerosus et atrophicus or eosinophilic
fasciitis.17,19 Occasionally, the histological features may overlap with sclero-
myxedema.19 The juxta-articular fibrous nodules are characterized by fibrosis
of the superficial subcutaneous tissue, with hyaline collagen ­bundles ­encircling
clusters of adipocytes. There is an accompanying perivascular and interstitial
inflammatory infiltrate comprising lymphocytes and plasma cells.31 Smaller
periarticular fibrous nodules on the fingers show disorganized bundles of
thickened dermal collagen.58
The triad of meningitis, cranial neuropathy, and radiculopathy has
been said to be unique for Lyme disease. Central nervous system lesions
include cortical, perivascular chronic inflammatory cell infiltrates, mild
spongiform changes and gliosis. Plasma cells, however, are said to be
absent. The similarity of the late central nervous system changes of Lyme
disease and meningovascular syphilis has been stressed.19 Chronic lep-
tomeningeal inflammation may also be evident. Peripheral nervous sys-
tem lesions are characterized by nerve and ganglion lymphocyte and
occasional plasma cell infiltration.12,19 Adjacent vessels may show endar-
teritis obliterans.
Endocardial lesions are characterized by a lymphocytic and plasma cell
infiltrate; deep specimens show an interstitial myocarditis.12 Focal ­myonecrosis
may also be evident.19
Histological examination of the synovium may show periadventitial cell
onion-skinning proliferation and chronic inflammation.12,19
Fig. 18.137
Lyme disease: high-power view.
Endemic (nonvenereal) treponematoses
Endemic syphilis
Clinical features
Endemic syphilis (Syrian bejel) is a form of nonvenereal treponematosis
caused by Treponema pallidum subsp. endemicum, an organism nearly
identical to Treponema pallidum subsp. pallidum, the etiological agent
of venereal syphilis.1–4 The condition usually occurs in children living
in conditions of poor hygiene and is transmitted by cutaneous inocula-
tion.1,2,4–6 Other endemic forms have been associated with shared drinking
vessels and other contaminated domestic utensils when some members of
the community have oral or labial syphilitic lesions.1,2,4,5 The disease still
occurs in parts of the Middle East and Africa, especially in rural desert
regions.1,4,7
Unlike venereal syphilis, a primary chancre seldom occurs in endemic
syphilis; women suckling infected infants may, however, develop primary
infections of the nipple.4 The primary lesions usually involve the orophar-
ynx but are easily overlooked. Early secondary lesions manifest as soft,
oval mucous patches with a predilection for the buccal and labial ­mucosae,
sometimes accompanied by angular stomatitis. Mucous patches may also
occur in the perianal and genital areas, where they sometimes appear
­condylomatous. Osteoperiostitis may occur, and generalized lymphadenop-
athy is common.4
Late (tertiary) manifestations develop following a latent period of between
5 and 15 years. The lesions may evolve in the skin, nasopharynx, bone or joints
and are clinically similar to those encountered in late yaws.4 Articular and
osseous involvement is frequently destructive. Cardiovascular ­involvement
may also occur, but the disease does not affect the central nervous system. A
further point of distinction from venereal syphilis is the fact that there is no
congenital form of endemic syphilis.4
Histological features
The histopathology of the primary lesion is poorly documented. The light
microscopic features of the secondary lesions are virtually identical to those
encountered in venereal syphilis.4,8 Granulomatous dermal inflammation is
encountered in the tertiary skin lesions.8
 Endemic (nonvenereal) treponematoses 809

There may be a symptom-free period of 3–5 years before the lesions of

Yaws
Clinical features
Yaws (framboesia tropica) is a tropical disease occurring in people living in
poor conditions due to infection by the spirochete Treponema pallidum subsp.
pertenue.1–5 Although the disease was thought to have been almost eradicated
by the WHO treatment program, it continues to be encountered in a number
of warm, humid tropical regions including Africa, parts of Asia (including
Southeast Asia), Oceania, and parts of South America.1,6,7 The eradication
program, however, has attained success in India, where there have been no
recorded cases since 2004.6,8
Yaws is not transmitted sexually, but rather by close contact, for exam-
ple by inoculation of skin previously traumatized by insects or scratch-
ing.1,4,9 The disease is most common in children 6–10 years of age, who
present with lesions on the feet, legs, and buttocks.10 Clinically, it is divided
into early and late yaws.11–13 The initial lesion, known as a ‘mother yaw’,
develops 3–5 weeks after inoculation.10 It starts as a nontender papilloma,
which ulcerates and is then covered with a yellow crust (Fig. 18.138).10 It
resembles a raspberry, hence the alternative designation framboesia (Dutch
framboos, raspberry). This mother yaw may be surrounded by smaller
­papillomas, which develop 2–4 months after the initial lesion.4,9 Lesions in
the perineum and natal cleft may become condylomatous.9 Subsequently,
these warty lesions may become very widespread (‘daughter yaws’) (Fig.
18.139). Macules, papules, and nodules have also been described.10,14
They eventually resolve leaving a depressed and hyperpigmented scar.9 The
mucous membranes, bones (osteitis and periostitis), and joints may also be
affected in early yaws.11 Palmar and plantar hyperkeratosis, which can
be exceedingly painful and may result in walking difficulties (crab yaws),
are characteristic.14,15
late yaws arise. The late lesions, which develop in about 10% of patients, are
destructive ulcers and gummatous nodules which affect the skin, bones (e.g.,
saber tibia), and joints (Figs 18.140, 18.141).4,10,11,14 Cutaneous manifesta-
tions of late yaws include palmar and plantar hyperkeratosis (crab yaws),
loss of pigment (pintoid yaws), and gummata.4,11 Pintoid yaws includes
hyperkeratosis, contractures, juxta-articular nodules, and bony lesions.4,11
Gummata characteristically involve the long bones, the bones of the hands
and feet, and typically lead to gross destruction of the face (gangosa).16 The
­cardiovascular and nervous systems are said not to be involved, but there is
evidence to suggest that ophthalmic and myeloneuropathies may occur in
endemic areas.10,12,17
Pathogenesis and histological features
The spirochete responsible for yaws is morphologically indistinguishable from
T. pallidum subsp. pallidum.14 The organism is, however, differentiated from
other pathogenic treponemes by unique differences in the genetic sequences
flanking the 15-kD lipoprotein gene.5
Early lesions are characteristically parakeratotic, acanthotic, and papilloma-
tous. They show focal spongiosis and intraepidermal neutrophils with microab-
scess formation (Fig. 18.142).14 There is a dense perivascular dermal infiltrate
containing numerous plasma cells. The vascular changes in contrast to syphilis
are usually insignificant. Treponemes can be seen around the blood vessels, in
the tips of the dermal papillae, and within the epidermis (Fig. 18.143).15,18–20
The palmoplantar lesions are characterized by hyperkeratosis, parakerato-
sis, and acanthosis. A mild non-specific chronic inflammatory cell infiltrate is
present in the superficial dermis.
The gummata show central caseation necrosis surrounded by a rim of lym-
phocytes, plasma cells, histiocytes, epithelioid cells, and giant cells.15 There is
associated fibrosis.

A B

Fig. 18.138 Fig. 18.139

Early yaws: typical framboesiform ‘mother yaw’. Note
the yellow crust and surrounding hypopigmentation.
By courtesy of H.J.H. Engelkens, MD, and E. Stolz,
MD, University Hospital, Rotterdam-Dijkzigt and
Erasmus University, Rotterdam, The Netherlands.
(A, B) Early yaws: multiple smaller ‘daughter yaws’ may be widely distributed and usually present 2–4
months after the ‘mother yaw’. By courtesy of H.J.H. Engelkens, MD, and E. Stolz, MD, University Hospital,
Rotterdam-Dijkzigt and Erasmus University, Rotterdam, The Netherlands.
810 Infectious diseases of the skin

Fig. 18.140 Fig. 18.141 Fig. 18.142

Late yaws: note the bowing of the lower leg with
cutaneous ulcerated and crusted lesions in this
late stage. By courtesy of R.A. Marsden, MD, St
George's Hospital, London, UK.
Late yaws: note the cyst with an overlying periosteal
reaction. By courtesy of R.A. Marsden, MD, St
George's Hospital, London, UK.
Early yaws: biopsy through an evolving papilloma.
There is very marked parakeratosis associated
with abundant neutrophil debris. The epidermis
shows intense acute inflammation. By courtesy of
H.J.H. Engelkens, MD, and E. Stolz, MD, University
Hospital, Rotterdam-Dijkzigt and Erasmus University,
Rotterdam, The Netherlands.

Fig. 18.143
(A, B) Early yaws: same specimen as that shown in
Fig. 18.142. Note the presence of numerous spirochetes.
(A) Warthin-Starry; (B) immunofluorescence. By courtesy of
H.J.H. Engelkens, MD, and E. Stolz, MD, University Hospital,
A B Rotterdam-Dijkzigt and Erasmus University, Rotterdam, The
Netherlands.

Pinta
Clinical features
This is a nonsexually transmitted treponematosis characterized by depig-
mented skin lesions. It is caused by Treponema carateum (Treponema pal-
lidum subsp. carateum), an organism that is very similar to T. pallidum subsp.
pallidum.1–4 It is confined to remote primitive regions in tropical Central
and South America where the inhabitants live in poor hygiene and in close
­proximity.1,5–7 Children and young adults are primarily affected and transmis-
sion is thought to be by direct cutaneous or mucous membrane contact, pos-
sibly via minute abrasions.5,6,8
The lesions present as small scaly erythematous indurated papules and
plaques on exposed skin, usually on the hands and feet. These disappear, but
recur in a more disseminated form (pintids).5 Late stages of pinta are char-
acterized by disfiguring hyperpigmentation, achromia, hyperkeratosis, and
atrophy (Fig. 18.144).9
Unlike syphilis and yaws, there is no evidence of systemic disease.
Histological features
Histologically, there is hyperkeratosis with acanthosis or occasion-
ally epidermal atrophy. 4,9 Lymphocytic exocytosis, basal cell hydropic
degeneration, and pigmentary incontinence are evident.4 A perivascular
­lymphocytic infiltrate is usually seen without endothelial swelling.
Tuberculosis
Clinical features
Tuberculous (Mycobacterium tuberculosis complex) infection of the skin,
which was once common worldwide, had shown a declining incidence dur-
ing the latter decades of the last century, especially in developed countries.1,2
This was due in part to improved therapy, a reduction in the size of the
Fig. 18.144
Pinta: this is a late lesion
showing characteristic
complete loss of
pigmentation surrounded
by a hyperpigmented
border. By courtesy of
R. Arenas, MD, and
J. Salas, MD, Azteca,
Monterrey, Mexico.
Tuberculosis 811
active reservoir of infection, and increased immunoresistance to infection.
The late twentienth century, however, showed an apparent upward trend
in the incidence of cutaneous tuberculosis, especially in Asian countries.3 A
particularly important aspect of cutaneous tuberculosis is that skin lesions
can readily simulate other conditions, and may be insidious in onset. The
source of infection is sometimes not obvious, and tissue destruction may
be very marked. Cutaneous tuberculosis accounts for 1% to 1.5% of cases
of extrapulmonary tuberculosis and around 0.14% of all cases of tuber-
culosis.4,5 Although the global burden of tuberculosis is slowly declining,
data from the World Health Organization (WHO) remain disconcerting.
According to the WHO, the worldwide prevalence of tuberculosis in gen-
eral in 2007 was around 13.7 million cases, with an estimated 9.27 million
incident cases.6
Mycobacterial infections (tuberculous and atypical) are of increasing
importance in the context of acquired immunosuppression, whether due to
lymphoma, AIDS or aggressive chemotherapy. Atypical modes of presenta-
tion with microorganisms of borderline virulence have gained significance.7
Cutaneous tuberculosis has reemerged in those parts of the world where the
incidence of HIV infection and multidrug-resistant tuberculosis is high.2,6,8,9
An estimated 1.37 million of the incident cases of tuberculosis in 2007 were
HIV positive, with around 79% and 11% of these on the African conti-
nent and in Southeast Asia, respectively. Approximately 23% of the esti-
mated 2 million HIV-related deaths in 2007 were the result of concomitant
tuberculosis.6
In Europe and North America cutaneous infection is still relatively infre-
quent, due to a reduction in the numbers of infected cases by therapy and
immunization programs and to an increased standard of living. Nevertheless,
there remains an apparently irreducible number of people with tubercu-
losis, usually living in circumstances of poor hygiene and nutrition.10 This
is borne out by the number of unsuspected cases of tuberculosis diag-
nosed at autopsy. Moreover, there exists an important reservoir of infected
immigrants, ­particularly of Asian origin, who often present with cervical
lymphadenopathy.
The manifestations of the disease in the skin are influenced by previous
infection or immunity and by the route of infection. Because of the virulence
and resistance to phagocytosis by M. tuberculosis, neutrophils are completely
ineffective in dealing with this bacterial infection, whereas macrophages and
their derivatives are characteristically seen in the cellular response. These lead
on to (giant cell) granuloma formation with or without necrosis and this
underlies the varied clinical presentations of this infection.
The majority of cases of cutaneous tuberculosis are a manifestation of
systemic disease.2,8 The usual portals of entry of M. tuberculosis include the
lungs and intestine, but the mucous membranes and skin occasionally show
primary involvement.11 Cutaneous lesions include papules, nodules, plaques,
ulcerative lesions, warty tumors or scarring reactions.12 Although preferred,
it is not always possible to package cutaneous tuberculous lesions neatly
into the ­categories detailed below, and on occasion tuberculous skin disease
may be reported as of non-specific type, particularly in this current era of
profound immunosuppression. In this account a modified ‘Beyt’ classifica-
tion is used.2,11,13
Appropriate classification, when possible, is important because some
variants are associated with systemic lesions and therefore clinical manage-
ment and prognostic implications are highly variable.11 Tuberculids in which
bacilli are not detectable are now rare in the West, but are still common in
­developing countries and are considered separately below.
Infections by inoculation (exogenous source)
Tuberculous chancre, which is rare, occurs by direct inoculation of infected
material into the skin of a previously uninfected and nonimmune patient.
The response is analogous to a Ghon complex in the lung.13,14 These lesions
develop 2–4 weeks after inoculation, which may be through minor trauma to
the skin of various sites, such as the face and limbs of children (Fig. 18.145).
Infection may also follow minor surgery such as ear piercing, tattooing or
circumcision. The earliest lesion is a reddish-brown papule, which may rap-
idly progress to an ulcer with ragged undermined edges. The margins of the
812 Infectious diseases of the skin
Fig. 18.145
Tuberculous chancre: the
cutaneous equivalent of a
Ghon complex. Note the
healing lesion on the outer
aspect of the knee and the
ulcerated inguinal nodes
from this patient from
the 1950s. By courtesy of
M.M. Black, MD, Institute
of Dermatology, London,
UK.
Fig. 18.146
Warty lupus: in this example, there is a grossly hyperkeratotic lesion associated with
destruction of the nail. By courtesy of the Institute of Dermatology, London, UK.
lesion become indurated and lymphadenopathy is usually noted at this stage.
Satellite papules may be seen around the original lesion and this pattern of
spread is termed ‘lupoid’. Inoculation tuberculosis from Bacille Calmette-
Guérin (BCG) injection is a similar phenomenon.15
Warty lupus (tuberculosis verrucosa cutis) occurs by inoculation of
M. tuberculosis into the skin of individuals who have some degree of immunity
or may have active infection elsewhere. It is has been the most common vari-
ant in some series from Asia (Fig. 18.146).11,16,17 This lesion occurs classically
as ‘prosector's warts’ in pathologists or autopsy technicians, but may also be
seen in butchers dealing with infected cattle (Fig. 18.147).13 Inoculation of the
skin by infected sputum, even from the same patient, can cause a ­similar lesion.
Children tend to be affected on the lower limbs or b ­ uttocks (Fig. 18.148).
The lesion begins as a small indurated nodule with a keratotic warty
­surface at the site of inoculation and then slowly extends in a serpiginous
manner, producing an irregular reddish-brown warty plaque. Although much
of the lesion is firm, some softer areas may be present from which pus may
Fig. 18.147
Warty lupus: prosector's wart. This indurated lesion on the finger developed after
a pathologist had performed a tuberculous autopsy. By courtesy of R. Vellor, MD,
St Thomas' Hospital, London, UK.
Fig. 18.148
Warty lupus: in children,
the buttock is a commonly
affected site. By courtesy
of the Institute of
Dermatology, London, UK.
exude. In some areas the lesion continues to extend, but elsewhere it may
show focal involution to leave an atrophic pale scar. The warty component
may persist for years, but usually resolves eventually.
Secondary tuberculosis (endogenous source)
Orificial tuberculous ulcers are rare and occur in the skin or mucosa adjacent
to an orifice draining an active tuberculous infection. They represent auto-
inoculation and are most commonly seen around the nose, mouth, genitalia
or anus (Fig. 18.149). Patients are usually hyperreactive to tuberculin test-
ing. The lesions start as edematous red papules, which ulcerate and develop
undermined edges. These ulcers are painful and neither progress or regress.
Scrofuloderma (L. scrofula, brood sow; derma, skin) is a complication
of deep tuberculous infection of lymph node, bone, joint or subcutaneous
­tissue (Figs 18.150–18.152). The lesion is seen as a bluish-red nodule, which
 Tuberculosis 813

Fig. 18.149 Fig. 18.151

Orificial tuberculosis: widespread ulcerative lesions involving the upper lip and Scrofuloderma: in this case there was underlying tuberculous osteoarticular
nostril. By courtesy of S. Lucas, MD, St Thomas' Hospital, London, UK. disease. By courtesy of the Institute of Dermatology, London, UK.

Fig. 18.150
Scrofuloderma: (A) note
the marked axillary
swelling and scarring Fig. 18.152
with multiple sinuses; Scrofuloderma: lesions
(B) in this example in the midline of the back
there was underlying commonly complicate
cervical tuberculous vertebral tuberculous
lymphadenopathy. The osteomyelitis. By courtesy
puckered scarring is of the Institute of
characteristic. By courtesy Dermatology, London, UK.
of R.A. Marsden, MD,
A St George's Hospital,
London, UK.
­ lcerates and discharges pus or necrotic material.11 Lesions are commonly
u
seen in the neck, submandibular area or axilla. There is associated scarring,
and the combination of scarring and a chronic discharging ulcer may resem-
ble hidradenitis suppurativa. Very rarely, scrofuloderma may arise from the
lacrimal system.18

Infection by hematogenous spread

Lupus vulgaris may occur following inoculation of bacteria into individuals
showing some immunity (see above); more commonly, however, it represents
hematogenous or lymphatic spread from a tuberculous focus, which is usually
occult. Lesions occur mostly on the face (particularly around the nose), neck,
and earlobes in the West, and are more common in women (Figs 18.153,
18.154).15 The extremities and buttocks are more commonly involved in
patients in the East. The arms and legs may also be affected (Fig. 18.155). It
is a very chronic disease. This form of cutaneous tuberculosis used to be par-
ticularly evident in Northern Europe and is still the most frequently encoun-
B tered variant in the West.2, 11 It is a common form of cutaneous ­tuberculosis
in childhood.19
814 Infectious diseases of the skin
Fig. 18.153
Lupus vulgaris: the nose is a commonly affected site. By courtesy of N.C. Dlova,
MD, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, South
Africa.
Fig. 18.154
Lupus vulgaris: typical
plaque with golden-yellow
appearance. By courtesy
of R.A. Marsden, MD,
St George's Hospital,
London, UK.
Lupus vulgaris occasionally results from direct inoculation and may even
occur at the site of BCG inoculation.20
Lupus vulgaris is characterized by papules and raised erythematous and
sometimes scaly plaques of gelatinous consistency, said with diascopy to
resemble apple jelly. These lesions may gradually extend, while involuting
with scarring in other areas. There may be adjacent cellulitis or ulceration.
Extensive facial lesions can result in gross disfigurement.21,22 Squamous and
basal cell carcinoma, melanoma, and lymphoma may develop in chronic
lupus vulgaris.23–26 Contractures and lymphedema are late complications.
Ocular involvement is an additional serious complication. Lupus vulgaris is
a rare cause of alopecia.27
Tuberculous gumma represents a metastatic tuberculous subcutaneous
abscess derived from infection at another site by a hematogenous route.11 It
is most commonly seen in the malnourished, the immunodeficient or the
Fig. 18.155
Lupus vulgaris: this is a
chronic lesion showing
marked scaling, erythema,
and induration. Squamous
cell carcinoma may
occasionally supervene.
By courtesy of
R.A. Marsden, MD,
St George's Hospital,
London, UK.
i­mmunosuppressed.8,11,28 Clinically, it presents as a firm subcutaneous ­nodule,
­usually on the arms or legs. The lesion slowly becomes fluctuant and the overlying
skin perforates to form a chronic undermined ulcer as seen in scrofuloderma.
Miliary tuberculosis of the skin (tuberculosis cutis miliaris disseminata)
occurs in association with generalized miliary tuberculosis and is very rare. It
is usually seen in infants and has a poor prognosis. The infection may be seen
in mother and child concurrently and then the cutaneous lesions may be
scanty and the prognosis less grave.29 Other cases are associated with immu-
nodeficiency and may follow a minor systemic infection such as measles. In
these patients there are numerous lesions which are usually centrally crusted
papules or pustules, but they may be ulcerative, necrotic, hemorrhagic or
vesicular.11 In recent years there have been a number of reports in patients
with AIDS, especially those with multidrug-resistant tuberculosis.8,9,30–34
The cutaneous lesions can be confused with folliculitis, resulting in delayed
­diagnosis.30 The prognosis is poor.8,32
Comparison of the variants of cutaneous tuberculosis is shown in
Table 18.2.
Other rare manifestations of cutaneous tuberculosis that have been reported
include tuberculous cellulitis, neutrophilic tuberculous panniculitis, and the
presence of sporotrichoid lesions.35–40 These uncommon forms of tuberculosis
have occurred in patients who were iatrogenically immunosuppressed.
Pathogenesis and histological features
M. tuberculosis, an ‘obligate pathogen’, is a slender aerobic rod, characterized
by a high lipid content. This lipid is responsible for resistance to phagocyto-
sis. It also allows the bacterium to retain basic dyes, even during treatment
with strong differentiating agents, and this is the basis of the Ziehl-Neelsen/
acid-fast stain (Fig. 18.156). Organisms are easily identified in tuberculous
chancre, scrofuloderma, orificial lesions, and the miliary variant. They may
be difficult to find or absent in lupus vulgaris, gummata, and warty tuber-
culosis.11 Mycobacteria are found at water–air interfaces and were so named
because of their moldlike growths on the surface of liquid media.41
The organism is highly resistant to drying and therefore can retain
­infectivity by inoculation or contamination of minor wounds.
The reaction to the bacterium depends on:
• the size of the inoculums,
• the virulence of the organism,
• the immune state of the patient.
 Tuberculosis 815

Table 18.2
Variants of cutaneous tuberculosis

Variant Route of infection Association with other TB Level of infection Histological features Presence of bacilli
Tuberculous chancre Inoculation None Dermis Neutrophil abscess → caseating Present
granuloma, lymphadenopathy
Warty lupus Inoculation Previous or current Dermis Scanty granulomata, Absent or very
infection papillomatous acanthosis scanty
Orificial ulcers Autoinoculation Active infection in Submucosa dermis Mixed inflammation, few Numerous
associated organs granulomata, necrosis
Lupus vulgaris Inoculation and/or Previous or current, often Superficial dermis Variable but granulomata, little May be seen in deep
hematogenous occult, infection caseation prominent aspect
Scrofuloderma Extension from Active infection Subcutaneous and Mixed inflammation, granuloma, May be seen in deep
underlying infection dermal marked fibrosis aspect
Tuberculous gumma Hematogenous Systemic infection Subcutaneous Much caseation, granulomatous Scanty
fibrosis
Miliary tuberculosis Hematogenous Systemic infection Dermis Central abscess, with Absent or scanty
surrounding histiocytic infiltrate in benign form;
present in
aggressive form

Fig. 18.156 Fig. 18.157

Ziehl-Neelsen stain: in the center of the field is a small collection of red, acid-fast Tuberculosis: characteristic Langhans giant cells with horseshoe peripheral rim of nuclei.
rods (oil immersion).

In general, the cellular response is characterized by epithelioid macrophages,

Langhans giant cells, and caseous necrosis, with perivascular lymphocytes
in the surrounding tissue (tuberculous granuloma) (Figs 18.157, 18.158).
Tuberculoid granulomata, as seen for example in sarcoidosis, by definition
do not show caseation. The presence of large numbers of bacilli in a lesion
implies a nonimmune or anergic state, such as in tuberculous chancre or ori-
ficial lesions. Caseation is an indication of hypersensitivity and is not a toxic
effect of the organisms; it is clear that it is not always beneficial to the host
because it is invariably associated with destruction of surrounding tissue.
The recruitment of large numbers of macrophages is mediated by cytok-
ines released by T lymphocytes. In M. tuberculosis infections it appears that
various cytokines operate, some of which participate in toxic or necrogenic
functions, while others mainly activate macrophages. These responses are
graded and the balance between the various components determines the even-
tual response. It is by no means clear what determines the balance between
tissue damage and protective functions.

Primary chancre Fig. 18.158

The primary chancre is characterized by a neutrophilic abscess with numer- Tuberculosis (caseation necrosis): the cell outlines are not completely lost, giving an
ous bacilli, associated with necrosis leading to ulceration. This is gradually amorphous granular appearance.
816 Infectious diseases of the skin

surrounded by histiocytes; after 6 weeks, giant cells (derived by fusion of

­epithelioid cells) are seen. Central necrosis remains prominent, but diminishes,
along with the number of bacilli, as the granulomatous element increases.11

Warty lupus
Warty lupus is characterized by acanthotic papillomatosis with marked hyper-
keratosis (Fig. 18.159). The dermal infiltrate consists mainly of neutrophils
and lymphocytes, and abscesses may sometimes be present. Granulomata
are present in the deeper dermis and caseation is occasionally a feature (Fig.
18.160).11 Bacilli are found on careful searching.

Orificial lesions
Orificial lesions, in contrast, show extensive necrosis and numerous bacilli.
The inflammatory infiltrate is not conspicuously granulomatous and may
consist of lymphocytes and neutrophils, with few histiocytes.

Lupus vulgaris
Lupus vulgaris is more varied in its histological features. It is seen in the superfi-
cial dermis, consisting of tubercles, some of which coalesce, with scanty or absent Fig. 18.161
central caseation surrounded by epithelioid histiocytes and ­multinucleate giant Lupus vulgaris: there is a dense dermal infiltrate. Note the Langhans giant cell.
cells (Figs 18.161, 18.162). Peripheral lymphocytes are also usually prominent.

Fig. 18.159
Warty lupus: the epidermis is hyperkeratotic and shows marked irregular acanthosis.
An inflammatory cell infiltrate is present in the dermis.
Fig. 18.162
Lupus vulgaris: the granulomata are often surrounded by lymphocytes.
Bacteria are very infrequent. The overlying epidermis may be ulcerated (in which
case there is usually a more mixed inflammatory infiltrate), atrophic or acan-
thotic. The last may be severe (pseudoepitheliomatous hyperplasia), raising the
problem of distinction from invasive squamous carcinoma, especially as such
tumors are an important rare complication of lupus vulgaris. This may some-
times be impossible if only superficial specimens are submitted for pathological
interpretation. Transepithelial elimination of granulomata has been described.42
Lupus vulgaris typically presents around the nose: this location is deter-
mined by the presence of large venous channels with stasis of blood flow and
relative cold and hypoxia, which impair fibrinolysis and host defences. Lupus
vulgaris may affect other areas with relatively low temperature.

Miliary tuberculosis
Miliary lesions include a severe form in which numerous central bacilli within
a neutrophil abscess are surrounded by histiocytes (Fig. 18.163). Vascular
thrombi containing microorganisms may be seen.15 The less aggressive form
is similar, but lacks the large numbers of bacteria.
The skin lesions of disseminated miliary tuberculosis (especially in AIDS
patients) are often either devoid of granulomata or exhibit only poorly
formed granulomata. Extensive necrosis and abscess formation are often
Fig. 18.160 seen. Langhans giant cells are rare. Papillary dermal neutrophilic microab-
Warty lupus: in addition to neutrophils and lymphocytes, an occasional Langhans scesses reminiscent of those seen in dermatitis herpetiformis are sometimes
giant cell may be present. encountered. Special stains reveal numerous acid-fast bacilli.32,34
 Tuberculosis 817

A A

B B

Fig. 18.163 Fig. 18.164

Miliary tuberculosis: (A) a neutrophil abscess is present in the mid dermis; (B) it is (A, B) Scrofuloderma: there is extensive caseation necrosis.
surrounded by histiocytes. Occasional giant cells are also evident.

Scrofuloderma
Scrofuloderma usually appears as an ulcerated dermal abscess with an
­ill-defined histiocytic component. Peripheral granulomata may be present.
Marked caseation necrosis, in which bacilli may be numerous, can be seen in
the deeper tissues (Fig. 18.164).

Tuberculous gummata
Subcutaneous gummata are associated with marked caseation, but there are
few bacilli (Fig. 18.165). There is a surrounding granulomatous infiltrate,
which may be associated with dermal involvement.
Tuberculous cellulitic lesions are characterized by granulomatous inflam-
mation with giant cells and demonstrable bacilli.36,38,41 Panniculitis with
vasculitis may occasionally be seen in cutaneous tuberculous lesions.7 Rare
cases of subcutaneous mycobacterial granulomatous arteritis have been
documented.43

Differential diagnosis
The typical granulomatous and caseating picture is virtually pathognomonic
for tuberculous infection, although sarcoidosis can have a similar appearance.
Sarcoid, however, can be distinguished by the lack of caseation, but often this
is not particularly helpful since necrosis is seen in only a minority of cases Fig. 18.165
of tuberculosis. Necrosis when present in sarcoidosis is rather more fibrin- Tuberculous gumma: there is massive caseation surrounded by a well-defined
oid than caseating. More helpful is the lack of a surrounding lymphocytic granulomatous infiltrate.
818 Infectious diseases of the skin

i­nfiltrate and fewer giant cells in sarcoidosis and a more discrete arrangement
of the granulomata (the sarcoidal naked granuloma). Schaumann bodies are
characteristic of sarcoidosis, but may occasionally be seen in mycobacterial
infections.7
In less granulomatous forms of cutaneous tuberculosis a distinction from
leprosy must be made. The perineural distribution of the inflammation is a
pointer towards leprosy.
Deep fungal infections and leishmaniasis may also be confused with
tuberculosis and recognition of the organism is vital. Granulomatous late
secondary and tertiary syphilis is distinguished by the vascular changes and
numerous plasma cells. Caseation necrosis is typical of acne agminata and
may also be seen in foreign body reactions to beryllium and zirconium.44 It
may also be a feature of Wegener's granulomatosis, although this would be
distinctly unusual in cutaneous lesions.
Despite these points, diagnosis may still not be possible. The difficulty is Fig. 18.167
made worse by the frequent failure to demonstrate bacilli even in definite Papulonecrotic tuberculid:
cases of tuberculosis, and the results of culture take 3–4 weeks. Therefore, innumerable papules
occasionally, it may be a diagnosis of exclusion, which is confirmed by a are distributed on the
therapeutic trial of antituberculous drugs.11 The shortcomings of these tra- dorsal aspect of the legs.
ditional methods have led to increased use of PCR for confirmation of the Tuberculids imply an active
diagnosis.2,8,45 infection elsewhere in
the body. By courtesy of
N.C. Dlova, MD, Nelson
Tuberculids R. Mandela School of
Medicine, University of
Clinical features KwaZulu-Natal, South
Africa.
A tuberculid is a cutaneous immunological reaction to the presence of tuber-
culosis, which is often occult, elsewhere in the body.1–3 By definition, special
stains and cultures for tubercle bacilli from tuberculids are negative. Although
tuberculids are rare in Western countries, they are still important conditions in young people who otherwise often appear rather well. Occasional cases
in developing countries where tuberculosis is a common disease.3,4 have been reported to progress to lupus vulgaris.3,5
Tuberculids may be papular or nodular and can be separately classified on Lichen scrofulosorum characteristically presents as yellow or brown
that basis, but variations and combinations of those features may be seen and asymptomatic follicular papules, less than 3 mm across, on the trunk (Fig.
are only valid descriptively. 18.168). These lesions regress slowly and do not leave scars. This uncommon
One variety of papular tuberculid is the papulonecrotic tuberculid. This tuberculous reaction usually occurs in children and young adults.10–13 The
chronic condition presents as recurring crops of flesh-colored, erythematous eruption is said to be more frequently associated with tuberculous lymph-
or darkish red papules, most often on the ears and the limbs and in particular adenitis (cervical, hilar or mediastinal) or osseous tuberculosis than with
on extensor aspects around the elbows and knees (Figs 18.166, 18.167).4–6 pulmonary tuberculosis.11 The latter observation has not been supported by
Lesions may occur widely or present in isolated sites.6,7 The papules may others.10,11
become pustular, ulcerate or develop crusts. They are often symmetrically dis-
tributed.8 Genital involvement may occasionally occur.6 They regress slowly
over several weeks, leaving depressed, varioliform scars.8,9 Usually they occur

Fig. 18.168
Lichen scrofulosorum:
note the numerous tiny
papules on the chest
Fig. 18.166 and upper abdomen. By
Papulonecrotic tuberculid: widely distributed small purple papules are present. By courtesy of S. Lucas,
courtesy of N.C. Dlova, MD, Nelson R. Mandela School of Medicine, University of MD, St Thomas' Hospital,
KwaZulu-Natal, South Africa. London, UK.
 Cutaneous complications of Bacille Calmette-Guérin vaccination 819

Until recently, the only nodular tuberculid that was generally accepted
was erythema induratum (Bazin's disease, nodular vasculitis). This condi-
tion presents as ill-defined nodules on the calves of women, characteristically
those who are obese and have erythrocyanotic skin in this area. The lesions
may be worse in cold weather, which raises the problem of distinction from
pernio. With progression, the nodules eventually form irregular ulcers, which
tend to have bluish undermined edges. Resolution is slow.
More recently, the term nodular tuberculid has been applied to a rare sub-
set of patients with nonulcerated nodules on the lower legs and in whom the
pathological changes are centered on both the dermis and the subcutaneous
fat.14,15 It has been proposed that this entity represents a hybrid between pap-
ulonecrotic tuberculid and erythema induratum of Bazin.14 Rare cases of pap-
ulonecrotic tuberculid coexistent with erythema induratum have also been
reported.16,17
The terms nodular granulomatous phlebitis of the skin and superficial
thrombophlebitic tuberculid have been proposed for an additional type of
tuberculid which presents as subcutaneous nodules along the course of a leg
vein. There is histological evidence of granulomatous inflammation centered A
on the wall of the affected vessel.18,19 This condition should be distinguished
from true tuberculous phlebitis as a consequence of miliary tuberculosis.

Pathogenesis and histological features

All tuberculids are immunological reactions thought to be due to hematog-
enously disseminated M. tuberculosis antigens or small numbers of dead bac-
teria, possibly opsonized. These embolize to produce lesions, particularly in
areas of slow circulation. As a result of changes in small dermal vessels (either
an Arthus reaction or a lymphohistiocytic vasculitis), degenerative responses
develop in the dermal collagen. In the case of papulonecrotic tuberculid, this
amounts to frank necrosis. Histologically, the lesions show variable combi-
nations of vasculitis with necrosis, a moderate to intense lymphohistiocytic
infiltrate, and granulomatous inflammation.
Papulonecrotic tuberculid, when fully developed, shows cutaneous infarc-
tion comprising a necrotic epidermis with ulceration and an underlying
V-shaped zone of dermal coagulative necrosis accompanied by a dense chronic
inflammatory cell infiltrate with scattered giant cells.4,8,9 Necrosis of hair fol-
licles may occur.20 On occasion, a histiocytic palisade has been described, B
resulting in features reminiscent of granuloma annulare. Neutrophils are gen-
erally inconspicuous. Well-formed granulomata can be present but bacilli Fig. 18.169
(A, B) Lichen scrofulosorum: note the perifollicular distribution of this well-defined
cannot be identified. Vasculitis may be present.5,8 These features can some-
granulomatous infiltrate.
times be histologically confused with pityriasis lichenoides et varioliformis
acuta.7,20
In lichen scrofulosorum, a granulomatous infiltrate in which Langhans
tuberculosis remains a serious public health problem.1 In recent years a num-
giant cells are conspicuous is centered around hair follicules and eccrine units
ber of cutaneous and other complications have been recorded, especially in
(Fig. 18.169).4
infants with primary immunodeficiency syndromes, including X-linked severe
Erythema induratum has a less histiocytic infiltrate and is indistinguish-
combined immunodeficiency.2–6 Complications have also been documented in
able from nodular vasculitis. The presence of both primary vasculitic changes
infants and children infected with HIV.7,8
and granulomatous inflammation suggests that type III and type IV hypersen-
Local infection may develop at the vaccination site, with abscess forma-
sitivity reactions are important in the latter condition.21
tion.4,6 Regional lymphadenitis is another well-recognized complication (Fig.
Although acid-fast organisms are not detectable by special stains, and
18.170), and may be accompanied by cutaneous fistula formation or scrof-
mycobacterial cultures from these lesions invariably are negative, M. tuber-
uloderma.2,5,7,9 Disseminated skin lesions may also occur, manifesting with
culosis DNA has been detected by PCR in a number of cases; this suggests
a widespread papular eruption or multiple nodules or abscesses in the skin
that mycobacterial components are indeed responsible for the pathological
and even the subcutis.1–8 Dissemination of disease can prove fatal.10 Organs
manifestations.9,22–24
that may potentially be involved include the spleen, mesenteric and medi-
The validity of the concept of the tuberculids rests on the association
astinal lymph nodes, bone marrow, liver, and lungs.2,7 Other documented
with underlying tuberculosis, a strong tuberculin reaction, and an invariable
cutaneous manifestations include lupus vulgaris, erythema induratum, and
response to antituberculous drugs.
­papulonecrotic tuberculid-like lesions.11–14 A case with cutaneous ­involvement
­secondary to intravesical BCG instillation has been reported.15
Cutaneous complications of Bacille Histological features
Calmette-Guérin vaccination In immunocompetent individuals, skin and lymph node biopsy material may
reveal multiple epithelioid cell granulomas with admixed Langhans giant cells
Clinical features and minimal caseous necrosis, with or without concomitant suppuration.10
For almost a century, the Bacille Calmette-Guérin (BCG) vaccine, which Conversely, involved tissues obtained from immunosuppressed ­individuals
employs a live but attenuated form of Mycobacterium bovis, has been admin- are characterized by a diffuse infiltrate of plump histiocytic cells, with poorly
istered to newborns for the prevention of tuberculosis. BCG immunization is developed or absent granuloma formation. The cytoplasm of these ­histiocytes
currently carried out in more than 100 countries worldwide where endemic is distended by large numbers of acid-fast M. bovis bacilli.2,8,10 The ­histological
820 Infectious diseases of the skin

diffuse inflammation, and frequent abscess formation.6–8 Systemic spread is

obviously of particular importance in this latter group. As the features may be
atypical, diagnosis is facilitated by a healthy index of suspicion.

Fig. 18.170
BCG reaction: there is marked swelling with overlying erythema and sinus
formation. Histologically, massive caseation with innumerable acid-fast bacilli was
present. Courtesy of W. Hendson, MD., Rahima Moosa Mother and Child Hospital
and the University of the Witwatersrand, Johannesburg, South Africa
Clinical features
Mycobacterium marinum
M. marinum (balnei) is a slow-growing photochromogen, which is associated
with injuries in aquatic environments or by fish or equipment, usually under
water.9 The upper limb is the site of infection in more than 90% of cases.10
Infections have been contracted most often in swimming pools (swimming
pool granuloma, fish tank granuloma), usually on the elbows and knees of
children, or from aquaria, usually on the hands (Fig. 18.171).11 In some stud-
ies inoculation related to fish tank exposure has accounted for more than
80% of cases.10 The lesions usually present 1 week to 2 months (average 2–3
weeks) after superficial injury and are typically painless inflammatory nod-
ules or plaques.12 They may ulcerate and discharge yellow fluid and older
lesions can be warty (Fig. 18.172). Occasionally abscesses are seen. Quite
often there is extension along lymphatics, with the development of second-
ary nodules in a pattern comparable to sporotrichosis (Fig. 18.173).11,13,14

findings in this latter group are similar at all sites of involvement, including
cutaneous, subcutaneous, lymph node or visceral tissues. The diagnosis may
be confirmed by PCR.16,17

Differential diagnosis
Mycobacterial culture and PCR studies facilitate distinction between
cutaneous, subcutaneous or disseminated BCG infection in immunocom-
promised hosts from infection with Mycobacterium avium-intracellulare
complex and other nontuberculous mycobacterial infections. The degrad-
ing intracytoplasmic organisms contained within macrophages in the
­subcutaneous nodules of Whipple's disease are PAS-positive but fail to stain
with ­Ziehl-Neelsen method.

Nontuberculous environmental
mycobacterial infections Fig. 18.171
Mycobacterium marinum (balnei): inflammatory nodule on the finger of an aquarium
Nontuberculous mycobacteria (atypical mycobacteria; mycobacteria other enthusiast. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
than tubercle bacilli), which are usually nonpathogenic, are widespread in
varied sites throughout the world.1–3 They inhabit vegetation and water (stag-
nant, fresh or salty), and are saprophytic in soil, on animals, and within ani-
mal feces. They are traditionally subdivided according to their growth rate on
culture media and by their ability to produce a yellow pigment in culture with
and without exposure to light. There are therefore four categories:3,4
• Group I organisms are photochromogens, which produce pigment after
exposure to light (e.g., Mycobacterium marinum and Mycobacterium
kansasii).
• Group II organisms are the scotochromogens, which produce
pigmented colonies whether light is present or not (e.g., Mycobacterium
scrofulaceum and Mycobacterium szulgai).
• Group III organisms are consistently nonpigmented and include
Mycobacterium avium and Mycobacterium intracellulare.
• Group IV organisms are the fast growers and include Mycobacterium
chelonei, Mycobacterium fortuitum and Mycobacterium abscessus.
Exact species identification may also be facilitated by PCR performed on
mycobacteria that are grown in liquid media.5 The environmental mycobac-
terial infections are becoming of increasing importance in immunocompro-
mised patients, particularly in those with HIV/AIDS. Cutaneous infection
with these organisms in the immunocompent patient usually follows an epi-
sode of trauma and gives rise to a localized lesion often clinically resembling Fig. 18.172
panniculitis. In the immunosuppressed, a history of trauma is usually lack- Mycobacterium marinum (balnei): close-up view of an erythematous plaque with
ing and patients tend to present with multiple subcutaneous nodules, more scaling. By courtesy of the Institute of Dermatology, London, UK.
 Nontuberculous environmental mycobacterial infections 821

Fig. 18.174
Mycobacterium fortuitum
Fig. 18.173 chelonae: numerous
Mycobacterium marinum (balnei): this example demonstrates sporotrichoid spread. abscesses are distributed
By courtesy of the Institute of Dermatology, London, UK. along this patient's
leg. This infection is
more often seen in the
Sporotrichoid spread has also been reported in the context of HIV infection immunosuppressed. By
and following infliximab therapy.15,16 Penetrating injuries sometimes result in courtesy of the Institute of
tenosynovitis.17,18 Infection in immunodeficient individuals produces a deeply Dermatology, London, UK.
undermined ulcer; otherwise, lesions usually resolve within a few months. In
one large retrospective study the mean duration of disease was 19 months.19

Mycobacterium fortuitum chelonae (M. fortuitum complex)

M. fortuitum chelonae (M. fortuitum complex) comprises a group of rapid-
growing organisms found in soil and water and occasionally nonpatho-
genically in sputum. The organisms are M. fortuitum, M. chelonae, and M.
chelonae subsp. abscessus (M. abscessus). Lesions, which are uncommon, usu-
ally develop 3–4 weeks after contamination of skin wounds, including surgi-
cal incisions, injections, liposuction, liposculpture, and even acupuncture.9,20–22
Outbreaks of mycobacterial furunculosis due to M. fortuitum have occurred
due to communal use of footbaths at nail salons during pedicures.23–25 Reports
emerged of M. fortuitum and M. abscessus infection among survivors of the
2004 tsunami disaster off Thailand; these patients had sustained contaminated
crush trauma injuries to their lower extremities.26 A large subcutanous abscess
due to M. abscessus has been described in a patient with systemic lupus ery-
thematosus.27 Disease may present in a disseminated form, often associated
with immunosuppression, including HIV/AIDS (Figs 18.174, 18.175).7,28
Pulmonary infection with subsequent cutaneous dissemination has also been
reported in an apparently immunocompetent patient.29 The lesions comprise
indolent abscesses with fistula formation, purulent discharge, and scarring. A
sporotrichoid distribution has also been recorded (Fig. 18.176).6,30 Healing
Fig. 18.175
is usually delayed for many months, but may be helped by adequate debride-
Mycobacterium fortuitum chelonae: close-up view. By courtesy of the Institute of
ment. The M. chelonae variant is the more refractory to treatment. Dermatology, London, UK.

Mycobacterium kansasii
M. kansasii is a slow-growing photochromogen found worldwide in various
habitats. This is a disease mainly of the lungs and lymph nodes; it only rarely
causes skin lesions and these are most common in the immunosuppressed,
when they are usually associated with disseminated disease.31–33 Iatrogenically
immunosuppressed patients and patients with HIV/AIDS may, however,
also present with primary cutaneous infection.34,35 Cases of infection by
M. kansasii are varied in their presentation: they may appear as nodules
(which can be verrucous), crusted ulcers, papulopustules, cellulitis or as a
spreading infection resembling sporotrichosis.36,37
Mycobacterium ulcerans
M. ulcerans infection is a rapidly reemerging disease, and is currently
­recognized as the third most common mycobacterial disease in immunocom-
petent people (after tuberculosis and leprosy).38–42 The causative organism is
a slow-growing nonchromogen, which is present sporadically on lush vegeta-
tion in swampy areas in the tropics.43–45 It is particularly seen in the tropical
wetlands of West and Central Africa (Buruli ulcer), but was characterized
in Australia (Bairnsdale ulcer). It has subsequently been recorded in the
koala bear in the same region.46 The condition also occurs in tropical regions
of Asia and South America.45 Comparative genomic studies indicate that
M. ulcerans recently evolved from M. marinum to become a niche-adapted
specialist.47–49 Two distinct lineages exist: the ‘classic’ lineage comprising more
virulent strains from Africa, Australia, and Southeast Asia, and an ‘ancestral’
lineage, which includes genotypes encountered in China, Japan, and South
America.48 Although it has been stated that M. ulcerans infection is not linked
to HIV infection, a recent study from Benin suggests that there might indeed
be an association.45,50 Genetic polymorphism in the SLC11A1 gene may play
a role in susceptibility to the disease.51
822 Infectious diseases of the skin
Fig. 18.176
Mycobacterium fortuitum chelonae: note the indurated, nodular, ulcerated lesion
on the hand with sporotrichoid spread. By courtesy of S. Lucas, MD, St Thomas'
Hospital, London, UK.
The lesion develops about 8 weeks after minor trauma or skin abra-
sions which came into contact with contaminated water, soil or vegeta-
tion.38,52 Consequently, the infection usually appears on the legs and tends
to occur more often in children.52,53 A second peak occurs in late adult
life.53 Serological evidence, however, suggests that only a relatively small
proportion of infected patients develop clinical disease.54 The initial ery-
thematous nodule progresses to an indolent ulcer, which may be very
large, up to 50 cm across (Fig. 18.177). The ulcer is without exudate or
surrounding reaction, but extends to involve underlying fascia or fat and
typically has an undermined border.41,52 There is little or no malaise or
fever. After 6–9 months, a granulomatous response develops, which pre-
cedes healing. This is usually associated with scarring, which may lead
to severe deformity and contractures.38 Surgery remains the treatment of
choice.40
The extensive tissue necrosis and ulceration that are hallmarks of the
infection are attributable to production of mycolactone, a potent soluble
toxic macrolide possessing both cytotoxic and immunosuppressive proper-
ties.41,44,55–59 Mycolactone leads to cell death via both apoptosis and necro-
sis. This polyketide toxin has antiphagocytic properties and not only limits
the initiation of a primary immune response, but also impedes the recruit-
ment of inflammatory cells to the site of infection.41,56,58,59 A nonulcerative
form of the disease is recognized with increasing frequency in highly endemic
areas.55 Associated osteomyelitic bone lesions are not uncommon, espe-
cially when multiple cutaneous lesions are present on the lower extremities.53
Occasionally, severe systemic disease and death may result from secondary
infection or tetanus.38 Rarely, squamous cell carcinoma can arise in a chronic
Buruli ulcer.60,61
M. ulcerans infection tends to occur in parts of Africa where there is a
high prevalence of Schistosoma haematobium infection. This observation
led some authors to suggest that schistosomiasis may be a risk factor for
the development of Buruli ulcer by driving the host immunological reac-
tion away from a Th1 response and toward a Th2 response.45 This appar-
ent association with schistosomiasis, however, is purely fortuitous, with no
clear evidence to support the hypothesis that coinfection with Schistosoma
spp. confers susceptibility to infection with M. ulcerans.62 Instead, trans-
mission of the disease appears to be related to the close spatial proximity
of human activities to high-risk aquatic environments.63 Current epidemio-
logical and experimental evidence suggests that predatory aquatic insects act
as a potential vector of M. ulcerans, and that the aquatic snails on which
these insects feed serve as passive intermediate hosts.64,65 In the Australian
­context, however, mosquitoes have been implicated in the transmission of
M. ulcerans.66,67
B
Fig. 18.177
Mycobacterium ulcerans: (A) note the extensive ulceration with undermining of the
edge; (B) gross specimen showing opaque necrosis of the central subcutaneous
fat. (A) By courtesy of S. Lucas, MD, St Thomas' Hospital, London, UK; (B) by
courtesy of the late M. Hutt, MD, St Thomas' Hospital, London, UK.
Mycobacterium avium-intracellulare (M. avium complex)
M. avium-intracellulare (MAI) complex is a group of slow-growing nonchro-
mogens, which are present widely in dust, soil, and water.68,69 Exposure to soil
appears to represent an important environmental risk factor for infection.70
They are seen most commonly causing a cervical lymphadenitis or dissemi-
nated infection in immunocompromised hosts. MAI is one of the commonest
causes of bacteremia in AIDS patients and is also frequently isolated from the
liver, bone marrow, lung or gastrointestinal tract. Although the skin may be
involved as part of disseminated MAI disease, primary cutaneous infection
is uncommon.71 A disseminated varioliform pustular eruption due to MAI
has been described in a patient with AIDS.72 Primary infections may develop
in immunocompetent individuals who present with subcutaneous nodules,
which subsequently undergo ulceration.73–75 Isolated lesions such as perineal
ulcers or subcutaneous masses may also occur in AIDS patients.71 Skin and
soft tissue involvement can occur as part of the immune reconstitution inflam-
matory syndrome in HIV-infected patients receiving highly active antiretro-
viral therapy.76,77 Dermal and subcutaneous infection has been reported in an
iatrogenically immunosuppressed individual receiving ­treatment for ­systemic
lupus erythematosus.78
Generally, the skin lesions present as a panniculitis, often in relation to
affected lymph nodes, or as nodules progressing to abscesses and ulcers (Fig.
18.178). Healing is slow, even with appropriate drug therapy, and excision
may be necessary.
 Nontuberculous environmental mycobacterial infections 823

Fig. 18.178
Mycobacterium avium Fig. 18.180
intracellulare: these Mycobacterium marinum (balnei): conspicuous Langhans giant cells are present.
multiple nodules on
the thighs resemble encountered more frequently than with other nontuberculous mycobacte-
panniculitis. By courtesy rial infections.80 Caseation is absent, but there may be fibrinoid necrosis.
of S. Lucas, MD,
Langhans cells may be conspicuous or scanty (Fig. 18.180). A lymphohistio-
St Thomas' Hospital,
London, UK.
cytic infiltrate is present in the surrounding dermis. The overlying epidermis
is parakeratotic, acanthotic or ulcerated. Pseudoepitheliomatous hyperplasia
may occur (Fig. 18.181).7 The sporotrichoid nodules, which are frequently
Other mycobacteria present, are tuberculoid granulomata without the preceding abscess phase.
There is often a poor yield of positive isolates from culture specimens, and
An expanding number of other mycobacteria, including M. scrofulaceum,
PCR (including PCR restriction analysis) may thus be a more useful means of
M. gordonae, M. simiae, M. xenopi, M. malmoense, and M. haemophilum
confirming the diagnosis.19,81
may rarely cause cutaneous lesions, mostly following inoculation, to produce
nodules and abscesses, usually with ulceration and sinus formation.2,18
Mycobacterium fortuitum chelonae (M. fortuitum complex)
Histological features M. fortuitum chelonae (M. fortuitum complex) infection shows early acute
inflammation, which progresses to ill-defined granulomata with occasional
Most of these,atypical, mycobacteria show early cutaneous necrosis with
necrotic foci. Panniculitis and acute suppurative folliculitis may also be
neutrophil abscess formation. This phase is usually associated with readily
observed (Fig. 18.182).7 Bacilli are easily seen and are present in clusters
demonstrable bacilli. The abscess phase is gradually replaced by granuloma-
(Figs 18.183, 18.184).30,82
tous inflammation and fibrosis, often with sinus formation.

Mycobacterium marinum
M. marinum follows the common histological progression from abscess to
granuloma, but few of the broad, long bacilli are seen, except in immuno-
compromised patients (Fig. 18.179).7,79 Granulomatous inflammation is

Fig. 18.181
Mycobacterium marinum
(balnei): abscess formation
and granulomatous
inflammation have eroded
the overlying epidermis.
The features of this
Fig. 18.179 condition closely mimic
Mycobacterium marinum (balnei): there is hyperkeratosis and very marked acanthosis. the deep fungal infections.
824 Infectious diseases of the skin

Mycobacterium kansasii
M. kansasii infection shows a pattern similar to other nontuberculous
mycobacterial infections. The early mixed inflammation is usually intense
before becoming tuberculoid. Abscesses may be present. Bacilli are frequent.
M. kansasii organisms are larger, broader, and more coarsely beaded.83 Some
cases show overlying acanthosis with hyperkeratosis and parakeratosis. The
acute lesions seen in immunosuppressed patients typically show an intense
neutrophil infiltrate with abscess formation.32,36

Mycobacterium ulcerans
M. ulcerans infection is characterized by extensive coagulative necrosis
and ulceration with very little inflammatory reaction for a few months
(Fig. 18.185).43,52,84 Tissue destruction is mediated by the production of
mycolactone, which induces both necrosis and apoptosis.57,83 In this aner-
gic stage, bacilli are very numerous and are seen clustering in the collagen
of fascia or in fat at the base of the ulcer (Fig. 18.186). Leukocytoclastic
vasculitis has been described in both the dermis and septa of the sub-
cutaneous fat.52,85 Focal calcification may be seen. Healing of the ulcer
Fig. 18.182 corresponds with progressive positivity of the ‘burulin’ test and a granu-
Mycobacterium fortuitum chelonae: this is a predominantly neutrophil-mediated lomatous reaction. Mycobacteria are then sparse or absent.52 Caseation is
infection.

Fig. 18.183
Fig. 18.185
Mycobacterium fortuitum chelonae: aggregates of bacilli are typically visible in the
(A, B) Mycobacterium
hematoxylin and eosin stained sections.
ulcerans: there is
widespread coagulative
necrosis. Note
A the absence of an
inflammatory reaction.

Fig. 18.184 B
Mycobacterium fortuitum chelonae: the bacilli are strongly acid fast.

Fig. 18.186
Mycobacterium ulcerans: the lesions contain numerous acid-fast bacilli (Ziehl-
Neelsen).
not a feature. Variable septolobular panniculitis can be present. Resolving
lesions may exhibit pseudoepitheliomatous hyperplasia of the epidermis.86
In the nonulcerated form there is massive contiguous necrosis of the der-
mis and subcutaneous tissue.55 The ulcerated lesions may demonstrate
immunoreactivity for phenolic glycolipid-I (PGL-I).85 Local recurrence
has been linked to the presence of persistent infection in macroscopi-
cally healthy tissue beyond the surgical excision margins.87 A sensitive
dry reagent-based PCR method for confirmation of the diagnosis has been
described.88,89
Mycobacterium avium-intracellulare (M. avium
complex)
M. avium-intracellulare (M. avium complex) infection sometimes appears to
have an early abscess phase before the granulomatous phase, but in other
cases the inflammatory infiltrate is more lymphohistiocytic, so that it resem-
bles lepromatous leprosy (Fig. 18.187).68,69 Bacilli are present, but are usually
intracellular. Rarely, infected histiocytes become large and voluminous and
have been referred to as pseudogaucher cells.90 The histological picture may
also mimic histoid leprosy.91 A case of cutaneous mycobacterial spindle cell
tumor due to M. intracellulare has also been reported.78
A B
Fig. 18.187
(A, B) Mycobacterium avium intracellulare: in this variant, the infiltrate typically consists of histiocytes, lymphocytes, and neutrophils. Bacteria are often numerous.
Leprosy 825
Other mycobacteria
M. haemophilum may produce a mixed suppurative and granulomatous
­reaction in addition to a paucigranulomatous reaction, lichenoid interface
dermatitis, and lymphocytic vasculitis.92
Leprosy
Clinical features
Mycobacterium leprae is the bacillus recognized as causing leprosy, and until
recently could only be cultured in experimental animals, particularly the nine-
banded armadillo. It is an obligate intracellular, Gram-positive, weakly acid-
fast organism. The disease is found worldwide, due to extensive traveling
and migration, but is endemic in the tropics.1–4 The past two decades have
seen a dramatic decrease in the global disease burden from over five million
people in the mid-1980s to around 800 000 by the mid-1990s. More than
250 000 new cases were detected in 2006, a decrease of more than 13% when
compared with 2005. The gobal registered prevalence of leprosy was around
224 000 at the beginning of 2007.5–8
Although the disease has been recognized for many centuries and its
causative organism has been known for over 100 years, many aspects of
the pathogenesis remain unclear, and leprosy is still a problem to diagnos-
ticians, epidemiologists, and pharmacologists. The complexity of the pre-
sentation is related intimately to the varied immunological responses. The
incubation period may be as short as 1–2 years, but is usually 3–5 years,
and may be 10 years or more. The recent ability to culture infected
­macrophages isolated from patients with multibacillary leprosy holds
promise for the ex vivo study of M. leprae and its interaction with its
host.9
There are two extreme modes of presentation:
• the tuberculoid form, tuberculoid leprosy (TT),
• the lepromatous form, lepromatous leprosy (LL).
Between these are:
• borderline tuberculoid leprosy (BT),
• borderline lepromatous leprosy (BL),
• borderline leprosy (BB) occupying an intermediate position.1–4
Tuberculoid leprosy
Tuberculoid leprosy (TT) is associated with high resistance to the lepra bacil-
lus, but in the lepromatous form resistance to the lepra bacillus is low.3,4,10
TT occurs in individuals with good cell-mediated immunity, but low
antibody titers to M. leprae. It appears as localized, sometimes single, asym-
metrical truncal or limb lesions. The lesion is typically an erythematous
plaque with raised margins and a flat hypopigmented center (Fig. 18.188).
826 Infectious diseases of the skin

Fig. 18.190
Lepromatous leprosy:
Fig. 18.188 note the symmetry and
Tuberculoid leprosy: note the hypopigmentation and erythema. By courtesy of B characteristic loss of the
Al-Mahmoud, MD, Doha, Quatar. eyebrows. By courtesy of
N.C. Dlova, MD, Nelson
Sensory impairment is invariable because of associated involvement of R. Mandela School of
nerves by the bacilli; these nerves may be palpably thickened. Alternatively, Medicine, University of
KwaZulu-Natal, South
the skin lesion may be an erythematous macule, hypopigmented in dark
Africa.
skins. Sometimes the skin is not involved primarily, cutaneous manifes-
tations being seen as a result of minor trauma associated with anesthesia
from the neural lesion.
groins, and perineum. These lesions become anesthetic due to widespread
Lepromatous leprosy neural involvement with resultant claw hand and foot drop (Fig. 18.191).
Lepromatous leprosy (LL) is a systemic disease that occurs in patients with A rare phenomenon occurring in patients with LL is the development of numer-
poor cell-mediated immunity to M. leprae, but with higher levels of anti- ous histiocytoma-like lesions: the histoid variant (Fig. 18.192).11–13 Large
bodies. The cutaneous lesions are multiple, symmetrical, and may affect cutaneous and subcutaneous nodules and plaques, sometimes ­measuring in
the whole skin, giving a sclerodermatous appearance (diffuse or Lucio-type excess of 3 cm in diameter have been described.14–16
­leprosy). The lesions are typically firm and nodular and are concentrated on
the face and backs of hands, facial lesions being associated with hair loss Borderline leprosy
round the eyes (Figs 18.189, 18.190). The distribution of the lesions is said Lesions in BT, BL and BB manifest in a form intermediate between the polar
to be favored by lower skin temperature. The mucosa of the nose is character- forms TT and LL (Figs 18.193–18.195). The lesions are fewer in number
istically involved and becomes hyperemic with frequent epistaxes. The nasal and less symmetrically distributed than in LL and there is less localization and
cartilages and bone may be affected, and collapse can result in a picture simi- nerve involvement than in TT. There is, however, a continuous spectrum and
lar to the saddle nose of congenital syphilis. A variety of macules, papules, individual patients may downgrade to more closely resemble LL or upgrade
and plaques may be present at one time, characteristically sparing the axillae, towards the tuberculoid pole.

Fig. 18.191
Fig. 18.189 Lepromatous leprosy: these hands show loss of the digits and trauma-related
Lepromatous leprosy: numerous nodules are present on the face. By courtesy of ulcers due to gross nerve damage. By courtesy of S. Lucas, MD, St Thomas'
S. Lucas, MD, St Thomas' Hospital, London, UK. Hospital, London, UK.

Fig. 18.192
Histoid leprosy: these numerous brown papules and nodules may be histologically
mistaken for a ‘fibrohistiocytic’ tumor if the clinical information is not available. By
courtesy of S. Lucas, MD, St Thomas' Hospital, London, UK.
Fig. 18.193
Borderline tuberculoid leprosy: an early hypopigmented macule. By courtesy of
S. Lucas, MD, St Thomas' Hospital, London, UK.
Fig. 18.194
Borderline tuberculoid leprosy: note the ulceration and muscle wasting due to median and
ulnar nerve involvement. By courtesy of S. Lucas, MD, St Thomas' Hospital, London, UK.
Leprosy 827
Fig. 18.195
(A, B) Borderline
lepromatous leprosy:
there are gross infiltrated
erythematous plaques
with well-defined borders.
(A) By courtesy of
S. Lucas, MD, Institute
of Dermatology, London,
UK; (B) by courtesy of
N.C. Dlova, MD, Nelson
R. Mandela School of
Medicine, University of
A KwaZulu-Natal, South
Africa.
B
Lepra reactions
Type I Lepra (reversal) reactions, which usually develop in BL patients, are
associated with an upgrading to a more resistant tuberculoid pole of the
spectrum and the development of a positive Mitsuda (lepromin) reaction.3,17
Patients therefore have developed an improved immunological reaction. Less
often, type I reactions may be associated with downgrading. They may be
associated with treatment, and consequently are characterized by an accel-
erated destruction of bacilli. Type I Lepra reactions are also associated with
pregnancy, stress, and intercurrent infections. The upgrading causes marked
inflammatory changes within the skin: nerve lesions manifest as nerve swell-
ing and pain; cutaneous lesions may become tender and edematous with an
increased cellular infiltrate (Fig. 18.196).3
Type II reaction, also known as erythema nodosum leprosum (ENL),
occurs in LL and BL, usually during treatment. It may also be provoked
by physical or mental stress, injury, other infections, vaccinations or preg-
nancy.3,18,19 There appears to be a direct relationship between an increasing
bacterial index and the risk of developing ENL. Increasing age, on the other
hand, has been found to have an inverse relationship with ENL. The reac-
tion may occur prior to, during or after the introduction of multidrug ther-
apy.20 The changes of ENL are believed to be due, at least in part, to immune
828 Infectious diseases of the skin
Fig. 18.196
Type I Lepra reaction: note the unilateral edema and intense erythema. By courtesy
of S. Lucas, MD, St Thomas' Hospital, London, UK.
Fig. 18.197
Erythema nodosum leprosum: note the erythematous nodules on the dorsal aspect
of the forearms and shins. By courtesy of S. Lucas, MD, St Thomas' Hospital,
London, UK.
complex deposition in vessels following the release of bacterial antigens in
patients who have high levels of antibodies. Both immunoglobulins and com-
plement have been identified in blood vessel walls. Delayed hypersensitivity
mechanisms, however, are also thought to have a pathogenetic role. In ENL
there are, therefore, increased numbers of T-helper cells and an increased
lesional helper:suppressor T-cell ratio is characteristic.18 Studies performed on
lesional tissue have confirmed a preponderance of CD4+ T cells and a Th1
type immune response.21 The symptoms are nocturnal pains, mainly of the
face, thighs, and arms. Lesions include tender erythematous or deep purple
nodules with fever and painful nerve swelling, swollen joints, myositis, pain-
ful fingers, iritis, lymphadenitis, glomerulonephritis, and epididymo-orchitis
(Fig. 18.197).18 Cases with bullous skin lesions have been reported.22–25
Lucio's phenomenon
Lucio's phenomenon (erythema necroticans) is seen in Mexican and Central
American patients who present with untreated, diffuse, non-nodular lep-
romatous leprosy (pure and primitive diffuse lepromatous leprosy (PPDLL);
diffuse leprosy of Lucio and Letapí) associated with hemorrhagic infarc-
tion and epidermal necrosis (Fig. 18.198).18,26–30 Lesions, which are initially
Fig. 18.198
Lucio's phenomenon: note the multiple infarcted cutaneous nodules, which have
developed against a background of diffuse lepromatous leprosy. By courtesy of
R. Arenas, MD, and J.C. Salas, MD, Monterrey, Mexico.
­ acular, then soon break down to become irregular jagged ulcerations, which
m
heal to leave irregular atrophic scars. The extremities are most commonly
affected. Although Lucio's phenomenon, like ENL, was considered to be
mediated by immune complexes, this concept has since been challenged. It
has recently been suggested that the triggering event is thrombotic vascular
occlusion secondary to massive invasion of vascular endothelial cells by the
bacilli, r­ esulting in necrosis.30
Indeterminate leprosy
Indeterminate leprosy is an early form of leprosy, which often resolves spon-
taneously.31 However, in 25% of patients, evolution to one of the determinant
types occurs. It appears as poorly defined areas of slight hypopigmentation
or erythema, without systemic or neural changes. The condition is only likely
to be recognized readily in endemic areas where there is a high awareness of
leprosy. It must be carefully distinguished from other dermatoses.
The Mitsuda reaction (intradermal injection of armadillo-derived Lepra
bacilli) has proved useful for classification purposes.4 Tuberculoid patients
develop a granulomatous response; lepromatous patients do not (Fig.
18.199).3
Although leprosy has been reported in patients infected with HIV, cur-
rent evidence suggests that M. leprae is not an opportunistic pathogen in
these individuals.32–34 In recent years there have been a number of reports of
leprosy occurring as a manifestation of the immune reconstitution inflamma-
tory ­syndrome (IRIS) following the initiation of highly active antiretroviral
therapy in HIV-infected individuals.35–38 Leprosy is only rarely encountered in
immunosuppressed organ transplant recipients.39
Leprosy patients with chronic cutaneous ulcers (especially plantar lesions)
are at increased risk for the development of squamous cell carcinoma.40,41
Pathogenesis and histological features
The varied clinical manifestations of leprosy are the result of a number of fac-
tors, including the host's immune response, the mode of infection, and cer-
tain genetic factors.42 It was long assumed that transmission of leprosy was
by long-term close direct skin contact, but this can be seriously questioned
as there is no evidence that infection can occur through intact skin. LL is far
more infective than other forms and the nasal mucosa and nasal secretions
of patients with LL are heavily infected with bacilli. This is a most ­important
source of infection, but it is not clear that the route of transmission is via
the lungs or gastrointestinal tract, even though inhalation of droplets and
ingestion of bacilli do occur. Lactating mothers with LL produce high counts
of bacilli in milk and yet do not appear to spread leprosy to their babies.
 Leprosy 829

Fig. 18.199 Fig. 18.200

Mitsuda reaction: this is Tuberculoid leprosy:
positive in a patient with there is extensive
tuberculoid leprosy. infiltration of the dermis
By courtesy of R. Arenas, and subcutaneous
MD, and J.C. Salas, MD, fat by noncaseating
Monterrey, Mexico. granulomata.

It seems most likely that infection in leprosy occurs by a combination of nasal Histologically, TT is characterized by an epithelioid histiocyte response
discharge and digital impregnation of the skin, as bacilli can be carried under around small cutaneous nerves (Figs 18.200–18.202). It may be entirely
the nails and inoculated into the skin by scratching. A recent study revealed confined to the immediate vicinity of nerves in highly immune patients, but
that untreated patients with multibacillary leprosy may shed organisms into it often extends into the adjacent dermis. When there are clinical cutaneous
the environment via their skin and nasal epithelia.43 Inoculation leprosy is a lesions the infiltrate involves the papillary dermis up to the epidermis. In con-
rare phenomenon acquired through skin tattooing.44 trast, BT and more lepromatous forms have a preserved Grenz zone in the
The responses of those that are infected may be determined by a genetic papillary dermis. Tuberculoid lesions usually contain a number of Langhans
predisposition, as suggested by associations with human leukocyte antigen giant cells, but necrosis is not a feature. Bacilli are so scarce in tuberculoid
(HLA) types (e.g., DR2 and DR3). In tuberculoid lesions there is an efficient lesions that they are usually not identified; they are present in increasing num-
granulomatous macrophage response, associated with a preponderance of bers in variations closer to the lepromatous type of response. Distinguishing
T-helper (CD4+) cells over T-suppressor cells (CD8+) and no antibody pro- TL from other forms of granulomatous infiltrate of the skin is dependent on
duction. There is associated elimination of the bacteria, which are therefore noting the association with nerves, which often gives the granuloma a ser-
difficult to find in tuberculoid lesions. The tuberculoid response is therefore pentine shape. In addition, there are numerous lymphocytes, largely T-helper
characterized by a persistent or chronic delayed hypersensitivity reaction, type, which may infiltrate the nerves in highly immune cases; the lymphoid
with a Th1 immune response.3,9 A Th2 response characterizes multibacillary infiltrate may be intense and extensive.
leprosy.3,9 In lepromatous lesions T-suppressor cells are more numerous and
IL-2 producing cells are scarce, whereas they are 10 times more common in
TT. One explanation for the different response suggests that T-helper cells are
defective or absent in individuals who develop LL. An alternative theory sug-
gests that T-suppressor cells are activated by the leprosy bacilli in patients of
certain HLA-DR types. It is proposed that this represents a response to PGL-I,
which is peculiar to the cell envelope of the leprosy bacillus. The T-suppressor
cells effect a reduction of T-helper cells reactive to M. leprae. In this way
the T-suppressor and T-helper theories are not incompatible. The variable
immune response to the Lepra bacillus is manifest in the wide variety of clini-
cal manifestations in leprosy.45 Other genetic factors including Lewis factor
and natural resistance-associated macrophage protein 1 (NRAMP1) may also
play a role.42 A recent study from India found that BCG vaccination played a
beneficial role in the prevention of leprosy.46
In LL there is an inability to develop a significant T-cell-mediated delayed
hypersensitivity reaction to the leprosy bacillus.3 The high level of antibodies
in LL appear to have no beneficial effect, but are relevant to the development
of the immune complex-mediated ENL lesions (see above). Lucio's phenom-
enon, in which purpura and leg ulcers develop, was thought to involve a simi-
lar immune complex-mediated mechanism to produce episodes of necrotizing
vasculitis in this diffuse type of leprosy. Others, however, have since suggested
that direct invasion of vascular endothelium by large numbers of bacilli, with Fig. 18.201
subsequent thrombosis of vessels, is the major factor in the evolution of this Tuberculoid leprosy: lymphocytes are present in addition to giant cells and
reaction.30 Antiphospholipid antibodies may also play a role.47 granulomata.
830 Infectious diseases of the skin
A B
Fig. 18.202
Tuberculoid leprosy: (A) this small nerve is almost completely replaced by the granulomatous infiltrate; the residual nerve tissue is arrowed; (B) S-100 protein immunohistochemistry
is invaluable in identifying damaged nerves.
Fig. 18.203
Lepromatous leprosy:
there is infiltration of the
dermis by large numbers
of histiocytes.
In LL, as in TL, the macrophage is the most important cell, but it
is not arranged in discrete granulomata nor clearly related to nerves.
Rather, macrophages are found in poorly circumscribed masses in the
dermis with few, if any, lymphocytes (Figs 18.203, 18.204). Those lym-
phocytes that are present are T-suppressor cells. The macrophages are
inert and often vacuolated or foamy (Fig. 18.205). They may be dis-
tended with large groups (or globi) of leprosy bacilli. These give the cyto-
plasm a grayish tinge on staining with hematoxylin and eosin; the bacilli
are revealed more clearly with a modified Ziehl-Neelsen stain (Wade-
Fite) (Fig. 18.206). The bacteria are present in large numbers of cutane-
ous nerves and are also seen in that site in the borderline forms of leprosy.
Bacilli may also be present in the endothelium and media of small and
large vessels, in arrector pili muscles, and in the eccrine secretory and
ductal cells.48 Exceptionally, clumps of bacilli may even be encountered
in epidermal keratinocytes.49
Fig. 18.204
Lepromatous leprosy: a
Grenz zone of sparing of
the papillary dermis is
characteristic.
Plasma cells are rarely seen in leprosy. They may, however, be found
in subpolar LL, which clinically lies between BL and polar LL (Figs
18.207–18.209).
In borderline leprosy perineural fibrosis with a lamellar or ‘onion skin’
pattern may be seen. Borderline leprosy shows increased circumscription of
the granulomatous response, more lymphocyte, and more relation to nerves
as it approaches the polar tuberculoid form.
Indeterminate leprosy shows only a scanty superficial and deep lympho-
histiocytic infiltrate in the dermis, with some tendency to localization around
appendages (Fig. 18.210). Bacilli are infrequent, but scantily present in
nerves (Fig. 18.211). Mast cells are increased.50 S-100 protein immunohis-
tochemistry is a useful means of identifying dermal nerves and foci of nerve
damage in skin biopsy specimens.51,52
Histologically, in most instances Lucio's phenomenon is characterized by
the features of a leukocytoclastic vasculitis and epidermal infarction.18,30,53
 Rhinoscleroma 831

Fig. 18.205
Lepromatous leprosy: the cytoplasm of the histiocytes is bubbly and has a
grayish hue.
Fig. 18.207
Subpolar lepromatous
leprosy: there is a dense
dermal infiltrate. A Grenz
zone is present.

Fig. 18.206
Lepromatous leprosy: large numbers of bacilli are present; note the globi (Wade-
Fite).

Severe passive venous congestion of the superficial veins is common.18

Occasionally, however, some vessels are thrombosed and there is endothe-
lial cell proliferation and swelling.26,53,54 Marked intraendothelial cell bacil-
lary proliferation is characteristic.18,53 It has been suggested that this feature
is indicative of a very poor immune response facilitating antigen–antibody
interaction with consequent acute necrotizing vasculitis. This seems to be
rather unlikely (on its own) as similar numbers of leprosy bacilli have been
described in the endothelium of 100% of small vessels in untreated polar and
subpolar LL.30,48
Histoid leprosy shows a spindle cell proliferative pattern suggestive of
fibrous histiocytoma (Figs 18.212, 18.213). A storiform pattern may be
conspicuous. Careful examination, however, will reveal foci of Lepra cells.
A Wade-Fite reaction reveals large numbers of bacilli, often arranged in
sheaves.13
ENL is characterized by an inflammatory cell infiltrate in the der-
mis and adjacent subcutaneous fat (Figs 18.214–18.216). In addition to
Lepra cells, large numbers of neutrophils are typically present, and there
is often an acute vasculitis (Fig. 18.217).21,55 Bullous lesions are charac-
terized by dermal edema.25 Organisms are demonstrable within capillary
endothelium.25,30
Fig. 18.208
Subpolar lepromatous leprosy: in addition to histiocytes and lymphocytes, there are
conspicuous plasma cells.
Molecular techniques (PCR) may prove useful in confirming the diagno-
sis of leprosy, especially in paucibacillary forms or when organisms are not
r­eadily apparent in sections stained with the Wade-Fite method.56–58
Rhinoscleroma
Clinical features
Rhinoscleroma is usually seen in adults and is now confined to the trop-
ics, although it was previously common in Eastern Europe.1–3 The disease
has been linked to poor socioeconomic conditions and is still encountered
in parts of Africa, Southeast Asia, Mexico, Central and South America, and
Central and Eastern Europe.3,4 Rhinoscleroma has also been described in the
Arabian Gulf.5 It is a severe chronic infection of the upper respiratory tract,
832 Infectious diseases of the skin

Fig. 18.209
Subpolar lepromatous leprosy: leprosy bacilli are numerous (Wade-Fite).

Fig. 18.211
Indeterminate leprosy: (A) the inflammation involves the small nerve trunks; (B) a
Wade-Fite reaction may reveal one or two bacilli (arrowed). By courtesy of S. Lucas,
MD, St Thomas' Hospital, London, UK.
Fig. 18.210
(A, B) Indeterminate
leprosy: a perivascular
chronic inflammatory cell
infiltrate is present in the
deep dermis. Diagnosis
A depends on a high index
of suspicion.

Fig. 18.212
B Histoid leprosy: in this field appearances are highly suggestive of a fibrohistiocytic
tumor. By courtesy of S. Lucas, MD, St Thomas' Hospital, London, UK.

Fig. 18.213
Histoid leprosy: there is a well-developed storiform pattern. By courtesy of
S. Lucas, MD, St Thomas' Hospital, London, UK.
Fig. 18.214
Erythema nodosum
leprosum: an intense
inflammatory cell infiltrate
outlines the dermal
vasculature and extends
into the subcutaneous fat.
e­ specially the nose. The disease is contracted by direct droplet infection or,
more ­indirectly, by contamination of material that is subsequently inhaled. It
has a very long incubation period.
There are three phases to the clinical features of the disease:
• It begins with a catarrhal phase, with symptoms suggesting a non-specific
rhinitis or coryza with frontal headaches.2 These symptoms persist for weeks
or months, becoming gradually more severe with superimposed epistaxes and
difficulty in nasal breathing associated with swollen mucous membranes.
• An infiltrative phase follows during which the nasal septum and base
of the nasal fossa become swollen by a reddish waxy induration.2 This
change is painless and the soft palate is anesthetic. Similar involvement of
the larynx causes changes in the voice.
• The infiltrative phase merges into a nodular phase during which there is
increasing deformity as the nose, upper lips, and gums become grossly
enlarged and distorted.2 Involvement of regional lymph nodes is not
Rhinoscleroma 833
Fig. 18.215
Erythema nodosum
leprosum: note the
perivascular lymphocyte
and histiocyte infiltrate.
Fig. 18.216
Erythema nodosum leprosum: numerous polymorphs are intermingling with the
Lepra cells.
usual, but has been reported.6 Nasal obstruction, loss of smell, loss of
voice, laryngeal stenosis, and increasing difficulty with breathing may
follow.4,7 Respiratory obstruction may cause death; alternatively, the
process can persist with some temporary remissions for years. Squamous
carcinoma is an occasional late complication.
Contiguous involvement of the soft and hard palate, the upper lip, and the
maxillary sinuses may occur; the term respiratory scleroma has been ­proposed
for these cases with extranasal extension of the disease.8 ­Rosai-Dorfman
­disease has been documented in the regional lymph nodes of a patient with
rhinoscleroma.9
Pathogenesis and histological features
The causative bacterium Klebsiella rhinoscleromatis is a Gram-negative
aerobic diplobacillus.8,10 It is spread during the rhinitis (catarrhal) phase
of the disease and appears to be confined to close-living groups, and has
834 Infectious diseases of the skin
Fig. 18.217
Erythema nodosum leprosum: several small vessels show fibrinoid necrosis.
This type II reaction develops on the basis of an immune complex-mediated
vasculitis.
even been documented in siblings.11 There is no animal reservoir. An HLA-
DQA1*03011-DQB1*0301 haplotype has been identified as a poten-
tial risk factor for development of the disease, while other investigators
have ­suggested that altered lymphocyte subsets may play an important
­pathogenetic role.12,13
The incubation period is very long, so that presentation is most often
in adults. The organism is phagocytosed, but not killed by neutrophils.
When the neutrophils rupture the still viable bacteria are phagocytosed
by histiocytes, which become greatly distended. These eventually appear
vacuolated with an eccentric nucleus (Fig. 18.218). Warthin-Starry or
Giemsa staining reveals that this vacuole contains bacteria (Fig. 18.219).
This cell, 10–100 μm in diameter, is termed a Mikulicz cell and, together
with Russell bodies (plasma cells grossly distended with proteinaceous
product), is characteristic of the disease. As well as these characteristic
cells, there is a dense infiltrate of plasma cells and lymphocytes, which
becomes very extensive and eventually causes such gross thickening of the
mucosae that the respiratory tract tends to be occluded at several points.
The mucosa can be ulcerated or atrophic. Amyloid deposition has been
described.14
A B
Fig. 18.218
(A, B) Rhinoscleroma: in addition to lymphocytes and numerous plasma cells, foamy macrophages (Mikulicz cells) are present.
Fig. 18.219
Rhinoscleroma: numerous organisms are revealed by the Warthin-Starry reaction.
By courtesy of S. Lucas, MD, Institute of Dermatology, London, UK.
Differential diagnosis
This includes midfacial granulomata, lymphoma, tertiary syphilis,
­lepromatous leprosy, leishmaniasis, and rhinosporidiosis. The histology, as
described above, should exclude these clinical alternatives.
Nocardiosis
Clinical features
Nocardia is found in soil and rotting vegetation worldwide and man
is only rarely infected.1–4 Initially, three main pathogenic species were
recognized:
• Nocardia asteroides, which is most common in North America,
• Nocardia brasiliensis in South America,
• Nocardia caviae in Southeast Asia.1,3,5
Other species of Nocardia have since been associated with infection in
humans, including N. transvalensis, N. otididiscaviarum, N. nova, N. ­farcinica,
N. paucivorans, N. abscessus, N. cyriacigeorgici, and N. asiatica.1,4,6–17 Infection
 Botryomycosis 835

complicates inhalation or direct inoculation into a wound.1,3 Nocardiosis

therefore represents a respiratory illness, with or without ­dissemination (the
majority), or a primary cutaneous disease.1,2
N. asteroides, N. caviae, and N. farcinica most often affect immunocom-
promised hosts, causing pulmonary lesions from which systemic dissemina-
tion may involve the skin.3 Predisposing factors include steroid therapy, HIV
infection, and solid organ transplantation.1,4,11–13,18–21 Central nervous system
involvement is an important cause of morbidity and high mortality.11,19 Primary
cutaneous infection has been reported in an immunocompetent adult follow-
ing a cat scratch.22 Dissemination is a frequent complication of N. paucivorans
infection in both immunocompromised and immunocompetent hosts.14
N. brasiliensis causes primary skin lesions in immunocompetent individu-
als and can also cause primary pulmonary lesions.4,23 The cutaneous lesions
are varied and usually follow trauma. They include a mycetoma, usually on
the limbs, and a sporotrichosis-like pattern (including a cervicofacial variant
that occurs in children), i.e., with multiple lesions following the line of lym-
phatics.3,24,25 In addition, superficial nodules, ulcers, and abscesses, with or
without fistulae and pustules, may occur (Fig. 18.220).26,27 Some more trivial
infections resemble staphylococcal infections and are usually self-limiting; the
deeper infections are progressive and can be destructive without treatment. Fig. 18.221
Nocardia: the organisms appear mainly as irregularly staining filaments in this
Dissemination of primary cutaneous nocardiasis is exceptionally uncom-
specimen, but a variety of forms, including rods and cocci, is often seen. By courtesy
mon.28 Infection has been reported after an insect bite.29 Lymphocutaneous of A.E. Prevost, MD, and H.P. Lambert, MD, St George's Hospital, London, UK.
nocardiosis may also be caused by N. transvalensis.6 Mycetomas due to
N. nova and N. otididiscaviarum have been reported.7,10 N. otididiscaviarum
is a rare cause of cellulitis.9 histologically by its weak acid-fastness, distinguishing it from Actinomyces.
Differential culture may be necessary to distinguish the two, although the
Pathogenesis and histological features presence of sulfur grains is a pointer towards actinomycosis.31
Nocardia is a Gram-positive, partially acid-fast aerobic beaded rod, which
grows with branching filaments in a way similar to Actinomyces (Fig.
18.221).30 Infection by N. asteroides, a relatively avirulent organism, is usu- Botryomycosis
ally by inhalation. N. brasiliensis is more virulent and can infect the immu-
nocompetent through inoculation of soil into skin. It is the most commonly Clinical features
identified organism in the sporotrichoid form of nocardiosis.4,24 Botryomycosis (Gr. botrys, bunch of grapes) is also known as bacterial
Grains, analogous to the sulfur granules of actinomycosis, can develop pseudomycosis and is due to a chronic bacterial infection, usually of skin.1,2 It
in the mycetoma lesions of the immunocompetent. Filamentous growth is has also been described in lung, bone, kidney, and liver.1–6 A case of gingival
a ­feature of greater virulence or less immunity; methenamine silver is most botryomycosis resembling a pyogenic granuloma has been reported.7
­satisfactory for demonstrating the filaments in tissue sections. In the skin, the lesions are chronic suppurative nodules which may resem-
The histological features in the skin are of ulcers, abscesses with pus, necro- ble infected epidermoid cysts, plaques, and ulcers. The interconnecting fis-
sis, hemorrhage, and fibrosis associated with sinus tracks. The organism is not tulae which develop give it a similarity to acne conglobata and hidradenitis
readily seen with hematoxylin and eosin staining, but can be demonstrated suppurativa, but the sites commonly involved are the hands, feet, and head.1

Fig. 18.220
Nocardiosis: (A) this cutaneous nodule developed in an
immunocompromised young male; (B) a different lesion
A B is shown in close-up. By courtesy of R.A. Marsden,
St George's Hospital, London, UK.
836 Infectious diseases of the skin
There may be a history of preceding trauma or the presence of a foreign
body. Deeper tissues, including muscle and bone, may become involved.
Botryomycosis of the cervicofacial region has also been described in a patient
with mandibular chronic osteomyelitis.3
The pulmonary involvement has the radiological features of lobar consoli-
dation, sometimes with adjacent osteomyelitis. Involvement of liver, tongue,
orbit, bowel, and brain has also been described. Cystic fibrosis appears to
predispose to some pulmonary cases. Although immunodeficiency has been
noted in some cases and the condition has been reported in association with
HIV/AIDS, most patients who develop botryomycosis have no detectable
abnormality of the immune system.8–13 The cutaneous lesions of botryomyco-
sis in patients with HIV/AIDS may, however, present with atypical features;
lesions resembling prurigo nodularis, lichen simplex chronicus, and pruritic
papules have been described.11,13
Pathogenesis and histological features
The lesions of botryomycosis include a characteristic granule surrounded by
suppuration and the features of a chronic abscess. The granule consists of
nonfilamentous bacteria in a hyaline matrix, containing IgG and complement
C3 (the Splendore-Hoeppli phenomenon), and is a lobulated or ‘bunch of
grapes-like’ structure (Figs 18.222, 18.223).10 The granule is basophilic in
the center and eosinophilic at the periphery.1 It is PAS positive. The ­bacteria
Fig. 18.222
(A, B) Botryomycosis:
there are multiple dermal
A abscesses surrounding
discrete bacterial colonies.
B relative preservation of antimicrobial monocytic function.5,7 The skin lesions
Fig. 18.223
Botryomycosis: note the blue-staining bacteria surrounded by an intensely eosinophilic
fibrillary coat (the Splendore-Hoeppli phenomenon). The inflammatory response is characteri­
stically neutrophil mediated.
present are not specific to the condition; S. aureus is most common, but
Pseudomonas, E. coli, Proteus, Micrococcus, and streptococci may also
be found.1,3,11,14 Fungi, actinomycetes, and Nocardia are not causes. There
have, however, been isolated case reports of botryomycosis due to combined
S. aureus and Actinobacillus actimomycetemcomitans infection, and S. aureus
in association with Pneumocystis jiroveci.12,15
The abscess persists with numerous sinuses and extensive fibrosis, and may
extend to involve deep adjacent structures. Rarely, the granules are eliminated
transepithelially.16 The reasons for the persistence and for granule formation are
not fully understood. Although some patients show immunodeficiency, sometimes
analogous to the anergy of lepromatous leprosy, this is not so for most cases. The
size of the original inoculum appears to be critical – excessive numbers of bacte-
ria produce an overwhelming abscess and cellulitis, too few bacteria are rapidly
eliminated by normal inflammatory responses – but an intermediate size of inoc-
ulum can produce what may be interpreted as a ­balance between the bacteria and
the inflammatory response, with granule and chronic abscess ­formation.1,2,17 This
balance may be attained more easily with less virulent strains.
A foreign body may contribute to the initiation of the lesion, but is not
invariable. A local factor may be important, such as some as yet undemon-
strated defect in the cutaneous immune mechanisms, diabetes mellitus or an
underlying dermatosis such as follicular mucinosis.18 In pulmonary cases,
­cystic fibrosis represents that local underlying defect. Botryomycosis with
concurrent cutaneous small vessel vasculitis has been documented.19
Malakoplakia
Clinical features
Malakoplakia (soft plaque) most often affects the urinary tract, but it can
involve many other organs including the gastrointestinal tract, lymph nodes,
genitalia, brain, bone, lungs, retroperitoneum, adrenals, and skin.1–4 The
median age at presentation is approximately 53 years, and the disease appears
to be twice as common in males as in females.3 Cutaneous lesions are most
common around the genitalia or perineum, but are occasionally seen in other
sites.2–4 Their appearance is variable and includes plaques, ulceration, polyps,
and sinuses, with surrounding induration, as well as nodules and papules.4,5
They may be associated with malakoplakia elsewhere.
Underlying or associated conditions (which are usually linked with immu-
nosuppression) can include carcinoma, rheumatoid arthritis, systemic lupus
erythematosus, diabetes mellitus, leukemia, lymphoma, and immunosuppres-
sion following transplantation.2,3,6 However, the condition remains distinctly
uncommon in patients with HIV/AIDS; this has been ascribed to selective or
are nonprogressive but are persistent.

Pathogenesis and histological features
Lesions of malakoplakia are characterized by confluent sheets of histiocytes
(von Hansemann cells) with eosinophilic granular cytoplasm and small,
usually eccentric nuclei. These cells also contain characteristic cytoplas-
mic basophilic bodies shown to be calcified with von Kossa staining (Figs
18.224, 18.225). These round, sometimes laminated structures are known as
Michaelis-Gutmann bodies. Their targetoid pattern is accentuated by staining
with periodic acid-Schiff. They may also be positive on staining with Perls'
reaction for iron. The Michaelis-Gutmann body is sufficiently distinctive
to allow cytological distinction of malakoplakia in a preparation from skin
scrapings.8 Immunohistochemistry with an antibody to BCG may highlight
the intracytoplasmic bacteria.9
The histiocytic infiltrate may be mixed with neutrophils, lymphocytes,
and plasma cells, with associated granulation tissue. Electron microscopy
of malakoplakia shows that the histiocytes contain numerous phagolyso-
somes that occasionally contain intact and partly digested bacteria. It has
been suggested that phagolysosomes in macrophages accumulate in response
to chronic ­bacterial infection. The infection is not by one specific ­organism,
but the agent is usually E. coli.3 The phagolysosomes tend to fuse and
Fig. 18.224
Malakoplakia: the infiltrate consists of histiocytes with eosinophilic granular
cytoplasm. Note the pale blue, laminated Michaelis-Gutmann bodies.
Fig. 18.225
Malakoplakia: use of the von Kossa reaction renders the Michaelis-Gutmann bodies
more conspicuous and reveals that they are much more numerous than was
apparent in the hematoxylin and eosin stain.
Actinomycosis 837
then calcify; the reason for these changes is not clear, although some cases
occur in systemic disease associated with a probable impairment of mac-
rophage ­function.1,4 Other organisms that have been cultured from lesions
of ­malakoplakia include Gram-negative bacilli (Klebsiella spp., Enterobacter
spp., Proteus spp., Pseudomonas spp.) and Gram-positive cocci, including
Staphylococcus aureus, Streptococcus spp., and enterococci.3,4,9
Differential diagnosis
Malakoplakia should be distinguished from infectious granulomata, histio-
cytosis, and granular cell tumor, and from pseudomalakoplakia,3,9,10 which
refers to an abnormal histiocytic proliferation in a previous surgical site.
Although pseudomalakoplakia also comprises sheets of large histiocytes with
intracytoplasmic calcific material, this condition is distinguished from true
malakoplakia by the lack of concentric lamination of the granules.9,10
Actinomycosis
Clinical features
Actinomyces israelii is a commensal in the human mouth, along with other
organisms including Aggregatibacter (formerly Actinobacillus) actinomycet-
emcomitans.1 A. israelii is the usual pathogen but occasionally other species
including A. viscosus, A. naeslundii, A. odontolyticus, A. meyeri, A. ­turicensis,
and A. radingae are implicated.2–5 The most common manifestation is cervi-
cofacial actinomycosis, but more grave pulmonary and intestinal infections
can occur and, rarely, purely cutaneous lesions.1,6–9 The cervicofacial form is
common in farm workers and is associated with poor oral hygiene, usually
starting from carious teeth and following dental extractions or oral trauma.
The condition is infrequent in children and most common in young men.
Respiratory involvement as lung abscess and fistulae may ‘point’ through
the thoracic wall (Fig. 18.226).10 Abdominal lesions include appendiceal and
colonic actinomycosis and hepatic involvement and it may complicate the
use of intrauterine contraceptive devices, with lesions affecting the internal
female genitalia. Cutaneous fistulae may subsequently develop.11,12
The cervicofacial lesion presents as a hard swelling on the lower jaw or
occasionally as a plaquelike infiltration of the cheek from the upper jaw
(cf. bovine lumpy jaw). These firm thickened areas tend to discharge through
sinuses and are associated with scarring and the formation of new nodules
(Fig. 18.227). Yellow granules measuring up to 2 mm in diameter – the
so-called ‘sulfur granules’ – are occasionally found in the discharging pus.
Extensions of some maxillary lesions may reach the orbit and base of the
skull. Uncommonly, a large facial mass may develop.5,13
Fig. 18.226
Actinomycosis: extensive intrathoracic disease has resulted in involvement of the
anterior chest wall. Numerous sinuses are evident. By courtesy of P. Duhra, MD,
Coventry and Warwickshire Hospital, Coventry, UK.
838 Infectious diseases of the skin
Fig. 18.227
Actinomycosis: infection of the cervicofacial region; note the scarring and dimple at
the site of the draining sinus. By courtesy of T.F. Sellers, MD, and H.P. Lambert, MD,
St George's Hospital, London, UK.
Fig. 18.228
Actinomycosis: multiple sinuses are present about the lateral malleolus. By courtesy
of R. Hay, Institute of Dermatology, London, UK.
Rarely, direct inoculation of skin may produce a similar chronically dis-
charging abscess with adjacent scarring (Fig. 18.228). Alternatively, a myce-
toma or chronic discharging abscess mass with multiple sinuses may develop.
This primary form of cutaneous actinomycosis is rare. Sites have included the
thigh, the arm, and the nose.14–17 Most cases are the result of external trauma
and local ischemia, but this is not always the case.14,15,17,18 Some infections
have been acquired through injection wounds, including one report where
an A. odontolyticus-associated subcutaneous abscess evolved in an intrave-
nous cocaine user who admitted to licking his hypodermic needle prior to
injection.14,19
An uncommon form of the disease is the presence of disseminated cutane-
ous lesions in the absence of demonstrable extracutaneous infection; this has
been reported in a patient with acute leukemia.20
Pathogenesis and histological features
The mixture of organisms involved in actinomycosis is not purely accidental
but is synergistic. A. israelii is a Gram-positive, nonacid-fast, microaerophilic
bacterium with filamentous branching organisms. A. actinomycetemcomitans
Fig. 18.229
Actinomycosis: a bacterial colony lies in the center of an abscess.
Fig. 18.230
Actinomycosis: high-power view.
is a Gram-negative coccobacillus which inhibits growth of fibroblasts and
­keratinocytes. It is speculated that this, together with its different susceptibil-
ity to antibiotics, helps to maintain the actinomycotic lesion.
Histologically, the lesions have the features of chronic abscesses and
sinuses, containing pus and surrounded by fibrosis and a mixed inflammatory
infiltrate (Fig. 18.229). Locules separated by granulation tissue are present.
Sulfur granules of intertwined bacteria are seen, radiating mycelial filaments,
often with opaque clubs at their tips (Figs 18.230, 18.231).21 These granules
may be associated with the Splendore-Hoeppli phenomenon.
Whipple's disease
Clinical features
Whipple's disease is a rare, chronic multisystem infective disorder caused by
Trophyrema whippelii, a Gram-positive bacillus and member of the actino-
mycetes.1–3 The condition has a propensity to occur in middle-aged Caucasian
males.1 The gastrointestinal tract is the main target of infection, resulting
in low-grade fever, weight loss, abdominal pain, diarrhea, and malabsorp-
tion syndrome. Other potential manifestations include lymphadenopathy,
seronegative arthritis, neurological signs, uveitis, endocarditis, and pleuritis,
­sometimes in the absence of concomitant gastrointestinal symptoms.1,4

Fig. 18.231
Actinomycosis: Gram-positive bacteria with club-shaped ends are present at the
periphery of the granule.
Skin involvement in the form of cutaneous hyperpigmentation is rela-
tively common, occurring in 17% to 40% of patients.4,5 Rarely, erythema
­nodosum-like subcutaneous nodules may develop as a result of infective pan-
niculitis. The latter comprise painful red-brown nodules. Lesions may occur
on the thighs, arms, buttocks, lower legs and, rarely, the chin and neck.6–9
Erythema nodosum is another potential cutaneous manifestation.6
Pathogenesis and histological features
Although T. whippelii is a ubiquitous organism in the environment, Whipple's
disease remains a very rare condition.10 It would seem that susceptible indi-
viduals have defects in T-cell immunity and impaired ability of macrophages
to degrade the intracellular organisms.11 The subcutaneous nodules have
the appearance of a predominantly septal panniculitis, with a conspicuous
infiltrate of foamy macrophages. Careful examination reveals cytoplasmic
distension of these histiocytes by PAS-positive, diastase-resistant intracyto-
plasmic material representing degenerate bacteria.2,8,9 These macrophages
closely resemble those encountered in duodenal biopsy material. The viable
bacilli have a characteristic double-walled (trilaminar) appearance on ultra-
structural examination.1,6 The organism may be cultured in specialized lab-
oratories. PCR and immunohistochemical methods for confirmation of the
diagnosis exist.10–12
Differential diagnosis
Whipple's disease should be distinguished from histoplasmosis, histoid lep-
romatous leprosy, and infection with Mycobacterium avium-intracellulare
(MAI) complex, as all of the aforementioned conditions are characterized by
intracytoplasmic organisms contained within macrophages. PAS-positive fun-
gal yeasts, however, are observed in histoplasmosis, whereas Ziehl-Neelsen
and Wade-Fite stains will confirm the presence of acid-fast mycobacterial
bacilli in MAI infection and lepromatous leprosy, respectively.
Erythrasma
Clinical features
Erythrasma is a bacterial infection caused by Corynebacterium minutissi-
mum, a Gram-positive bacillus.1,2 It characteristically presents as asymptom-
atic, well-defined, scaly red patches on the inguinal and intergluteal skin
(Fig. 18.232). It has a predilection for obese and diabetic patients and it
is more common in areas with a humid and hot climate. The clinical diag-
nosis is easy because of the demonstration of a typical coral-red fluores-
cence under Wood's light.3 This fluorescence is the result of production of
coproporphyrin III by the organism. In exceptional cases, fluorescence is
Erythrasma 839
Fig. 18.232
Erythrasma: (A) note the
well-demarcated axillary
scaly red patch; (B)
there is a scaly inguinal
patch with associated
hyperpigmentation.
By courtesy of the
A Institute of Dermatology,
London, UK.
B
not seen.4 Erythrasma rarely presents as a disciform eruption with an atro-
phic appearance involving nonintertriginous areas.5,6 Involvement of the feet
(particularly the toe webs) and toenails has also been documented.7–9 Rarely,
lesions on the feet have a vesiculobullous appearance.10 Nail involvement is
characterized by hyperkeratosis and onycholysis. Erythrasma may coexist
with a dermatophyte infection or, rarely, pityriasis versicolor.11,12 An associa-
tion with trichomycosis axillaris and pitted keratolysis may also occur.13,14
A biopsy is only exceptionally performed as the diagnosis is confirmed by
the use of Wood's light or scrapings stained by Gram, PAS, Grocott, Giemsa
or methylene blue.
Corynebacterium minutissimum has rarely been associated with bacter-
emia, abscess formation, cellulitis or visceral involvement in immunocompe-
tent or immunocompromised patients.15–18
Histological features
A skin biopsy usually appears unremarkable when stained with hematoxylin
and eosin except for mild hypergranulosis and occasional superficial perivas-
cular lymphocytes. The special stains mentioned before, particularly Gram,
show the presence of bacilli in the stratum corneum (Fig. 18.233).
840 Infectious diseases of the skin

the nodules are usually black and the disease mainly involves the scalp.
Distinction from white piedra may be more difficult as the disease has a wide
anatomical distribution and it has been suggested that the latter disease is the
result of a synergistic interaction between corynebacteria and Trichosporon
beigelii, the organism previously implicated in white piedra.10 Trichomycosis
has been reported in association with erythrasma and pitted keratolysis.11,12

Fig. 18.233
Erythrasma: bacilli are evident in the stratum corneum.
Trichomycosis
Clinical features
Despite the name, trichomycosis is a bacterial infection caused by different
species of corynebacteria, including Corynebacterium tenuis.1,2 The Gram-
positive bacteria invade the cuticle of the hair and it has been suggested that
they adhere to the hair shaft by producing a cement-like substance.3 However,
this view has been challenged and it is proposed that the material that pro-
vides support for the organisms is the apocrine sweat.4 The disease typically
involves the axillary hair (trichomycosis axillaris) and exceptionally may be
seen in the pubic hair and scrotum (trichomycosis pubis) (Fig. 18.234).5–9
The disease is characterized by yellow, red or (more uncommonly) black nod-
ules along the hair shaft. These nodules may be confused with nits. However,
the nodules in trichomycosis fluoresce under Wood's light. In black ­piedra,
Pitted keratolysis
Clinical features
Pitted keratolysis (keratolysis plantare sulcatum) is an unusual bacterial infec-
tion of plantar skin occurring predominantly but not exclusively in humid
tropical regions of the world.1,2 The condition has been recorded in soldiers
and paddy field workers.3,4 The cause of the disease remained elusive for many
years although it was initially ascribed to infection with Corynebacterium
spp. Two Gram-positive organisms have since been implicated in the patho-
genesis of pitted keratolysis: Dermatophilus congolensis (accounting for the
majority of infections) and Kytococcus (Micrococcus) sedentarius.1,2,5,6 The
disease occurs predominantly in young men. Children are rarely affected.7
Frequent presenting symptoms include hyperhidrosis, malodor or even slimi-
ness of the feet.2 Soreness and pruritus may also occur. D. congolensis causes
a variety of dermatidites in domesticated herbivores, and it has been sug-
gested that human infections result from contact with infected animals or
contaminated soil.8
As indicated by the name, pitted keratolysis is associated with superficial
pitlike erosions of the stratum corneum of the plantar skin. These coalesce
to form characteristic crateriform defects which are concentrated on the
­pressure-bearing areas of the foot (Figs 18.235, 18.236). The circular cra-
teriform pits measure 0.7– mm or more in diameter and appear to be distrib-
uted along the plantar furrows.1,2 Rarely, the palms may be involved.9 In one
recent report, treatment of hyperhidrosis with botulinum toxin injection lead
to resolution of pitted keratolysis, suggesting that hyperhidrosis itself could
play a pathogenetic role in the condition.10 An increased prevalence among
hepatitis B virus surface antigen carriers was suggested in a recent study.11
Pathogenesis and histological features
In vitro studies have shown that both D. congolensis and K. sedentarius pro-
duce keratinolytic enzymes, thus accounting for the superficial defects in the
stratum corneum.5,12 The early lesions demonstrate stratum corneum pallor.
Biopsies of the plantar pits show small defects in the upper stratum cor-
neum, the walls being almost vertical in configuration.1,2 Special stains (Gram,

Fig. 18.234
Trichomycosis: this matted
appearance of the hair
results from the presence
of multiple tiny nodules.
By courtesy of the Fig. 18.235
Institute of Dermatology, Pitted keratolysis: note the typical scaliness and pitlike areas. By courtesy of the
London, UK. Institute of Dermatology, London, UK.
 Sago palm disease 841

Differential diagnosis
Cutaneous infection by C. ulcerans may mimic true cutaneous diphtheria
both clinically and histologically.9 The distinction is made by microbiological
investigations. A case of cutaneous ulceration due to C. ­pseudodiphtheriticum
infection was reported recently.10

Sago palm disease

Clinical features
Sago palm disease is an exceedingly uncommon chronic bacterial infection
of the skin which appears to be restricted to a swampy region of Papua
New Guinea where there are groves of sago palms.1–3 The disease was first
described in 1973 and is caused by a hitherto unclassifiable Gram-positive
bacillus.2,3 Infection is acquired by traumatic inoculation while handling the
palms.1
The primary cutaneous lesions manifest only months later and tend
to spread contiguously over a prolonged period, ranging from months to
years. The limbs, trunk, and face are the major sites of predilection.1–3 The
Fig. 18.236 clinical appearances are those of verrucous, hyperkeratotic nodules which
Pitted keratolysis: note
are not associated with ulceration or hemorrhage (Fig. 18.237).2 Systemic
the tiny pits on the
spread has not been documented thus far.2 The infection is resistant to
weight-bearing aspect of
the foot. By courtesy of treatment.
S. Glassman, MD, Division
of Dermatology, University
of Witwatersrand,
Johannesburg, South
Africa.

methenamine silver, PAS or Giemsa) are required to visualize the organisms,

which comprise both coccoid and filamentous forms.1,2,6 The coccoid forms
tend to be concentrated near the surface of the pit whereas the filamentous
forms are present in relation to the deeper portions of the defect.2,6 The fila-
mentous forms show both branching and septation. The filamentous form
of D. congolensis is characteristically composed of chains of small coccoid
bodies.1

Cutaneous diphtheria
Clinical features
Cutaneous diphtheria is an uncommon condition caused by the Gram-positive
bacillus Corynebacterium diphtheriae.1,2 Toxicogenic and nontoxicogenic A
strains exist. Although cutaneous diphtheria is essentially a tropical condi-
tion, increasing tourism to tropical regions and a decline in adult booster vac-
cination against diphtheria have resulted in numerous cases being reported
from developed countries.2–6 The disease usually results from inoculation of
C. diphtheriae organisms into pre-existing lesions such as burns, ulcers, and
eczematous rashes; cutaneous diphtheria may also manifest in apparently
normal skin.1–3 The condition has been reported in intravenous drug users.7
The lower legs and feet are sites of predilection but sites such as the face,
trunk, and even the genitalia may be involved.1,8 Initially there is a vesicle
or pustule. This later evolves into an ulcer which is often reddish-purple in
color, with rolled and undermined borders, and a yellow-gray membrane or
dark crust covering its base.1,3 The ulcers are painful initially but are later
hypoanesthetic.3 Regional lymphadenopathy may occur, and toxicogenic
strains may result in systemic complications involving the nervous system or
heart.1

Histological features
Histological examination of the ulcer reveals a necrotic epidermis and der- B
mis. The dermal base of the ulcer contains necrotic debris, fibrin, and an
admixture of acute and chronic inflammatory cells.2 Since the club-shaped Fig. 18.237
and beaded Gram-positive rods are often difficult to visualize in histological (A, B) Sago palm disease: widely distributed keratotic nodules and plaques
material, microbiological examination of swabs from the center of the lesion are present. By courtesy of E. Wilson Jones, MD, Institute of Dermatology,
is required for confirmation of the diagnosis.1 London, UK.
842 Infectious diseases of the skin
Histological features
The pathological changes in sago palm disease are centered on the dermis,
which is expanded by a relatively circumscribed nodular mass composed of
sheets of foamy histiocytes, lymphocytes, plasma cells, and fibroblasts.1,2 The
overlying epidermis is hyperkeratotic. The causative bacteria are difficult to
identify in routinely stained sections. The Gomori methanamine silver stain
reveals large numbers of bacteria which appear to be embedded in amorphous
ground substance.1,2 The bacilli measure approximately 1.8 μm in length and
0.5 μm in width; beading and branching of the organisms may be observed.1,2
The ultrastructural features are characteristic.2
Since the etiological agent has not been cultured successfully, the diagno-
sis of sago palm disease is based upon the clinicopathological features, sup-
ported by electron microscopy.2
Tularemia
Clinical features
Tularemia is a zoonotic infection caused by Francisella tularensis, a nonmotile
Gram-negative bacillus.1–3 Five subspecies exist, but only F. tularensis subsp.
tularensis and F. tularensis subsp. holarctica are known to be associated with
disease in humans.4 The infection is usually acquired via the bite of an arthro-
pod (such as a tick or deerfly) or by handling the carcasses of infected animals,
especially rabbits, hares, and rodents.1–3 Tularemia is a disease of the northern
hemisphere, with the majority of infections reported from North America,
Scandinavia, and other parts of Europe.2,3,5–10 The incubation period is approx-
imately 3–6 days.5 The potential threat of the organism being used as a bioter-
rorism agent has led to renewed interest in the disease in recent years.4
The most common form of tularemia is the ulceroglandular type, which
accounts for 80% or more of infections.3,9 Other clinical forms include
typhoidal, oculoglandular, oropharyngeal, and primary pulmonary tulare-
mia.3 The ulceroglandular form is characterized by a small, painful erythema-
tous papule at the site of inoculation, usually on an exposed limb. After a
few days the papule breaks down to form a punched-out ulcer which may
discharge seropurulent material.2 This is almost invariably associated with
lymphangitis and severe, acute painful lymphadenitis of the regional lymph
nodes.2,7 Other potential cutaneous manifestations, which may develop in all
of the clinicopathologic forms of tularemia, include macular, papular, vesicu-
lar or pustular eruptions, erythema nodosum lesions, and erythema multi-
forme.2,6 Vesicular lesions may be mistaken clinically for herpes simplex or
varicella-zoster virus infection.11 Skin lesions (other than a primary lesion)
were documented in 43% of patients in a recent analysis of 234 Scandinavian
cases.9 Associated constitutional symptoms and signs may be pronounced
and include fever, chills, headache, weakness, myalgia, and coughing.2,7,9
Ulceroglandular tularemia generally carries a good prognosis, although death
due to septicemia may occur in untreated patients.3,5 Acute tularemic pneu-
monia, which is acquired by inhalation of aerosolized organisms, carries a
high mortality.3
Pathogenesis and histological features
F. tularensis is a highly virulent pathogen; as few as 10 organisms inocu-
lated into the subcutis may initiate infection.5 The organism is also extremely
hazardous to laboratory personnel. It is an elusive facultative intracel-
lular pathogen that possesses novel mechanisms to ensure its survival in
macrophages.12,13
The early papular lesions show non-specific features, including intercel-
lular and intracellular edema of the epidermis, sometimes accompanied by
vesiculation.2 There is also dermal edema, telangiectasia, and a mild perivas-
cular infiltrate. Early cutaneous ulcers are characterized by fibrinopurulent
exudation and an accompanying infiltrate of lymphocytes and macrophages.2
Later, there is a well-developed zonal pattern of suppurative granulomatous
inflammation, a phenomenon that is recapitulated in the affected regional
lymph nodes.3 The central zone contains necrotic material and karyorrhectic
debris. An intermediate zone comprising epithelioid histiocytes and giant cells
envelops this. An outer mantle containing lymphocytes, histiocytes, plasma
cells, and extravasated erythrocytes in turn surrounds the latter zone.2,5
The diagnosis of tularemia is usually confirmed by serology or culture
of the organism.2 F. tularensis is not demonstrable in routinely stained
sections. It may, however, be detected in histological material by direct
­immunofluorescence or PCR.2,3,14
Infections caused by Rickettsiae
Clinical features
Rickettsiae are small, obligate, intracellular pathogens. Rickettsial infections
can be divided into three groups:
• The typhus group includes epidemic typhus fever (a louse-borne infection
caused by Rickettsia prowazekii), the recrudescent form of the latter
(Brill-Zinsser disease), murine (endemic) typhus fever (a tick-borne
infection caused by R. typhi), and R. felis infection (which is clinically
indistinguishable from classic murine typhus).
• The spotted fever group includes Rocky Mountain spotted fever
(a tick-borne infection caused by R. rickettsii), other spotted fevers/
forms of tick typhus (e.g., Boutonneuse fever and Mediterranean
spotted fever caused by R. conorii conorii, geographically specific
strains of R. conorii resulting in conditions such as South African
tick-bite fever, Israeli spotted fever, Astrakhan spotted fever or Indian
tick typhus, Queensland tick typhus caused by R. australis, African
tick-bite fever caused by R. africae, etc.), and rickettsial pox (caused
by R. akari, and the only infection in this group to be transmitted by
a mite).
• Scrub typhus is caused by Orientia tsutsugamushi (formerly R. tsutsugamushi)
and transmitted by infected chiggers or larval mites of Leptothrombium
spp.1–11
Coxiella burnetii (the cause of Q fever), Ehrlichia spp. (the cause of ehrli-
chiosis), and Bartonella (formerly Rochalimaea) spp. represent a separate
group of rickettsia-like organisms and are not discussed here.
Advances in molecular taxonomic methods have led to not only the
reclassification of rickettsial diseases but also recognition of an ever increas-
ing spectrum of rickettsial pathogens.11 In addition, there has been renewed
interest in pathogenic rickettsiae as potential agents of bioterrorism.2,12
Although all of the true rickettsial infections listed above are associated
with variable cutaneous manifestations, there is great diversity in the extent
of involvement and degree of clinical severity. A detailed discussion of the
epidemiological, clinical, and pathological characteristics of each entity is
beyond the scope of this text; for more information the reader is referred to
reference numbers 1, 2, and 3, which provide outstanding overviews of the
subject.
Endemic typhus and rickettsial pox are mild infections, whereas Rocky
Mountain spotted fever is a severe multisystem disease which may involve
the central nervous system, kidneys, lungs, heart, and liver. Gangrene of the
extremities and a coagulopathy may also occur.3,13 Scrub typhus is extremely
variable, ranging from an asymptomatic illness to a severe infection with
significant mortality if untreated. The earliest symptoms of rickettsial infec-
tion are non-specific and include fever, headache, chills, and myalgias. Rocky
Mountain spotted fever often has additional symptoms of nausea, vomiting,
and abdominal pain. Lymphadenopathy is encountered in rickettsial pox, tick
typhus, and scrub typhus.
An eschar characteristically develops at the site of the arthropod bite in
the spotted fever group (with the exception of Rocky Mountain spotted
fever) and in scrub typhus; eschar formation is not a feature of the typhus
fever group (Fig. 18.238).13 Eschars may be multiple.14 Initially, there may
be a papule or papulovesicle. After a variable interval a skin rash evolves. In
most cases this is macular, eventually becoming maculopapular. Generally,
the rash commences on the trunk and spreads to the extremities, frequently
involving the palms and soles; the converse is true for Rocky Mountain spot-
ted fever. Vesiculation and scab formation are features of rickettsial pox,
and the palms and soles are usually not involved in the latter condition.
A petechial or hemorrhagic rash may occur in epidemic typhus fever, Rocky
Mountain spotted fever, and the other spotted fevers but is not observed in
scrub typhus.3

Fig. 18.238
South African tick bite fever: an eschar marks the site of the arthropod bite on
the inner thigh. The patient also had lymphadenopathy. By courtesy of M. Hale,
MD, National Health Laboratory Service and University of the Witwatersrand,
Johannesburg, South Africa.
Pathogenesis and histological features
A hallmark of the rickettsial infections is the presence of vascular endothe-
lial invasion by the organisms. Following the bite of the vector, the
Rickettsia organisms adhere to vascular endothelium and later become
internalized into the cytoplasm of these cells. Replication occurs, followed
A B
Infections caused by Rickettsiae 843
by ­hematogenous dissemination. R. rickettsii has the unique capacity to
also invade and induce necrosis of vascular smooth muscle cells, thereby
accounting for the greater severity of the illness and multiorgan involve-
ment.3 In vitro studies performed on the spotted fever group of rickettsiae
have shown that infection of endothelial cells leads to induction of cycloox-
ygenase 2 (COX-2) and the release of vasoactive prostaglandins.15 Vascular
leakage appears to be the consequence of gaps forming in interendothelial
adherens junctions.16
Histological examination of the eschar reveals wedge-shaped coagulative
necrosis of the epidermis and superficial dermis, sometimes accompanied by
necrotizing vasculitic changes in small venules and arterioles, and an infil-
trate of macrophages at the base. A dense backgroud perivascular lympho-
cytic infiltrate often accompanies these changes (Fig. 18.239).14,17 A small
vessel lymphocytic vasculitis of variable severity is encountered in biopsies
from the maculopapular lesions. This is usually mild in cases of endemic
typhus and scrub typhus, whereas the dermal vessels in established cases
of Rocky Mountain spotted fever show severe involvement, with endothe-
lial hyperplasia and nonocclusive intravascular fibrin-platelet thrombi, focal
lymphocytic vasculitis, and leukocytoclastic vasculitis.3,18–20 Dermal eryth-
rocytic extravasation is a feature of the petechial and hemorrhagic lesions.
There is epidermal basal layer vacuolar degeneration. Biopsies from the
vesicular lesions of rickettsial pox will show an intraepidermal vesicle, some-
times accompanied by a neutrophilic infiltrate at the base or subepidermal
edema.21,22
In the past, the diagnosis was confirmed by the Weil-Felix test. Although
this has been superseded by tests employing complement fixation, latex agglu-
tination, and immunofluorescence methods, these are generally not capable of
yielding a more rapid result. Immunofluorescence studies on frozen skin biopsy
material, however, may be a useful and relatively rapid means of confirming
the diagnosis of a suspected rickettsial infection. Immunohistochemistry and
PCR have also been used with success.3,13
Fig. 18.239
South African tick bite fever: (A) there is upper dermal
edema, vascular ectasia, and a dense perivascular chronic
inflammatory cell infiltrate; (B) note the thrombosed vessel.
844 Infectious diseases of the skin

Protozoal infections

Leishmaniasis
Clinical features
Leishmania is an organism related to the trypanosomes. The life cycle con-
tains a flagellate phase (promastigote) which occurs in the intestine of its vec-
tor, a female Phlebotomus or Lutzomyia sandfly, and a phase in which the
flagellum is retracted (amastigote). The latter is the form seen in the human
host. Various mammals, including gerbils, rodents, dogs, jackals, and foxes,
may act as reservoirs of infection.1–5
An estimated 12 million people are affected worldwide, with as many as
2 million new cases occurring annually, including 1.5 million with cutaneous
leishmaniasis and some 500 000 with visceral leishmaniasis.6,7 Visceral leish-
maniasis and to a lesser extent cutaneous leishmaniasis are increasingly rec-
ognized as opportunistic diseases in immunocompromised patients, especially
those infected with HIV.6,8,9
The various species of Leishmania are distinguished on the grounds of bio-
A
chemical and antigenic differences. Although leishmaniasis tends to be seen in
Asia, Africa, the Americas, and the Mediterranean countries, it is being seen
more often in nonendemic countries, particularly among refugees and return-
ing holidaymakers.10,11 There are eight main types of cutaneous presentation,
with many local geographic and species variations.
In endemic regions a significant number of people appear to have asymp-
tomatic (subclinical) infection, so-called cryptic leishmaniasis.10
Confirmation of the diagnosis has traditionally been achieved by visual-
ization of the organisms in smears or tissue sections, or with the aid of the
Montenegro (leishmanin) skin test, especially in the developing world. Over
the years these investigations have been complemented or superseded by
serology, culture or PCR-based methods.5,7

Cutaneous leishmaniasis
Cutaneous leishmaniasis has many local names, including oriental sore,
Baghdad boil, Chiclero's ulcer, and Aleppo boil. It is caused by Leishmania
tropica, Leishmania major, and Leishmania aethiopica and affects men,
women, and children. Mediterranean cutaneous leishmaniasis is caused pre-
dominantly by Leishmania infantum.10
Lesions occur on any site accessible to biting by the sandfly vector, most
commonly the hands, arms, and face (Fig. 18.240). They present as an ery-
thematous papule that enlarges over the course of a few weeks into an ulcer-
ated and crusted nodule. Occasionally, multiple lesions are seen. Lesions
show a tendency to orientation along the skin creases, and grossly the ulcers
have been compared to a volcano in surface appearance and configuration.12
Variants may be hypoesthetic, psoriasiform, eczematous, varicelliform,
paronychial, chancriform, zosteriform, annular, whitlow-like, erysipeloid,
verrucous or keloidal or present as macrocheilia.10,13,14 Regional lymphade-
nopathy can be a feature.15
In the Eastern hemisphere, where the disease has traditionally been referred
to as, “Old World”, leishmaniasis, these lesions may be ‘wet’ or ‘dry’:
• The wet type has a short incubation period (2 weeks) and occurs in rural
areas. It is caused by L. major and develops like a suppurative folliculitis
which ulcerates, the surrounding edematous, indurated erythema
extending gradually to reach a maximum of 6 cm. Small secondary
nodules may be seen around this. Slow resolution with cribriform
scarring occurs over 3–12 months.
• The dry form is caused by L. tropica, has a longer incubation period
(2 months), and is mostly seen in urban areas.16 The initial lesion is a brown
nodule and this becomes a plaque up to 2 cm across. It may ulcerate centrally
with a firm crust. Resolution occurs with scarring over 12 months or longer.
The American forms, traditionally referred to as ‘New World’ leishma-
niasis, are caused predominantly by L. mexicana and L. (subgenus Viannia)
­braziliensis. Other species implicated recently include L. amazonensis,
L. (V.) guyanensis, L. (V.) panamensis, and L. (V.) peruviana.17,18 The lesions
of L. mexicana are usually like those of cutaneous leishmaniasis in the Eastern
B
Fig. 18.240
Cutaneous leishmaniasis: (A) this healing lesion shows crusting and scarring; (B)
there is an extensive ulcerated erythematous plaque with scaling. (A) By courtesy
of J.C. Pascual, MD, Alicante-Spain; (B) From the collection of the late NP Smith
MD., the Institute of Dermatology, London, UK.
­ emisphere, but some subvariants can cause destructive ulceration of the ear. Most
h
infections with L. (V.) braziliensis are local and heal without much damage.
Chronic cutaneous leishmaniasis represents persistence (or spread) of an
acute lesion for more than 1 year. Lesions are particularly seen on the face as
raised erythematous plaques which may resemble erysipelas (Fig. 18.241).10
The erysipeloid lesions are erythematous and infiltrative and are said to occur
more frequently in women above the age of 50 years.19
The acute lesions may be followed by a relapsing chronic or lupoid stage
(leishmaniasis recidivans or leishmaniasis recidiva cutis) in which brownish
papules develop close to the scar of the earlier stages. This occurs in 3–10%
of patients.20 These papules extend to resemble lupus vulgaris; they may
develop hypertrophic scars or become verrucous. They are extremely slow to
resolve, even under treatment, and may persist for many years. It is thought
that a change in local immunity results in reactivation of intracytoplasmic
organisms.20 The leishmanin or Montenegro skin test for cellular immunity to
Leishmania is strongly positive in nearly all cases. It has been suggested that
leishmaniasis recidivans represents a hypergic form of the disease, but this has
been disputed by others.21 Although this presentation is typically encountered
in Eastern hemisphere leishmaniasis, a small number of cases of leishmaniasis
recidiva cutis complicating American leishmaniasis have been reported.21–23
 Leishmaniasis 845

A
Fig. 18.241
Cutaneous leishmaniasis:
chronic cutaneous
leishmaniasis showing
intense edema, erythema,
and scaling. By courtesy
of S. Lucas, MD,
St Thomas' Hospital,
London, UK.

Skin infections with L. (V.) braziliensis are liable to recur as mucosal

lesions, known as espundia (in which there is much tissue destruction), some-
times years later. The mucosal lesions occur most often in the nasal septum
and mouth and rarely around the eyes, genitalia, and anus (Fig. 18.242).
Patients may also develop ‘tapir nose’ in which there is considerable damage
to the nasal cartilage resulting in a free-hanging nose.10 The mucosal lesions
start as superficial erosions, but become deeply ulcerative and destructive.
The Montenegro skin test is almost always positive.
Diffuse cutaneous leishmaniasis, also known as pseudolepromatous leish-
maniasis, is caused by variants of L. mexicana and L. aethiopica. The former
occurs in Bolivia, Venezuela, Mexico, and Brazil, while the latter is seen pre-
dominantly in Ethiopia. It develops as a consequence of an impaired cellu-
lar immune response.20 A study from Egypt showed a significant association
between histocompatibility antigens HLA-A11, B5, and B7 and the occur-
rence of this disease.24 It begins as a nodule, which grows and becomes sur-
rounded by other similar lesions. This process is repeated until eventually,
over many years, most of the skin becomes nodular (Fig. 18.243). The nod-
ules do not ulcerate and can closely resemble lepromatous leprosy. Although
lesions may develop in the nasal mucosa, these are not destructive like those
of the mucocutaneous form of American leishmaniasis. Response to therapy
is slow and relapse is common. The Montenegro test is invariably negative.
L. major and L. (V.) panamensis may be associated with a sporotrichoid
spreading reaction.6
There have been rare reports of neoplasms such as basal cell carcinoma,
squamous cell carcinoma or even dermatofibrosarcoma protuberans arising
in scars associated with cutaneous leishmaniasis.25–28
Visceral leishmaniasis
Visceral leishmaniasis (kala-azar, black fever) is due to infection by L. donovani
complex and occurs widely in South America (L. chagasi), Africa (L. infantum),
the Mediterranean (L. infantum), and Asia (L. donovani and L. ­infantum).7,29,30
It may be a manifestation of HIV infection.6,8,31 In patients with HIV/AIDS,
leishmaniasis may occur in herpes zoster lesions and dermatofibroma cells
may be parasitized by the organisms. Nodular cutaneous lesions arising in
AIDS-related visceral leishmaniasis may mimic Kaposi's sarcoma clinically.32
Following inoculation, the organisms multiply in histiocytes; the onset of
disease is insidious, taking 2–4 months. The macrophages of the liver and
spleen take up the organisms, resulting in hepatosplenomegaly associated
Fig. 18.242
(A, B) Mucocutaneous
leishmaniasis: the lesions
are destructive and very
disfiguring. By courtesy of
B S. Lucas, MD, St Thomas'
Hospital, London, UK.
with lymphadenopathy, pancytopenia, irregular and intermittent fever, and
marked weight loss. In India, some patients develop earthy-gray pigmenta-
tion, particularly on the temples, around the mouth, and on the hands and
feet.10
A small number of patients who recover subsequently develop ­post-­kala-
azar dermal leishmaniasis.33 This has been reported from India and East Africa.
The lesions start as erythematous or hypopigmented macules (particularly
on the face) and become nodular and coalesce so that they closely resemble
lepromatous leprosy, but they lack sensation abnormalities. The lesions are
persistent, but resolve slowly on treatment.34,35
Pathogenesis and histological features
In all variants of the disease the amastigote form of the parasite multiplies
within the histiocytes of the mammalian host. The host response is related to
the number of amastigotes and the degree of cellular immunity. Large num-
bers of amastigotes are associated with an anergic response and many histio-
cytes without other inflammatory cells. Moderate numbers of amastigotes
are usually associated with necrosis, which is an important mechanism for
eliminating infection. Smaller numbers are associated with a good epithe-
lioid granulomatous response after the necrosis phase. Some infections are
846 Infectious diseases of the skin

degeneration of the basal keratinocytes has been described.20 The epidermis

Fig. 18.243
Diffuse cutaneous
leishmaniasis: note the
widespread lesions,
many of which appear
keloidal. By courtesy
of the late M.S.R. Hutt,
MD, St Thomas' Hospital,
London, UK.
may show pseudoepitheliomatous hyperplasia, and intraepidermal neutro-
phil microabscesses are not infrequent. The dermis typically contains an
intense infiltrate of histiocytes, lymphocytes, and plasma cells. Rarely, a
Grenz zone is evident. Neutrophils and eosinophils are usually sparse.39 Large
­numbers of amastigotes are evident and these may be seen within the overly-
ing ­keratinocytes (Fig. 18.245).20,39 Foci of dermal necrosis may be evident.
Vascular changes are usually not seen.39 Perineural and intraneural chronic
inflammatory changes associated with perineural Leishmania organisms
have been described.40 The patient was found to be hyperesthetic clinically.
In chronic lesions the dermis contains large numbers of small noncaseating
granulomata (Fig. 18.246). Giant cells tend to be sparse. Leishman bodies
are sparse or absent.20 Necrosis is very rare at this stage.39
Histologically, mucocutaneous leishmaniasis is extensively necrotic, with
many plasma cells, lymphocytes, neutrophils, and macrophages, but few
organisms. Occasional tuberculoid or suppurative granulomata may be
present.1,3
As with lepromatous leprosy, diffuse cutaneous leishmaniasis is character-
ized histologically by numerous macrophages distended with amastigotes and
a lack of granuloma formation. There are few lymphocytes and plasma cells.
These features indicate anergy, but not primary immunodeficiency.

eliminated by an effective granulomatous response without necrosis, while

others are associated with focal necrosis and ulceration when organisms are
released. In others there is more extensive necrosis. The events following
necrosis depend on the rate at which an effective epithelioid granulomatous
reaction develops.36,37 An unusual case of late-stage cutaneous leishmaniasis
harboring foci of caseous necrosis with no demonstrable organisms has been
reported.38
Healing is often relatively rapid once necrosis has occurred. In parallel with
developing immunity, the overlying epidermis shows pseudoepitheliomatous
hyperplasia. Lymphocytes and plasma cells also become more numerous at
the periphery of the granuloma. Scarring eventually replaces the granuloma.
Histologically, the acute lesion (oriental sore) is characterized by hyperker-
atosis and acanthosis although occasionally epidermal atrophy and parakera-
tosis are features.20 Ulceration is frequently seen (Fig. 18.244). Liquefactive
Fig. 18.245
Oriental sore: the infiltrate consists of parasite-laden histiocytes with small numbers
of lymphocytes.

Fig. 18.244 Fig. 18.246

Oriental sore: there is extensive ulceration and the adjacent epithelium is acanthotic; Oriental sore: epithelioid cell granulomata as seen in this field are a feature of
intense inflammation is seen deep to the ulcer bed. chronic lesions.
 Leishmaniasis 847

The features of post-kala-azar dermal leishmaniasis are similar to those

of the diffuse cutaneous variety; the overlying epidermis is atrophic, but is
not usually ulcerated (Figs 18.247–18.249). Nodular lesions show a dense
dermal lymphohistiocytic infiltrate. There are a variable number of organ-
isms. Vascular hyalinization is evident, and marked follicular plugging may
be observed.41 Degeneration of basal epidermal keratinocytes was observed in
one recent study. The dermal infiltrate was noted to comprise T-lymphocytes
and macropahges, with a preponderance of CD4+ T-cells over CD8+ lympho-
cytes. Plasma cells, however, were inconspicuous or absent.42
The lupoid form of chronic cutaneous leishmaniasis may be difficult to
diagnose because it represents an exaggerated tuberculoid response to very
few organisms (and as such closely resembles lupus vulgaris) or perhaps only
leishmanial antigen; it is best distinguished from other tuberculoid diseases
on the basis of its positive Montenegro skin test.20 There is no necrosis, and
plasma cells are sparse.

Fig. 18.249
Post-kala-azar dermal leishmaniasis: in this example, organisms are no longer visible.

Fig. 18.247
Post-kala-azar dermal
leishmaniasis: there is
a dense dermal nodular
infiltrate. The Grenz zone Fig. 18.250
is spared. Visceral leishmaniasis: promastigote forms of Leishmania donovani; note the
anterior kinetoplast and flagellum (the latter is not seen in human infection) (Giemsa
stain). By courtesy of H.P. Lambert, MD, and the London School of Hygiene and
Tropical Medicine, London, UK.

In all other forms of cutaneous leishmaniasis the diagnosis is confirmed

by the demonstration of amastigotes in a smear or skin section.43 The organ-
isms are best revealed by Giemsa stain as reddish cytoplasmic round to
oval structures measuring from 1.5 × 2.5 μm to 4.5 × 6.8 μm.6 They appear
blue-gray on hematoxylin and eosin staining. A small rodlike similarly
stained kinetoplast may be visible (Fig. 18.250). Many of the organisms
are within macrophages, but some occur extracellularly. They are termed
Leishman-Donovan bodies. These features must be distinguished from the
similar ­bodies of histoplasmosis and, to a lesser extent, those of granuloma
­inguinale and rhinoscleroma. The clinical features will usually be distinctive;
skin testing, serology, and ­culture of the organisms will confirm the diagno-
sis. PCR may be useful in providing a rapid diagnosis with precise species
identification.44,45

Differential diagnosis
A diagnosis of cutaneous leishmaniasis may easily be overlooked by histo-
Fig. 18.248 pathologists who are seldom exposed to biopsy material from such cases, espe-
Post-kala-azar dermal leishmaniasis: there is a heavy mixed infiltrate of histiocytes, cially when not alerted to a significant travel history. This is particularly the
lymphocytes, and plasma cells. case when organisms are sparse or if unusual histological features are present,
848 Infectious diseases of the skin
such as sarcoidal granulomas, palisaded granulomas with central ­fibrinoid
change, elastophagocytosis, and conspicuous numbers of ­multinucleated
­histiocytic giant cells. Lesions may thus be misdiagnosed as sarcoidosis,
­foreign body granuloma, granuloma annulare or lupoid rosacea.46
Amebiasis cutis
Clinical features
Entamoeba histolytica can cause cutaneous lesions, although this is rare.1,2
These are most commonly seen after surgical treatment of intestinal or hepatic
amebiasis, but may also occur by direct extension perianally from the bowel
or from hepatic involvement, and by direct inoculation of the skin from other
infected lesions. In recent years, a number of cases have been recorded in
HIV-infected patients, who may have an increased mortality due to other
coinfections.1,3 Penile amebiasis can follow anal intercourse.4 Cutaneous
lesions have been recorded on the trunk, abdominal wall, buttocks, genita-
lia, and perineum and on the legs.1,3–7 In addition to ulcers, cutaneous ame-
biasis may present with fistulae, fissures, abscesses, and polypoid or warty
lesions.1 Subcutaneous swellings called amebomas have also been described.8
Primary disease is uncommon; the majority of patients develop contiguous
skin lesions in the presence of underlying visceral infection.1,9 Although the
condition is encountered mainly in adults, amebiasis cutis may sometimes
occur in children.2,6,10
The lesions have a central necrotic zone with a purulent exudate, gray
slough, an undermined margin, and an erythematous halo. The ulcers are
irregular but sharply defined. They spread and do not heal spontaneously.
They are extremely painful and may be destructive. Occasionally, the lesions
resemble ulcerating tumors and are associated with surrounding verrucous
lesions.
Histological features
The trophozoites of E. histolytica are found among the purulent exudate of
the ulcer and are seen more clearly with PAS staining (Fig. 18.251). They
are 12–20 μm in diameter and are distinguished by their tendency to phago-
cytose red cells. Lesions may be superficial or deep, with the latter involv-
ing the subcutis. Necrosis is common and may be liquefactive, coagulative
or suppurative.1,2 Trophozoites and cysts are usually found in the patient's
feces. The organisms are surrounded by neutrophils, with some lymphocytes
and plasma cells. The adjacent epidermis appears acanthotic and this may
be marked or pseudoepitheliomatous in verrucous forms. Spongiosis may be
conspicuous in superficial lesions.1
A B
Fig. 18.251
Amebiasis cutis: (A) this biopsy is from a woman with vulval ulceration due to direct spread from the anus; the epithelium is hyperplastic and the lamina propria is chronically
inflamed. (B) There are numerous trophozoites present; note the ingested red cells.
Differential diagnosis
E. histolytica infection is distinguished from infection with free-living
­amebae (Acanthamoeba spp. and Balamuthia mandrillaris) by the presence
of e­ rythrophagocytosis in the former condition.
Infections caused by free-living amebae
Clinical features
Four free-living amebae are responsible for human disease, namely, Naegleria
fowleri (the cause of primary amebic meningoencephalitis), Acathamoeba
spp. (which cause granulomatous amebic encephalitis), Balamuthia man-
dillaris (another cause of granulomatous amebic encephalitis), and, more
recently, Sappinia diploidea, an exceptionally rare cause of encephalitis.1–3 Of
these, only Acathamoeba spp. and B. mandillaris are potentially associated
with cutaneous lesions. These latter two free-living amebae are seldom impli-
cated in human disease with the possible exception of Acanthamoeba contact
lens-associated keratitis.2,3 However, in recent years acanthamebiasis and bal-
amuthiasis have received increasing recognition as opportunistic pathogens
in immunocompromised patients, especially debilitated, malnourished hosts
and those with HIV/AIDS.1–13 Acanthamoeba spp. appear to be more impor-
tant in immunosuppressed organ transplant recipients.14,15 Infection with
B. mandrillaris (formerly referred to as leptomyxid ameba) may nevertheless
occur in immunocompetent individuals, including children.1,2,16,17
Infection with Acathamoeba spp. B. mandrillaris results in an often fatal
progressive encephalitis, and associated cutaneous lesions are a frequent
occurrence.1–4,6,11 Acanthamebiasis is a condition reported almost exclu-
sively from the United States, although cases have occurred in Korea.1,2,18
Similarly, the majority of cases of balamuthiasis have been reported from the
United States.1–3,11 The latter condition has nevertheless occurred in patients
from a number of South American countries and rarely, Thailand, India, and
Australia.13,16,17,19–25 B. mandrillaris infection of the CNS carries a mortality
in excess of 98%.10
Spread of Acanthamoeba spp. to the central nervous system (CNS) and
skin is usually from a primary source of infection in the lungs or paranasal
sinuses.1,5,18 Involvement of the skin may be the presenting manifestation of
disseminated infection.4 Isolated cutaneous disease with chronic, nonhealing
skin lesions may be the sole manifestation in patients with AIDS-associated
acanthamebiasis (Fig. 18.252).7
Acanthamebiasis of the skin presents as multiple deep dermal and subcu-
taneous nodules, usually on the extremities and face.4,6,9,12,14,15 Necrotizing
­panniculitis may occur.8 Pustular, ulcerating, purpuric, and sporotrichoid
lesions have also been described.5,6,26
 Toxoplasmosis 849

Fig. 18.252
Acanthamebiasis: there are widespread ulcers in this HIV-positive patient.
There was underlying vasculitis. Courtesy of N.-N. Moti-Joosub, MD. Division of
Dermatology, University of the Witwatersrand, Johannesburg, South Africa.

B. mandrillaris is present worldwide and is encountered in fresh

water, soil, and dust. It is thought that the organism gains access to the
CNS via hematogenous spread from a focus of primary infection in the
upper or lower respiratory tract or the skin.2,21 Transmission is ­probably
through the inhalation of airborne cysts or contamination of a skin
lesion.19,21,22 Cutaneous involvement is usually in the form of multiple
nodular or ­ulcerative lesions, similar to those encountered in cutaneous
­acanthamebiasis. One reported case developed an ulcerative mass 10 cm
in ­diameter on the thigh.20 A number of patients, however, have presented
with a ­centrofacial or sometimes destructive nasal lesion, which preceded
­symptoms and signs of CNS involvement by several months.17,21,23 In fact, B
the cutaneous signs may antedate the neurological signs by months.27
Some cases have evolved following penetrating injury or a prior Fig. 18.253
fracture.16,23,28 Acanthamebiasis (A, B): trophozoites and cysts are present. The wall of the latter is
characteristically double layered (B).
Histological features
Cutaneous infection with Acanthamoeba spp. results in severe suppurative
inflammation in the dermis with extension into the subcutis, where necro- Toxoplasmosis
tizing neutrophilic lobular panniculitis, tuberculoid granulomatous inflam-
mation, and vasculitis may occur.4,6,8,9,16 The epidermis is usually intact. Clinical features
Purpuric lesions are associated with leukocytoclastic vasculitis.5 B. mandril-
Toxoplasmosis is the result of infection with Toxoplasma gondii, an obli-
laris is associated with granulomatous and suppurative inflammation. This
gate intracellular parasite.1 Infection in humans, who serve as the interme-
inflammation is frequently angiocentric and direct invasion of vessel walls
diate host, usually occurs following ingestion of T. gondii oocysts that are
by trophozoites results in vasculitis and necrosis.21 The trophozoites of both
present in the feces of infected cats, or via consumption of undercooked,
genera, which tend to concentrate near blood vessels, generally measure
contaminated meat containing tissue cysts. The oocysts and tissue cysts then
20–30 μm in diameter, but may range from 15–50 μm.1,3,8,18,21 Recognition
transform into tachyzoites, which in turn develop into bradyzoites after local-
of the trophozoites may be difficult in view of their macrophage-like appear-
ization in brain or muscle tissue. These slowly replicating forms are contained
ance.6,11 The trophozoites have abundant vacuolated cytoplasm and a nucleus
within pseudocysts in the involved tissues.1
containing a discrete nucleolus. PAS and Gomori methenamine silver stains
The zoonosis exists in a number of clinical forms: as an acute infection in
highlight the amebic cyst walls. The cysts possess an outer wrinkled cyst wall
immunocompetent individuals, the vast majority of whom are asymptomatic;
(ectocyst) and a thin inner wall (endocyst) (Fig. 18.253).1,3,11,21 The tropho-
congenital toxoplasmosis due to transplacental spread of a maternal infection,
zoites and cysts of Acanthamoeba spp. are virtuallly indistinguishable from
forming part of the TORCH group of infections; and acute disease in immu-
those of B. mandrillaris by routine light microscopy. Diagnosis is therefore
nocompromised hosts, which is either acquired or the result of reactivation of
confirmed by culture, immunofluorescence studies, immunohistochemistry or
latent infection.1,2 Although fever, lymphadenopathy, chorioretinitis, and cerebral
PCR.4.11,12,22,29
involvement are well-recognized manifestations of symptomatic toxoplasmosis in
general, presentation with skin lesions is uncommon. Cutaneous involvement is
Differential diagnosis encountered more frequently in immunocompromised patients with ­disseminated
Acanthamebiasis and balamuthiasis are distinguished from cutaneous infec- infection, such as those with HIV/AIDS or in immunosuppressed recipients of bone
tion with Entamoeba histolytica by the presence of erythrophagocytosis in marrow, hematopoietic or solid organ transplants.1,3–10 Toxoplasmosis-associated
the latter condition. N. fowleri does not form cysts, and infection is not hemophagocytic syndrome has been reported in a renal allograft recipient.11 The
­associated with skin involvement. disease has also occurred following chemotherapy for lymphoma.10
850 Infectious diseases of the skin

Skin manifestations of the disease are very rare but may be encountered
in cases of acquired or congenital toxoplasmosis.12 Potential dermatologi-
cal manifestations include a maculopapular skin rash, widespread purpuric
papules and nodules, thrombocytopenic purpura, lichenoid and erythema
multiforme-like eruptions, ulcerative and vegetating lesions, panniculitis, and
erythroderma.7,8,10,13–17
for the intracellular yeast forms and amastigotes usually contained within
macrophages in the aforementioned conditions, respectively. Leishmania
organisms have a discernible kinetoplast. Rare cases of cutaneous toxoplas-
mosis following hematopoietic stem cell transplantation may mimic interface
­dermatitis, resulting in confusion with an adverse drug reaction or graft-
­versus-host disease if the encysted bradyzoites are overlooked.9

Histological features
A majority of reported cases have shown a superficial and deep perivascular
inflammatory cell infiltrate composed of lymphocytes and histiocytes.3,13,15
Small ‘cysts’ containing tiny bradyzoites may be encountered in the der-
mis, including vascular endothelial cells, follicular epithelium, and the sweat
glands and their ducts (Fig. 18.254).7 Rarely, similar structures are observed
within in the epidermis.8 The organisms may be highlighted by staining tis-
sue sections with the May-Grünwald-Giemsa method.13 Free parasites are
sometimes haphazardly distributed in the dermis, and there may be dermal
edema, erythrocytic extravasation, necrobiotic collagen bundle, and karyor-
rhectic debris.7 Biopsies from severely immunocompromised patients may
reveal little by way of a host response.7 Interface dermatitis and panniculi-
tis have been described.9,10 One reported case presenting with erythroderma
showed features of exfoliative dermatitis, with no discernible organisms.16
Vegetating lesions are characterized by pseudoepitheliomatous hyperplasia,
sometimes accompanied by necrosis.13 The diagnosis may be confirmed by
ultrastructural examination, immunohistochemistry or polymerase chain
reaction.7,8,10

Differential diagnosis Fig. 18.254

Toxoplasmosis: a cyst containing numerous bradyzoites is present within a
Cutaneous toxoplasmosis should be distinguished from histoplasmosis superficial blood vessel. By courtesy of H. Diwan, MD, Baylor College of Medicine,
and leishmaniasis. Toxoplasma bradyzoites may potentially be mistaken Houston, Texas, USA.

Algal infections

Protothecosis
Clinical features
Protothecosis is a rare condition, representing infection by the achloric
(achlorophyllic) alga Prototheca, usually P. wickerhamii.1–3 Approximately
100 cases have been reported.4–6 P. zopfii is also responsible for occasional
human cases.1,7 The alga is assumed to be inoculated into the skin by minor
trauma, presumably from contaminated water or soil. Prototheca are ubiq-
uitous in nature, being found in the mucus flux of trees, water stabilization
ponds, acid rivers and lakes, and a variety of animals including cows, dogs,
cats, and deer.8,9 The disease has been reported worldwide.10 One recorded
case occurred after an arthropod bite.9
Diseases caused by Prototheca include isolated cutanous lesions, olecranon
bursitis, and disseminated infection.1 Protothecosis occurs in both iatrogeni-
cally immunosuppressed patients and those with AIDS.1,4,6,7,9–14 The condition
manifests as a papular or eczematoid dermatitis, usually over an extremity.4,10
The dermatitis form is often extensive and scaly, hypertrophic, and resistant to
therapy. Vesicular, herpetiform, pustular, plaquiform, ulcerative, granuloma-
tous, and verrucous variants have been described (Fig. 18.255).1,4,15,16 Lesions
may also resemble pyoderma gangrenosum.4 Disseminated lesions have been Fig. 18.255
rarely reported.9,10,17 In immunocompetent patients the infection is most Protothecosis: numerous
crusted and ulcerative
often localized to the olecranon bursa following trauma.1,10 Localized teno-
lesions are present.
synovial involvement of the finger has been reported, one in an HIV-positive By courtesy of the
patient.5,11 Institute of Dermatology,
London, UK.
Histological features
The localized lesions consist of necrotic centers surrounded by granulation occasional multinucleate giant cells (Fig. 18.256). Organisms (3–15 μm in
and fibrous tissue with a few multinucleate giant cells. The algae are found diameter) can be found at all levels of the epidermis and in the superficial
in the necrotic centers. dermis (Figs 18.257, 18.258).3,10 Infection can also involve the regional
In the dermatitis lesions the epidermis is parakeratotic, acanthotic, and lymph nodes. Only basophilic spherical bodies are seen with hematoxylin
papillomatous, and there is a mixed infiltrate in the upper dermis, ­including and eosin staining, while a silver stain or a PAS reaction reveals sporelike

Fig. 18.256
Protothecosis: note the crusting, marked acanthosis, and heavy dermal infiltrate.
By courtesy of I. Van den Berghe, AZ, Sint-Jan AV Hospital, Bruges, Belgium.
Fig. 18.257
Protothecosis: numerous organisms are present in the dermis. By courtesy of I. Van
den Berghe, AZ, Sint-Jan AV Hospital, Bruges, Belgium.
bodies in the epidermis and among the inflammatory infiltrate. Sporangia
with symmetrically arranged endospores is characteristic; these have been
described as morula-like or daisy-like.4,11,18 Identification of the organism
depends on culture characteristics. Diagnosis may also be confirmed by direct
immunofluorescence.11
Fungal infections
Fungal infections include:
• superficial variants involving skin, hair, nails, and mucous membranes,
for example ringworm (dermatophytosis), and the dermatomycoses (tinea
versicolor and candidiasis),
• subcutaneous lesions,
• disseminated infection.1,2
Ringworm fungi include three species: Microsporum, Trichophyton,
and Epidermophyton.3,4 Epidermophyton invades epidermal keratin while
Microsporum and Trichophyton also affect the hair. Cutaneous ringworm
on nonhairy skin presents as slowly enlarging, scaly, erythematous, annular
lesions with central clearing (Fig. 18.259).
Protothecosis 851
Fig. 18.258
Protothecosis (A, B): (A) the internal septation is characteristic; (B) the organisms
have thick cell walls and are PAS positive. (A) By courtesy of I. Van den Berghe, AZ,
Sint-Jan AV Hospital, Bruges, Belgium; (B) By courtesy of C. Thatcher, MD, Eritzman &
Thatcher Inc. Anatomical Pathologists, Johannesburg, South Africa.
Bursal lesions show stellate caseating necrosis surrounded by a palisade of
epithelioid cells, Langhans giant cells, plasma cells, and lymphocytes.10,11 The
organisms are present within the necrotic centers. Sinus tracts may be evident.
There is associated fibrosis.
Differential diagnosis
Prototheca are distinguished from green algae (Chlorella) by the absence of
chloroplasts and from Coccidiodes immitis by its smaller size.2,19
Dermatophytes can infect the keratin of the stratum corneum, hair or nail,
without extending into deeper parts of the skin. They may also be associated
with intradermal spread (Majocci granuloma). Causative organisms may be
anthropophilic, zoophilic or geophilic. With few exceptions, identification
of pathogenic fungi is better served by culture rather than by histological
scrutiny.5–7 Dermatophytes use the soluble nonkeratin parts for nutrition and
rely on the keratin for protection from serum and the host response.8,9 The
keratin is penetrated by means of putative keratinases. Other virulence fac-
tors include elastase and proteinases.9,10 T. rubrum produces mannan, which
suppresses or diminishes the host immune response, presumably by inhibit-
ing critical steps in antigen presentation or processing.9,11 The epidemiology
852 Infectious diseases of the skin

Fig. 18.260
Fig. 18.259 Tinea capitis: there is
Tinea corporis: note the annular configuration and erythematous margin. From the marked hair loss. In this
collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK. example scaling and
crusting are pronounced.
and pathogenesis of dermatophytosis is complex and beyond the remit of From the collection of the
late N.P. Smith, MD, the
this text. For suitable review articles the reader is referred to references 1,
Institute of Dermatology,
3, 4, and 10. London, UK.

Tinea capitis
Dermatophyte infections of the scalp are characterized by involvement
of the hair shaft by pathogenic fungi. The pattern of hair invasion, related to
the type of dermatophyte, determines the degree and site of hair damage and
the clinical picture. Patients therefore present with variable features includ-
ing hair loss with scaling, follicular inflammation, pustulation, and kerion
formation, often in association with drainage lymphadenopathy. A carrier
state is recognized. Infection depends upon contact with spores and follicular
trauma. Tinea capitis (scalp ringworm) frequently presents as small epidem-
ics (e.g., in schools). Disease may develop as a consequence of sharing combs
or hairbrushes. Tinea capitis is the most common dermatophytosis of child-
hood. The disease may also occur in adults, the elderly, and even infants. The
past two decades have seen a rise in its prevalence and a change in the pattern
of etologic agents, both in Europe and the USA.

Infections caused by Microsporum canis

and Microsporum audouinii
Clinical features
M. canis and M. audouinii grow on the outside of the hair shaft, an ectothrix
type of hair involvement.1–3 The lesions present as areas of alopecia, with
numerous broken-off, dull hairs (Fig. 18.260). Some scaling is present, but
overt inflammation is not marked. The infected areas are recognized by fluo-
rescence under Wood's lamp (Fig. 18.261). The process commonly affects
children, boys much more often than girls. Microsporum ferrugineum may
also cause this picture.
M. canis and M. audouinii were once the most common causes of tinea capi-
tis in North America and Western Europe.3,4 M. canis, a zoophilic dermato-
phyte, is the organism most frequently implicated in cases of tinea capitis in
Europe. Urban areas of Europe (and France in particular) have shown a shift
towards infection with M. audouinii, an anthropophilic dermatophyte.5,6
Histological features
The fungal arthrospores coat the outside of the hair shaft and the hyphae
extend into the hair shaft down to the level of the mid follicle. The epidermis
shows some acanthosis and patchy parakeratosis and there is usually a mixed
inflammatory infiltrate in the superficial dermis, more marked with M. canis.
Fig. 18.261
Tinea capitis: note the characteristic fluorescence under Wood's light. By courtesy
of M.M. Black, MD, Institute of Dermatology, London, UK.
Kerion
Clinical features
Kerion (kerion celsi) is a severe, boggy inflammatory form of tinea, most
often caused by Trichophyton mentagrophytes.1,2 Kerion is seen as an area
of inflamed alopecia in which the broken-off hairs are loose in their folli-
cles and are associated with suppuration (Figs 18.262, 18.263). This may
be severe enough to discharge via sinuses, with the formation of fibrin-
opurulent crusts around adjacent hairs. Secondary bacterial infection
may play a part. Fluorescence is not a feature. Involvement of the beard
area (tinea barbae, tinea sycosis), which occurs most often in farm work-
ers, invariably affects adult males.3 The lesions appear as erythematous
areas of pustular folliculitis in the beard area and may present as a kerion
(Fig. 18.264).
 Infections caused by Microsporum canis and Microsporum audouinii 853

Fig. 18.264
Kerion: in males, dermatophyte infection of the beard area may also present as a
Fig. 18.262 kerion. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Kerion: in addition to alopecia there is marked erythema and matting of hairs due
to purulent exudate. By courtesy of R.A. Marsden, MD, St George's Hospital,
London, UK.

Fig. 18.263
Kerion: there is marked
alopecia and crusting.
From the collection of the
late N.P. Smith, MD. the
Institute of Dermatology,
London, UK.
Histological features
Trichophyton is a large-spored fungus with an ectothrix pattern of hair
involvement. There is much associated pus with abscess formation. The epi-
Fig. 18.265
Kerion: there is hyperkeratosis, acanthosis, epidermal edema with acute
inflammation, and abscess formation.
tinea capitis in a recent study from Nigeria.5 T. violaceum is the most com-
mon cause of tinea capitis in South Africa.6 The hair break is at the ostium
of the follicle so that broken hairs are seen as dots rather than stumps. The
intervening skin usually shows only slight scaling, but occasionally pus-
tules and kerion can develop.7 Drainage lymphadenopathy may be evident.
The hairs do not fluoresce with a Wood's lamp.
Histological features
The hyphae of T. tonsurans and T. violaceum exten