Survival Guide to Gastrointestinal

Mucosal Biopsies.

Pathology Survival Guides

hil novatiw·e
.·
Pathology
Press
 PATHOLOGY SURVIVAL GUIDES

First Series
Volume 1

Survival Guide
to Gastrointestinal Mucosal Biopsies
by
Elizabeth A. Montgomery, MD
Professor of Pathology, Oncology, and Orthopedic Surgery
The Johns Hopkins Medical Institutions
Baltimore, Maryland

Kiyoko Oshima, MD, Dr. Se.

Director of Clinical Hepatic Pathology
Assistant Professor of Pathology
Johns Hopkins Medical Institutions

Lysandra Voltaggio, MD
Director, Gastrointestinal Pathology Fellowship
Assistant Professor of Pathology
Johns Hopkins Medical Institutions

Published by the
Innovative Pathology Press
2017

I Innovative
~)' Pathology
...;.s;.. Press
 Pathology Survival Guides

EDITOR

Elizabeth A. Montgomery, MD
Professor of Pathology, Oncology, and Orthopedic Surgery
The Johns Hopkins Medical Inst itutions
Baltimore, Maryland

EDITORIAL BOARD

Jerad M. Gardner, MD
Associate Professor of Pathology and Dermatology
Dermatopathology, Bone & Soft Tissue Pathology
Program Director, Dermatopathology Fellowship
University of Arkansas for Medical Sciences

Kiyoko Oshima, MD, Dr. Se.

Director of Clinical Hepatic Pathology
Assistant Professor of Pathology
Johns Hopkins Medical Institutions

Lisa M. Rooper, MD
Assistant Professor of Pathology
Johns Hopkins Medical Institutions

Lysandra Voltaggio, MD
Director, Gastrointestinal Pathology Fellowship
Assistant Professor of Pathology
Johns Hopkins Medical Institutions

Available from the Innovative Pathology Press

Virginia
www.innovativepathologypress.com
ISBN 1-933477-62-8
978-1-933477-62-6

Copyright © 2017 The Innovative Pathology Press

Printed in South Korea

 Preface

With this slim volume, we introduce the Pathology Survival Guide series from Innovative
Pathology Press. Although there are many excellent sources for learning·diagnostic pathology, those
directed at medical students are too simplified to be practical for daily work with diagnostic pathology,
and many other texts assume a foundation of more knowledge than many of us have as we begin to
learn about a new area of diagnostic pathology. This series is intended to help residents and colleagues
who begin to tackle an organ system that is unfamiliar to them. Further, in the interest of making the
volumes affordable to trainees and those beginning, we have chosen a soft cover format to contain
costs but not at the expense of high quality images, which we believe will enhance the availability of the
books to those who will benefit most from them.
We begin with mucosal gastrointestinal pathology with the basics and a framework to diagnose
the common lesions together with a few exotic lesions that are important. In some sections, the focus is
on patterns of injury whereas in others, the key is paying attention to the specific type of mucosa that is
injured. We have tried to point out a few pitfalls in each section. We will not be able to create experts
with the material presented, but a road map is provided to set the stage to learn more, and we hope to
pique interest in the topic.
Upcoming volumes will cover breast, liver, prostate, head and neck, frozen sections, skin,
pancreas, bone, soft tissue pathology, hematopathology, and cytopathology, and feature a host of
authors who are superb educators. On behalf of ourselves and the rest of the Editorial Board, we hope
that many colleagues and residents will find the series useful and enjoyable to read.

Elizabeth A. Montgomery, MD
Kiyoko Oshima, MD, Dr. Se.
Lysandra Voltaggio, MD

Acknowledgments and dedication

We acknowledge the team at Innovative Pathology Press and the editorial board members for
their expertise and advice.

We dedicate this volume to the residents, fellows, and colleagues who love diagnostic
pathology.
 CONTENTS

1. Non-Neoplastic Esophagus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Intraepithelial Eosinophils. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Intraepithelial Lymphocytes with or without Apoptotic Bodies. . . . . . . . . . . . . . . . 8
Ulcers and Erosions (Neutrophils) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Apoptotic Injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Esophagitis Dissecans Pattern . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Granulomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Hyperkeratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . 15
2. Barrett's Esophagus and Esophageal Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Dysplasia in Barrett's Esophagus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Barrett's Esophagus: Negative for Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Barrett's Esophagus: Indefinite for Dysplasia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Barrett's Esophagus: Low-Grade Dysplasia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Barrett's Esophagus: High-Grade Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Intramucosal Carcinoma ......................................... : . . 31
Variant Dysplasia and Carcinoma Patterns. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Treatment Issues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Endoscopic Mucosal Resection (EMR) Specimens . . . . . . . . . . . . . . . . . . . . . . . . . 36
Adenocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Squamous Precursor Lesions and Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . 37
Precursor Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Squamous Cell Carcinoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Other Esophageal Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Granular Cell Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Leiomyoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3. Non-Neoplastic Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
What Type of Gastric Mucosa is Present? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Is the Mucosa Inflamed? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
H. Pylori Gastritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Autoimmune Gastritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Lymphocytic Gastritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Is there Prominent Pit Apoptosis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Other Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
4. Gastric Polyps and Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Polyps.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Fundic Gland Polyps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Hyperplastic Polyps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
 Swvival Guide to Gastrointestinal Mucosal Biopsies

Adenomas ...... . . . ........ .......... ...... . .. .. ... , . . . . . . . . . . . . . . 70

Adenocarcinoma and Mimics ........... ·. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Metastatic Carcinomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 ·
Neuroendocrine Tumos .................................. ·. . . . . . . . . . . . . 81
Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Mucosa-Associated Lymphoid Tissue Lymphomas.. . . . . . . . . . . . . . . . . . . . . . . 85
Inflammatory Fibroid Polyp. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Gastrointestinal Stromal Tumors (GISTs) of the Stomach. . . . . . . . . . . . . . . . . . . . . 88
5. Non-Neoplastic Small Intestine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Normal and Reactive Conditions.. ..... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Infectious Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Celiac Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Autoimmune Enteropathy and Common Variable Immunodeficiency . . . . . . . . . . 109
Medication-Associated Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
6. Small Bowel Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Polyps. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Tubular/Tubulovillous Adenoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Pyloric Gland Adenoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
Brunner Gland Lesions- and Pancreatic Heterotopia . . . . . . . . . . . . . . . . . . . . . . . 124
Peutz-Jeghers Polyps. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Adenocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
Ampullary Carcinomas.... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Neuroendocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Gangliocytic Paraganglioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
Follicular Lymphoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 7
Mantle Cell Lymphoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
T-Cell Lymphomas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Mesenchymal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Gastrointestinal Stromal Tumors (GISTs) of the Small Bowel. . . . . . . . . . . . . . . . 140
Gastrointestinal Tumors of Duodenum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Gastrointestinal Tumors of]ejunum and Ileum . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Vascular Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
7. Non-Neoplastic Colon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Normal Colonic Mucosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
Infections with Characteristic Features . . . ....... ..... .. . . ... . . ...... . ... . 148
Acute Colitis. . . . . . . . . . . . . . . . . . . . . . . . ....... ..... .. . . ... . . ...... . ... . 148
Ischemic Colitis Pattern . . . . . . . . . . . . . . . ....... ..... .. . . ... . . ...... . ... . 148
Active Chronic Colitis . . . . . . . . . . . . . . . . ....... ..... .. . . ... . . ...... . ... . 153
Active Chronic Colitis Mimickers of Inflammatory Bowel Disease. . . . . . . . . . . . . . 156

ii
 Contents

Lymphocytic and Collagenous Colitis............... . . . . . . . . . . . . . . . . . . . . . 157

Apoptotic Colopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
8. Colon Polyps and Neoplasms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
Benign Findings that Can Mimic Neoplasms or Other Diseases. . . . . . . . . . . . . . . . 167
Mucosal Prolapse Polyps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Polyps: Conventional Adenomas, Hyperplastic Polyps, and Other Serrated Polyps. 174
Tubular Adenomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 4
High-Grade Dysplasia and Villous Features in Adenomas . . . . . . . . . . . . . . . . . . 17 6
Pseudoinvasion (Mucosal Prolapse Change) in Adenomas. . . . . . . . . . . . . . . . . . 178
Evaluation of Adenomas that Contain Carcinomas in Polypectomy Specimens
("Malignant Polyp"). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
Serrated Polyps. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Colorectal Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Colitis-Associated Neoplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Juvenile Polyps. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Neuroendocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Other Colorectal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
9. Non-Neoplastic Anus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
He1norrhoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
Papillary Endothelial Hyperplasia (Vegetant Intravascular Hemangioendo-
thelioma) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
Infectious Proctitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
Herpes Simples Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
Cytomegalovirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
Syphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
Lymphogranuloma Venereum.. . ... .... .... . ......... . . .... .. . ....... 211
Crohn's Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
10. Anal Polyps and Neoplasms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Hidradenoma Papilliferum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Polyps........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Inflammatory Cloacogenic Polyp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Fibroepithelial Polyps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Anal Squamous Intraepithelial Neoplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Anal Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Paget Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
Adenocarcinoma and Anal Gland Adenocarcinomas . . . . . . . . . . . . . . . . . . . . . . . . 228
Other Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
Granular Cell Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
Melanoma and Nevi. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

iii
 1 NON -NEOPLASTIC ESOPHAGUS

Although it takes many years and constant
evaluation of the literature to develop a deep
~xpertise in gastrointestinal pathology, it is rel-
atively easy to master the foundations of dealing
with gastrointestinal biopsies. The objective is to
offer tips for getting started as well as examples
of some of the pitfalls that can be encountered.
We will begin in the esophagus and review topics
from proximal to distal beginning in the esoph-
agus and ending with the anal canal.
Esophageal biopsies often lack lamina pro-
pria because the normal esophagus is slippery,
strong and difficult to biopsy (fig. 1-1). If lamina
propria is present, don't mistake it for submu-
cosa (figs. 1-2-1-5). This can lead to errors in
determining depth of invasion when confront-
ed with an early invasive carcinoma. In general,
lamina propria is only present on biopsies of
esophageal squamous mucosa that is dam-
aged. There is often only epithelium present

Figure 1-1
NORMAL ESOPHAGEAL
SQUAMOUS EPITHELIUM
The basal cells are darker and
have less cytoplasm than the
more superficial mature squa-
mous cells, which are oriented
with their cytop lasm parallel
to the basement membrane.
The indicated vascular papilla
extends for less than half the
thickness of the epithelium.

Figure 1-2
LAYERS OF THE ESOPHAGUS
The important feature to note
is that the lamina propria lies
beneath the epithelium, between
the epithelium and muscularis
mucosae. This layer is often
misinterpreted as submucosa.
This is from a resection specimen.
Note that the tissue at the left of
the image has been crushed. At
the right part of the image, the
ti ssue has curled, creating an
impression that the lateral edge
is a deep one.

1
 Survival Guide to Gastrointestinal Mucosal Biopsies

I '':-: "'

Figure 1-3 -. ..
ESOPHAGEAL BIOPSY WITH
ATTACHED LAMINA PROPRIA
AND SUBMUCOSAL
GLAND AND DUCT
It is unusual to see submucosal
glands (lower right) or ducts
(left) in biopsies unless there has
been prior damage to the tissue.
Ducts are typically surrounded
by a brisk lymphoplasmacytic
infiltrate. .
~.(
~~~:tP«;·,.:.tl~-,
~ ;, .,
':;'\. '1.; ..
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rf ·'
~f-1~;·t;-, ~ · . .... ..-·-
1. .i-,v~: "}). . ,. ~ ~
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·.:.;". ''1\-::.~'\!fl:~' /, .: . ,., _..,-..~. ~~-"H ;.,.pr,);:-.,.,~;.. ,.

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Figure 1-4
ESOPHAGEAL BIOPSY WITH ATTACHED LAMINA PROPRIA AND SUBMUCOSAL GLAND
Left: The submucosal gland (lower right) is present beneath muscularis mucosae.
Right: In this high magnification, there is small duct at the left of the glands (center). These glands produce mucin to
lubricate the esophagus.

in biopsies. The vascular papillae should only
extend halfway up to the surface. The basal
cells should be only a few layers (2 to 4layers).
Most of the time the consequences of what is
written in pathology reports of squamous mu-
cosal biopsies are minimal but there are several
patterns that offer clues to inquire further. If
normal versus "reactive epithelial changes"
is reported, no one will call with queries, so
most of these samples can be handled quickly.
Although reflux disease has traditionally been
associated with basal layer proliferation and

2
 Non-Neoplastic Esophagus

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• •
. ."
-.
•
• -~
'
( t .•.•
' t ~
J
•, •
.' . ....
.' '... . •'
~ "' .'

•
Figure 1-5
ESOPHAGEAL BIOPSY FROM A PATIENT WITH AMYLOIDOSIS
Left: The presence of lamina propria and muscularis mucosae indicate prior damage. There is prominent chronic
inflammation in the lamina propria investing the cardiac glands at the right side of the image. On careful examination thick
vessels laden with amyloid are apparent.
Right: High magnification of the muscularis mucosae from the sample is shown on the left. Note the waxy appearance
of the amyloid that thickens the vessels.

extension of the vascular papillae with scat-
tered eosinophils, a thickness of more than 430
microns has been better correlated with reflux
disease than these traditional features (1). This
is equivalent to 0.43 mm. It is easy to estimate
1 mm on a glass slide, so finding well oriented
squamous epithelium measuring 1 mm or more
is a great clue that the patient has reflux disease
before the slide is even reviewed.
The gastric cardia lies between the esophagus
and stomach. It is lined by foveolar epithelium
and cardiac glands are found underneath in a
generous lamina propria. Note that the lamina
propria in the stomach, small intestine, and co-
lon consists of loose connective tissue by which
glands are invested, whereas it sits beneath the
epithelium and above the muscularis mucosae
in the esophagus.
The gastric cardia does not produce hor-
mones of interest in clinical diagnosis, so, for
example, gastrin stains are negative in the gas-
tric cardia. An example of a damaged gastro-
esophageal junctional mucosa is seen in figure
1-6. The most likely etiology for the damage is
reflux disease.
The esophagus and the gastric cardiac area is
frequently damaged in adults, most commonly
as a result of reflux. Repeated cycles of damage
and repair produce disordered anatomy and
the most important of these ana to mic disorders
is the duplication or general expansion of the
muscularis mucosae. This change is seen in most
examples of Barrett's esophagus but it can also
be found in the adjoining squamous mucosa
(figs. 1-6, 1-7). It is important to be aware of
this anatomic alteration as it becomes an issue

3
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 1-6
INFLAMED GASTROESOPHAGEAL
]UNCTIONAL MUCOSA
There is inflamed squamous
epithelium on the left, together with
lamina propria (the edematous tissue
containing inflammatory cells just
beneath the epithelium; this layer
is NOT the submucosa). Note that
the basal cells involve about half the
thickness of the squamous epithelium.
On the right is reactive gastric cardiac
mucosa, with mucin-containing
epithelium on top of lamina propria.

Duplicated disorganized Figure 1-7

ENDOSCOPIC MUCOSAL RESECTION
SAMPLE TO DEMONSTRATE LAYERS
OF THE MUCOSAL/SUBMUCOSA
An early adenocarcinoma is present
at the right part of the field and the
,\. · · ' '• original and duplicated muscularis
\ •1 . mucosae are indicated. Since the tissue
•' •••
>
has curled, the lateral margin at the
right has the appearance of a deep
margin. The lateral (mucosal) margins,
consisting of epithelium, lamina
propria, and muscularis mucosae, are
indicated by the thick black lines,
Submucosa whereas the deep (submucosal) margin
is indicated by the orange line.

Figure 1-8
DUPLICATED MUSCULARIS
MUCOSAE IN PREVIOUSLY
DAMAGED SQUAMOUS MUCOSA
ADJOINING BARRETT MUCOSA
It is easy to mistake the original
muscularis mucosae for muscularis
propria.

4
 Non-Neoplastic Esophagus

Figure 1-9
GASTRIC CARDIAC MUCOSA
In this image, four layers/lines are
present. The first consists of the apical
mucin cap of the foveolar epithelium,
the second consists of the base of
this cap, the third of the remaining
cytoplasm, and the last of the row
of nuclei.

in evaluating mucosal resection samples or even

esophagectomy specimens (fig. 1-8).
If gastric mucosa is encountered in the upper
esophagus, it is an embryologic rest termed inlet
patch. It is an incidental finding although, very
rarely carcinomas are believed to arise within
this tissue.
Reflux disease sets the stage for columnar
metaplasia in the esophagus with or without
goblet cells. In figure 1-9, the concept of four
layers in surface cardiac mucosa is demonstrat-
ed, a concept that we can use when we evaluate
Banett's dysplasia later in this volume. There are
several patterns of injury to the esophagus that
can be seen: 1) intraepithelial eosinophils; 2) in-
traepitheliallymphocytes with or without apop-
totic bodies; 3) ulcers and erosions (neutrophils);
4) apoptotic injury; 5) esophagitis dissecans
pattern; 6) granulomas; and 7) hyperkeratosis.
Figure 1-10
INTRAEPITHELIAL EOSINOPHIL$
FELINE ESOPHAGUS
In theory there should be no eosinophils in This pattern of ridges is reminiscent of the appearance
esophageal epithelium or lamina propria. They of the esophagus in cats and is characteristic of eosinophilic
are found in the setting of reflux disease and esophagitis.
allergic disease (eosinophilic esophagitis) . It is
currently believed that there is frequent over- ologic exercise. Some cases are, however, slam
lap in these diseases (2,3), but some cases are dunks! If there is striking basal cell hyperplasia at
readily attributable to one or the other. We are low magnification and eosinophils are numerous
often asked to determine whether biopsies show (no need to count them), the patient has eosin-
eosinophilic (allergic) esophagitis versus reflux ophilic esophagitis (figs. 1-10-1-12). If there is
esophagitis. We are only part of the equation and only slight basal cell hyperplasia and a search
these conditions are separated as a clinicopath- is required to find eosinophils, the patient has

5
 Survival Guide to Gastrointestinal Mucosal Biopsies

,..
' T •

,._ J •
,t'fi ~t;, ·,·. J
:......~ ~.

. .. . . . ..
,.;: ,.· ; ..... •• c

Figure 1-11
EOSINOPHILIC ESOPHAGITIS
A: There is striking basal cell hyperplasia although the intraepithelial eosinophils are not particularly conspicuous at this
magnification . The attached lamina propria is scarred/fibrotic.
B: There is striking basal cell hyperplasia and eosinophils are plentiful.
C: There is no need to count to see that there are far too many eosinophils. Report a large number thereof!
D: There is striking basal cell hyperplasia and prominent edema between the epithelial cells such that the intercellular
bridges are easy to see.

6
 Non-Neoplastic Esophagus

••

Figure 1-12
EOSINOPHILIC ESOPHAGITIS
Left: This example features an eosinophilic microabscess.
Right: Food impaction is a classic presentation. Note the adjoining skeletal muscle fibe rs in keeping with ingested
impacted meat.

Figure 1-13
REFLUX ESOPHAGITIS
Left: The basal cell h yperplasia is far less striking than that associated with eosinophilic gastritis.
Right: Scattered eosinophils are present.

7
Swvival Guide to Gastrointestinal Mucosal Biopsies
Figure 1-14
PROMINENT INTRAEPITHELIAL LYMPHOCYTES, A MARKER FOR CROHN'S DISEASE IN CHILDREN
Left: This is a nonspecific finding in adults but very characteristic of Crohn's disease in children .
Right: High magnification of left image.
reflux disease (fig. 1-13). If the endoscopist has
sampled both the mid esophagus and the distal
esophagus and there are loads of eosinophils in
the mid esophagus, the patient probably has
allergic/eosinophilic esophagitis. In truth there
is no need to count the eosinophils-an estimate
will do as it is desired by colleagues even though
in some respects it is meaningless because there is
tremendous variability of the eosinophil counts in
different biopsy fragments from the same patient
at the same time. Society guidelines suggest a 15
eosinophils per high power field cutoff for eosino-
philic esophagitis in the correct clinical setting. Of
course if there is a history of eosinophilic esopha-
gitis that has been treated, the counts go down.
Finding scarring in the lamina propria (fig.
1-llA,B) is very typical of eosinophilic esoph-
agitis and the scarring, which itself contains
eosinophils, tends to persist after the epithelial
eosinophil counts decrease. For biopsies in
which the history and microscopic findings
are not clear cut, the following report style is
acceptable: "Squamous mucosa with reactive
epithelial changes with up to X eosinophils per
high power field."
Reflux disease is classically encountered in
obese white males and eosinophilic esophagitis
8
in white male children with food impaction
(fig. 1-12, right) but there are many exceptions.
Reflux is treated with proton pump inhibitors
and other medications intended to reduce the
mucosal damage from the gastric contents that
bathe the esophagus. In contrast, the idea for
eosinophilic esophagitis is to reduce dietary
allergens but the diets are inedible for some
such that steroids are used. The so-called six
food elimination diet is quite unpalatable. Few
adults among us could follow it but it can be
forced on small children who don't know better:
INTRAEPITHELIAL LYMPHOCYTES W ITH
OR W ITHOUT APOPTOTIC BODIES
Finding lymphocytes in esophageal squa-
mous epithelium is often a nonspecific finding
and it is attributed to reflux disease in adults but
there are a few situations for which this finding
offers a clue.
If intraepithelial lymphocytes without asso-
ciated apoptotic squamous epithelial cells are
found in biopsies from children, this is very
strong evidence that the child has Crohn 's
disease (fig. 1-14). It cannot be reported un-
equivocally as such but should prompt a note
indicating that the patient should be further

evaluated for Crohn's disease. Of course,
occasional lymphocytes are acceptable in the
esophageal squamous epithelium but if they
are readily noted at 4x, there are too many. In
adults, esophageal intraepitheliallymphocyto-
sis is wholly nonspecific.
If intraepitheliallymphocytosis accompanied
by apoptotic bodies is encountered, the patient
will nearly invariably be an adult (figs. 1-15, 1-16).
This is the pattern encountered in esophageal or
oral lichen planus but it is indistinguishable from a
pattern of injury that has been termed "lichenoid
esophagitis," which is associated with vaiious med-
Non-Neoplastic Esophagus
Figure 1-15
LICHEN PLANUS ESOPHAGITIS
A: There is prominent lamina propria
chronic inflammation, marked intra-
epithelial lymphocytosis, and so m e
hyperke ratosis at the surface of the
epithelium. Diagnosing esophageal
lichen planus can require correlation
with a history of skin involvement or
oral involvement or even immuno-
fluorescence studies since it is indistin-
guishable from lichenoid esophagitis.
B: Note the apoptotic epithelial cell
in the center of the field (Civatte body).
C: High magnification of an apoptotic
epithelial cell.
•
•
c
ications and viral hepatitis (4). If the patient has a
known history of skin lichen planus, the esopha-
geal disease can be assumed to be a component
but otherwise the diagnosis must be descriptive.
Esophageal lichen planus tends to be encoun-
tered in middle aged to elderly women. The
esophagus lacks a granular layer so the findings
of esophageallichen planus do not fully mirror
those of skin disease. When a lichenoid pattern
is encountered, especially if there are a few neu-
trophils, it is always worthwhile to also assess for
Candida, which may be superimposed. In general
Candida alone does not cause this type of injury.
9
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 1-16
LICHENOID ESOPHAGITIS
Left: This example was seen in a patient taking a monoclonal immunomodulatory medication. There is lymphocytosis
and an apoptotic epithelial cell at the bottom of the field.
Right: High magnification of the apoptotic epithelial cell on the left. The findings are identical to those associated with
lichen planus.

Similarly, if there are numerous monocytic cells/
macrophages, infection with herpes simplex virus
and cytomegalovirus should be sought, even if
immunolabeling is required (5,6).
ULCERS AND EROSIONS (NEUTROPHIL$)
Ulcers and erosions merit a search for in-
fectious agents (figs. 1-17, 1-18). An erosion
destroys part of the mucosa whereas an ulcer
destroys it all, down to the submucosa or deeper.
Of course the key viruses to consider are herpes
simplex virus (HSV) and cytomegalovirus (CMV)
whereas in general Candida esophagitis that is
encountered on biopsies results in parakeratosis
(below) rather than ulcers. Remember that HSV
viral cytopathic change is found in epithelial
cells and CMV is almost always detected in en-
dothelial cells. As such, endoscopists are taught
to sample the edges of ulcer beds tohave both
types of "hunting ground" in their samples.
However, ulcers are also likely to result from
reflux disease and from medications (figs. 1-19-1-
23). The list of medications that can result in
esophageal injury is long but some produce
characteristic patterns of injury and sometimes
pill fragments (polarizable material) can be found
embedded in the ulcers or erosions. Sodium poly-
styrene sulfonate (Kayexalate), an exchange resin
used to reduce serum potassium in renal failure
patients results in deposition of characteristic
crystals (fig. 1-19) (7). Doxycycline often results
in nonspecific ulcers, but a characteristic pattern
of vascular injury can also be encountered (fig.
1-20) (8,9). Iron pills can also cause esophageal
damage or potentiate existing damage (fig.
1-21) (10). Agents to treat osteoporosis (the bi-
sphosphonates) are well-known for resulting in
esophageal damage (11) but after a spate of legal
actions, patients are currently instructed to take
these with copious amounts of water and not to

10

Figure 1-18
HERPES SIMPLEX VIRUS ESOPHAGITIS
Note that epithelial cells are affected.
lie down shortly after taking them, so this type of
injury, which lacks a characteristic morphology,
is encountered less frequently than in the past.
Of course, ulcers initiated by one form of injmy
can always be complicated by another, so ulcers
and erosions should always be studied carefully.
Lastly, ulcers can be associated with striking
reactive stromal changes (fig. 1-24) (12), which
Non-Neoplastic Esophagus
Figure 1-17
CYTOMEGALOVIRUS ESOPHAGITIS
An infected cell is in the center of the
image and it is an endothelial cell. Note
the monohistiocytic background, a clue
to search for the viral cytopathic effect.
In this case, the viral cytopathic effect is
somewhat subtle.
Figure 1-19
KAYEXALATE CRY STAL
This kayexalate crystal found in an ulcer bed has a
cracked appearance and purple calor.
are vastly more common than sarcomas or sar-
comatoid carcinomas involving the esophagus.
APOPTOTIC INJURY
Esophageal apoptotic injury has fewer as-
sociations than such injury in the stomach
and intestines, but they are important. If there
is associated lymphocytosis, as noted above,
11
 Swvival Guide to Gastrointestinal Mucosal Biopsies

Figure 1-20
EROSIVE ESOPHAGITIS ASSOCIATED WITH DOXYCYCLINE
Left: The appea rance of the lamina propria vessel is a clue. Review of the chart indicated that the patient was taking
doxycycline (a history of severe acne is common). Note that there are Candida organisms embedded in the epithelium at
the upper right. It is not clear which of the two initiated the mucosal in jury, but probably the candidiasis is a superinfection .
Right: High magnification of the lesfon shown on the left. Note the fibrinoid necrosis of the vessel.

Figure 1-21
IRON PILL ESOPHAGITIS
Left: The iron has oxidized, imparting a blue to black tint. The key is to note the reactive epithelial cha nges, which can
be mistaken for dysplasia/intra-epithelial neoplasia.
Right: This is an iron stain.

12
 Non-Neoplastic Esophagus

Figure 1-22
EROSIVE ESOPHAGITIS
WITH REACTIVE CHANGES
A: This erosion was found at the gastro-
esophageal junction in a patient without
eosinophilic esophagitis in undamaged mucosa, so
the significance of the eosinophils is not clear; it is
perhaps allergic or a florid response to the refluxate.
Note the epithelial changes, which are reparative.
B: This high power image shows the lamina
propria scarring and inflammation.
C: Note that the regenerating squamous
epithelium features squamous cells that are clearly
separated from one another and the intercellular
bridges are readily apparent. This is a clue that the
cells are reactive rather than dysplastic, although
occasional squamous dysplasia cases display
prominent intercellular bridges.

·v_,,,
•I '
'j I

Figure 1-23
PILL ESOPHAGITIS
Note the pill fragments . Note also the
striking reactive changes and that the upper
half of the epithelium has become necrotic
in an esophagitis dissecans pattern.

13
Swvival Guide to Gastrointestinal Mucosal Biopsies

Figure 1-24
PSEUDOSARCOMATOUS CHANGES
ASSOCIATED WITH ULCER
A: There is Barrett's mucosa in the center, ulcer exudate at
the upper left, and another fragment of interest at top center.
B: Note the fragment at the upper portion of the image,
which contains exudate and plump spindle cells.
C: These are not sarcoma cells but reactive fibroblasts
deprived of oxygen. They generally have a low nuclear
to cytoplasmic ratio and are found in ulcer beds at the
interface between exudate and fully viable tissue. When the
fragments are tangentially embedded, these cells can suggest
sarcoma but they disappear once ulcers heal.

this differs from apoptotic injury without
lymphocytosis. Viral infections can result in
apoptosis, but there is predominantly an ero-
sive or ulcerative appearance as the diagnostic
clue. The main issue is graft-versus-host disease,
which can be diagnosed in the setting of bone
marrow transplantation, often accompanied by
skin changes. It is diagnosed simply by finding
apoptotic bodies in the squamous mucosa in the
correct clinical setting (fig. 1-25). The epithelial
apoptosis in graft versus host disease is usually
unaccompanied by much inflammation unless it
is severe and there are ulcers. If that is the case,
it is important to address viral infections since
they themselves can result in apoptosis. If they
are seen, all bets are off in diagnosing graft ver-
sus host disease AND a viral infection, but the
patient's infection must be treated before giving
steroids to treat the graft versus host disease so
the uncertainty is not of clinical importance.
Mycophenolate (Cellcept), administered
to reduce host immunologic damage to solid
organ transplant patients by blocking nucleic
acid synthesis in lymphocytes, can result in
striking injury in the duodenum or stomach
but usually not much injury to the esophagus

14

Figure 1-25
GRAFT VERSUS HOST DISEASE
Note the striking basal zone apoptosis unaccompanied
by inflammation.
since esophageal squamous cells are less depen-
dent on the blocked pathway than enterocytes
(13, 14). Thus if a bone marrow transplant
patient has been taking mycophenolate and
esophageal squamous apoptosis is seen, the
damage is probably attributable to graft versus
host disease.
ESOPHAGITIS DISSECANS PATTERN
This pattern is also termed "sloughing
esophagitis" because large strips of epithelium
are seen sloughing into the lumen at the time
of endoscopy (15,16). It is sometimes report-
ed incorrectly as esophagitis "dissecans." The
surface is dissecting, not dry. Endoscopically it
can be mistaken for Candida esophagitis and
for bullous skin disease. It is more common
that bullous skin disease and the crack in the
epithelium is in a different location.
This pattern is associated with debilitation,
alcoholism and polypharmacy but it is poorly
understood. There may be some evidence that it is
Non-Neoplastic Esophagus
Figure 1-26
ESOPHAGITIS DISSECANS/ SLOUGHING ESOPHAGITIS
The epithelium sloughs off in strips.
initiated by mechanical or thermal (hot beverages)
esophageal injury. It is generally self-limited.
A cleft is seen in the middle of the squamous
epithelium and results in sloughing of the upper
half of the epithelium as strips of squamous
tissue with nuclear coagulative necrosis. Some-
times inflammatory cells are seen in the cleft but
no fungal elements are seen (figs. 1-26-1-28).
GRANULOMAS
Although in theory, esophageal granulomas
might be associated with fungal infections and
mycobacterial disease, in practice they are usu-
ally encountered in children as a manifestation
of Crohn's disease (fig. 1-29).
HYPERKERATOSIS
There are three main benign associations
with hyperkeratosis, namely reflux, candidiasis,
and a rarer presumed precursor to squamous cell
carcinoma termed epidermoid metaplasia. The
hyperkeratosis associated with reflux is brightly
15
 Survival Guide to Gastrointestinal Mucosal Biopsies

. _-...-- .:

:-
__- .. __- _ -- ___ _ ...,. :. - _r"
- -
_ J _ - :-_

... -. -
- -~- ~ -
-
--- -~ - : -:::, --::.,-::--- ... - -- ... _-_.....
... ..--
Figure 1-27 -..'
ESOPHAGITIS DISSECANS/ ·-
SLOUGHING ESOPHAGITIS
In this image, the upper half of the
epithelium is nonviable but has yet to ' -~·~ c:,•
slough off the surface. .-

::- .'
·. : ~

--> ..: ~: ~

Figure 1-28
ESOPHAGITIS DISSECANS/SLOUGHING ESOPHAGITIS
Left: The cleft is in the middle of the epithelium rather than at the base as in pemphigus vulgaris.
Right: At high magnification, there are some inflammatory cells in the cleft but no fungal elements.

eosinophilic compared to the squamous cells be-
neath it and adheres tightly to the surface, some-
times associated with neutrophils (fig. 1-30).
The hyperkeratosis associated with Candida
is the same calor as the other squamous epithe-
lium and flakes off the surface into the lumen
(fig. 1-31). Scanning for this pattern at low
magnification allows the pathologist to focus
on where to search for organisms.
Epidermoid metaplasia simply means that
the esophagus acquires an abnormal granular
layer akin to that in skin (figs. 1-32, 1-33). It is
easy to overlook. Epidermoid metaplasia has
the appearance of leukoplakia endoscopically

16
 Non-Neoplastic Esophagus

Figure 1-29 Figure 1-30

CROHN'S DISEASE MILD PARAKERATOSIS ASSOCIATED WITH REFLUX
There is a granuloma in the lamina propria. The lamina The squamous cells are plump and more or less adherent
propria is patt of the biopsy since the tissue has been damaged. to the surface.

1 ·.f
··,··'
• : 1'-
..~ . ,t!.

'•
...
,.. ... '
. / t..
..
0

.
c; ,'\ ~r- .

.' .
~

., ·' •
..
Figure 1-31
PARAKERATOSIS ASSOCIATED WITH CANDIDIASIS
Left: The parakeratotic cells flake off the surface. The organisms are found in the flaked zones.
Right: Note the pseudohyphae.

17
 Survival Guide to Gastroin.testin.al Mucosal Biopsies

.r
Figure 1-32
EPIDERMOID METAPLASIA
This manifests as a white plaque.

Figure 1-33
EPIDERMOID METAPLASIA
Left: A granular layer, normally absent in esophageal squamous epithelium, is present. The epithelium is otherwise
unremarkable. This seems to be a precursor to squamous neoplasia .
Right: Hyperkeratosis and a prominent granular layer are shown in this example.

and has been termed as such. It is probably a ageal squamous cell carcinoma such as smok-
precursor to squamous cell carcinoma but the ing and alcohol use (17). This contrasts with
rate of progression is not known. It is associated sebaceous heterotopia, which is an incidental
with the same risk factors as those for esoph- finding (fig. 1-34).

18
 Non-Neoplastic Esophagus

Figure 1-34
SEBACEOUS HETEROTOPIA
A: Note the oily appearing nodules.
B: Sebaceous glands identical to those in skin are found
in the lamina propria . Note that there is no granular layer
in the overlying epithelium such that one can exclude a
sample switch.
C: High magnification.

19
Swvival Guide to Gastrointestinal Mucosal Biopsies
REFERENCES
1. Vieth M, Mastracci L, Vakil N, et al. Epith eli-
a! Thickness is a marker of gastroesophageal
reflux disease. Clin Gastroenterol Hepatol
2016;14):1544-1551.
2. Cheng E, Souza RF, Spechler SJ. Eosinophilic
esophagitis: interactions with gastroesophageal
reflux disease. Gastroenterol Clin North Am
2014;43:243-256.
3. Molina-Infante}, Bredenoord A], Cheng E, et al.
Proton pump inhibitor-responsive oesophageal
eosinophilia: an entity challenging current di-
agnostic criteria for eosinophilic oesophagitis.
Gut 2016;65:524-531.
4. Salaria SN, Abu Alfa AK, Cruise MW, Wood LD,
Montgomery EA. Lichenoid esophagitis: clinico-
pathologic overlap with established esophageal
lichen planus. Am J Surg Pathol 2013;37:1889-
1894.
5. Greenson}K. Macrophage aggregates in cytomega-
lovirus esophagitis. Hum Pathol 1997;28:375-
378.
6. Greenson}K, Beschorner WE, Boitnott}K, Yard-
ley ]H . Prominent mononuclear cell infiltrate is
characteristic of herpes esophagitis. Hum Pathol
1991;22:541-549.
7. Abraham SC, Bhagavan BS, Lee LA, Rashid A,
Wu TT. Upper gastrointestinal tract injury in
patients receiving kayexalate (sodium polysty-
rene sulfonate) in sorbitol: clinical, endoscopic,
and histopathologic findings. Am J Surg Pathol
2001;25:637-644.
8. Xiao SY, Zhao L, Hart ], Semrad CE. Doxycy-
dine-induced gastric and esophageal mucosal
injuries with vascular degeneration. Am J Surg
Pathol2013;37:1115-1116.
20
9. Xiao SY, Zhao L, Hart J, Semrad CE. Gastric
mucosal necrosis with vascular degeneration
induced by doxycycline. Am J Surg Pathol
2013;37:259-263.
10. Abraham SC, Yardley JH, Wu TT. Erosive injury
to the upper gastrointestinal tract in patients
receiving iron medication: an underrecognized
entity. Am] Surg Pathol1999;23:1241-1247.
11. Abraham SC, Cruz-Correa M, Lee LA, Yardley
]H, Wu TT. Alendronate-associated esophageal
injury: pathologic and endoscopic features . Mod
Pathol1999;12:1152-1157.
12. Shekitka KM, Helwig EB. Deceptive bizarre
stromal cells in polyps and ulcers of the gastro-
intestinal tract. Cancer 1991;67:2111-2117.
13. Nguyen T, Park ]Y, Scudiere JR, Montgomery
E. Mycophenolic acid (cellcept and myofortic)
induced injury of the upper GI tract. Am J Surg
Pathol 2009;33:1355-1363.
14. Vieth M, Montgomery EA. Medication-associat-
ed gastrointestinal tract injury. Virchows Arch
2017;470:245-266.
15. Cannack SW, Vemulapalli R, Spechler SJ, Genta
RM. Esophagitis dissecans superficialis ("slough-
ing esophagitis"): a clinicopathologic study of
12 cases. Am] Surg Pathol2009;33:1789-1794.
16. Purdy ]K, Appelman HD, McKenna B]. Sloughing
esophagitis is associated with chronic debilita-
tion and medications that injure the esophageal
mucosa. Mod Pathol 2012;25 :767-775 .
17. Singhi AD, Amold CA, Crowder CD, Lam-Himlin
DM, Voltaggio L, Montgomery EA. Esophageal
leukoplakia or epidermoid metaplasia: a clinico-
pathological study of 18 patients. Mod Pathol
2014;27:38-43.
 2 BARRETT'S ESOPHAGUS AND
ESOPHAGEAL NEOPlASMS
Many biopsies from the esophagus are taken
to address Barrett's esophagus or other colum-
nar epithelium found in the esophagus. The
risk factors for Barrett's esophagus are chronic
gastroesophageal reflux (more than 5 years), age
over 50 years, male gender, smoking, central
obesity and Caucasian race. Alcohol use is not
a significant factor and some data suggest a pro-
tective effect for wine drinking (1) . Bottoms up!
Many of the issues surround the source of
the biopsy (proximal stomach versus tubular
esophagus). There are many articles concern-
ing special stains to address these issues but a
good hematoxylin and eosin (H&E) stain is all
Figure 2-1
OXYNTIC MUCOSA
This is gastric type mucosa of the type found in the gastric
body and fundus. The gastric pits are convoluted tubules
that connect to the surface such that a two dimensional
section shows crowded glands lined by parietal cells (the
pink ones in the center of the field). The deep portion of
the mucosa contains bluish chief cells. The surface foveolar
cells each have an apical mucin cap.
you need once you recognize the findings (2).
Knowing the endoscopic appearance is import-
ant but recording precisely which epithelial
types are encountered is the main issue. There
are a number of types of mucosa that can be
encountered: 1) oxyntic mucosa (fig. 2-1); 2)
cardiac mucosa (fig. 2-2); 3) pancreatic het-
erotopia/metaplasia (fig. 2-3); 4) multilayered
epithelium (figs. 2-4, 2-5) (3); 5) squamous ep-
ithelium; and 6) esophageal ducts (see chapter
1, fig. 1-3).
Finding either multilayered epithelium or
ducts on a biopsy confirms that a sample is from
the esophagus rather than the stomach.
Figure 2-2
GASTRIC CARDIAC MUCOSA
There are no parietal cells and there is lamina propria
chronic inflammation , a common finding in patients
who undergo biopsies after presenting reflux symptoms.
Since reflux results in cycles of damage and repair, there is
disorga nized smooth muscle in the lamina propria between
cardiac type glands, which produce mucin. The surface has
foveolar cells just as the oxyntic mucosa does. Some samples
show a combination ("cardia-oxyntic mucosa").
21
 Survival Guide to Gastrointestinal Mucosal Biopsies

'·

Figure 2-3
PANCREATIC AC INAR CELL
HETEROTOPIA IN CARDIAC TYPE MUCOSA
Th e tubules are closely packed, arranged in lobules,
and the cells formi ng them are more amphophilic (neither
eosinophilic nor basophilic) than parietal cells. This is a
common finding.
Figure 2-4
MULTILAYERED EPITHELIUM
This type of epithelium is common in persons with reflux
an d is fou nd in the tubular esophagus. The appearance
is reminiscent of that of immature squamous metaplasia
of the uterine cervix. The surface appea rs co lumnar
whereas the base is squamous. Note that this finding is in
a background of cardiac type mucosa. There is no need to
report this finding; it is simply important to know abo ut it
and not diagnose it as dysplasia. The presence of this type
of epith elium proves that the sample was taken from the
esoph agus despite the presence of gastric mucosa.

Figure 2-5
MULTILAYERED EPITHELIUM
Left: Note th e mucin in the surface cells. These cells can be shown to demonstrate MUC2 and CDX2 in a subset of
examples; there is no reason to perform these studies in daily practice.
Right: This is a PAS/Aician blue stain. Some of the cells have a bluish tint but they lack th e morphologic features of goble t
cells. There is no reason to perform this staining in daily practice to identify these cells.

22

Much of the evaluation concerns whether
goblet cells are present in any columnar epithe-
lium sampled from the esophagus. Although the
British criteria for Banett's esophagus do not re-
quire goblet cells, they do have a segment length
requirement (1 cm) (4). This length requirement
was adopted by the American College of Gastro-
enterologists in 2016 (1) although the American
Gastroenterological Association has yet to do so
as of this writing (5). The objective is to collect
the patients at highest risk for the development
of adenocarcinoma for screening.
The recommendation by the ACG to intro-
duce a disease length criterion is problematic
for the pathologist since endoscopic findings
are often unknown. When the pathologist has
documentation that the segment is less than 1
cm, the term specialized intestinal metaplasia of the
esophagogastric junction has been suggested (1).
When samples are received that are labeled
"esophagus" and contain goblet cells with-
out documentation of segment length, the
following comment can be added to reports:
"Note: The above diagnosis of Barrett's esophagus
is made due to presence of goblet cells (intestinal
metaplasia) with the assumption that the biopsies
were obtained from columnar mucosa in the distal
esophagus located at least 1 cm proximal to the top
of the gastric folds as per 2016 American College of
Gastroenterology (ACG) guidelines" (1).
If a sample is labeled "gastroesophageal junc-
tion" and goblet cells are present, an alternate
comment can be added: "Note: This biopsy shows
gastric-type mucosa with scattered goblet cells. The
diagnosis in this case depends on the location of this
biopsy. If this biopsy was taken from the tubular
esophagus at least 1 cm above the gas tric folds, it
shows Barrett mucosa of the distinctive type. If this
biopsy was taken from the gastric cardia, it shows
intestinal metaplasia of the gastric cardia" (1) .
Barrett's esophagus (with goblet cells) can
be documented in about 1 to 2 percent of the
general population (6) and in up to about 15
percent of people with reflux disease. Banett's
esophagus does not alter life expectancy (7). A
large Danish epidemiologic study found that
the annual incidence of progression to cancer
in Banett's esophagus was only 0.12 percent. As
a follow-up, the AGA analyzed a large data set
and noted that in the first 5 years of follow-up,
a mean 0.19 percent annual rate of progression
Barrett's Esophagus and Esophageal Neoplasms
could be expected but that after 20 years, a 9.1
to 9.5 percent cumulative cancer incidence was
predicted, suggesting that intensified surveil-
lance is indicated for patients with longstanding
Barrett's esophagus (8). Presently identification
of the key patients for screening and surveil-
lance is poor (9) such that most patients present
with symptoms of advanced incurable disease.
DYSPLASIA IN BARRETT'S ESOPHAGUS
There are four main features to study when
evaluating Barrett's esophagus for dysplasia (10),
although there can be some variations in mor-
phology (11): 1) surface maturation compared to
underlying glands; 2) architecture of the glands;
3) cytologic features; and 4) inflammation, espe-
cially erosions/ulcers.
Surface Maturation. This refers to the obser-
vation that, in nondysplastic Barrett's esophagus,
the nuclei in the basal glands are larger and more
hyperchromatic than those at the surface. Surface
nuclei are generally arranged in a monolayer
featuring polarized basal nuclei. In contrast, the
glands in Banett's esophagus are mildly atypical
compared to nearby gastric cardiac or fundic
glands, gradually maturing at the surface.
Architecture. The glandular architecture is
the relationship between glands and the lamina
propria, and also encompasses the shapes of the
glands. Increased numbers of glands and changes
in their shape are architectural alterations. In
nondysplastic mucosa, glands are round with
minimal budding set in abundant lamina pro-
pria. Crowding of normal-appearing glands is a
mild architectural abnormality and a reparative
change. Crowding of abnormal glands is a hall-
mark of dysplasia or early carcinoma. Cribriform
glands, cystic dilation, and necrotic luminal
debris are severe architectural abnormalities.
Cytologic Features. These are the key com-
ponent of diagnosis. Some degree of nuclear
alterations is inherent in nondysplastic Banett
mucosa, especially in the basal zone and in the
columnar epithelium adjoining squamous mu-
cosa. Cytologic atypia can indicate dysplasia,
reparative changes, and inherent changes in the
deeper glands of Banett's esophagus .
Determining whether dysplasia is low- or
high-grade is somewhat subjective since altera-
tions arise along a morphologic continuum, a
point noted years ago (12). An important
23
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 2-6
BARRED'S ESOPHAGUS, NEGATIVE FOR DYSPLASIA
A: There are well formed goblet cells that are crisply
delineated, separated by foveolar cells. This pattern
is termed incomplete intestinal metaplasia because
the tissue has incompletely transformed from gastric
foveolar type epithelium to intestinal type epithelium
that features a brush border. This is the characteristic
appearance of mucosa in Barrett's esophagus.
B: The presence of the four lines/levels in areas
that are well oriented provides a clue that there is no
dysplasia. The first line/row is formed by the neutral
mucin cap of the foveolar cells, the second by the base
of the surface mucin cap, the third by the cytoplasm and
the fourth by the row of stratified nuclei.
C: Note the lines that are demonstrated at low
magnification in "B". These helpful lines vanish in zones
that are tangentially embedded such as the area at the
left part of the field.

component of assessment of cytologic features
is evaluation of the alignment of one nucleus
compared to others: nuclear polarity. When
"normal polarity" is present, the long axes of
the nuclei are perpendicular to the basement
membrane, and the nuclei are aligned paral-
lel to one another. "Loss of nuclear polarity"
indicates loss of this orientation and a random
array of the nuclei in relation to the basement
membrane and one another.
Barrett's Esophagus: Negative for Dysplasia
Nondysplastic Barrett's esophagus (fig. 2-6)
shows surface maturation such that the nucle-
ar-to-cytoplasmic ratio of surface cells is lower
than that of the deeper glands. The architecture
is normal, and thus there is abundant lamina
propria. The cytologic features are normal;
mitoses may be present in deeper glands. Indi-
vidual nuclei have smooth nuclear membranes,
and nucleoli, if present, are small with smooth
outlines. Nuclear polarity is maintained.
A characteristic feature of nondysplastic Bar-
rett mucosa, even reactive changes, is the pres-
ence of four lines/tiers. The first tier is formed by
the surface gastric foveolar type mucin droplet,
the second by the base of the foveolar mucin vac-
uole, the third by the cytoplasm below the mucin
vacuole, and the last by the row of nuclei. This
pattern is fourid in both gastric cardiac mucosa

24
 Barrett's Esophagus and Esophageal Neoplasms

Figure 2-7
BARRED'S ESOPHAGUS, INDEFINITE FOR DYSPLASIA
Left: Given that the term "indefinite" is used, this can be a subjective interpretation. In this sample, there is poor orientation
and plentiful inflammation such that the surface epithelial changes are concerning but could be reparative.
Right: This is a high magnification of the lesion seen on the left. The surface lines are absent but the surface nuclei are
not particularly enlarged and the lamina propria is quite inflamed.

(see chapter 1, fig. 1-11) and nondysplastic
Barrett mucosa (fig. 2-6B). Using this criterion
helps reduce the number of lesions regarded as
"indefinite for dysplasia" as below.
Barrett's Esophagus: Indefinite for Dysplasia
The indefinite category describes cases that
have deeper cytologic changes suggestive of
dysplasia, but that show surface maturation but
are often cases in which inflammation obscures
the findings (figs. 2-7, 2-8).
Barrett's Esophagus: Low-Grade Dysplasia
The surface appears similar to the underlying
glands at low magnification in low-grade dyspla-
sia (figs. 2-9, 2-10), or displays only slight matu-
ration. Lamina propria should be identifiable
between glands. The cytologic changes should
extend at least focally to the surface. Finding foci
with abrupt transition between non-dysplastic
and dysplastic epithelium is a clue that the
changes are indeed neoplastic as opposed to reac-
tive. Superficially located nuclei can be irregular,
hyperchromatic, mildly enlarged, and may show
some degree of stratification and mucin loss.
Imp01tantly, the four lines/four tiers are lost.
Some examples of low-grade dysplasia are
essentially indistinguishable from tubular ad-
enomas (fig. 2-IOC). Do not use the term tubular
adenoma. Polypoid low-grade columnar epithelial
dysplasia is preferable.
Barrett's Esophagus: High-Grade Dysplasia
Surface maturation is lacking in high-grade
dysplasia (figs. 2-11-2-16). Architecturally, there
may be crowding of cytologically abnormal
glands, but many cases show normal amounts of
lamina propria. Prominent nucleoli are usually
absent. They tend to be present in the setting
of either reactive changes or invasive carcino-
ma, both of which are associated with ulcers.
Markedly enlarged hyperchromatic cells that
extend to the surface characterize high-grade
dysplasia (HGD). Loss of nuclear polarity is a
key feature of HGD.
HGD associated with certain features should
suggest early carcinoma (figs. 2-17-2-19). Con-
cerning features are: 1) cribriform architecture,
2) dilated tubules containing necrotic debris,
3) associated ulceration, 4) neutrophils within
dysplastic glands, and 5) extension of single
neoplastic cells into the overlying squamous

25
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 2-8
BARRETT'S ESOPHAGUS, INDEFINITE FOR DYSPLASIA
Left: The gland in the center co uld be dysplastic but there is ample inflammation and some surface maturation. The
surface lines are lost but the surface nuclei are smaller tha n the nuclei in the deeper glands.
Right: This is a higher magnification of the left figure .

.,, . (

. ..

r:
:t·
: I \

Figure 2-9
BARRETT'S ESOPHAGUS, LOW-GRADE DYSPLAS IA
Left: The surface lines are absent and there is minimal inflammation. The surface nuclei have similar appearances to
th e deep ones. There is no loss of nuclear polarity in that the long axes of the nuclei are perpendicular to the basement
membrane. This lesion h as overt intestinal type differentiation.
Right: Note the sharp abrupt transition between the gastri c foveo lar type epithelium on the top and the dysplasia at the
left and bottom. A few dysplastic glands are also present at the lower right.

26
 Banett's Esophagus and Esophageal Neoplasms

.
r •
0 ~
·~ •4

Figure 2-10

BARRETT'S ESOPHAGUS, LOW-GRADE DYSPLASIA

A: A striking abrupt change is seen in the epithelium at the right.
B: This is a high magnification image of the surface. The surface lines are absent in the well oriented zone on the right
but the long axes of the nuclei are perpendicu lar to the basement membrane, which supports an interpretation of low-grade
dysplasia rather than high-grade dysplasia.
C: This lesion resembles a colorectal tubular adenoma.

27
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 2-11
BARRETT'S ESOPHAGUS, HIGH-GRADE DYSPLASIA
Left: In this example, the glands are pressed together ("back to back") but it is easy to trace the outline of each tubule.
Even at this magnification, it is apparent that surface nuclear polarity is lost and many of the nuclei are round and detached
from the basement membrane.
Right: This is a high magnification view of the surface showing rounded nuclei.

r
,._
..
.. - •
0 •
'
• • •• •
.. •
•
0
•
• ,. • ~
•
•
"•
' 0
• (I

• '
!,
~
..
• '
•
q

'

Figure 2-12
BARRETT'S ESOPHAGUS, HIGH-GRADE DYSPLASIA
This is a p53 immunostain. There is strong nuclear
labeling in most of the cells .
Figure 2-13
SQUAMOUS EPITHELIUM, p53 STAIN
It is entirely normal to find labeling in the basal
layer of squamous epithelium, which is the proliferative
compartment of the squamous epithelium. In this layer,
the TP53 gene is "turned on" and performing its duties of
abundant production of normal p5 3 (a tumor suppressor
molecule) rather than mutated and producing an aberrant
gene product (protein) that is not degraded and thus
accumulates in the nuclei.

28
 BaiTett's Esophagus and Esophageal Neoplasms

Figure 2-14 Figure 2-15

HIGH-GRADE DYSPLASIA AND BARRED'S ESOPHAGUS, HIGH-GRADE DYSPLASIA
INTRAMUCOSAL CARCINOMA Note the nuclear membrane alterations.
There is high-grade dysplasia at the upper right but the
area in the center has poorly formed tubules with luminal
necrosis, feature of early lamina propria invasion. Note the
cardiac glands at the upper left.

Figure 2-16
BARRED'S ESOPHAGUS,
HIGH-GRADE DYSPLASIA,
p53 "NULL" PADERN
The cardiac glands at the lower
right show weak labeling in th eir
proliferative compartment in keeping
with physiologic activity of the
p53 protein. However, in the high-
grade dysplasia at the left , there
is complete absence of nuclear
labeling, supporting biallelic loss of
the TP53 gene. This complete loss,
when encountered, is a wonderful
confirmation of an interpretation of
high-grade dysplasia or carcinoma.

29
Swvival Guide to Gastrointestinal Mucosal Biopsies

Figure 2-17
BARRETT'S ESOPHAGUS, HIGH-GRADE DYSPLASIA AND INTRAMUCOSAL CARCINOMA
Left: This lesion shows at least high-grade dysplasia but areas in the center in which the glands are smeared and the presen ce
of glands with neutrophils suggest that there is early lamina propria invasion. Separating the two is of little importance in
the era of endoscopic treatment and indeed this is an area of interobserver variability.
Right: This is a PAS/Alcian blue stain of the lesion seen at left. Note the presence of both acid (blue) and neutral (pink) mucin.

Figure 2-18
BARRETT"S ESOPHAGUS,
HIGH-GRADE DYSPLASIA AND
INTRAMUCOSAL CARCINOMA
This lesion has a pS3 "null" pat-
tern. Note the internal control of weak
labeling in the proliferative com-
partm ent of a few entrapped cardiac
glands at the right.

30
 Barrett's Esophagus and Esophageal Neoplasms

Figure 2-19
ESOPHAGEAL ADENOCARCINOMA, PAGETOID SPREAD INTO
SQUAMOUS EPITHELIUM BY A DEEPLY INVASIVE CARCINOMA
Left: The intraepithelial cells are seen in clusters and singly and have mucin vacuoles. Encountering such cells on a
mucosal sample is evidence that a deeply invasive adenocarcinoma is present.
Right: This is a PAS/Alcian blue stain from the adenocarcinoma depicted on the left.

epithelium in a Pagetoid pattern. A Pagetoid managed identically (with mucosal ablation/

pattern is always associated with deeply invasive
carcinomas whereas the others overlap with fea-
tures ofintramucosal carcinoma (fig. 2-19) (13).
lntramucosal Carcinoma
Distinguishing HGD from the earliest carcino-
mas (invasion through the basement membrane
into the lamina propria or muscularis mucosae;
Tla) is difficult. Such cases show effacement
of lamina propria architecture and a syncytial
growth pattern, back-to-back microglands, cells
with prominent nucleoli, and an intermingling
of single cells and small clusters within the lami-
na propria (figs. 2-20, 2-21). Desmoplasia is either
absent or minimal. Some observers believe that
the earliest sign of intramucosal carcinoma is
the presence of glands with abnormal cytology
(round hyperchromatic nuclei) that have begun
to "grow sideways" instead of perpendicular to
the surface. Interobserver variability is a factor
in diagnosis of intra mucosal carcinoma in small
biopsies. However, this distinction is less im-
portant than it was in the past since both high
grade dysplasia and intramucosal carcinoma are
endoscopic resection) (1,5).
Variant Dysplasia and Carcinoma Patterns
Some lesions show basal pit alterations
with surface maturation. The term basal oypt
dysplasia (BCD) has been used to describe this
finding (note that the term oypt is inaccurate
since the cardia has pits, but it could be argued
that, since the tissue has intestinal metaplasia,
then the pits have become crypts) (figs. 2-22,
2-23) (14). In some cases of BCD, the nuclear
alterations are identical to those of HGD. The
term "indefinite for dysplasia" can be applied to
these cases and regarded as an interim diagnosis
until conventional dysplasia can be confirmed
or excluded and resampling can be suggested in
a note. Although the use of the p53 staining is
not warranted for all cases (2), BCD often shows
nuclear labeling in the affected pits.
Other examples of dysplasia lack classic
intestinal type differentiation, showing dif-
ferentiation along gastric foveolar or pyloric/
cardiac type lines (figs. 2-24-2-26) . Reports
of "non-adenomatous" (15) or "gastric" (16)

31
Swvival Guide to Gastrointestinal Mucosal Biopsies

Figure 2-20
INTRAMUCOSAL CARCINOMA
A: Note the syncytial growth pattern in this example.
B: Although this lesion proliferates as angulated tubules invading into the muscularis mucosae, there is no desmoplasia.
C: Note the lack of desmoplastic response to the glands that invade the muscularis mucosae.
D: This lesion consists of back-to-back glands, some with luminal necrosis. This case also features promin ent Russell
bodies (plasma cells with ab undant intracytoplasmic globules of immunoglobulin) at the top left. This phenomenon can be
mistaken for signet ring cell carcinoma but note that th e nuclei are ti ny.

32
 Banett's Esophagus and Esophageal Neoplasms

Figure 2-21
INTRAMUCOSAL CARCINOMA
Left: Many of the glands are oriented parallel to the surface, an abnormal architectural pattern.
Right: Note the nucleoli in the gland in the center of the image and the truncated gland at the left that is oriented parallel
rather than perpendicular to the surface.

Figure 2-22 Figure 2-23

INTRAMUCOSAL CARCINOMA
This lesion is easy to diagn ose as neoplas tic but notice
that the surface is uninvolved. This is an unusual pattern.
Often it is unclear whether atypical glands that mature at
the surface are neoplastic or reparative. Sometimes recuts
resolve th e issue but, in many cases, an interpretation of
indefinite for dysplasia is in order.
BASAL PATTERN DYSPLASIA, p53 STAIN
Diffuse strong staining in a basal lesion supports an
interpretation of dysplasia. In this case, there is striking
nuclear enlargement. There are no good criteria for grading
but whether this pattern is interpreted as low or high
grade dysplasia, the interpretation will prompt additional
sampling.

33
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 2-24
LOW -GRADE DYSPLASIA,
GASTRIC FOVEOLAR PATTERN
A: This is an uncommon pattern with
pure gastric foveolar differentiation but
hyperchromatic nuclei at the surface. The
nuclei are slightly stratified.
B: There are no goblet cells and each
lesional cell has an apical mucin cap in the
manner of gastric foveolar cells.
C: This is a PAS/ Alcian blue stain. Note
the prominent foveolar type mucin at the
left. There are no well-formed goblet cells .

•B

describe these lesions that lack the classic
stratification of intestinal type dysplasia. Such
cases seem to account for 10 to 15 percent of
dysplastic lesions. Lesions with cardiac/pylor-
ic differentiation consist of numerous, tiny
glands that appear bland at low magnification,
but that display nuclear alterations at high
magnification. Criteria to grade such lesions
are not well-established (11), but essentially,
in dysplasia with gastric type differentiation,
since the nuclei are round and in a monolayer
rather than stratified, the criteria for HGD simply
involve loss of polarity whereas at baseline (low-
grade dysplasia) there are closely packed tubules.
Glandular crowding is far less prominent in
intestinal-type dysplasia. Rare lesions have pure
gastric foveolar differentiation (fig. 2-24), but
many lesions have combinations of the various
types of epithelium. Occasionally dysplasia spreads
laterally over the surface of non-neoplastic cardiac
or cardia-oxyntic glands (fig. 2-27).
Treatment Issues
In the past esophagectomy was the sug-
gested treatment for HGD since there were no
better alternatives. As techniques have evolved,

34
 Barrett's Esophagus and Esophageal Neoplasms

Figure 2-25
HIGH-GRADE DYSPLASIA, GASTRIC TYPE DIFFERENTIATION
Left: There are tiny tubules lined by a monolayer of hyperchromatic cells with round nuclei.
Right: This is a high magnification view of the lesion seen on the left.

Figure 2-26
HIGH-GRADE DYSPLASIA, PYLORIC/CARDIAC TYPE DIFFERENTIATION
Left: The lesion is polypoid and complex, consisting of closely packed tubules.
Right: This is a MUC6 immunostain, performed strictly for interest.

35
 Survival Guide to Gastrointestinal Mucosal Biopsies
Figure 2-27
HIGH-GRADE DYSPLASIA EXTENDING ONTO THE SURFACE OF CARDIAC TYPE MUCOSA
Left: This pattern can also be seen extending onto the surface of oxyntic mucosa.
Right: High magnification of the case seen on the left.
endoscopic treatment is now the standard
of care both for HGD and early carcinomas
(1 ,5,17). Once occult, more deeply invasive
carcinoma is excluded, endoscopic resection for
visible lesions followed by ablation using radiof-
requency ablation (RFA) is the current protocol.
Other available endoscopic treatments in-
clude multipolar electrocoagulation, argon
plasma coagulation, photodynamic therapy,
and cryotherapy. RFA has become the preferred
technique since there are fewer complications
associated with it than the others (18,19), but
some patients require other ablation methods.
Although in theory these techniques could
fail to ablate dysplastic mucosa underneath
squamous mucosa (buried BE) this is a minor
issue in practice (20). Endoscopic submucosal
dissection, a more time-consuming method
of removal of macroscopic lesions, results in a
greater likelihood of achieving negative mar-
gins but is really not necessary for esophageal
lesions, for which EMR is adequate (21) .
Recurrences of Barrett mucosa following
ablation are common although recurrence of
neoplasia is unusual. Regardless, continued
surveillance is indicated (22,23). Not surprising-
ly, those patients with extensive intramucosal
36
carcinoma are the most likely to have recurrent
and persistent lesions (22) .
Endoscopic Mucosal
Resection (EMR) Specimens
To perform an EMR, the endoscopist injects
the submucosa with fluid and then applies a
cap to the lesion followed by suction through
the endoscope, thereby creating an artificial
"polyp" that is then resected. The EMR speci-
men allows for good characterization of dys-
plasia and neoplasia but there are pitfalls: The
surface epithelial layer of the EMR sample may
be damaged by application of the suction cup
such that dysplasia must be evaluated in the
absence of an intact surface.
Duplicated muscularis mucosae is very com-
mon in Barrett's esophagus (see chapter 1, figs.
1-5, right; 1-6). The original muscularis mucosae
is accompanied by a second delicate smooth
muscle layer closer to the luminal surface, a fea-
ture found in over 90 percent of resection sam-
ples (24) and nearly 70 percent of EMR samples
(25) . Duplicated muscularis mucosae creates a
pitfall when examining superficial biopsies since
lamina propria that underlies the more superfi-
cial duplicated layer of muscularis mucosae is
 Banett's Esophagus and Esophageal Neoplasms

Figure 2-28
SQUAMOUS DYSPLASIA
Left: The alterations involve less than half the thickness of the epithelium in low grade displacia
Right: The alterations involve the entire thickness of the epithelium in high grade displacia.

readily mistaken for submucosa. Awareness of this /

phenomenon prevents diagnosis of submucosal SQUAMOUS PRECURSOR LESIONS AND

invasion (Tl b) in patients whose invasive carcino-
ma is restricted to the lamina propria (Tla). This
is a critical distinction because T1a lesions can be
treated endoscopically whereas submucosal inva-
sive lesions (T1b) often require esophagectomy.
Cautery results in contraction of the muscu-
laris mucosae, pulling the lateral edges of the
sample together (see chapter 1, figs. 1-5, right;
1-6) resulting in the false impression that lateral
margins are instead deep margins.
An attempt should be made to characterize
the depth of any invasion in EMR samples in ad-
dition to assessing the margins. It is our practice
to provide a description, such as "invading the
lamina propria" or "invading the space between
the original and duplicated muscularis mucosae,
T1a"; reporting the precise depth seems of value
to facilitate dialogue when patients are referred
between institutions.
Adenocarcinoma
Generally, adenocarcinomas are not difficult
to diagnose; desmoplasia is well developed on bi-
opsies as soon as submucosal invasion is present.
SQUAMOUS CELL CARCINOMA
Precursor Lesions
Epithelial changes confined the bottom half
of the epithelium are graded as low-grade dys-
plasia (intra-epithelial neoplasia terminology
is preferred in Europe) and into the top half
as high-grade dysplasia (fig. 2-28). It should be
noted, however, that severe epithelial changes
in the bottom half of the epithelium often sug-
gest an adjoining unsampled carcinoma that has
spread in the space between the basement mem-
brane and the normal squamous epithelium.
A pattern of hyperkeratosis and hypergranu-
losis has been termed "esophagealleukoplakia"
(white plaques are encountered at endoscopy).
This pattern is associated with squamous dys-
plasia and carcinoma (26,27) and also termed
epidermoid metaplasia. Essentially a granular
layer is seen, whereas it is normally absent
in esophageal squamous mucosa (fig. 2-29).
Genetic alterations detected in epidermoid
metaplasia mirror those in associated dysplasias
and carcinomas (28).

37
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 2-29
EPIDERMOID METAPLASIA
A: At first glance, this biopsy simply shows the junction of the squamous and cardiac mucosa but the pattern of
hyperkeratosis is unusual.
B: This is high magnification of the lesion seen in "A." An abnormal granular layer is present just beneath the surface
hyperkeratosis.
C: In this case, epidermoid metaplasia is seen on top of high-grade squamous dysplasia.
D: High magnification of the lesion depicted in "C."

son syndrome (dysphagia, iron-deficiency ane-

Squamous Cell Carcinoma
Squamous cell carcinoma (in contrast to ad-
enocarcinoma) is associated with low socioeco-
nomic status. Happily, some of the deficiency
syndromes associated with esophageal squa-
mous cell carcinoma, such as the Plummer-Vin-
mia, and esophageal webs), are becoming rare
in the developed world with the improvement
of overall nutrition. A role for human papillo-
ma virus (HPV) in esophageal squamous cell
carcinoma is debatable. HPV DNA detection
rates are insignificant (0 to 2 percent) in some

38

Figure 2-30
SQUAMOUS CELL CARCINOMA
Left: The appearances are those of squamous cell carcinoma throughout the body.
Right: Keratin pearls are present.
studies from low incidence areas (29,30). On the
other hand, in a study from Mexico, an area of
low tumor incidence, high risk HPV DNA was
detected in 25 percent of esophageal squamous
cell carcinomas (31) and rates of up to 50 per-
cent are reported. The rate in the United States
is on the order of 10 percent (32).
Squamous carcinomas are often found in
the middle third of the esophagus. On imaging
studies, the presence of an esophageal mass in
the middle third of the esophagus is formed
by squamous cell carcinoma until proven
otherwise, but there are no specific radiologic
features of this type of tumor. Multifocality is
not uncommon.
On biopsies, esophageal squamous carcino-
mas of the esophagus appear similar to squamous
carcinomas elsewhere (fig. 2-30). They are usually
well differentiated with prominent keratiniza-
tion but can be basaloid, spindled, papillary or
verrucous; the latter is virtually impossible to
diagnose on superficial samples and based only
on histologic features. Spindle cell squamous cell
Barrett's Esophagus and Esophageal Neoplasms
carcinomas tend to present as a polypoid masses.
Squamous cell carcinomas of the esophagus,
like squamous carcinomas in other sites, express
p63, p40, and CKS/6. When these carcinomas
are spindled, melanoma and sarcomas must be
excluded but it is important to remember that
most spindle cell lesions of the esophagus are sar-
comatoid squamous cell carcinomas. Sampling
as much of the overlying squamous mucosa
as possible can sometimes disclose an in situ
component or a zone of conventional-appearing
squamous cell carcinoma.
OTHER ESOPHAGEAL LESIONS
Granular Cell Tumor
Granular cell tumors are rare. The most com-
mon sites for them are the tongue and skin (33).
A subset is multicentric and malignant histolog-
ic features and behavior are sometimes reported
(34). Those of the esophagus account for about 1
to 2 percent of all granular cell tumors (33), and
the esophagus is the commonest gastrointestinal
39
Survival Guide to Gastrointestinal Mucosal Biopsies

•, :·;
'
• ......... I
. ~
' \o
...·'·,••... ......-
'v • ~

' '
''
... · ".
' '
.•
': ..... ;, .....
'I
.~~~ .. '
~ ;:· ,.; ""

..
"'

. ~' _. -' "' - •t, , I I

' ~ ~~~ V
' .~ .
' ,;: .·.
t T ' ...
;· • '
•\· ,, I
'
' ..
.• -
...._ \ )
:
1 " ' ''

Figure 2-31
GRANULAR CELL TUMOR
Left: There is a proliferation of squamous epithelium overlying the lesion.
Right: The cells have granular cytoplasm and small pyknotic nuclei. Compare their sizes to those of the overlying
squamous basal cell nuclei.

site (35). Most arise in the distal esophagus and it is prudent to scan the lamina propria in bi-
about 5 to 10 percent are multicentric. There is opsy samples showing hyperplastic squamous
a female predominance and these tumors are epithelium.
overrepresented in Mrican-Americans compared Granular cell tumors express S-100 protein,
to whites. Rare cases require radical surgery but calretinin, inhibin alpha, myelin basic protein,
many are managed endoscopically. Rare histo- and CD68/Kp1, but not muscle markers and
logically malignant examples have been report- melanoma markers. Unfortunately, like alveolar
ed in the esophagus (36,37); there is a report of soft part sarcoma (ASPS), they can also react
a large cytologically bland example that spread with TFE3 antibodies.
to the liver (38).
Leiomyoma
The microscopic features of granular cell
tumor in the esophagus are identical to those Leiomyoma is the most common esophageal
at other sites. Esophageal granular cell tumors spindle cell tumor of the esophagus, arising in
are centered in the submucosa, with extensions a relatively young population (median age, 35
into mucosa and muscularis propria. They are years) (39) with a male predominance. Leiomy-
well-marginated but not encapsulated. They omas of the esophagus are, by definition, benign.
consist of plump closely packed cells with abun- They consist of cells with eosinophilic cytoplasm,
dant amphophilic granular cytoplasm (fig. 2-31). and are positive for desmin and alpha-smooth
Nuclei are small to pyknotic, with occasional muscle actin (alpha-SMA), and negative for CD117
nucleoli. Associated squamous ("pseudoepitheli- and CD34. The key pitfall in diagnosing esopha-
omatous") hyperplasia in the overlying mucosa geal leiomyomas is that if immunolabeling for
is common, which can raise the possibility of CD 117 and DOG 1 is performed, it highlights
squamous cell carcinoma on superficial biopsies. Cajal cells that are either entrapped or prolifer-
Often, since the squamous epithelium is thick, ate with the lesion (fig. 2-32). For this reason, a
only a few lesional cells are present on biopsies; confident morphologist eschews these stains.

40
 Barrett's Esophagus and Esophageal Neoplasms

.. .( .I
!•

..
I •

·. . I·
'
~
I
/

i'

..
'!
,
' .

. I • -·
f
" ' I .,
... I
'
/
~ :
. r

' .
. li) .·
Figure 2-32

ESOPHAGEAL LEIOMYOMA
A: The lesion is not particularly cellular, and consists of cells with small nuclei and brightly eosinophilic cytoplasm.
B: Note that the cytoplasm contains delicate longitudinal striations typical of smooth muscle differentiation.
C: This is a desmin stain of the lesion seen in "A" and "B."
D: This is a CD117 stain of the lesion seen in figures "A" and "B." Ignore the mast cells and incorporated Cajal cells.
With this morphology, there is no need to stain. Esophageal gastrointestinal stromal tumors are vanishingly rare and usually
overtly malignant.

41
Survival Guide to Gastrointestinal Mucosal Biopsies
REFERENCES
1. Shaheen N], Falk GW, Iyer PG, Gerson LB,
American College of Gastroenterology. ACG
clinical guideline: diagnosis and management
ofBarrett's esophagus. Am] Gastroenterol2016;
111:30-50; quiz 51.
2. Panarelli NC, Yantiss RK Do ancillary studies aid
detection and classification of Banett's esopha-
gus? Am] Surg Pathol 2016;40:e83-93.
3. Glickman ]N, Chen YY, Wang HH, Antonioli
DA, Odze RD. Phenotypic characteristics of a
distinctive multilayered epithelium suggests that
it is a precursor in the development of Barrett's
esophagus. Am] Surg Pathol2001;25:569-578.
4. Fitzgerald RC, di Pietro M, Ragunath K, et al.
British Society of Gastroenterology guidelines
on the diagnosis and management of Barrett's
esophagus. Gut 2014;63:7-42.
5. American Gastroenterological Association,
Spechler S], Sharma P, Souza RF, Inadomi ]M,
Shaheen N]. American Gastroenterological As-
sociation medical position statement on the
management of Barrett's esophagus. Gastroen-
terology 2011;140:1084-1091. .
6. Ronkainen], Aro P, Storskrubb T, et al. Prevalence
of Barrett's esophagus in the general popula-
tion: an endoscopic study. Gastroenterology
2005;129: 1825-1831.
7. Sikkema M, de ]onge P], Steyerberg EW, Kui-
pers EJ. Risk of esophageal adenocarcinoma and
mortality in patients with Banett's esophagus: a
systematic review and meta-analysis. Clin Gas-
troenterol Hepatol 2010;8:235-244; quiz e232.
8. Kroep S, Lansdorp-Vogelaar I, Rubenstein JH,
et al. An accurate cancer incidence in Barrett's
esophagus: a best estimate using published data
and modeling. Gastroenterology 2015;149:577-
585; quiz e514-575.
9. Vaughan TL, Fitzgerald RC. Precision preven-
tion of oesophageal adenocarcinoma. Nat Rev
Gastroenterol Hepatol 2015;12:243-248.
10. Montgomery EA, Bronner MP, Goldblum JR, et
al. Reproducibility of the diagnosis of dysplasia
in Barrett's esophagus: a reaffirmation. Hum
Pathol 2001;32:368-3 78.
11. Vieth M, Montgomery EA, Riddell RH. Observa-
tions of different patterns of dysplasia in Barrett's
esophagus-a first step to harmonize grading.
Cesk Patol2016;52:154-163.
12. Reid B], Haggitt RC, Rubin CE, et al. Observer
variation in the diagnosis of dysplasia in Banett's
esophagus. Hum Pathol 1988;19:166-178.
13. Abraham SC, Wang H, Wang KK, Wu TT. Paget
cells in the esophagus: assessment of their
42
histopathologic features and near-universal as-
sociation with underlying esophageal adenocar-
cinoma. Am] Surg Pathol2008;32:1068-1074.
14. Lomo LC, Blount PL, Sanchez CA, et aL Crypt
dysplasia with surface maturation: a clinical, patho-
logic, and molecular study of a Barrett's esophagus
cohmt. Am] Surg Pathol2006;30:423-435.
15. Rucker-Schmidt RL, Sanchez CA, Blount PL, et al.
Nonadenomatous dysplasia in Barrett's esophagus:
a clinical, pathologic, and DNA content flow cyto-
metric study. Am] Surg Pathol2009;33:886-893.
16. Mahajan D, Bennett AE, Liu X, Bena], Bronner
MP. Grading of gastric foveolar-type dysplasia in
Banett's esophagus. Mod Pathol 2010;23:1-11.
17. Pech 0, May A, Manner H, et al. Long-term effica-
cy and safety of endoscopic resection for patients
with mucosal adenocarcinoma of the esophagus.
Gastroenterology 2014; 146:652-660.
18. Shaheen NJ, Sharma P, Overholt BF, et al. Radio-
frequency ablation in Barrett's esophagus with
dysplasia. N Engl] Med 2009;360:2277 -2288.
19. Spechler S], Fitzgerald RC, Prasad GA, Wang KK.
History, molecular mechanisms, and endoscopic
treatment of Banett's esophagus. Gastroenterol-
ogy 2010;138:854-869.
20. Bronner MP, Overholt BF, Taylor SL, et al. Squa-
mous overgrowth is not a safety concern for
photodynamic therapy for Barrett's esophagus
with high-grade dysplasia . Gastroenterology
2009;136:56-64; quiz 351-352.
21. Terheggen G, Horn EM, Vieth M, et al. A ran-
domised trial of endoscopic submucosal dissec-
tion versus endoscopic mucosal resection for
early Barrett's neoplasia. Gut 2017;66:783-793.
22. Agoston AT, Strauss AC, Dulai PS, et al. Predictors of
treatment failure after radiofrequency ablation for
intramucosal adenocarcinoma in Barrett's esoph-
agus: a multi-institutional retrospective cohort
study. Am] Surg Pathol2016;40(4):554-562.
23 . Krishnamomthi R, Singh S, Ragunathan K, A Katzka
D, KWangK, G Iyer P. Risk ofrecunence ofBanett's
esophagus after successful endoscopic therapy.
Gastrointest Endosc 2016;83:1090-1106.
24. Abraham SC, Krasinskas AM, Correa AM, et al.
Duplication of the muscularis mucosae in Bar-
rett's esophagus: an undenecognized feature and
its implication for staging of adenocarcinoma.
Am] Surg Pathol 2007;31:1719-1725.
25 . Lewis]T, Wang KK, Abraham SC. Muscularis mu-
cosae duplication and the musculo-fibrous anom-
aly in endoscopic mucosal resections for Barrett's
esophagus: implications for staging of adenocarci-
noma. Am] Surg Pathol2008;32:566-571.

26. Singhi AD, Arnold CA, Crowder CD, Lam-Himlin
DM, Voltaggio L, Montgomery EA. Esophageal
leukoplakia or epidermoid metaplasia: a clinico-
pathological study of 18 patients. Mod Pathol.
2014;27(1):38-43 .
27. Taggart MW, Rashid A, Ross WA, Abraham SC.
Oesophageal hyperkeratosis: clinicopathological as-
sociations. Histopathology. 2013;63(4):463-473.
28. Singhi AD, Montgomery EA. Genetic alterations
in epodermoid metaplasia of the esophagus and
the associated neoplasms. JOURNAL?? 2017.
29·. Turner JR, Shen LH, Crum CP, Dean PJ, Odze
RD. Low prevalence of human papillomavirus
infection in esophageal squamous cell carcino-
mas from North America: analysis by a highly
sensitive and specific polymerase chain reaction-
based approach. Hum Pathol1997;28:174-178.
30. Poljak M, Cerar A, Seme K. Human papillomavi-
rus infection in esophageal carcinomas: a study
of 121 lesions using multiple broad-spectrum
polymerase chain reactions and literature review.
Hum Pathol 1998;29:266-271.
31. Herrera-Goepfert R, Lizano M, Akiba S, Car-
rillo-Garcia A, Becker-D' Acosta M. Human
papilloma virus and esophageal carcinoma in
a Latin-American region . World J Gastroenterol
2009;15:3142-3147.
32. Syrjanen K. Geographic origin is a significant
determinant of human papillomavirus preva-
lence in oesophageal squamous cell carcinoma:
systematic review and meta-analysis. Scand J
Infect Dis 2013;45:1-18.
Barrett's Esophagus and Esophageal Neoplasms
33 . Lack EE, Worsham GF, Callihan MD, et al. Granu-
lar cell tumor: a clinicopathologic study of 110
patients. J Surg Oncol1980;13 :301-316.
34. Fanburg-Smith JC, Meis-Kindblom JM, Fante R,
Kindblom LG. Malignant granular cell tumor of
soft tissue: diagnostic criteria and clinicopathologic
correlation. Am] Surg Pathol1998;22:779-794.
35. Johnston ], Helwig EB. Granular cell tumors of
the gastrointestinal tract and perianal region: a
study of 74 cases. Dig Dis Sci 1981;26:807-816.
36. Ohmori T, Arita N, Uraga N, Tabei R, Tani M,
Okamura H. Malignant granular cell tumor of
the esophagus. A case report with light and
electron microscopic, histochemical, and im-
munohistochemical study. Acta Pathol Jpn
1987;37:775-783.
37. Yoshizawa A, Ota H, Sakaguchi N, et al. Ma-
lignant granular cell tumor of the esophagus.
Virchows Arch 2004;444:304-306.
38. Christopher PR, Kingsley PA, Singh Bedi H,
Singh Kwatra K, Rathore S, Das KC. Large Mid-
esophageal granular cell tumor: benign versus
malignant. Rare Tumors 2015;7:5772.
39 . Miettinen M, Sarlomo-Rikala M, Sobin LH, La-
sota]. Esophageal stromal tumors: a clinicopath-
ologic, immunohistochemical, and molecular
genetic study of 17 cases and comparison with
esophageal leiomyomas and leiomyosarcomas.
Am J Surg Pathol 2000;24:211 -222.
43
 3 NON-NEOPLASTIC STOMACH
There are many obscure causes of gastritis, but
most stomach biopsies can be addressed by pay-
ing attention to just a few features in each and
every case. In many centers in the United States,
the majority of gastric biopsies are essentially
normal. For example, in the population having
gastric biopsies at]ohns Hopkins, H. pylori is only
detected in 6 percent (1) and autoimmune gastri-
tis in about 2 to 3 percent (2,3). There are a few
unusual types of gastritis also encountered but
most samples show normal histologic features
or minimal alterations. All biopsies, however,
should be scanned carefully since it is easy to
overlook tiny foci of signet ring cell carcinoma.
There are several patterns of gastritis and gas-
tropathy that can be recognized but the first step
is to understand the difference between the mu-
cosa of the body and fundus (oxyntic mucosa)
and that of the antrum, which appears similar to
that of the cardia but differs in important ways.
The questions that should be posed as a gastric
biopsy is evaluated are as follows:
WHAT TYPE OF GASTRIC
MUCOSA IS PRESENT?
Normal antral mucosa consists of surface
foveolar cells and antral glands that are re-
plete with neutral mucin but their cytoplasm
'· •• ,,.
•.
.:._:,..•
. :. ·-,.:~"-.
has a more bubbly appearance compared to
the crisply delineated apical mucin caps that
characterizes surface foveolar cells throughout
the stomach. Overall, the antrum appears very
similar to the cardia but differs by having a more
organized architecture and by the endocrine cell
constituents (figs. 3-1, 3-2). Most importantly,
antral mucosa produces gastrin via the G cells
and the cardia does not. Gastrin from the antrum
stimulates enterochromaffin-like (ECL) cells in
the gastric body and fundu s to produce hista-
mine, which in turn stimulates parietal cell to
secrete acid for digestion. Gastrin also has a tro-
phic effect on parietal cells and is necessary to
maintain them in good working order. Some of
the antral endocrine cells secrete somatostatin
(D cells), but this is not of much interest for the
purpose of interpreting gastric biopsies. There
should be only sparse lymphocytes, plasma
cells, and eosinophils in the lamina propria of
the stomach and a few intraepitheliallympho-
cytes. It should be difficult to find apoptotic
bodies in the pits. There should only be 1 or
possibly 2 in a pinch biopsy (4).
As noted in chapter 2, mucosa from the gas-
tric body has a surface with foveolar cells and
complex pits. The pits contain parietal and chief
cells. Between the pits and the surface are mucus
Figure 3-1
ANTRAL MUCOSA
At low magnification, there
is only minimal inflammation
in the lamina propria. Th ere
are surface fov eolar cells and
mucin-producing antral glands
in the bottom of the im age.
This exa mple has slight reactive
changes but it lacks significant
findings. There is no muscularis
mucosae in the sample.
45
 Survival Guide to Gastrointestinal Mucosal Biopsies

•• • I

. ... ,.
. , ·: .:... ·.··:.·. ....
. .,
·.>

' ' \I ,. I ..
. _. ' • ' 1, i- : .
, , I\

Figure 3-2
ANTRAL MUCOSA
Left: This is a chromogranin stain. It labels G cells, which secrete gastrin and D cells, which secrete somatostatin.
Right: This is a gastrin stain. It labels cells situated in between the antral glands at the base and the surface foveolar cells.

neck cells, which have a proclivity to resemble

Figure 3-3
CRUSHED OXYNTIC MUCOSA
The crushed parietal cells have formed an eosinophilic
sludge in the midst of which crushed mucus neck cells
reside. In the clusters at the upper right and center,
their appearance is reminiscent of that of signet ring cell
carcinoma cells but they are smaller and not in intact
lamina propria.
signet ring cell carcinoma in crushed biopsies
(fig. 3-3). The endocrine cells, as above, secrete
histamine in order to entice the parietal cells
to secrete acid. A common finding in biopsies
of oxyntic mucosa is the alterations associated
with proton pump inhibitor therapy (fig. 3-4).
Similarly, sometimes there are unusual vacu-
olated cell changes that are probably also related
to these medications (fig. 3-5) (5). These effects
need not be reported, but can be striking, con-
sisting of plump apocrine like parietal cells and
dilated oxyntic glands.
The transitional mucosa is found where the
antral and oxyntic mucosa meet, and features
parietal and chief cells as well as a few antral
type glands (fig. 3-6). The architecture should
be orderly. Knowing these normal features is
important because when stomach biopsies are
examined, it is important to decide if parietal
cells have been lost if a sample is derived from
the gastric body or fundus.
IS THE MUCOSA INFLAMED?
Uninflamed Mucosa. If the mucosa shows
scarcely any lamina propria inflammation at
low magnification, it is probably normal if it is

46
 Non-Neoplastic Stomach

l'\f
..'' ~-·.,'.' ~j

Figure 3-4 Figure 3-5

OXYNTIC MUCOSA WITH OXYNTIC MUCOSA WITH VACUOLATED
PROTON PUMP INHIBITOR EFFECT CELL CHANGE IN PARIETAL CELLS
The cytoplasm of the pink parietal cells has an apocrine This appearance can be alarming. This finding may
appearance. also be associated with proton pump inhibitors.

Figure 3-6
TRANSITIONAL MUCOSA
Left: There are foveolar cells at the surface and antral glands at the base, but scattered parietal and chief cells can be seen
in the zone between the base and surface of the mucosa. The overall architecture of the mucosa is well organized and there
is minimal lamina propria inflammation .
Right: This image allows brightly eosinophilic parietal cells to be readily recognized but there are antral glands composed
of cells with bubbly mucinous cytoplasm at the base. The surface cells each have an apical mucin cap. Knowledge of the
appearances of these cells types is useful when gastric neoplasms are encountered.

47
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 3-7
CHEMICAL GASTROPATHY
A: The basic architecture of the antral
mucosa is maintained but the foveolar
type glands at the surface have a corkscrew
configuration.
B: This example is particularly striking.
The mucin loss in the foveolar cells results
in a high nuclear to cytoplasmic ratio but
the architecture is maintained. There is
only mild lamina propria inflammation
and many of the nuclei seen at low
magnification are stromal cell nuclei.
C: This is the surface of the lesion seen
in "B." The nuclei are enlarged but their
nuclear membranes are smooth. Another
name for this type of injury is reactive
gastropathy.

oxyntic mucosa. If it is antral mucosa, the most
likely findings is so called reactive gastropathy
or chemical gastropathy (figs. 3-7, 3-8). Some
observers refer to this pattern as chemical gastritis
even though there is minimal inflammation.
Reactive gastropathy is associated with nonste-
roidal anti-inflammatory drug (NSAID) use (6)
and bile reflux. Persons with Barrett's esophagus
tend to reflux their duodenal contents into their
stomachs, and this refluxate in turn passes into
the esophagus. A reactive gastropathy (chemi-
cal gastropathy/gastritis pattern) is observed in
these people and is quite common. The findings
consist of foveolar cell mucin loss, proliferation
of the foveolar glands imparting a corkscrew
configuration to them, and the presence of
smooth muscle cells in the lamina propria.
Some patients with portal hypertension
display this pattern associated with vascular
ectasia (fig. 3-9) without fibrin thrombi. If fibrin
thrombi are present, the key consideration is
so-called watermelon stomach (7), based on the
endoscopic appearance that is reminiscent of
the outside of a watermelon (stripes) (figs. 3-10).
This condition is probably related to mucosal
prolapse but patients present with anemia and

48
 Non-Neoplastic Stomach

. - . _-·...
...

-
' -' ... - - . '• ,· - ~··..:~~
Figure 3-8
EROSIVE CHEMICAL GASTROPATHY
Left: An erosion refers to necrosis that involves part of the mucosa (the mucosa consists of the epithelium, lamina propria
and muscularis mucosae) whereas an ulcer describes injury that extends into the submucosa or deeper. This example shows
striking reactive epithelial changes.
Right: This is a higher magnification of the lesion seen on the left. The degree of cytologic atypia raises the possibility
of malignancy but note that the architecture is intact. The nuclear to cytoplasmic ratio of the cells is only mildly increased .

Figure 3-9
PORTAL GASTROPATHY
Left: At a glance this process is very much like that of chemical gastropathy but the presence of the dilated lamina propria
vessels suggests portal hypertension.
Right: The lamina propria smooth muscle is a feature of chemical gastropathy but the dilated capillary to th e left of the
smooth muscle is a feature of portal gastropathy.

49
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 3-10
GASTRIC ANTRAL VASCULAR ECTASIA (WATERMELON STOMACH)
Left: This endoscopic image shows erythematous stripes in the antral mucosa, an appearance reminiscent of the pattern
of stripes on a watermelon rind.
Right: The appearance is similar to th_at of chemical or portal gastropathy but differs by featuring fibrin thrombi, as seen
in the lower right part of the field.

tend to be older women with collagen vascular
diseases. Some of them require mucosal ablation
or even resection to control their anemia. The
mucosa of the antrum features fibrin thrombi.
Curiously, hemosiderin is absent.
Sometimes a chemical gastropathy pattern
can be accompanied by acute inflammation or
erosions or ulcers but there is minimal chron-
ic inflammation (fig. 3-8). Reactive epithelial
changes can be striking but the normal archi-
tecture of the glands is preserved. An erosion
is an injury that results in damage to some of
the mucosal layer whereas an ulcer penetrated
into the submucosa. A cause of normal appear-
ing body mucosa that belies a true condition
is gastric siderosis, which can result from iron
overload due to hemochromatosis or from mul-
tiple transfusions. The appearance is quite subtle
but it is a good practice habit to check for it in
deep pits (fig. 3-11) (8). The pattern contrasts
sharply with that of iron pill gastritis, in which
the findings are mostly in the surface gastric
epithelium with some deeper extension, and
reactive epithelial changes tend to be prominent
(fig. 3-12) (9).
Inflamed Mucosa. Are both oxyntic and
antral mucosa present in the sample and do
the site agree with the sample label provided
by the endoscopist?
Although there are many causes of gastritis,
those commonly encountered in a United States
population are Helicobacter pylori gastritis and
autoimmune gastritis. Helicobacterpylori gastritis
is more common than autoimmune gastritis but
both are regularly encountered in daily practice.
As above, in the population at ]ohns Hopkins,
about 6 percent of gastric biopsies show infec-
tion with H. pylori gastritis and 2 to 3 percent
show autoimmune gastritis.
H. PYLORI GASTRITIS
H. pylori gastritis results in a superficial pattern
of lamina propria chronic inflammation, some
acute inflammation in the pits, and tends to af-
fect the antrum more than the body (figs. 3-13).
Some patients have infection with an alternate
species, H. heilmannii (figs. 3-14), which produces
a less dramatic gastritis than H. pyloli (10), and
seems to be associated with exposure to house
cats. After treatment, organisms tend to "hide"

so
 Non-Neoplastic Stomach

- ,. .. ,.
• -
.,.,
.. >· ,·

• ,' '·· ...

.:.
~
I
.:
> •
'
•
..
1

c
Figure 3-11
GASTRIC SIDEROSIS
A: The appearance is unremarkable at low power. This condition is seen in oxyntic mucosa.
B: This is high magnification of the deep portion of the biopsy seen in "A." Note the brownish hemosiderin granules.
This sample was from a patient who had received multiple blood transfusions but these findings can also accompany
hemochromatosis.
C: This is an iron stain. Note the bottom heavy staining qualities.

51
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 3-12
·''
IRON PILL GASTRITIS
,·.
.,..;l"
A: The iron is m ostly deposited at th e surface and is ))J
go lden brown. ! '\
•'
B: Note the striking associated reactive epithelial changes.
C: This is a periodic acid-Schiff (PAS)/AB stai n, which
hi gh lights the gastric foveolar cells.
D: Since th e epithelia l cells sh owed strik ing reacti ve
changes, the conce rn fo r carcin o m a was rai sed. This
reticulin sta in shows investm ent of individual glands in
keeping with a reactive lesion rath er th an a carcinom a.
E: This is an iron stain. It con t rasts rem ark ably with th e
iro n stain from gastric siderosis (fig. 3-11 , right), showing
predo min ant ly extracellular iron.

.,.,.E-.

52
 Non-Neoplastic Stomach

Figure 3-13
HELICOBACTER PYLORI GASTRITIS
A: There is striking lamina propria chronic inflammation in this antral sample.
B: Organisms are adherent to th e surface foveolar cells in an area with abundant mucus.
C: Numerous organisms coa t the surface.
D: This is the gastric body from th e sa me patient as the one whose gastric antral body is seen in "A." It is far less inflamed.

53
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 3-14
HELICOBACTER HEILMANN/1 GASTRITIS
A: The organisms are longer and more
tightly coiled than those of H. pylori. They are
treated the same and result in similar 1isks.
B: This is a Diff Quik stain, which high-
lights the tightly coiled configuration of the
organisms.
C: This is an immunostain for H. pylori,
which cross reacts with H. heilmannii.

in the body, and immunolabeling may be required
to detect them. In general, it is not necessary to
perform "up front" testing for H. pylori since it is
readily seen on routine stains (11), but staining
biopsies that have inflammation in which no
organisms are detected can increase the yield (1).
Organisms are sought in areas of abundant mucus
associated with foveolar cells. It is a waste of time to
search for them in normal gastric mucosa. Organ-
isms are only detected if there is inactive chronic
gastritis or active chronic gastritis, rather than
simply lamina propria chronic inflammation.
Here are some definitions derived from a study
of H. pylori (1) : 1) chronic inflammation: increased
inflammation, primarily plasma cells, within the
lamina propria in a patchy loose distribution
without epithelial destruction. Review at 10x
magnification is required to identify clusters; 2)
inactive chronic gastJitis: dense lymphoplasmacyt-
ic lamina propria infiltrate readily identifiable
at 4x that infiltrates and destroys glands; and 3)
active chronic gastritis: neutrophilic infiltration of
the epithelium in addition to lymphoplasmacyt-
ic infiltration of the lamina propria.
Over time, persons with H. pylori gastritis can
develop intestinal metaplasia, primarily in the

54
 Non-Neoplastic Stomach

Figure 3-15
ANTRAL MUCOSA WITH INACTIVE CHRONIC GASTRITIS AND INTESTINAL METAPLASIA
Left: Generally H. pylori organisms are absent in zones of intestinal metaplasia and when intestinal metaplasia is prominent
in the antrum, organisms tend to be found instead in the body. This case is interesting because incomplete and complete
intestinal metaplasia are present in adjacent glands . The one at the top perfectly recapitulates small intestine and there is
even a brush border. The gland on the bottom with intestinal metaplasia shows both goblet cells and gastric foveolar type
cells such that is has incompletely transformed to intestinal epithelium . Epidemiologically, the incomplete type is more
likely to progress to adenoca rcinoma .
Right: Complete intestinal metaplasia is present in the gland at the top and incomplete intestinal metaplasia is found in
the gland at the bottom, with goblet cells interspersed with gastric foveolar cells.

antrum, but sometimes extending proximally. It
tends to be of the "complete" type, with changes
that recapitulate small intestine, including the
presence of a brush border (fig. 3-15).
AUTOIMMUNE GASTRITIS
Autoimmune gastritis (or autoimmune met-
aplastic atrophic gastritis; AMAG) results in
autoimmune damage to oxyntic glands with re-
sultant loss of the parietal cell mass and gradual
inability to absorb both iron (since the resultant
high gastric pH impedes iron absorption) and
vitamin B12. The condition is most common in
middle aged to elderly females, but men are not
spared. Many data suggest that it is triggered by
early H. pylori gastritis in the susceptible host.
Over time, patients become anemic, but their
lack of vitamin B12 leads to central nervous
system complications that can include paresthe-
sias, memory loss, and loss of balance (12,13).
They can be treated with large doses of vitamin
B12 (sometimes by intramuscular injection) to
prevent these complications.
Unfortunately, autoimmune gastritis is easy
to overlook (figs. 3-16, 3-17). The damage to
the parietal cells can result in biopsies that, at
a glance, resemble antrum, but to the trained
eye, the appearance is quite different from that
of antrum. The glands are disorganized and the
oxyntic glands become replaced by metaplastic
glands, namely intestinal metaplasia, pancreatic
metaplasia, and pyloric metaplasia. Some refer

55
 Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 3-16
AUTOIMMUNE GASTRITIS
A: This is the antral biopsy from a patient with autoimmune gastritis. It is normal. Note the surface foveolar cells and
deep antral glands that contain mucin.
B: This is a gastrin stain for the biopsy shown in" A." Note the orderly distribution of the G cells in the zone between the
antral deep glands and the surface foveolar type cells.
C: This is a biopsy of the gastric body. The parietal cells are gone and the glands that have replaced them are arranged in
a disorderly fashion. The inflammation is in the deep part of the sample where the oxyntic glands previously resided such
that th e antral type glands are metaplastic (pyloric metaplasia). Those features are all clues that this sample is not from the
true antrum should a sample be labeled in an unclear fashion.
D: This example shows prominent intestinal metaplasia and bottom heavy inflammation. This sample was from the
gastric body.

56
 Non-Neoplastic Stomach

,. '',J,>

Figure 3-17
AUTOIMMUNE GASTRITIS
A: The parietal cells are gone and replaced by disorganized metaplastic antral type glands (pyloric metaplasia) and
intestinal metaplasia.
B: This example shows pyloric and pancreatic acinar metaplasia . This biopsy from the gastric body lacks parietal cells.
C: This is a gastrin stain from the gastric body. It is wholly negative, which can be helpful in confirming that the sample
is from the gastric body. Note the disorganized metaplastic pyloric type glands.
D: This is a chromogranin stain from the sample that was stained for gastrin in "C." There is linear (>6 cells in a line) and
nodular enterochromaffinlike (ECL) cell hyperplasia. These are the cells that are stimulated by gastrin to secrete histamine,
which, in turn, stimulates parietal cells to secrete acid. Since parietal cells are absent, this feedback loop is interrupted and
the affected patients have hypergastrinemia.

57
 Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 3-1 8 .
GASTRIC TRANSITIONAL MUCOSA
IN A PATIENT WITH
EVOLVING AUTOIMMUNE GASTRITIS
A: There is inactive chronic gastritis and
this patient in fact had H. pylori gastritis
in addition to evolving autoimmune
gastritis. The H. pylori was detected on
an immunostain. Sometimes eradication
of H. pylori can forestall development of
autoimmune gastritis.
B: Parietal cells are present but the
inflammation is bottom heavy.
C: The deep glands are undergoing
destruction predominantly by lymphoid
cells, but focal acute gastritis is also present.

\··" ...' ' .' { ;:t.~; ..~: =:.,'

~~.~· -~.. ~..:-1 """ ·ti< • ::.:rc{v} · \, ..~.; · "" ·.... ·. . •· · ~~ ·· :~

r;.'>i-..~jt,'fr/;;'{f'~:\1~~~: ·-.· . "'.\'l~g
'";:-·-"··.;·.~!:{~J?-'-''/
~··· • he ~P' ikf"Y <'t f
v:~~~:.~E"tft :'
~~\ 11D.':o.,.
;"!~;·L .·~--.
~_!.:.' ~

to the last type as pseudopyloric metaplasia is full loss of parietal cells by noticing foci of
because there is no gastrin production. When damage to parietal cells (figs. 3-18, 3-19) .
learning to recognize this pattern, it can be The loss of parietal and chief cells in patients
helpful to perform gastrin labeling (a negative with autoimmune gastritis results in a loss of
gastrin stain confirms that the sample if from acid production. This in turn cases the antral
oxyntic mucosa that has lost its parietal cells G cells to secrete abundant gastrin in order to
rather than from the antrum) to recognize better stimulate acid production so the patient
the affected fragments when endoscopists put becomes hypergastrinemic. Since there are no
samples from both the body and antrum in the parietal cells, the hypergastrinemia does not
same container. Frequently the patient's antrum result in acid secretion. Gastrin exerts its effect
appears normal and the gastric body appears by stimulating the ECL cells of the gastric body
damaged. The inflammation is "bottom heavy". to secrete histamine, so hypergastrinemia in
It is possible to detect the findings before there these patients results in hyperplasia of ECL

58
 Non-Neoplastic Stomach

A-
...·' ·-
.:; • : ••· .. ;.+
., ,~· :~:- ...

:.
...,
....
•:
. .., .,,,
... ·.
·~

"'.~:1:
.· . :·.. <
• : .~ ...... -:./ • :! '!
J . '•,

.. -~-.... -i'

Figure 3-19
GASTRIC BODY MUCOSA IN A PATIENT WITH EVOLVING AUTOIMMUNE GASTRITIS
A: Lymphoid cells are attacking parietal cells at the lower right part of the image.
B: High magnification of the area in figure "A."
C: Note the damaged appearance of the parietal cells. Some are apoptotic.
D: ECL cell hyperplasia can be detected in such cases on chromogranin staining.

cells, which can ultimately lead to very indo-
lent well-differentiated neuroendocrine tumors.
Patients can have other types of polyps too (2) .
These changes happen over a period of many
years so there is usually ample chance to pre-
vent the neurodegenerative complications if the
findings are recognized .
However, if a report simply states "autoim-
mune gastritis," there is a good chance that the
colleague receiving the report will not be aware
of a need for vitamin B12 replacement or the
patient may only have iron deficiency. Because
of this, reports should probably indicate that the
patient may only have iron deficiency anemia

59
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 3-20
LYMPHOCYTIC GASTRITIS PATTERN
A: The lamina propria shows both
superficial and deep inflammation in this
antral biopsy. Celiac disease is a common
association with a lymphocytic gastritis
pattern.
B: There is mucin loss (a reactive
change) in the foveolar cells and striking
intraepitheliallymphocytosis.
C: Note the intraepitheliallymphocytosis
in both the surface epithelium and the
epithelium in the glands.

and that the patient is at risk for both pernicious
anemia arid various polyps and neoplasms (3).
The associated neoplasms and polyps are fea-
tured in chapter 4.
LYMPHOCYTIC GASTRITIS
This is a pattern of inflammation rather than
a real diagnosis. It simply indicates that there are
abundant intraepitheliallymphocytes in gastric
epithelium (fig. 3-20). It is strongly associated
with celiac disease (14), as well as with H. pylori
gastritis, and several medications, including
proton pump inhibitors and drugs in the class
of medications termed angiotensin receptor II
antagonists, the prototype of which is olme-
sartan (Benicar), and all of which are used as
antihypertension drugs (15).
IS THERE PROMINENT PIT APOPTOSIS?
Finding prominent pit apoptosis in gastric
samples always requires correlation with the
clinical history. The key causes: graft versus
host disease (usually unaccompanied by inflam-
mation), any of a large number of medications
(mycophenolate, idelalisib, many monoclonal
antibodies, angiotensin receptor II antagonists,
and many others) (15) . If the apoptosis is ac-
companied by abundant inflammation and loss
of glands, autoimmune pangastritis can also be
considered (it responds to steroids) (16) but it is

60

Figure 3-21
MYCOPHENOLATE-ASSOCIATED GASTRIC INJURY
There is striking pit apoptosis. This pattern can also
accompany graft versus host disease, viral infections, and a
host of other medications. Mycophenolate is administered
to persons who have had solid organ transplantation.
a diagnosis of exclusion. Prominent pit apopto-
sis is also likely in the setting of cytomegalovirus
infection (figs. 3-21-3-23) .
Collagenous gastritis is a poorly understood
condition that can manifest in children and
adults and is an immune disorder with many
associations, including medications (fig. 3-24).
The sample features prominent intraepithelial
lymphocytosis and a thick, irregular subepithe-
lial collagen table.
OTHER CONDITIONS
Finding prominent eosinophils in the epithe-
lium or muscularis mucosae is usually an allergic
condition (fig. 3-25) and may accompany eo-
sinophilic esophagitis. The normal number of
eosinophils in the lamina propria is not clear
and it probably varies geographically, but some
authors have suggested that finding more than
Non-Neoplastic Stomach
Figure 3-22
CYTOMEGALOVIRUS GASTRITIS
There is an apoptotic body in the pit at the lower right
but there are no viral inclusions in this field . When this
pattern is seen in a patient in whom a diagnosis of graft
versus host disease (GVHD) or medication-associated
gastropathy is being considered, it is important to also
consider cytomegalovirus infection. Apoptotic pit damage
is the hallmark of the findings associated with several
medications and is often also a prominent feature in
cytomegalovirus-associated injury.
30 eosinophils per high power field in at least
5 fields is abnormal (17).
Patients with renal failure often have disor-
ders of calcium metabolism, which can result in
deposition of calcium in their gastric mucosa,
which should not be mistaken for parasitic or-
ganisms (fig. 3-26). This differs from the injury
associated with doxycycline, which features
vessels with fibrinoid change (fig. 3-27) (18,19).
Lanthanum carbonate, administered to reduce
serum phosphate in renal failure patients, can
accumulate in histiocytes in the gastric lamina
propria and is illustrated in the small intestinal
chapter (20). Recall that patients with renal fail-
ure also develop hyperkalemia and are treated
61
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 3-23
CYTOMEGALOVIRUS GASTRITIS
Left: In most organs, cytomegalovirus preferentially infects endothelial cells but, in the stomach, epithelial cells are
frequently the target, as in this example. There is a background of gastritis and several enlarged nuclei are apparent.
· Right: There is an infected cell in the center with nucleomegaly and an intranuclear inclusion.

Figure 3-24
COLLAGENOUS GASTRITIS
Left: Note the striking thickness and irregularity of the subepithelial collagen.
Right: In addition to prominent subepithelial collagen, there is intraepitheliallymphocytosis.

62
 Non-Neoplastic Stomach

Figure 3-25
EOSINOPHILIC
GASTRITIS PATTERN
There are eosinophils present in
the muscularis mucosae, where they
are not a normal finding, and they are
numerous in the lamina propria.

Figure 3-26
MUCOSAL CALCINOSIS
Left: There is a background of antral mucosa with chemical gastropathy and numerous deposits of dystrophic calcium.
The variable size is against an interpretation as parasites.
Right: High magnification of the calcium deposits. These are found in patients with disorders of calcium metabolism so
most have renal failure, but occasionally, this pattern is seen in persons with parathyroid adenomas.

63
Survival Guide to Gastrointestinal Mucosal Biopsies

!·.· ·
.\ }
,·
,. ·~
'I '•
i .. ~

Figure 3-27
DOXYCYCLINE-ASSOCIATED INJURY
Left: Note the mineralized appearing surface of this oxyntic mucosa.
Right: The superficial capillaries have an appearance of fibrinoid necrosis.

with sodium polystyrene sultanate (kayexalate),
which can be associated with mucosal necrosis
throughout the gastrointestinal tract. It was il-
lustrated in chapter 1 (fig. 1-19) but can also be
encountered in gastric biopsies (21).
Gastric Crohn's disease can be virtually im-
possible to diagnose in the absence of pertinent
history but tends to be characterized by patchy
inflammation, as it is in the intestines (fig. 3-28).
Occasionally numerous Russell bodies are en-
countered in plasma cells in the gastric lamina
propria but most examples are incidental findings
unassociated with plasma cell disorders (fig. 3-29).
Amyloidosis can also affect the stomach (fig. 30).
Lastly, unusual infections can be encountered
in the stomach. In patients with gastric outlet
obstruction or other causes of gastric stasis
(such as diabetes), Sarcina ventriculi is an asso-
ciated organism. Treating it seems to alleviate
symptoms, but Koch's postulates have not been
fulfilled (fig. 3-31) (22). In men who have sex
with men (MSM) and are infected with human
immunodeficiency virus, syphilis gastritis is a
possibility (fig. 3-32) although syphilis is far
more likely to be encountered as an agent in
proctitis in MSM patients (23).

64
 Non-Neoplastic Stomach

--
Figure 3-28
GASTRIC CROHN'S DISEASE
Other than the granuloma,
the features are those of severe
act ive chronic gastritis and the
diagnosis can only be made as a
clinicopathologic correlation.

Figure 3-29
RUSSELL BODY GASTRITIS
Left: There are numerous lamina propria plasma cells with prominent cytoplasmic immunoglobulin (Russell bodies).
This is usually an incidental finding.
Right: This is a PAS/ AB stain. Immunoglobulin is PAS positive, which can result in a concern for carcinoma.

65
Swvival Guide to Gastrointestinal Mucosal Biopsies

Figure 3-30
GASTRIC AMYLOIDOSIS
A: Note the abundant waxy deposition of amyloid in this gastric resection. The amyloid had formed a pseudotumor.
B: There is a foreign body response to the amyloid, with giant cell formation.
C: This is a kappa stain from the lesion depicted in "A" and "B."
D: This is a lambda stain from the lesion seen in "A" and "B.". The process appears to be lambda restricted and thus
reflects a plasma cell disorder.

66
 Non-Neoplastic Stomach

Figure 3-31
SARCINA VENTRICULI-ASSOCIATED GASTRITIS
Left: The bacteria are quite large and organized in tetrads that are reminiscent of the chambers of the heart. The organism
is believed to cause disease in ruminants (cattle especially) but may cause disease in persons with delayed gastric emptying
and gastric stasis.
Right: High magnification of the organisms.

Figure 3-32
SYPHILIS GASTRITIS
Left: The inflammation is bottom heavy and has produced a destructive gastropathy.
Right: The lamina propria is expanded with plasma cells and there is apoptotic damage to the pits.

67
Survival Guide to Gastrointestinal Mucosal Biopsies
REFERENCES
1. PittrnanME, KhaiarjianA, WoodLD, Montgomery
EA, Voltaggio L. Prospective identification of Heli-
cobacter pylori in routine gastric biopsies without
reflex ancillary stains is cost-efficient for our health
care system. Hum Pathol2016;58:90-96.
2. Park ]Y, Cornish TC, Lam-Himlin D, Shi C,
Montgomery E. Gastric lesions in patients with
autoimmune metaplastic atrophic gastritis
(AMAG) in a tertiary care setting. Am] Surg
Pathol 2010;34: 1591-8.
3. Pittman ME, Voltaggio L, Bhaijee F, Robertson
SA, Montgomery EA. Autoimmune Metaplastic
atrophic gastritis: recognizing precursor lesions
for appropriate patient evaluation. Am ] Surg
Pathol 2015;39:1611-20.
4. Nguyen T, Park ]Y, Scudiere ]R, Montgomery
E. Mycophenolic acid (cellcept and myofortic)
induced injury of the upper GI tract. Am] Surg
Pathol 2009;33: 1355-63.
5. Rubio CA, Kato Y. Classification of vacu-
olated cells in the gastric mucosa. J Surg Oncol
1987;34:128-32.
6. Haber MM, Lopez I. Gastric hist-ologic findings
in patients with nonsteroidal anti-inflamma-
tory drug-associated gastric ulcer. Mod Pathol
1999;12:592-8.
7. Jabbari M, Cherry R, Lough]O, Daly DS, Kinnear
DG, Goresky CA. Gastric antral vascular ectasia:
the watermelon stomach. Gastroenterology
1984;87:1165-70.
8. Marginean EC, Bennick M, CyczkJ, Robert ME,
Jain D. Gastric siderosis: patterns and signifi-
cance. Am J Surg Pathol 2006;30:5 14-20.
9. Abraham SC, Yardley JH, Wu TT. Erosive injury
to the upper gastrointestinal tract in patients
receiving iron medication: an underrecognized
entity. Am] Surg Pathol1999;23:1241-7.
10. Jhala D, Jhala N, Lechago J, Haber M. Helicobacter
heilmannii gastritis: association with acid peptic
diseases and comparison with Helicobacter pylori
gastritis. Mod Pathol1999;12:534-8.
11. Batts KP, Ketover S, Kakar S, et al. Appropriate
use of special stains for identifying Helicobacter
pylori: Recommendations from the Rodger C.
Haggitt Gastrointestinal Pathology Society. Am
] Surg Pathol 2013;37:e12-22.
68
12. Stabler SP. Vitamin B12 deficiency. N Engl] Med
2013;368:2041-2.
13. Stabler SP. Clinical practice. Vitamin B12 defi-
ciency. N Engl] Med 2013;368:149-60.
14. Wu TT, Hamilton SR. Lymphocytic gastritis: as-
sociation with etiology and topology. Am] Surg
Pathol 1999;23:153-8.
15. Vieth M, Montgomery E. Medication-associ-
ated gastrointestinal tract injury. Virchows Arch
2017;470:245-266.
16. ]evremovic D, Torbenson M, MmTay JA, Burgart
LJ, Abraham SC. Atrophic autoimmune pangas-
tritis: a distinctive form of antral and fundic
gastritis associated with systemic autoimmune
disease. Am] Surg Pathol2006;30:1412-9.
17. Lwin T, Melton SD, Genta RM. Eosinophilic
gastritis: histopathological characterization and
quantification of the normal gastric eosinophil
content. Mod Pathol 2011;24:556-63.
18. Xiao SY, Zhao L, Hart], Semrad CE. Doxycycline-
induced gastric and esophageal mucosal injuries
with vascular degeneration. Am ] Surg Pathol
2013;37:1115-6.
19. Xiao SY, Zhao L, Ha.J.t], Semrad CE. Gastric mucosal
necrosis with vascular degeneration induced by
doxycycline. Am] Surg Pathol2013;37:259-63.
20. Haratake ], Yasunaga C, Ootani A, Shimajiri S,
Matsuyama A, Hisaoka M. Peculiar histiocytic
lesions with massive lanthanum deposition in
dialysis patients treated with lanthanum carbon-
ate. Am J Surg Pathol 2015;39:767-71.
21. Abraham SC, Bhagavan BS, Lee LA, Rashid A,
Wu TT. Upper gastrointestinal tract injury in
patients receiving kayexalate (sodium polysty-
rene sulfonate) in sorbitol: clinical, endoscopic,
and histopathologic findings. Am J Surg Pathol
2001;25:637-44.
22. Lam-Himlin D, Tsiatis AC, Montgomery E, et al.
Sarcina organisms in the gastrointestinal tract:
a clinicopathologic and molecular study. Am ]
Surg Pathol2011;35:1700-5.
23. Arnold CA, Limketkai BN, Illei PB, Montgomery
E, Voltaggio L. Syphilitic and lymphogranu-
loma venereum (LGV) proctocolitis: clues to a
frequently missed diagnosis. Am ] Surg Pathol
2013;3 7:38-46.
 4 GASTRIC POLYPS AND NEOPLASMS
Gastric polyps and neoplasms are very dif-
ferent from neoplasms in the small bowel and
colon and are somewhat akin to esophageal neo-
plasms since they usually arise in a background
of damaged mucosa. A key point is that many
gastric neoplasms arise in the setting of atrophic
gastritis. As such, if attention is paid to the back-
ground flat mucosa, it can be easier to diagnose the
polyps and neoplasms that arise. For example, the
following types of polyps and neoplasms, which
account for the majority of entities that can be
encountered, are associated with autoimmune
gastritis and H. pylori gastritis (1): 1) Hyperplas-
tic polyp: autoimmune and H. pylori; 2) Gastric
adenoma, pyloric type (pyloric gland adenoma):
autoimmune; 3) Gastric adenoma, intestinal
type: autoimmune and H. pylori; 4) Gastric ad-
enocarcinoma: autoimmune and H. pylori; 5)
Well-differentiated neuroendocrine (carcinoid)
tumor: autoimmune; and 6) Mucosa-associated
lymphoid tissue lymphoma: H. pylori.
Discussion of every possible neoplasm and
polyp is beyond the range of this slim volume,
but the commonest can be addressed.
POLYPS
Gastric polyps are common in gastrointes-
tinal biopsies. The term polyp simply means a
projection from the surface, and some are neo-
plasms, as opposed to hamartomas or reactive
nodules. Using data from a large commercial
laboratory, about 6 percent of patients undergo-
ing upper endoscopy have gastric polyps; most
(77 percent) are fundic gland polyps followed by
hyperplastic polyps/polypoid foveolar hyperpla-
sia (17 percent), adenomas (0.69 percent), and
inflammatory fibroid polyps (0.1 percent) (2).
Fundic Gland Polyps
There are two forms of fundic gland polyps
(FGPs): sporadic, and those associated with
familial adenomatous polyposis (FAP). Sporadic
FGPs are found in about 2 percent of routine
upper endoscopic examinations, usually in
middle-aged females. Most are small (a few
millimeters), sessile, and dome-shaped (fig. 4-1).
Sporadic FGPs are commonly multiple (usually
a few polyps). There are rare families who have
a variant of FAP termeci gastric adenocarcinoma
and proximal polyposis of the stomach (GAPPS)
(3). In contrast to hyperplastic polyps, FGPs are
not associated with any type of inflammatory
or atrophic background mucosal pathology and
are inversely correlated with H. pylori infection
(2). They are asymptomatic but some studies
suggest a temporal association between use of
proton pump inhibitors and the development
of FGPs (4). Some authors have questioned it
(5), but most believe that proton pump inhib-
itors prompt the development of fundic gland
polyps (6). Histologically, they consist of dilated
oxyntic glands that contain parietal cells with
apocrine-like snouts (fig. 4-2). Because it is
sometimes difficult to distinguish between these
two processes, correlation relies chiefly on the
presence of an endoscopic lesion.
Figure 4-1
FUNDIC GLAND POLYP
This endoscopic image features a pair of dome shaped
polyps.
69
Survival Guide to Gastrointestinal Mucosal Biopsies
Figure 4-2
FUNDIC GLAND POLYP
Left: The polyp arises in uninflamed oxyntic (fundic) mucosa, and is characterized by cystic dilation of the glands.
Right: The cysts are lined by parietal cells.
Hyperplastic Polyps
Hype1plastic polyps are the second most com-
mon gastric epithelial polyps (2,7). They can
range from a few millimeters to large masses that
mimic carcinoma. They are composed of hy-
perplastic, elongated, disorganized, and dilated
foveolae within an edematous, inflamed stroma
(fig. 4-3). Some have intestinal metaplasia, and
rare cancers arise in them (8). As for when to
diagnose foveolar hyperplasia versus hyperplas-
tic polyps, a simple approach can be taken: if a
polyp is seen at endoscopy and biopsy shows a
proliferation with prominent gastric foveolar
cells, hyperplastic polyp can be diagnosed. How-
ever, some such polyps simply reflect mucosal
prolapse, especially in the antrum (9).
Hyperplastic polyps can arise anywhere in the
stomach, with a slight preference for the antrum,
and appear in multiples in approximately 20
percent of cases. Though often considered to
arise as a result of inflammation due to reflux
of duodenal contents (and so called chemical
gastropathy) or gastritis, a study by Melton and
Genta (10) that included 330 of such polyps
and over 120,000 controls found no association
between gastric hyperplastic polyps and inflam-
70
matory or neoplastic processes. Regardless, in
other studies, they are most strongly associated
with atrophic gastritis of either autoimmune or
environmental (e.g., H. pylori-associated) types
(1). As discussed in more detail in chapter 2, the
diagnosis of autoimmune gastritis is suggested
histologicallywhen biopsies show corpus-predom-
inant gastritis, glandular atrophy, and intestinal,
pyloric, or pancreatic metaplasia (11).
Knowing these associations with background
mucosal pathology can be important since stom-
ach polyps encountered in patients with juvenile
polyposis or Peutz-Jeghers polyposis can appear
essentially identical to gastric hyperplastic polyps
(figs. 4-4, 4-5). Sadly, the best clue is knowledge
that the patient has one of those syndromes
diagnosed by small bowel or colon samples
(12,13). However, if there are available biopsies
of flat mucosa, the absence of atrophic gastritis
is a clue to a syndromic polyp.
Adenomas
Gastric adenomas are essentially polypoid
dysplasia and most are a result of inflammation,
which leads to metaplasia and neoplasia (14).
Most are associated with background atrophic
gastritis (either H. pylori-driven or autoimmune
 Gastric Polyps and Neoplasms

Figure 4-3
GASTRIC HYPERPLASTIC POLYP
Left: There is a disorganized proliferation of glands lined by foveolar cells.
Right: This unusual example harbors a gastric adenocarcinoma (left side of image) but the polyp itself on the right features
disorganized glands in edematous stroma lined by foveolar cells. ·

gastritis/pernicious anemia) and they have in-

testinal differentiation such that they resemble
colon adenomas. However, in contrast to colon
adenomas, they arise in abnormal background
mucosa that may also have flat dysplasia. In this
respect, they are very much like the previously
termed DALM (dysplasia-associated lesion or
mass) of ulcerative colitis or Crohn's colitis. Of
course most polyps in the colon are sporadic in
otherwise normal colons, which is very different
from the situation with stomach adenomas.
As above, gastric adenomas with intestinal
differentiation have goblet cells and appear
very similar to colorectal tubular adenomas (fig.
4-6). Some have admixed intestinal and gastric
type differentiation, and these seem more likely
to progress to adenocarcinoma that those that
have pure intestinal differentiation (15).
In patients with autoimmune gastritis, since
there is pyloric metaplasia, occasionally ade-
nomas with pyloric type differentiation are en-
countered (figs. 4-7, 4-8) (16-18). Like adenomas
with intestinal differentiation, pyloric gland Figure 4-4
adenomas can progress to adenocarcinoma.
GASTRIC JUVENILE POLYP
This type consists of closely packed tubules
This lesion is difficult to distinguish from a gastric
composed of cells with ground glass cytoplasm hyperplastic polyp but it arose in otherwise normal gastric
that lack either apical mucin caps like those seen mucosa in a patient known to have juven ile polyposis.

71
Survival Guide to Gastroirztestinal Mucosal Biopsies

Figure 4-5
GASTRIC PEUTZ-JEGHERS POLYP
A: This example shows arborizing cords of smooth muscle separating groups of gastric glands but were the endoscopist to
sample only the superficial parts of the polyp, the appearance would be indistinguishable from that of a hyperplastic polyp.
B: This is a periodic acid-Schiff (PAS)/ Alcian blue stain from the lesion shown in figure "A." It highlights the foveolar cells.
C: The cords of smooth muscle can be seen separating zones of gastric mucosa.
D: This is a high magnification of the base of a gastric Peutz-Jeghers polyp. It shows the smooth muscle component well.

72
 Gastric Polyps and Neoplasms

\ .•.

Figure 4-6
GASTRIC ADENOMA, INTESTINAL TYPE
Left: This is from a resection. The adenoma has an appearance similar to that of a colorectal tubular adenoma. This
particular example shows herniation of the adenoma glands into the submucosa (gastritis cystica profunda pattern). The
muscularis propria can be seen at the bottom of the image.
Right: This image is from a clinical polyp. The adenoma has high grade dysplasia with loss of nuclear polarity and goblet
cells. Were this sample taken from flat mucosa, the lesion would be classified as high grade dysplasia. Both polypoid and flat
gastric dysplasia nearly always arise in damaged gastric mucosa with metaplasia.

Figure 4-7
PYLORIC GLAND ADENOMA
When these polyps are encountered
in the stomach, there is frequently a
background of autoimmune gastritis
with pyloric metaplasia . These neoplasms
harbor GNAS mutations and consist of
closely packed tubules composed of cells
with basally placed nuclei in a monolayer
(rather than stratified as in intestinal
adenomas) with ground glass cytoplasm
that Jacks conspicuous mucin.

73
 Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 4-8
PYLORIC GLAND ADENOMA
Left: This image shows the nuclear and cytoplasmic characteristics.
Right: This example shows low grade dysplasia on the right and high grade dysplasia on the left. The nuclei at the left
have small nucleoli and some have lost t_heir polarity.

on foveolar cells or brush borders or goblet cell

type mucin. The nuclei are round and arranged
in a basal monolayer. Loss of polarity of these
cells indicates high-grade dysplasia.
Management of both intestinal type and
pyloric gland type adenomas requires complete
polypectomy and mapping biopsies of the flat
mucosa to assess for flat dysplasia.
On the other hand, there are gastric adenomas
that are quite rare, quite indolent and unlikely to
progress to gastric carcinoma. This is the gastric
foveolar type, which is essentially analogous to
sporadic colorectal adenomas. This rare type
arises in normal (usually oxyntic type) mucosa
and has pure gastric foveolar differentiation (fig.
4-9). It is most common in patients with familial
adenomatous polyposis. In fact, the fundic gland
polyps in patients with familial adenomatous
polyposis often have surface foveolar cells with
low grade dysplasia that appears identical to
gastric foveolar adenomas and these types can
· be impossible to separate. However, this is of no
consequence because gastric foveolar adenomas
and fundic gland polyps with surface dysplasia
never progress to cancer in the sporadic setting
(19) and only rarely do in syndromic cases.
ADENOCARCINOMA AND MIMICS
The estimate for 2016 was about 26,000 new
cases of gastric carcinoma (63 percent in men)
with about 11,000 deaths in the United States
(20). A wide geographic variation in incidence
of gastric cancer is known; high-risk areas in-
clude China,] apan, Eastern Europe, and parts of
South and Central America (21). Gastric cancer
is the fifth most common cancer worldwide
after cancers of the lung, breast, colorectum,
and prostate. This is major change since 1975,
when the stomach was the commonest site of
cancers worldwide.
Usually, diagnosing gastric cancer on mucosal
biopsies is not difficult, but there a few pitfalls.
In chapter 3, reactive changes that can mimic
dysplasia and early carcinomas are highlighted.
Additionally, xanthomas (fig. 4-10) and so-
called signet ring cell change (fig. 4-11) (22-25),
seen usually in mucosa with ulcers or ischemic
changes, are pitfalls to be aware of. Signet cell
change differs dramatically from the findings in
hereditary diffuse gastric cancer in patients with
CDHl (the gene that encodes for E-cadherin)
germline mutations (fig. 4-1 2).

74
 Gastric Polyps and Neoplasms

Figure 4-9
GASTRIC ADENOMA, GASTRIC FOVEOLAR TYPE
Left: This type of adenoma is rare in general but seen with some freq u ency in patients with familial adenomatous polyposis.
The surface foveo lar cells have dysplastic nuclei. The flat mucosa is uninflamed.
Righ t: This is the surface of the lesion seen on the left. Note that each cell has the usual apical mucin cap of a foveolar
cell but t h e nuclei are enlarged and hyperchromatic.

Figure 4-1 0

GASTRIC XANTHOMA
Left: These are incidental lesions.
Right: The lesion consists of lipid-laden macrophages.

75
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 4-11
SIGNET RING CELL CHANGE
A: In damaged columnar mucosa such as
this (with hemorrhage and ischemic injury),
when epithelial cells slough from the basement
membrane into the lumina, they round up and
become edematous, thereby mimicking the
appearance of the malignant cells in signet ring
cell carcinoma. However, they are not in the
tissue itself, but sloughed into the lumina and
the basement membranes are intact.
B: The sloughed damaged cells have an alanning
appearance but they are in the lumina rather than
in the lamina propria.
C: This e-cadherin stain highlights the cell
membranes of the damaged sloughed cells. 'J Q

There is massive lamina propria edema but the •·•it

concerning cells are not in the lamina propria.
~

Figure 4-12
IN SITU SIGNET RING CELL
CARCINOMA IN A PATIENT WITH
A CDH1 GERMLINE MUTATION
The lesion consists of tumor cells that
are situated between the normal epithelium
and the basement membrane in undamaged
mucosa.

76
 Gastric Polyps and Neoplasms

Figure 4-13
GASTRIC CARCINOMA
Left: This would conform to the classic intestinal type gastric adenocarcinoma, presenting as a bulky mass in gastric
mucosa. The spleen is at the top.
Right: This thickened stomach lacks a discrete mass and would be expected to have a diffuse type carcinoma that infiltrates
randomly through the tissue.

Adenocarcinomas of the stomach can have
intestinal differentiation as well as mixtures of in-
testinal and foveolar differentiation and pyloric
type differentiation but they are usually easy to
recognize as carcinomas. Poorly cohesive carci-
noma, some with signet ring morphology, can be
easy to overlook. The key is to study any area of a
gastric biopsy that shows architectural alterations
at low magnification (figs. 4-13-4-17).
Some neoplasms can be poorly differentiated
and are difficult to diagnose as carcinoma, lym-
phoma, melanoma, or even something else on
small biopsies. When this is the case, it is very
important to avoid performing a "shotgun" im-
munolabeling panel since the tissue may become
exhausted. Starting with a pankeratin, S-100
protein, and CD20 and additional unstained
sections is a good approach. Starting with specific
keratins (such as CK7 /CK20) will miss poorly
differentiated carcinomas. Expression of S-100
protein captures melanomas and CD20 captures
the most likely type of lymphoma (diffuse large
B cell lymphoma). Never order a vimentin. It
wastes the tissue and yields no information.
METASTATIC CARCINOMAS
The commonest metastases to the stomach
are from breast carcinoma, renal carcinoma,
and hepatobiliary carcinomas, but any type of
carcinoma can spread to the stomach (figs. 4-18,

77
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 4-14
GASTRIC CARCINOMA
A: There is a poorly differentiated carcinoma at the upper right. This cancer arose in the gastric body but note that there
are no parietal cells although there is some pancreatic acinar cell metaplasia in the lower center and lower right. Those
features indicate autoimmune gastritis. In general the adenocarcinomas arising in patients are of the intestinal type (and
thus appear similar to colorectal carcinomas), that is not invariably the case .
B: This is a subtle lesion, seen in scarred mucosa.
C: This is a high magnification of the area seen in the bottom right of figure B. The carcinoma cells are singly distributed
in the lamina propria. A residual damaged gland appears at the lower left and allows comparison with the nuclei of the
carcinoma cells, which contain cytoplasm with mucin vacuoles.

78
 Gastric Polyps and Neoplasms

-~
/t, t
'1 .
, /
...•
I'
•• ,
Figure 4 -15
GASTRIC CARCINOMA
A: At first glance, there appears to be chronic inflammation in the lamina propria but the cells are too large to be plasma cells.
B: This is high magnification of the lamina propria seen in A. The nuclei of the lamina propria smooth muscle cells at
the left center (from mucosal prolapse) offer a good internal size control, as do the epithelial cell nuclei.
C: This is an AEl/3 keratin stain from the lesion seen in A & B. It shows the raggedly infiltrating appearance of the
carcinoma.

79
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 4-16
GASTRIC CARCINOMA
A: This carcinoma has infiltrated into the omentum.
B: High magnification of the carcinoma seen in A.
C: This is a keratin stain of the carcinoma seen in A. The highlighted spindle cells (top left) are submesothelial cells that are
found beneath the mesothelial cells that coat the omentum. This staining can be a pitfall in nonneoplastic omental samples.

80
 Gastric Polyps and Neoplasms

Figure 4-17
GASTRIC CARCINOMA
Left: This is a DOG 1 stain. About a third of gastric adenocarcinomas and more esophageal adenocarcinomas express
DOGl. Beware on small samples!
Right: This is a KIT stain of the adenocarcinoma seen on the left.

4-19). The most important one to consider in
any patient in which a new diagnosis of gastric
carcinoma is contemplated is breast carcinoma,
particularly lobular carcinomas. Have a very low
threshold to perform GATA3 staining in a woman
in whom gastric carcinoma is considered.
NEUROENDOCRINE TUMORS
Though historically known as carcinoid
tumors, these are classified as well-differentiat-
ed neuroendocrine tumors (WDNET or NET G1,
neuroendocrine tumor, grade 1) by the World
Health Organization (WHO) (26). Using pre-
cise terminology, a "carcinoid" tumor is sero-
tonin-producing and is associated with clinical
evidence of carcinoid syndrome and hence the
well-differentiated neuroendocrine tumors ter-
minology has been adopted officially, but the
term "carcinoid" remains in widespread use.
Gastric WDNETs can be divided into three cat-
egories: 1) type 1: tumors associated with chronic
atrophic gastritis with hypergastrinemia (this is
the most common); 2) type 2: tumors associated
with Zollinger-Ellison syndrome or multiple
endocrine neoplasia (and thus with hypergastrin-
emia from a gastrinoma); and 3) type 3: sporadic
lesions (without hypergastrinemia).
Gastric WDNETs associated with hypergas-
trinemia (types 1 and 2) are relatively benign,
whereas sporadic lesions require aggressive sur-
gical management. Gastric WDNETs, however,
can be managed initially by endoscopic excision
of accessible tumors, evaluation of the setting in
which they have arisen, and follow-up by regu-
lar endoscopic surveillance. A striking increase
in gastric WO NETs over 50 years was reported in
2004, including an 800 percent increase in gas-
tric carcinoids in white women (27). However,
patients did not routinely undergo endoscopies
65 years ago and tiny WDNETs are commonly
found in women as a result of autoimmune
gastritis. They were not sought until recently.

81
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 4-18
PANCREATIC CARCINOMA THAT HAS SPREAD TO TH E GASTRIC ANTRUM
Left: This deceptively bland carcinoma at the bottom center of the biopsy consists of large aberrantly shaped glands.
Right: This is a SMAD4/DPC4 stain of the lesion seen on the left. There is loss of nuclear labeling in the malignant glands.

Figure 4-19
LUNG ADENOCARCINOMA METASTATIC TO THE STOMACH
Left: A few entrapped gastric glands are at the upper left. This metastasis superficially mimics a pyloric gland adenoma.
Right: This is a TTFl stain. The entrapped gastric mucosa lacks th e nuclear labeling.

82

As for the "white" women demographic, that
may reflect patterns of patient referral or the
demographics of the studied population; no
racial predilection was found among patients
with autoimmune gastritis in a large East coast
urban study, although females were much more
commonly affected than males (1).
Type 1 and type 2 carcinoids are essentially
a nuisance with little metastatic risk. Concern
with the size of a very early lesion is of no value.
There is no need to be concerned with neuro-
endocrine dysplasia versus neoplasia. The term
"tumor" can be used when the endoscopist sees
a nodule; there is no need to measure small pro-
Gastric Polyps and Neoplasms
Figure 4-20
TYPE 1 WELL-DIFFERENTIATED
NEUROENDOCRINE (CARCINOID) TUMOR
A: This neoplasm arose in the gastric body and is at the
bottom of the field. It displays a pseudoglandular pattern.
Note that the overlying gastric mucosa lacks parietal cells
since the patient has autoimmune gastritis.
B: This is a high magnification of the tumor seen in A.
C: This is a chromogranin stain from the tumor seen in
A. There is enterochromaffin-like (ECL) cell hyperplasia in
the overlying gastric mucosa.
liferations because it is not clinically important.
It is more important to determine the source of
the excess gastrin. This is accomplished by at-
tention to background gastric changes: atrophy
(fig. 4-20) versus hyperplasia of the acid-pro-
ducing cells. Hyperplasia of intact parietal cells
is the hallmark of Zollinger-Ellison syndrome,
in which there is a gastrin-secreting neoplasm
(often in the pancreas or duodenum). In such
a case the type 2 WDNET is gastrin negative on
immunolabeling since it is composed of ECL
cells whereas the gastrinoma of the pancreas or
duodenum expresses gastrin on immunolabel-
ing (figs. 4-21, 4-22).
83
Survival Guide to Gastrointestinal Mucosal Biopsies

{
\

t
J

Figure 4-21
TYPE 2 WELL-DIFFERENTIATED NEUROENDOCRINE (CARCINOID) TUMOR
A: This is not a gastric lesion. This is a duodenal gastrinoma in a patient with multiple endocrine neoplasia (MEN) I.
B: This is higher magnification of the neoplasm seen in A.
C: This is a gastrin stain of a duodenal gastrinoma.
D: This is a gastric lesion from a patient with the gastrinoma seen in A and B.

84
 Gastric Polyps and Neoplasms

In contrast, type 3 WDNETs (those that are the GI tract is the most common site for MALT
not associated with hypergastrinemia; fig. 4-23) lymphomas. MALT lymphoma accounts for
are likely to be metastatic at presentation (about about half of gastric lymphomas.
70 percent) and associated with patient deaths MALT lymphomas show lamina propria
in about 25 percent of patients. expansion with small uniform cells, some of
Mitotic activity or Ki-67 immunolabeling which have a "halo" around them (fig. 4-24). A
should be used for grading Type 3 tumors clue is that the muscularis mucosae is infiltrated,
(26,28): 1) G1: less than 2 mitoses/10 high
power fields or up to 2 percent Ki-67 index; and
2). G2: mitotic count 2 to 20 per 10 high power
fields or 3 to 20 percent Ki-67 index.
However, up to a third of type 1 WDNETs
show a Ki-67 index that reaches grade 2 and
yet they essentially never cause patient deaths
and only rarely metastasize as above (29). For
this reason, performing Ki-67labeling on type 1
WDNETs can result in misleading information.
Type 1 carcinoids (WDNETs) can express both
hormone receptors and GATA3 such that they
can masquerade as metastatic breast carcino-
mas. Since autoimmune gastritis affects the
same demographic group as metastatic breast
carcinoma, it is important to bear this in mind.
LYMPHOMAS

Mucosa-Associated Lymphoid
Tissue Lymphomas
Low-grade B-cell lymphomas of mucosa-asso-
ciated lymphoid tissue (MALT) are believed to
arise within organized lymphoid tissue in the
gastric mucosa that is most frequently acquired
in response to H. pylori infection. They are also Figure 4-22
termed "extranodal marginal zone lymphomas. " TYPE 2 WELL-DIFFERENTIATED
Overall, MALT lymphomas account for about 7 NEUROENDOCRINE (CARCINOID) TUMOR
to 8 percent of lymphomas throughout the body This negative gastrin stain is from the gastric type 2
and are less common than diffuse large B cell well differentiated neuroendocrine (ca rcinoid) tumor that
has resulted from the hypergastrinemia produced by the
lymphoma or follicular lymphoma. However, gastrinoma. This tumor is composed of ECL type cells.

Figure 4-23
TYPE 3 WELL-
DIFFERENTIATED
NEUROENDOCRINE
(CARCINOID) TUMOR
This lesion has arisen in
normal gastric body mucosa
in the absence of hypergas-
trinemia. This type tends to
be aggressive.

85
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 4-24
GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA
A: The lesion is deep in the mucosa and has destroyed the muscularis mucosae (at left) such that only a few eosinophilic
wisps remain.
B: The infiltrate has destroyed the pits (lymphoepitheliallesions) .
C: Note the monotonous appearance of the lymphoid cells. Many have a halo around them.
D: This cytokeratin stain highlights residual epithelial cells in so called lymphoepithelial lesions.

something that can be assessed at low magni-
fication. The classic "lymphoepithelial lesion,"
in which lymphocytes invade residual gland
epithelium, is not present in every case. Finding
an expansion of B cells in the deep mucosa ac-
companied by lymphoepithelial lesions allows
a confident interpretation. Numerous plasma
cells often indicate a reactive lesion (Helicobacter
gastritis). On immunophenotyping, there can
be CD20-reactive B cells that aberrantly express
CD43. A CD3 stain highlights normal admixed
T cells. Also, if one has mistaken the intraepi-
thelial T cells that can accompany celiac disease
(lymphocytic gastritis pattern), learning that the
intraepithelial cells are T cells rather than B al-
lows for consideration of alternate interpretations.

86

MALT lymphomas have the following profile:
CD20(+), CD79a (+), BCL2(+), CDS(-), CDlO(-),
CD23(-), CD43(+/-). The cells often express IgM;
immunoglobulin light chain restriction may be
encountered in cells having plasmacytoid differ-
entiation (26,30). The pitfall with plasmacytoid
MALT is that it can lack CD20 expression.
Only half of MALT lymphomas coexpress
CD20 and CD43, but the diagnosis can still
be made on a B-cell rich infiltrate with typical
morphology. It is important to document the
presence (or absence) of Helicobacter.
It is sometimes worthwhile to add CDS testing
to exclude chronic lymphocytic leukemia/small
lymphocytic lymphoma (CLL/SLL) since the B cell
Gastric Polyps and Neoplasms
Figure 4-25
LARGE B-CELL LYMPHOMA IN GASTRIC MUCOSA
A: The infiltrate is monotonous and highly cellular.
B: Such tumors often feature prominent apoptosis.
C: This is a CD20 immunostain.
lesions aberrantly eo-express CDS. CD10 can be
added since follicular lymphoma expresses CD10
and MALT lymphoma does not. Cyclin D1 (BCLl)
can be added, which labels the nuclei in mantle
cell lymphoma but not MALT lymphoma.
Treatment involves eradication of H. pylori ini-
tially and a few patients require other treatments.
For gastric lesions, radiation therapy is the most
common used. Many chemotherapy regimens
have been used but rarely as first line treatments.
These are summarized by Raderer et al. (31).
Most high grade gastric lymphomas are diffuse
large B-celllymphomas (DLBCL) (fig. 4-25), some
presumably tr·ansforming from MALT lymphomas.
The 2016 classification has separated DLBCL into
87
Survival Guide to Gastrointestinal Mucosal Biopsies
Figure 4-26
INFLAMMATORY FIBROID POLYP
Left: The tumor is centered in the antral submucosa and features scattered lymphoid aggregates.
Right: This is a CD34 stain.
germinal center B (GCB) cell type and activated
B cell (ABC) type as follows using immuno-
labeling although many oncologists prefer to
see results of gene expression profiling in order
to best manage patients (32). The reasoning is
that so-called GCB DLBCL is associated with a
better outcome than ABC type DLBCL. The ABC
type requires more aggressive treatment: GCB =
CD10+ OR CDlO-, BCL6+, and MUMl-; and ABC
= CDlO-, BCL6-, OR CDlO-, BCL6+ and MUMl +.
INFLAMMATORY FIBROID POLYP
Most of these tumors occur in the stomach,
where they account for up to 3 percent to 4
percent of all gastric polyps (7,33), but they
can arise throughout the gastrointestinal tract.
Patients with gastric examples were typically
60 to 80 years old, These polyps are quite rare
in children (34) . Most are antral. Presentation
is somewhat site-specific-small intestinal ex-
amples often lead to intussusception (35) or
obstruction, and gastric examples are found in
patients with pain, nausea, and vomiting. These
polyps were considered reactive in the past but
they harbor mutations in the platelet-derived
growth factor receptor alpha (PDGFRA) gene
(36), a feature that they share with a subset of
88
gastric gastrointestinal stromal tumors (GISTs).
In contrast to GISTs, inflammatory fibroid pol-
yps are always benign.
Inflammatory fibroid polyps arise in the sub-
mucosa and are well-marginated, but nonencap-
sulated. They are composed of uniform spindled
cells, mixed inflammatory cells, and prominent
vasculature (figs. 4-26, 4-27). The spindle cells
have amphophilic elongate cytoplasm and pale
nuclei, ranging from ovoid to spindle shape,
that display variable collagen deposition. Most
examples display a whorled, "onion skin" pro-
liferation around vessels, and all examples have
variable numbers of background eosinophils,
lymphocytes, and plasma cells. Mitoses are in-
frequent. These polyps express CD34 but lack
CD117 and DOGl expression.
GASTROINTESTINAL STROMAL
TUMORS (GISTS) OF THE STOMACH
The stomach is the most common site for
gastrointestinal stromal tumors (GISTs) and they
are occasionally diagnosed on mucosal biopsies
(fig. 4-28).
Overall, GISTs are the most common mesen-
chymal lesions throughout the entire GI tract
with two exceptions: leiomyomas outnumber
 Gastric Polyps and Neoplasms

Figure 4-27
INFLAMMATORY FIBROID POLYP
Left: This example happens to be associated with gastric intestinal type low grade dysplasia, which resembles a colorectal
adenoma, a very unusual finding in Western patients. However, note that the inflammatory fibroid polyp whorls around
the two superficial submucosal vessels in an onion skin fashion.
Right: The tumor cells are quite bland appearing and associated with eosinophils.

GISTs in both the esophagus and the colon (37).
The majority harbor either a KIT (CD117, a
receptor tyrosine kinase) or a PDGFRA (platelet
derived growth factor alpha) mutation. PDG-
FRA mutated GISTs are nearly always gastric
(37). Some GISTs lack both of these mutations,
especially those found in children and asso-
ciated with various genetic syndromes and
harbor different mutations that affect down-
stream signaling. With the exception of those
found in patients with neurofibromatosis type
1 (NF1), GISTs that lack KIT and PDGFRA mu-
tations nearly always affect the stomach. The
histologic appearance of the cells comprising
GISTs varies from spindled to epithelioid. GISTs
(including all sites) usually arise in adults over
age 50 (median age, 55 to 60 years) and are rare
in children (less than 1 percent). There is no
gender predilection overall, but there is a male
predominance for malignant GISTs. GISTs are
encountered throughout the gastrointestinal
tract: about 60 percent in the stomach, 35
percent in the small intestine, and less than 5
percent in the rectum, esophagus, omentum,
and mesentery; most GISTs found in the last
site are metastatic rather than primary. About
five percent of GISTs are found in patients
with neurofibromatosis type 1 (multiple small
intestinal tumors (38) and Carney triad (para-
ganglioma, GIST, and pulmonary chondroma,
usually in young females (39). Familial GISTs
arise in patients with inherited germline KIT or
PDGFRA mutations.
Most recently, succinate dehydrogenase defi-
cient GISTs have been described (40-54). These
tumors are restricted to the stomach and do
not conform to the typical risk stratification of
non-SDH deficient GISTs.

89
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 4-28

GASTROINTESTINAL STROMAL TUMOR (GIST)

A: These tumors nearly invariably arise in the muscularis propria so are seldom detected on mucosal biopsies, but there
are exceptions, as in this case.
B: This example extended into the submucosa, entrapping ganglion cells in the center right of the field.
C: This is a KIT stain from the neoplasm depicted in A and B.
D: This example features stunning paranuclear vacuoles. Note that the tumor cells have very uniform nuclei. When gastrointestinal
lTact spindle cell tumors have nuclear pleomorphism, it is important to consider alternative diagnoses to GIST.

90

About 20 percent of gastric GISTs are malig-
nant. The consensus is that 5 mitoses per 50
high-power fields (hpf) and >5 cm are adverse
prognostic factors (55,56). With current target-
ed therapy using imatinib as a first line drug
and sunitinib or regorafinib as second and third
line drugs, outcome has improved (57). In the
past, the 5 year survival for malignant GISTs
was on the order of 50 percent, whereas now it
is <;loser to 75 percent. Unfortunately about 80
percent of these tumors develop resistance to
the available drugs over time.
REFERENCES
1. Park ]Y, Cornish TC, Lam-Himlin D, Shi C,
Montgomery E. Gastric lesions in patients with
autoimmune metaplastic atrophic gastritis
(AMAG) in a tertiary care setting. Am ] Surg
Pathol 2010;34:1591-8.
2. Carmack SW, Genta RM, Schuler CM, Saboorian
MH. The current spectrum of gastric polyps: a
1-year national study of over 120,000 patients.
Am] Gastroenterol 2009;104:1524-32.
3. Li J, Woods SL, Healey S, et al. Point mutations
in Exon 1B of APC reveal gastric adenocarcinoma
and proximal polyposis of the stomach as a
familial adenomatous polyposis variant. Am ]
Hum Genet 2016;98:830-42.
4. Choudhry U, Boyce HW Jr, Coppola D. Proton
pump inhibitor-associated gastric polyps: a
retrospective analysis of their frequency, and
endoscopic, histologic, and ultrastructural char-
acteristics. Am] Clin Pathol1998;110:615-21.
5. Vieth M, Stolte M. Fundic gland polyps are not
induced by proton pump inhibitor therapy. Am
] Clin Pathol 2001;116:716-20.
6. Zelter A, Fernandez JL, Bilder C, et al. Fundic
gland polyps and association with proton pump
inhibitor intake: a prospective study in 1,780
endoscopies. Dig Dis Sci 2011;56:1743-8.
7. Stolte M, Sticht T, Eidt S, Ebert D, Finkenzeller
G. Frequency, location, and age and sex distribu-
tion of various types of gastric polyp. Endoscopy
1994;26:659-65.
8. Abraham SC, Singh VK, Yardley ]H, Wu TT. Hy-
perplastic polyps of the stomach: associations
with histologic patterns of gastritis and gastric
atrophy. Am] Surg Pathol2001;25:500-7.
9. Gonzalez-Obeso E, Fujita H, Deshpande V, et
al. Gastric hyperplastic polyps: a heterogeneous
Gastric Polyps and Neoplasms
Epithelioid GISTs are most likely to cause
diagnostic problems on mucosal biopsies,
because they are readily mistaken for a host
of epithelioid and epithelial neoplasms. It is
advisable to perform an immunohistochemi-
cal panel in assessing them to include CD 117 I
KIT, S-100 protein (to address melanoma) and
a cytokeratin stain to address signet cell carci-
noma. Remember that up to a third of gastric
carcinomas express DOG 1 (58) and melanomas
are likely to express CD 117.
clinicopathologic group including a distinct sub-
set best categorized as mucosal prolapse polyp.
Am] Surg Pathol 2011;35:670-7.
10. Melton SD, Genta RM. Gastric cardiac polyps: a
clinicopathologic study of 330 cases. Am] Surg
Pathol2010;34:1792-7.
11. Pittman ME, Voltaggio L, Bhaijee F, Robertson
SA, Montgomery EA. Autoimmune metaplastic
atrophic gastritis: recognizing precursor lesions
for appropriate patient evaluation. Am ] Surg
Pathol2015;39:1611 -20.
12. Lam-Himlin D, Park ]Y, Cornish TC, Shi C,
Montgomery E. Morphologic characterization
of syndromic gastric polyps. Am ] Surg Pathol
2010;34:1656-62.
13. Ma C, Giardiello FM, Montgomery EA. Upper
tract juvenile polyps in juvenile polyposis pa-
tients: dysplasia and malignancy are associated
with foveolar, intestinal, and pyloric differentia-
tion. Am] Surg Pathol 2014;38:1618-26.
14. Abraham SC, Montgomery EA, Singh VI<, Yardley
]H, Wu TT. Gastric adenomas: intestinal-type and
gastric-type adenomas differ in the risk of adeno-
carcinoma and presence of background mucosal
pathology. Am] Surg Pathol2002;26:1276-85 .
15. Park DY, Srivastava A, Kim GH, et al. Adenoma to us
and foveolar gastric dysplasia: distinct patterns
of mucin expression and background intestinal
metaplasia. Am] Surg Pathol2008;32:524-33.
16. Chen ZM, Scudiere]R, Abraham SC, Montgom-
ery E. Pyloric gland adenoma: an entity distinct
from gastric foveolar type adenoma. Am ] Surg
Pathol 2009;33: 186-93.
17. Vieth M, Kushima R, Borchard F, Stolte M. Pyloric
gland adenoma: a clinico-pathological analysis
of 90 cases. Virchows Arch 2003;442:317-21.
91
Survival Guide to Gastrointestinal Mucosal Biopsies
18. Vieth M, Montgomery EA. Some observations on
pyloric gland adenoma: an uncommon and long
ignored entity!] Clin Pathol 2014;67:883-90.
19. Genta RM, SchulerCM, Robiou Cl, Lash RH. No
association between gastric fundic gland polyps
and gastrointestinal neoplasia in a study of over
100,000 patients. Clin Gastroenterol Hepatol
2009;7:849-54.
20. Siegel RL, Miller KD, ]emal A. Cancer statistics,
2016. CA Cancer] Clin 2016;66:7-30.
21. Parkin DM, Bray F, Ferlay ], Pisani P. Global cancer
statistics, 2002. CA Cancer] Clin 2005;55:74-108.
22. Boncher ], Bronner M, Goldblum ]R, Liu X. Re-
ticulin staining clarifies florid benign signet ring
cell change with mitotic activity in a penetrating
gastric ulcer. Am] Surg Pathol 2011;35:762-6.
23. Cameselle-Teijeiro ], Abdulkader I, Forteza ].
Signet-ring cell change in pseudomembranous
colitis versus signet-ring cell carcinoma. Am ]
Surg Pathol 2004;28:1111.
24. Dimet S, Lazure T, Bedossa P. Signet-ring cell
change in acute erosive gastropathy. Am ] Surg
Pathol 2004;28: 1111-2.
25. Wang K, Weinrach D, Lal A, et al. Signet-ring cell
change versus signet-ring cell carcinoma: a com-
parative analysis. Am] Surg Pathol2003;27:1429-33.
26. Bosman F, Carneiro F, Hruban· R, et al. WHO
Classification of Tumours of the Digestive Sys-
tem. In: Bosman F, Jaffee E, Lakhani S, Ohgaki
H, eds. World Health Organization Classification
of Tumours. Lyon: IARC Press; 2010.
27. Modlin IM, Lye KD, Kidd M. A 50-year analysis
of 562 gastric carcinoids: small tumor or larger
problem? Am] Gastroenterol 2004;99:23-32.
28. Washington MK, Tang LH, Berlin ], et al. Pro-
tocol for the examination of specimens from
patients with neuroendocrine tumors (carcinoid
tumors) of the stomach. Arch Pathol Lab Med
2010;134:187-91.
29. Chen WC, Warner RR, Ward SC, et al. Manage-
ment and disease outcome of type I gastric neu-
roendocrine tumors: the Mount Sinai experience.
Dig Dis Sci 2015;60:996-1003.
30. Swerdlow S, Campo E, Harris NL, et al. WHO
Classification of Tumours of Haematopoietic and
lymphoid tissues. In: Bosman F,] affee E, Lakhani
S, Ohgaki H, eds. World Health Organization Clas-
sification of Tumours. Lyon: IACR Press; 2008.
31. Raderer M, Kiesewetter B, Ferreri A] . Clinico-
pathologic characteristics and treatment of
marginal zone lymphoma of mucosa-associated
lymphoid tissue (MALT lymphoma). CA Cancer
] Clin 2016;66:153-71.
32. Swerdlow SH, Campo E, Pileri SA, et al. The
2016 revision of the World Health Organization
classification of lymphoid neoplasms. Blood
2016;127:2375-90.
92
33. Stolte M, Finkenzeller G. Inflammatory fibroid
polyp of the stomach. Endoscopy 1990;22:203-7.
· 34. Righetti L, Parolini F, Cengia P, et al. Inflam-
matory fibroid polyps in children: A new case
report and a systematic review of the pediatric
literature. World] Clin Pediatr 2015;4: 160-6.
35 . Liu TC, Lin MT, Montgomery EA, Singhi AD.
Inflammatory fibroid polyps of the gastrointes-
tinal tract: spectrum of clinical, morphologic,
and immunohistochemistry features. Am] Surg
Pathol 2013;3 7:586-92.
36. Schildhaus HU, Cavlar T, Binot E, Buttner R,
Wardelmann E, Merkelbach-Bruse S. Inflamma-
tory fibroid polyps harbour mutations in the
platelet-derived growth factor receptor alpha
(PDGFRA) gene.] Pathol2008;216:176-82.
37. Miettinen M, Lasota ]. Gastrointestinal stro-
mal tumors. Gastroenterol Clin North Am
2013;42:399-415.
38. Miettinen M, Lasota]. Gastrointestinal stromal
tumors: review on morphology, molecular pa-
thology, prognosis, and differential diagnosis.
Arch Pathol Lab Med 2006;130:1466-78.
39. Carney ]A, Sheps SG, Go VL, Gm·don H. The
triad of gastric leiomyosarcoma, functioning
extra-adrenal paraganglioma and pulmonary
chondroma. N Engl] Med 1977;296:1517-8.
40. Belinsky MG, Rink L, van Mehren M. Succinate
dehydrogenase deficiency in pediatric and adult
gastrointestinal stromal tumors . Front Oncol
2013;3:117.
41. Bolland M, Benn D, Croxson M, et al. Gastroin-
testinal stromal tumour in succinate dehydro-
genase subunit B mutation-associated familial
phaeochromocytoma/paraganglioma. ANZJ Surg
2006;76:763-4.
42. Celestino R, Lima J, Faustino A, et al. Molecular
alterations and expression of succinate dehydro-
genase complex in wild-type KIT/PDGFRA/BRAF
gastrointestinal stromal tumors. Eur ] Hum
Genet 2013;21:503-10.
43 . Doyle LA, Hornick JL. Gastrointestinal stromal
tumours: from KIT to succinate dehydrogenase.
Histopathology 2014;64:53-67.
44. Doyle LA, Nelson D, Heinrich MC, Carless CL,
HornickJL. Loss of succinate dehydrogenase sub-
unit B (SDHB) expression is limited to a distinc-
tive subset of gastric wild-type gastrointestinal
stromal tumours: a comprehensive genotype-
phenotype correlation study. Histopathology
2012;61:801-9.
45 . Dwight T, Benn DE, Clarkson A, et al. Loss of
SDHA expression identifies SDHA mutations
in succinate dehydrogenase-deficient gastro-
intestinal stromal tumors. Am ] Surg Pathol
2013;37:226-33.

46. Janeway KA, Kim SY, Lodish M, et al. Defects in
succinate dehydrogenase in gastrointestinal stro-
mal tumors lacking KIT and PDGFRA mutations.
Proc Natl Acad Sci US A 2011;108:314-8.
47. Jove M, Mora], Sanjuan X, et al. Simultaneous
KIT mutation and succinate dehydrogenase
(SDH) deficiency in a patient with a gastrointes-
tinal stromal tumour and Carney-Stratakis syn-
drome: a case report. Histopathology 2014;65:
712-7.
48. Killian JK, Kim SY, Miettinen M, et al. Succinate
dehydrogenase mutation underlies global epig-
enomic divergence in gastrointestinal stromal
tumor. Cancer Discov 2013;3:648-57.
49. Mason EF, Hornick JL. Succinate dehydroge-
nase deficiency is associated with decreased
5-hydroxymethylcytosine production in gas-
trointestinal stromal tumors: implications for
mechanisms of tumorigenesis. Mod Pathol
2013;26:1492-7.
50. Miettinen M, Killian JK, Wang ZF, et al. Immu-
nohistochemicalloss of succinate dehydrogenase
subunit A (SDHA) in gastrointestinal stromal
tumors (GISTs) signals SDHA germline mutation.
Am J Surg Pathol 2013;37:234-40.
51. Miettinen M, Lasota J. Succinate dehydrogenase
deficient gastrointestinal stromal tumors (GISTs)
-a review. IntJ Biochem Cell Biol2014;53:514-9.
52. Nannini M, Astolfi A, Paterini P, et al. Expression
of IGF-1 receptor in KIT/PDGF receptor-alpha
wild-type gastrointestinal stromal tumors with
Gastric Polyps and Neoplasms
succinate dehydrogenase complex dysfunction.
Future Oncol 2013;9:121-6.
53. Pantaleo MA, Nannini M, Astolfi A, Biasco G;
GIST Study Group Bologna . A distinct pediatric-
type gastrointestinal stromal tumor in adults: po-
tential role of succinate dehydrogenase subunit
A mutations. Am J Surg Pathol 2011 ;35:1750-2.
54. Wang JH, Lasota ], Miettinen M. Succinate De-
hydrogenase subunit B (SDHB) is expressed in
Neurofibromatosis 1-associated gastrointestinal
stromal tumors (GISTs): implications for the
SDHB expression based classification of GISTs. J
Cancer 2011;2:90-3 .
55. Miettinen M, Lasota]. Gastrointestinal stromal
tumors-definition, clinical, histological, im-
munohistochemical, and molecular genetic
features and differential diagnosis . Virchows
Arch 2001;438:1-12.
56. Miettinen M, Sobin LH, Lasota]. Gastrointestinal
stromal tumors of the stomach: a clinicopatho-
logic, immunohistochemical, and molecular
genetic study of 17 65 cases with long-term fol-
low-up. Am J Surg Pathol 2005;29:52-68.
57. Jakhetiya A, Garg PK, Prakash G, Sharma], Pan-
dey R, Pandey D. Targeted therapy of gastroin-
testinal stromal tumours. World J Gastrointest
Surg 2016;8:345-52.
58. Miettinen M, Wang ZF, LasotaJ. DOGl antibody
in the differential diagnosis of gastrointestinal
stromal tumors: a study of 1840 cases. Am J Surg
Pathol 2009;33 :1401-8.
93
 NON-NEOPlASTIC
5 SMAll INTESTINE

NORMAl AND REACTIVE CONDITIONS
·When reviewing small bowel samples without
neoplasms, the main questions revolve around
celiac disease and other entities that result in
damage to the mucosa in patients who present
with diarrhea. The key possibilities to consider
are celiac disease, medication-associated injury,
infections and inflammatory bowel disease.
However, many biopsies come from patients
who do not have malabsorption symptoms and
have undergone upper endoscopic biopsies for
another indication; the small intestinal samples
are "along for the ride." Most such samples are
normal but they have artifacts that can cause
concerns. Lastly, the small bowel only has a
limited set of responses to a host of injuries so
interpretation of small bowel pathology often
requires attention to the patient's medical
record, particularly reconciliation with the pa-
tient's medication list (Table 5-1).
Normal small intestinal mucosa should have
long slender villi that protrude from a base in
which there are crypts. The crypts at the bottom
of the sample are nearly identical to the ones
in the colon. If they are embedded perfectly,
they are aligned like test tubes in a rack (fig.
5-1) but in daily practice they seldom are and
often instead appear as lots of glands that are
organized in an orderly fashion akin to the test
tubes viewed from above (fig. 5-2). Frequently
samples are imperfectly embedded, impa1ting an
appearance of villous blunting. In general, if any
well-formed villi are present, in all likelihood,
villi that appear attenuated are probably simply
embedded sub-optimally. Figures 5-3-5-5 show
normal duodenum. Important feature to note:

SMALL INTESTINE PATTERNS OF INJURY
Feature
Intraepithelial lymphocytosis
Prominent crypt apoptosis; normal is
1-2 apoptotic bodies per pinch biopsy
Absent or markedly reduced lamin a
propria plasma cells
Absent or markedly reduced goblet cells
and/or Paneth cells
Erosions and Ulcers
Table 5-l
Associations
Celiac disease
Infections (small bowel bacterial overgrowth, giardiasis, "tropical sprue,"
cytomegalovirus)
Medications ("sartans" such as olmesartan and losartan (angiotensen Il recep-
tor antagonists), anti-CTLA4 drugs such as ipilimumab, PDL-1 blockade
drugs such as pembrolizumab and nivolumab, proton pump inhibitors)
Crohn disease
Medications ("sartans" such as olmesartan and losartan, mycophenolate, anti-
CTLA4 drugs such as ipilimumab, PDL-1 blockade drugs such as pembro-
lizumab and nivolumab)
Infe ctions (consider cytomegalovirus, cryptosporidium)
Graft versus host disease
Autoimmune enteropathy
Common variable immunodeficiency
Autoimmtme enteropathy
Nonsteroidal anti-inflammatory drugs
Infections (consider cytomegalovirus)
Crohn disease

95
 Survival Guide to Gastrointestinal Mucosal Biopsies

Figure S-1 Figure S-2

TEST TUBES IN A RACK TEST TUBES IN A RACK
While this applies most to colon rather than small This is as seen from above, much like mucosa embedded
intestinal samples, the crypts of the intestine can be en face. Note the round structures (the test tubes or crypts)
considered as analogous to text tubes with the muscularis are evenly spaced.
mucosae akin to the bottom of the rack upon which the
tubes rest. The crypts are separated by uniform amounts of
space {lamina propria) and are aligned in an orderly fashion.

Figure S-3
NORMAL SMALL INTESTINAL MUCOSA
Left: Long slender villi protrude into the lumen at the right of the image. The lamina propria contains abundant plasma
cells. Also, note that there are a few lymphocytes in the epithelium but not many.
Right: This is a high magnification of the bases of the crypts. Each crypt contains several Paneth cells, which contain
plump eosinophilic granules that are aimed towards the lumen of the crypt. The lamina propria (the loose connective tissue
between the glands/crypts) contains lymphocytes, plasma cells, and a few eosinophils.

96
 Non-Neoplastic Small Intestine

Figure 5-4
NORMAL SMALL INTESTINAL MUCOSA
Left: This is the surface. There are a few lymphocytes in the surface epithelium. The lamina propria beneath the surface
contains many plasma cells, a few lymphocytes, and a few eosinophils.
Right: In this tangentially embedded sample the villi are sliced both longitudinally and in cross section. Each contains
delicate capillaries, scattered lymphocytes and plasma cells and strands of smooth muscle.

1) Nearly every crypt has lots of Paneth cells.
This differs from the colon and finding lots of
Paneth cells in crypt bases can be a clue that
a damaged sample is from the small intestine
rather than the colon (fig. 5-3, right) .
2) There are delicate strands of smooth
muscle in the core of each villus. This smooth
muscle helps the villi beat to increase nutrient
absorption. It can be mistaken for other things
(Whipple disease, Gaucher's disease) in tangen-
tially embedded villi (fig. 5-5).
3) Some duodenal samples feature crushed
Brunner glands that can be mistaken for mesen-
chymal neoplasms and Whipple disease (fig. 5-6).
Brunner glands are strongly periodic acid-Schiff
(PAS)-reactive, which can add to the confusion.
4) Crushed samples also lose their epitheli-
um, akin to squeezing sebum from the pores of
nasal skin (fig. 5-7). This should not be mistaken
for ischemia, which will be illustrated later.
5) The ileum often appears damaged at scan-
ning magnification because there are prominent
lymphoid aggregates (Peyer patches). Histiocytes
in the lymphoid tissue in the ileum often contain
black material that corresponds to titanium in
toothpaste and various foods (figs. 5-8, 5-9).
There is an important pitfall in interpreting
duodenal biopsies. Well differentiated neuro-
endocrine (carcinoid) tumors of the duodenum
are easily crushed and are very vascular. They
tend to have an appearance similar to that of
lymphoid aggregates on crushed samples. Such
a case is seen in figure 5-10.
When the stomach or esophagus is damaged,
the mucosa tends to be replaced by intestinal
type mucosa as seen in chapters 2, 3 and 4. In
a similar vein, when the small intestine is dam-
aged, it is replaced by mucosa with gastric fea-
tures, either in the form of glands that resemble
gastric foveolar cells with surface neutral mucin

97
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure S-5
NORMAL SMALL INTESTINAL MUCOSA

Left: Note the delicate strands of smooth muscle in the lamina propria. The surface shows the brush border with microvilli
and a few goblet cells. The cells between the goblet cells are absorptive cells.
Right: This is a villus cut in cross section. Note the eosinophilic smooth muscle cells cut in cross section.

Figure 5-6
NORMAL SMALL INTESTINAL MUCOSA
Left: A few well preserved Brunner glands are present in the lower part of the center of the image. Their mucin globules
are multivacuolated. Some have become crushed and extruded into and amongst the crypts in the field. This is a common
artifact in duodenal samples.
Right: Note the crushed Brunner gland in the center of the image.

98
 Non-Neoplastic Small Intestine

Figure S-7
NORMAl SMAll
INTESTINAl MUCOSA
This sample was crushed and
the crypts have been squeezed
out. There is no response to the
missing epithelium, supporting
an interpretation of an artifactual
loss of glands/crypts.

Figure S-8
NORMAl SMAll INTESTINAl MUCOSA
Left: This is an ileal sample. Abundant lymphoid tissue is a normal finding in the ileum. The black pigment is not strictly
normal but commonly detected. It is titanium from toothpaste and food.
Right: This is a high magnification of the sample seen on the left. The titanium is found in macrophages.

99
Survival Guide to Gastroin.testinal Mucosal Biopsies

Cholesterol Less than 300mg 300mg

Sodium Less than 2,400mg 2,400mg
Total Carbohydrate 300g 375g
Dietary Fiber 25g 30g
INGREDIENTS:
CORN SYRUP; SWEETENED CONDENSED MILK (MILK;
Figure S-9 SUGAR); HIGH FRUCTOSE CORN SYRUP; PALM
LABEL FROM A CANDY BAR KERNEL OIL; SUGAR; GLYCERIN; DAIRYBUTIER(MILK);
CONTAINS 2% OR LESS OF: GLYCERYL MONOSTEA-
Note that titanium dioxide is listed as an ingredient.
RATE; SALT; TITANIUM DIOXIDE (COLOR); SOY
LECITHIN; NATURAL FLAVORS; DISODIUM
PHOSPHATE; TOCOPHEROLS, TO MAINTAIN
FRESHNESS; SODIUM CARBONATE; MINERAL OIL. @o

Dist. by The Hershey Company

Hershey, PA 17033-08 15, U. S.A.
Mfd. in Canada

Figure 5-10
WELL-DIFFERENTIATED NEUROENDOCRINE
(CARCINOID) TUMOR, DUODENAL BIOPSY
It is important to consider this possibility in samples
that appear cmshed and inflamed at low magnification.
B: This is a high magnification of the lesion depicted in
A. There are crushed lymphocytes at the lower right but the
lesion has a nested appearance in the periphery of the field.
C: This is a chromogranin stain of the lesion seen in A.

~ c

100

or glands that resemble cardiac or pyloric type
glands. Knowing about this is helpful because
reactive changes in the duodenum can resemble
adenomas. If the surface of such areas is coated
with gastric foveolar cells (fig. 5-11), this usually
indicates a reactive process. Sometimes these
reactive changes result in a nodular appearance.
The term "nodular duodenitis" can be applied
in this instance. A less common finding is
melanosis duodeni (fig. 5-12). It is also termed
"pseudomelanosis" and consists of accumula-
tion of pigmented macrophages in the lamina
propria of the small bowel. Patients may have a
Non-Neoplastic Small Intestine
Figure 5-11
DUODENITIS WITH GASTRIC
ML!CIN CELL METAPLASIA
A: This .pattern is often seen in the
presence of damage from gastric acid and
was initially recognized in the setting of
H. pylori gastritis. Some have used the term
"peptic duodenitis." However, any source of
chronic damage can produce gastric mucin
cell metaplasia, including Crohn disease
and nonsteroidal anti-inflammatory drug
use. Note the reactive appearance of the
surface at the right. This appearance can
be concerning for duodenal adenoma.
B: Some ·of the surface glands have an
apical cap of mucin that is of the gastric
foveolar type.
C: This is a high magnification showing
metaplastic gastric foveolar type mucin.
history of hemodyalisis, hypertension, diabetes
mellitus, coronary artery disease, and/or iron
deficiency anemia (1). The endoscopist may
note gray-black pigmentation. The pigment is
ingested in lysosomes and composed of varying
amounts of iron, sulfur, and calcium. Histologic
examination shows macrophages containing
granular black or brown pigment, which may
resemble melanin but is not. There is variable
staining with trichrome and iron stains. The
material is darker, larger, and denser than hemo-
siderin. Melanosis duodeni is usually regarded
as an incidental, benign finding.
101
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 5-12
MELANOSIS DUODENI
Left: The pigment is not melanin so the term "pseudomelanosis duodeni" is probably more accurate. Note that the
sample is otherwise normal with slender villi and nicely aligned crypts with an arrangement similar to that of the test tubes
seen figure 5-1.
Right: High magnification from the case seen on the left.

INFECTIOUS AGENTS present with loose stools, flatulence, malab-

Various organisms prone to infect the small
intestine include cytomegalovirus (fig. 5-13),
Giardia lamblia (fig. 5-14), Strongyloides stercoralis
(figs. 5-15, 5-16), Mycobacterium avium (figs. 5-17,
5-18), and Trophyrema whipplei (fig. 5-19).
Giardiasis is the most commonly encountered
parasitic infection in the United States. Giardia
lamblia cysts are transmitted by the fecal-oral
route, sometimes in contaminated food or wa-
ter. Cattle and sheep excrete abundant Giardia
cysts, which can contaminate water sources
and can survive for months. Once the cysts are
swallowed, gastric acid and intestinal proteases
allow excystation into the trophozoite.
Giardia infection may be asymptomatic or
result in acute symptoms including diarrhea,
steatorrhea, flatulence, nausea and vomiting,
and fever. Chronic infection occurs in approx-
imately half of infected individuals and may
sorption, weight loss, and in children, impaired
growth and cognitive development resulting
from iron and micronutrient deficiencies (2,3).
On hematoxylin and eosin (H&E), trophozoites
appear as pear-shaped structures. They have
two ovoid nuclei and four pairs of flagella, but
these structures are often difficult to identify on
H&E stain. The background duodenal mucosa
may be normal but more often shows acute
inflammation, villous attenuation, increased in-
traepitheliallymphocytes, lymphoid aggregates,
and/or gastric mucin cell metaplasia. Some
biopsies may lack organisms but still manifest
the inflammatory changes.
Strongyloides stercoralis is a nematodal infec-
tion endemic to Africa, Southeast Asia, South
America, and parts of the United States. In its
lifecycle, the female worm lays her eggs without
fertilization (parthenogenesis) in small intestinal

102
 Non-Neoplastic Small Intestine

Figure 5-13

t • ~~-·~ ~. •-:- I
..
I~•
CYTOMEGALOVIRUS ENTERITIS
A: This case has injury due to more than one thing.

I
'· .' .
..... .
;,
•
This patient had undergone a bone marrow transplant and
probably has graft versus host disease since most of the crypts
are gone and there was ample apoptotic injury. However,
. . ... . tl , apoptotic injury can also reflect cytomegalovirus enteritis.
·•
'· '
·~ ,;•
. '.. J.
'7' .
•·• . . . •
I It
, • o
e•
• .· w• B: The residuum of a few glands is apparent but a small
·' ~ . : .... \.r· , · ·.''· capillary at the lower right contains an endothelial cell with
a cytoplasmic inclusion. This is not diagnostic in isolation
' .~
but prompted obtaining cytomegalovirus immunolabeling.
C: This is an immunostain from the lesion depicted
in A and B. The patient probably also has graft versus
host disease, but the cytomegalovirus infection must be
addressed first .
•.
. ...
.
..' r ,. ' , . ·.. · ··,~:

...
\ b . "' ~· ·~ . f , ,
\
: .. i ' - . ~~; ;t, \ '
•• • ~ ,. a
I
•·
,'
.
crypts . Eggs hatch into rhabditifonn larvae, through blood vessels to the lungs and into the
which pass into the lumen and are expelled with upper airways. This results in coughing and the
feces. The passed rhabditiform larvae develop larvae are swallowed and reach the small intes-
into filariform larvae, which penetrate human tine to mature into adults. Males are rapidly
skin (often through bare feet) and penetrate expelled after fertilizing the females whereas

103
 Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 5-14
GIARDIASIS
Left: In this case, there is minimal tissue response, making it easy to overlook the organisms, which are present as debris
separate from the tissue itself.
Right: This is a high magnification from the sample seen on the left.

Figure 5-15
STRONGYLOIDIASIS
Left: The villi are shortened and the lamina propria is expanded with increased inflammation. The organisms are seen
in the crypts.
Right: In addition to organisms, there is abundant acute inflammation in both the lamina propria and the crypts.

104
 Non-Neoplastic Small Intestine

Figure 5-16
STRONGYLOIDIASIS
Note the inflammatory backdrop.

Figure 5-17
MYCOBACTERIUM AVIUM
COMPLEX ENTERITIS
A: The lamina propria is stuffed with pale
foamy macrophages in solid sh eets.
B: Each lamina propria macrop h age
contains ample fluffy pink cytoplasm.
C: This is a periodic acid-Schiff (PAS)
stain. It highlights the goblet cells, the brush
borders of the enterocyte surface and the waxy
mycobacterial organisms, which appear as
delicate slender rods.

105
Survival Guide to Gastrointestinal Mucosal Biopsies
Figure 5-18
MYCOBACTERIUM AVIUM COMPLEX ENTERITIS
Left: This PAS stain shows the delicate rods within the histiocytes to advantage. Note the brush border and goblet cells
on the luminal surface.
Right: This is an acid fast stain.
the female worms can remain in the intestine
for decades. If the patient becomes immuno-
suppressed (such as during chemotherapy for
a malignancy later in life), rhabditiform larvae
undergo a transformation into the penetrating
filariform larvae, penetrate intestinal mucosa,
and disseminate throughout the body, which
can sometimes prove lethal. Biopsies appear
damaged with ulceration and granulation tissue.
The organisms are found in mucosal crypts or
can invoke an eosinophilic response.
Mycobacterium avium complex infection is
a significant cause of opportunistic infection
in immunocompromised patients, notable in
patients with acquired immunodeficiency syn-
drome (AIDS). Disseminated GI tract infection
with Mycobacterium avium is common in AIDS
patients. Mycobacterium avium usually affects
both the small and large bowels. Endoscopically,
the small bowel mucosa either appears normal
or shows white nodules/plaques or a coarse
granularity (4) without significant exudate
(implying an attenuated local immunologic
response). The granular mucosa corresponds to
infiltration of small intestinal villi by histiocytes
loaded with acid-fast bacilli. Unlike the response
106
to Mycobacterium tuberculosis, well-defined gran-
ulomas are not seen.
Whipple disease is the differential diagnosis
for Mycobacterium avium infection. It is a rare
systemic bacterial infection caused by Trophe1Y'na
whippleii (an actinomycete). The small intestine is
the organ most commonly affected but infection
can also involve the brain, endocardium, and
other sites where it can mimic a neoplasm (5).
White males between the fourth and fifth decade
are most commonly affected. Patients present
with protean symptoms that include diarrhea,
low-grade fever, weight loss, malabsorption, ab-
dominal pain, chronic intermittent seronegative
polyarthritis (6), anemia,lymphadenopathy (50
percent), cardiac conditions, nausea, vomiting,
GI bleeding, and central nervous system symp-
toms (10 percent). Because of the unusual pre-
sentations, WD is challenging to recognize (7).
Small bowel samples show blunted and round-
ed villi, with distention of lamina propria by
foamy, pink macrophages. The villi show cystic
spaces that presumably correspond to dilated ob-
structed lacteals, a feature that allows distinction
from Mycobacterium avium infection on the H&E
alone. The macrophages contain PAS-positive,

diastase-resistant rod-, sickle-, or globular-shaped
bacterial inclusions. Whipple antigen can be also
detected by immunohistochemical staining (8).
CELIAC DISEASE
Celiac disease is often a consideration and
has characteristic but not specific features (fig.
5-20) . However, some examples lack the full
Non-Neoplastic Small Intestine
Figure 5-19
WHIPPLE DISEASE
A: On h ematoxylin and eosin (H&E),
the appearance is sim ilar to that of
Mycobacterium avium complex enteritis .
However, there are cystic dilations that are
presumably dilated lacteals.
B: This is a PAS stain . The chunky
disorganized deposits differ dramatically
from the delicate orga nism s of Myco-
bacterium avium seen in figure 5-18, left.
C: This is an immunohistochemical
stain for Troplmyma whipplei.
spectrum of findings and only display prom-
inent intraepithelial lymphocytes (fig. 5-21).
Unfortunately intraepitheliallymphocytosis is
a nonspecific findings and must be evaluated in
the setting of the clinical history and together
with assessment of the presence of crypt apop-
tosis and evaluation of the presence of absence
of plasma cells, goblet cells, and Paneth cells.
107
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 5-20
CELIAC DISEASE
A: There are no villi in this well-developed
example. The lamina propria is expanded with
plasma cells and lymphocytes and there are
many intraepitheliallymphocytes in the surface
epithelium. There is no need to count them to see
that they are too numerous. Unfortunately this
pattern is not specific and must be interpreted in
the context of laboratory findings.
B: This is the surface epithelium of the lesion
depicted in A. It is easy to see that there are too
many lymphocytes. Note all the plasma cells in
the lamina propria.
C: The crypts have intraepithelial lympho-
cytosis but the surface is the important area
to assess since intraepithelial lymphocytes are
normal in crypts. There is no increase in crypt
apoptosis.

108
 Non-Neoplastic Small Intestine

Figure 5-21
CELIAC DISEASE
Left: Some examples show a "latent" pattern with villi that are only slightly attenuated. However, even at low magnification ,
there are too many intraepitheliallymphocytes in the tips of the villi. This pattern is not specific for celiac disease. In this case,
the patient had appropriate serologic confirmation. Requests to "score" th e findings are useless unless a diagnosis of celiac
is already established. When this pattern is seen de novo, about 10 to 20 percent of the cases will prove to be celiac disease.
Right: High magnification of the lesion on the left. Note that the intraepitheliallymphocytosis is "top heavy."

Celiac disease is a relatively common sys-
temic autoimmune disorder induced by gluten
proteins found in wheat, barley, and rye. Injury
to the small intestine is the prototypic finding,
but manifestations are systemic. Lymphocytic
gastritis is a well-known association. The human
leukocyte antigens (HLAs) that confer the high-
est risk are HLA-DQ2 and HLA-DQS. Prevalence
of celiac disease has been reported as high as
1.5 percent in Finnish school children (9) and
only slightly less in the general population of
the United States (10). The incidence very low
in Southeast Asians, while there are endemic
populations in the Sahara/Middle East with a
high incidence of celiac disease (11,12).
The biopsy findings in celiac disease are
variable (13,14). Early or partly treated disease
shows only intraepitheliallymphocytosis that
is prominent in the tips of the villi. In the
normal small bowel biopsy, the number of in-
traepitheliallymphocytes decreases in the tips
of the villi when compared to the bases. The
finding of prominent "tip heavy" intraepithelial
lymphocytosis can prompt the pathologist to
suggest celiac disease serology as patients with
mild enteropathy and positive serology benefit
from early dietary treatment (15) . As a rapid and
simple method to assess whether there are too
many lymphocytes in the tips of the villi, count
20 enterocyte nuclei in the very tip of a villus
(10 on one side of the tip, and 10 on the other)
and (on H&E) count the lymphocytes in this
area. If there are six or more, this is too many.
It is not necessary to immunolabel T cells to as-
sess these biopsies. Scattered neutrophils can be
present. Crypt apoptosis is not a typical feature.
AUTOIMMUNE ENTEROPATHY AND
COMMON VARIABLE IMMUNODEFICIENCY
An important concept in assessing samples
from patients with dianhea is to assess for com-
ponent that are normally present! It is important
to always check for lamina propria plasma cells,
Paneth cells, and goblet cells. An absence of
lamina propria plasma cells indicates common
variable immunodeficiency (CVID) and an ab-
sence of goblet cells and/or Paneth cells suggests
autoimmune enteropathy, although the findings

109
Survival Guide to Gastrointestinal Mucosal Biopsies

:~'t . . • f: :.

Figure 5-22
AUTOIMMUNE ENTEROPATHY PATTERN IN A PATIENT WITH COMMON VARIABLE IMMUNODEFICIENCY
A: Something is missing! The sample appears normal at first glance but there are no goblet cells or Paneth cells! Notice
also that the lamina propria has fewer constituents than usual. Always have a mental checklist when reviewing small bowel
samples-be sure that plasma cells, Paneth cells, and goblet cells are present and , lastly, study the debris that is detached
from the mucosa to assess for Ginrdia.
B: High power shows that the lamina propria is devoid of plasma cells. There are also several apoptotic bodies in the crypts.
C: No plasma cells are present. In this case, the patient had minimal IgG formation, but what little that was produced
consisted of auto antibodies.
0: There are no Paneth cells in the bases of the crypts.

in these two entities overlap (fig. 5-22). Unfortu-
nately plasma cells are absent in only two thirds
of patients with CVID (16) but patients' samples
may show prominent lymphoid aggregates,
increased apoptosis, increased IELs with or
without villous blunting, and granulomas. Inter-
estingly, patients with CVID make few antibodies
but often the ones that they create are autoanti-
bodies so they can present with syndromes that
overlap with autoimmune enteropathy.

110

Autoimmune enteropathy is rare and char-
acterized by: 1) small intestinal villous atrophy
unresponsive to dietmy resnictions; 2) unrelenting
diarrhea; and 3) predisposition to autoimmune
disease 17. It was initially believed to affect
newborns and young children; adult onset
is well-documented in the literature (18-21).
Pathophysiology is poorly understood but a pro-
posed mechanism involves loss of self-tolerance
and a hyperreactive immune system with inap-
propriate T-cell activation and cytotoxicity Auto-
antibodies associated with this condition include
antigoblet cell and antienterocyte antibodies.
One variant of the syndrome is IPEX (immune
dysregulation, polyendocrinopathy, enterop-
athy, X-linked) syndrome. It is fatal, X-linked,
and characterized by polyendocrinopathy and
various autoimmune conditions in association
with severe, prolonged diarrhea (22). Another,
termed APECED (autoimmune polyendocr-
inopathy-candidiasis-ectodermal dystrophy)
syndrome or APS-1 (autoimmune polyglandular
syndrome 1), is autosomal recessive and affected
patients suffer from autoimmune enteropathy in
association with endocrine abnormalities (hy-
poparathyroidism, adrenocortical insufficiency,
diabetes mellitus, thyroid disease), mucocutane-
ous candidiasis, and skin manifestations such as
alopecia and vitiligo, and nail deformities (23).
Intestinal biopsies show total or partial vil-
lous atrophy, crypt hyperplasia, and expansion
of the lamina propria by a lymphoplasmacytic
infiltrate. Some cases display intact villous
architecture. Increased IELs may be seen but
often to a lesser degree than in celiac disease
(18,20). Crypt apoptosis is striking in some cases
but may be obscured in cases with significant
cryptitis (24). Goblet and/or Paneth cells may
be absent. The diagnosis should be considered
in biopsies from adult patients labeled as having
"refractory sprue" and from babies and children
with intractable diarrhea.
MEDICATION-ASSOCIATED INJURY
Medication-associated injury is always an
issue when assessing small bowel samples (25).
Medications that can be associated with small
intestinal findings include angiotensin II re-
ceptor antagonists. The prototype of these is
olmesartan but drugs in this class typically in-
clude" sartan" in their names (figs. 5-23, 5-24),
Non-Neoplastic Small Intestine
colchicine (fig. 5-25), kayexalate (fig. 5-26),
lanthanum carbonate (fig. 5-27), mycopheno-
late (fig. 5-28), and ipilimumab. Yttrium can be
associated with ischemic enteritis and radiation
change (fig. 5-29). The differential diagnosis in
this case can include amyloidosis (fig. 5-30).
A severe sprue-like enteropathy is associated
with olmesartan and other anti-hypertensives
in this class (angiotensin II receptor antagonists)
(26). Patients present with chronic diarrhea and
weight loss. Biopsies show villous blunting with
crypt hyperplasia and increased intraepithelial
lymphocytes with our without prominent sub-
epithelial collagen (collagenous sprue pattern).
An accompanying collagenous, lymphocytic, or
autoimmune gastroenteropathy-like gastritis or
colitis may be seen in a subset of cases. Crypt
apoptosis may be a prominent feature such that
autoimmune enteropathy can be considered.
Lanthanum (Fosrenol), is used in dialysis
patients to reduce their hyperphosphatemia.
Biopsies show lamina propria CD68-positive
macrophages (some multinucleated) containing
cytoplasmic non-birefringent, brown, finely
granular material that may be focally nee-
dle-shaped. These are rarely highlighted with
Prussian blue stain (27).
Many drugs are now used to harness the
body's immune system to kill cancer cells. The
key medications include CTLA4 antibodies and
antibodies to the PD-1 system. Both of these im-
munologic systems have to do with our bodies'
immune recognition of "self" and "non-self"
cells. Tumor cells sometimes evolve to display
antigens that are recognized as "self" and thus
the cancer cells can evade the immune system.
Programmed death-1 (PD-1) is an inhibitory
T-cell receptor that is involved in suppressing
antitumor immunity. PD-1 inhibitors have
been studied with promising results, especially
in patients with mismatch repair deficient col-
m·ectal and noncolorectal cancers but initially in
melanoma (28). Ipilimumab and related drugs
target the cytotoxic T-lymphocyte-associated
antigen 4 (CTLA4) to enhance T-cell mediat-
ed tumor destruction. The main side effect is
diarrhea. Small intestine biopsies can show
active inflammation, increased apoptosis and
villous blunting with prominent intraepithe-
lial lymphocytosis, mimicking celiac disease
(29). Ischemic enteritis usually results from
111
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 5-23
MUCOSAL INJURY ASSOCIATED WITH LOSARTAN
A: There is intra-epithelial lymphocytosis in the small intestine.
B: This is the colon from the same patient as that depicted in A. There is striking intraepitheliallymphocytosis.
C: Note the intraepitheliallymphocytes and eosinophils. These findings are not specific but should prompt a review of
pertinent serology findings and reconciliation with the patient's medication list.
D: Note the prominent crypt apoptosis.

112
 Non-Neoplastic Small Intestine

Figure 5-24
MUCOSAL INJURY
ASSOCIATED W ITH
OLMESARTAN
The findings are essentially
indistinguishable from those
associated with celiac disease
in this example where as some
examples show striking crypt
apoptosis and thus features that
overlap with those of autoimmune
enteritis and other medication
associated forms of injury.

Figure 5-25
COLCHICINE TOXICITY
Left: This sample is not particularly abnormal at low magnification but note the crypts in the center of the field .
Right: Ring mitoses are a characteristic feature.

113
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 5-26
ISCHEMIC ENTERITIS ASSOCIATED WITH KAYEXALATE
A: The medication crystals can be seen as purple structures
in the luminal exudate. The mucosa is hemorrhagic and
damaged.
B: The lamina propria is collapsed and the lamina propria
vessels are engorged. Note the luminal exudate at the top
of the field.
C: This is a kayexalate crystal. Note the rectangular
cracks in the crystal.

mechanical alterations (leading to resections)
rather than chronic vascular insufficiency. It is
seldom seen on endoscopic biopsies. A possible
scenario in which one might encounter an isch-
emic picture in duodenal biopsies involves the
utilization of selective internal radiation spheres
(SIRSs)-these are injected into metastatic tu-
c
mars (typically hepatic lesions) to radiate them
locally. SIRSs are Yttrium-90-incorporated mi-
crospheres that are embolized into the arterial
supply of the liver. The spheres may become
lodged in the duodenal or gastric circulation
resulting in ulceration and ischemic changes.
It should be remembered that whenever there

114
 Non-Neoplastic Small Intestine

Figure 5-27
LANTHANUM CARBONATE
A: The lamina propria contains macrophages filled with foreign material.
B: The material in the macrophages is purple to brown.
C: High magnification.
D: This particular example also had a component of calcium, as shown in this calcium stain.

115
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 5-28
MYCOPHENOLATE-
ASSOCIATED INJURY.
A: At low magnification this
example shows villous blunting.
B: This medication is admin-
istered to patients who have had
solid organ transplantation to
reduce the activity of cytotoxic T
cells and thereby protect the graft.
The finding associated with injury
is crypt apoptosis, which is seen
here. Of course, apoptosis is also
associated with cytomegalovirus
infection, so this must always also
be considered.
C: High magnification shows
several apoptotic bodies. The nuclei
show a popcorn type appearance.

is any doubt about injury to the GI tract, non-
steroidal inflammatory drugs (NSAIDs) can
be blamed! They are strongly associated with
mucosal damage in the small intestine. The
typical endoscopic findings consist of ulcers,
which may lead to strictures. The histologic
features are not specific and biopsies can show
mild to moderate active inflammation, ulcers or
erosions, reactive epithelial changes, and pyloric
metaplasia. Lymphoplasmacytic expansion of
the lamina propria is not a feature ofNSAID asso-
ciated injury (figs. 5-31, 5-32). NSAIDs may even
lead to a form of strictures called "diaphragm
disease," based on their macroscopic appearance
(30- 32). NSAID associated lesions tend to lack
chronic inflammation, which differs from Crohn
disease, which is discussed in chapter 7.

116
 Non-Neoplastic Small Intestine

Figure 5-29
ISCHEMIC/RADIATION
TYPE INJURY ASSOCIATED
WITH YTTRIUM SPHERES
The radiation spheres have
a characteristic appearance but
note the hyalinized lamina
propria and reactive epithelial
changes.

' .
I .
.. .;,.
_-j't
I . ,); '
'1

' •I
...
I .
,,
•'
'r
~ ..
'~

'·
' ·{
., ,~

. - ~.,·
·-

I
- I

..·.
•
(' !, •·
· '·.. -- .J ,...

Figure 5-30
AMYLOID DEPOSITION IN THE SMALL BOWEL MUSCULARIS MUCOSAE AND SUBMUCOSAL VESSELS
Left: Note the thick muscularis mucosae and submucosal vessels.
Right: The amyloid has an eosinophilic waxy appearance.

117
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 5-31
ULCER ASSOCIATED WITH
NONSTEROIDAL
ANTI-I NFLAMMATORY DRUGS
The lesion is "punched out"
and essentially devoid of chronic
inflammation.

Figure 5-32
DIAPHRAGM DISEASE
Left: The endoscopist has encountered a circumferential ridge that constricts the lumen.
Right: The obstructing ridge in diaphragm disease is formed by a proliferated submucosa with scarring and reactive
hyperplasia of nerves, fibrous tissue and smooth muscle that results in obstruction requiring resection. Note that chronic
inflammation is a minimal component of the process.

118

REFERENCES
1. Kim SY, Choung RS, Kwon BS, et al. Small bowel
pseudomelanosis associated with oral iron ther-
apy.] Korean Med Sci 2013;28:1103 -1106.
2. Van Lint P, Rossen ]W, Vermeiren S, et al. De-
tection of Giardia lamblia, Cryptosporidium
spp. and Entamoeba histolytica in clinical
stool samples by using multiplex real-time PCR
. after automated DNA isolation. Acta Clin Belg
2013;68:188-192.
3. Cantey PT, RayS, Lee B, et al. Study of non outbreak
giardiasis: novel findings and implications for re-
search. Am] Med 2011;124:1175 ell?l-1178.
4. Yamada E, Endo H, Nakajima A, Yamanaka S.
Disseminated Mycobacterium avium disease
with nodular infiltration in the small intestine,
detected by capsule endoscopy. Endoscopy
2011;43(Suppl 2);UCTN:E332-333.
5. Costa JH, Maciel AB, Godinho Mde N, Paula
RB, Gotardelo DR. Tumoural form of Whipple's
disease simulating carcinomatosis. Braz J Infect
Dis 2014;18:346-349.
6. Meunier M, Puechal X, Hoppe E, et al. Rheumatic
and musculoskeletal features of Whipple disease: a
repmt of 29 cases.] Rheumatol2013 ;40:2061-2066.
7. Arnold CA, Moreil·a RK, Lam-Himlin D, De Petris
G, Montgomery E. Whipple disease a century
after the initial description: increased recognition
of unusual presentations, autoimmune comor-
bidities, and therapy effects. Am ] Surg Pathol
2012;36:1066-1073.
8. Dumler ]S, Baisden BL, Yardley JH, Raoult D.
Immunodetection ofTropheryma whipplei in in-
testinal tissues from Dr. Whipple's 1907 patient.
N Engl] Med 2003;348:1411-1412.
9. Maki M, Mustalahti K, Kokkonen ], et al. Prev-
alence of Celiac disease among children in Fin-
land. N Engl J Med 2003;348:2517-2524.
10. Fasano A. European and North American pop-
ulations should be screened for coeliac disease.
Gut 2003;52:168-169.
11. Catassi C, Ratsch IM, Gandolfi L, et al. Why is
coeliac disease endemic in the people of the
Sahara? Lancet 1999;354:647-648.
12. Rostami K, Malekzadeh R, Shahbazkhani B,
Akbari MR, Catassi C. Coeliac disease in Middle
Eastern countries: a challenge for the evolution-
ary history of this complex disorder? Dig Liver
Dis 2004;36:694-697.
13. Marsh MN. Gluten, major histocompatibility
complex, and the small intestine. A molecular
and immunobiologic approach to the spectrum
of gluten sensitivity ('celiac sprue'). Gastroenter-
ology 1992;102:330-354.
14. Rostami K, Kerckhaert ], Tiemessen R, von
Blomberg BM, Meijer JW, Mulder CJ. Sensitivity
Non-Neoplastic Small Intestine
of antiendomysium and antigliadin antibodies in
untreated celiac disease: disappointing in clinical
practice. Am] Gastroenterol 1999;94:888-894.
15. Kurppa K, Collin P, Viljamaa M, et al. Diagnosing
mild enteropathy celiac disease: a randomized,
controlled clinical study. Gastroenterology
2009;136:816-823.
16. Daniels ]A, Lederman HM, Maitra A, Montgom-
ery EA. Gastrointestinal tract pathology in pa-
tients with common variable immunodeficiency
(CVID): a clinicopathologic study and review.
The Am] Surg Pathol2007;31:1800-1812.
17. Unsworth DJ, Walker-Smith ]A. Autoimmunity
in diarrhoea! disease.] Pediatr Gastroenterol Nutr
1985;4:375-380.
18. Akram S, Murray ]A, Pardi DS, et al. Adult au-
toimmune enteropathy: Mayo Clinic Rochester
experience. Clin Gastroenterol Hepatol 2007;5:
1282-1290; quiz 1245.
19. Carroccio A, Volta U, Di PrimaL, et al. Autoim-
mune enteropathy and colitis in an adult patient.
Dig Dis Sci 2003;48:1600-1606.
20. Casis B, Fernandez-Vazquez I, Barnardos E, et
al. Autoimmune enteropathy in an adult with
autoimmune multisystemic involvement. Scand
J Gastroenterol2002;37:1012-1016.
21. Volta U, De Angelis GL, Granito A, et al. Auto-
immune enteropathy and rheumatoid arthritis:
a new association in the field of autoimmunity.
Dig Liver Dis 2006;38:926-929.
22. Powell BR, Buist NR, Stenzel P. An X-linked syn-
drome of diarrhea, polyendocrinopathy, and fatal
infection in infancy.] Pediatr 1982;100:731-737.
23. Perheentupa]. APS-I/ APECED: the clinical disease
and therapy. Endocrinol Metab Clin North Am
2002;31:295-320, vi.
24. Singhi AD, Goyal A, Davison JM, Regueiro MD,
Roche RL, Ranganathan S. Pediatric autoimmune
enteropathy: an entity frequently associated
with immunodeficiency disorders. Mod Pathol
2014;27:543-553.
25. Vieth M, Montgomery E. Medication-associat-
ed gastrointestinal tract injury. Virchows Arch
2017;470:245-266.
26. Rubio-Tapia A, Herman ML, Ludvigsson JF, et
al. Severe spruelike enteropathy associated with
olmesartan. Mayo Clin Proc 2012;87:732-738.
27. Haratake ], Yasunaga C, Ootani A, Shimajiri S,
Matsuyama A, Hisaoka M. Peculiar histiocytic
lesions with massive lanthanum deposition in
dialysis patients treated with lanthanum carbon-
ate. The Am] Surg Pathol2015;39:767-771.
119
Survival Guide to Gastrointestinal Mucosal Biopsies
28. Le DT, Uram JN, Wang H, et al. PD-1 blockade
in tumors with mismatch-repair deficiency. New
Engl] Med 2015;372:2509-2520.
29. Oble DA, Mino-Kenudson M, Goldsmith], et al.
Alpha-CTLA-4 mAb-associated panenteritis: a
histologic and immunohistochemical analysis.
Am] Surg Pathol2008;32:1130-1137 .
30. Cortina G, WrenS, Armstrong B, Lewin K, Fajardo
L. Clinical and pathologic overlap in nonsteroi-
dal anti-inflammatory drug-related small bowel
diaphragm disease and the neuromuscular and
120
vascular hamartoma of the small bowel. Am ]
Surg Pathol1999;23:1414-1417.
31. Lang ], Price AB, Levi A], Burke M, Gumpel JM,
Bjarnason I. Diaphtagm disease: pathology of
disease of the small intestine induced by non-ste-
roidal anti-inflammatory drugs. ] Clin Pathol
1988;41:516-526.
32. Smith ]A, Pineau BC. Endoscopic therapy of
NSAID-induced colonic diaphragm disease: two
cases and a review of published reports. Gastro-
intest Endosc 2000;52:120-125.
 6 SMAll BOWEl NEOPlASMS

.Nodules and masses of the duodenum and POLYPS

ileum are often biopsied whereas few biopsies
are received from the jejunum or proximal
ileum (since these areas cannot be reached en-
doscopically). Many of the nodules sampled are
benign reactive lesions and they can often be
distinguished from adenomas by noting gastric
mucin cell metaplasia as discussed in chapter
5. The most important concept to recall is that
neoplasms from other sites that spread to the
small bowel tend to colonize the surface and
mimic an in situ component (figs. 6-1, 6-2).
However, there are a few types of adenomas that
can be encountered in the small bowel.
Tubular/Tubulovillous Adenoma
Small intestinal adenomas can be classified
as tubular, tubulovillmis, and villous (figs. 6-3,
6-4). So-called traditional serrated adenoma
(fig. 6-5) of the duodenum is rare and reported
cases have had inconsistent molecular profiles
(1). Adenomas usually arise in the colon and
are further presented in chapter 8.
Adenomas should be removed via endoscopic
polypectomy to prevent progression to carcino-
ma but large sessile lesions often require surgery.
Many surgical colleagues manage high grade

Figure 6-1
PANCREATIC CARCINOMA COLONIZING DUODENUM
Left: The tumor extends nearly to the surface thereby mimicking an in situ component.
Right: This is a CDX2 stain. It labels the nuclei of the duodenal mucosa but not of the cancer cells. Of course some
pancreatic carcinomas have intestinal diffe rentiation but this one does not.

121
Swvival Guide to Gastrointestinal Mucosal Biopsies

Figure 6-2
METASTATIC COLORECTAL
CARCINOMA COLONIZING DUODENUM
A: The cancer is on the left and has spread onto the
surface.
B: This is a CK20 stain, which labels the colorectal
carcinoma. This image is from the same case as figure
A. Primary small intestinal adenocarcinomas are often
CK7+/CK20- or CK7 /20 double positive whereas colorectal
carcinomas are generally CK20+/CK7-.
C: This is a negative CK7 stain. This image is from
the same case as figure 6-1, left. Primaiy small intestinal
adenocarcinomas are often CK7 +/CK20- or CK7 /20 double
positive whereas colorectal carcinomas are generally CK20+/
CK7- .

dysplasia in small bowel adenomas with radical
surgery so the pathologist should have a high
threshold for diagnosing high grade dysplasia.
Most small intestinal adenomas arises in the
duodenum where they are quite uncommon
and rare in the jejunum and ileum. Duodenal
adenomas are detected in 0.3 to 0.4 percent (2)
of persons undergoing upper endoscopy at a
median age of 65 years with no gender preva-
lence (3).
The difficulty in diagnosing adenomas in the
small bowel is the proclivity of reparative lesions
to mimic them and the capacity of carcinomas
that have spread from other sites to mimic them
by "colonizing" the surface epithelium. The
presence of gastric type surface cell metaplasia
is a clue to recognizing reactive lesions, as seen
in chapter 5. Remember that adenomas have
their initiation point just beneath the surface
epithelium (4), whereas reparative lesions that
occur with peptic duodenitis have theirs at the
base of the mucosa. The surface cells of duode-
nal adenomas tend to have lipid accumulation
in the neoplastic enterocytes.
Some lesions are reasonably interpreted "in-
definite for dysplasia/adenoma" with a request

122
 Small Bowel Neoplasms

Figure 6-3
DUODENAL TUBULAR ADENOMA
Left: This polyp is from a patient with familial adenomatous polyposis. There are numerous Paneth cells, a characteristic
feature of small intestinal adenomas.
Right: Note the Paneth cells. Note also the nuclear features . The nuclei are slim and elongated and more hyperchromatic
that those in normal colorectal epithelial cells. Their long axes are perpendicular to the basement membranes. Compare
them to the nuclei in the normal entrapped normal colorectal at the lower part of the field just left of center that contains
two plump goblet cells.

Figure 6-4
SMALL INTESTINAL TUBULOVILLOUS ADENOMA
Left: The villi are rather edematous in this example.
Right: This is th e surface of part of the lesion seen on the left. Note that the surface nuclei appear similar to the nuclei
below but that the cytoplasm is stuffed with lipid. Presumably adenomatous surface epithelium has the capacity to take in
lipid but not to process it for digestion in the manner of normal enterocytes. Cytoplasmic lipid is commonly seen at the
surface of small bowel adenomas.

123
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 6-5
TRADITIONAL SERRATED ADENOMA
Left: These polyps are further discussed in chapter 8. They are quite rare outside the distal colon. Even at this magnification
it is apparent that the nuclei are smaller than those in typical adenomas.
Right: This image shows nuclear detail, which can be compared to that of the tubulovillous adenoma seen in figure 6-3, right.

for additional samples. There is a precedent for
treating large ampullary adenomas with pancre-
atoduodenectomy, so only diagnose adenoma
if there is certainty.
Pyloric Gland Adenoma
Like their gastric counterparts, small bowel
pyloric gland adenomas harbor GNAS mutations
(5). It is not clear if they arise from a metaplasia
dysplasia sequence as in the stomach but small
bowel pyloric gland adenomas can also progress
to adenocarcinoma. As per gastric examples,
small bowel pyloric adenomas consist of closely
packed tubules of neoplastic glands lined by
cells with a monolayer of round nuclei and
amphophilic cytoplasm (fig. 6-6).
Brunner Gland Lesions
and Pancreatic Heterotopia
Submucosal Brunner glands are unique to the
duodenum. They usually form tightly packed
aggregates and have abundant grey, PAS-positive
cytoplasm and small, basally located nuclei.
Small Brunner gland nodules are commonly
encountered in daily practice, mostly as part
of reactive changes.
Brunnergland lesions are usually hyperplastic or
hamartomatous (6), but some are neoplastic (ade-
nomas and carcinomas) (figs. 6-7, 6-8). However,
it can be difficult to ascertain whether a Brunner
gland lesion is hyperplastic, hamartomatous, or
neoplastic, and hence, the noncommittal term
"Brunner gland polyp" can be used.
Tumors believed to be adenomas have larger
nuclei than those associated with hyperplasias
and hamartomas. Lesions reported as carcino-
mas and adenomas adjoining Brunner glands
have had overlapping morphologic, immuno-
histochemical, and genetic features with pyloric
gland adenomas (5, 7).
The presence of GNAS mutations in such
duodenal lesions is of interest, since GNAS

124
 Small Bowel Neoplasms

Figure 6-6
PYLORIC GLAND ADENOMAS
A: The cytoplasm has a ground glass appearance and the nuclei are round. There are no goblet cells but nor is there
gastric foveolar type mucin.
B: This high magnification image shows the nuclear detail. Nuclei are round and arranged in a monolayer.
C: This example shows high grade dysplasia. There is normal small intestinal mucosa in the fragment at the top and the
lesion is in the fragment at the bottom. The closely packed tubules appear eosinophilic.
D: There is high grade dysplasia with enlarged nuclei that have lost their polarity and no longer form a basal monolayer at
the left. Those at the right invade the lamina propria (intramucosal carcinoma). In the small bowel, stomach, and esophagus,
this is staged as Tla.

125
Survival Guide to Gastrointestinal Mucosal Biopsies

'l

Figure 6-7
BRUNNER GLAND POLYP
A: This impressive lesion, wholly benign,
resulted in obstruction . It is lobulated and
composed of closely packed Brunner glands. In
such cases, it is often not clear whether the lesion
is hamartomatous, hyperplastic, or adenomatous,
such that the noncommittal term "polyp", which
simply indicated a projection, can be useful. Some
observers believe that an admixture of adipose
tissue confirms an interpretation of hamartoma,
which is lacking in this lesion.
B: This is a MUC6 stain from the lesion seen
in A. This staining was performed for illustrative
purposes only and not for diagnosis.
C: The admixture of adipose tissue in this
example suggests that it is a hamartoma.

mutations are characteristic of pyloric gland
adenomas, and several other types of lesions,
including McCune Albright syndrome.
Sometimes pancreatic heterotopia can pro-
duce a small intestinal polyp and masquerade
as a neuroendocrine tumor (figs. 6-9).
Peutz-Jeghers Polyps
Peutz-[eghers (P]) syndrome is an inherited
cancer syndrome characterized by mucocutane-
ous melanin pigmentation and hamartomatous
intestinal polyposis, preferentially affecting the
small intestine (8). Patients with PJ syndrome
also develop colorectal cancer followed by
breast, small bowel, stomach, and pancreas
cancer. The cumulative lifetime risk of cancer
in such patients has been estimated at 93 percent
in one study (9) but others have recorded lower
figures. Extraintestinal neoplasms include those
of the endometrium, lung, ovary (sex cord tumor
with annular tubules), cervix (adenoma malig-
num), testis (sertoli cell tumors), pancreas (car-
cinomas) and breast (carcinomas). The average
age of malignancy in patients with PJ syndrome
is about 40 years (10). This syndrome is about
one tenth as common as FAP (the incidence of
FAP is between 1:7,000 and 1:30,000).
The diagnostic criteria include: 1) three or
more histologically confirmed PJ polyps; and/or
2) any number of P] polyps in an individual with
family history of this syndrome; and/or 3) prom-
inent mucocutaneous melanin pigmentation in

126
 Small Bowel Neoplasms

Figure 6-8
BRUNNER GLAND ADENOMA
Left: At least some of the glands in this lesion appear neoplastic.
Right: High magnification of the lesion seen on the left.

Figure 6-9
PANCREATIC ACINAR CELL HETEROTOPIA
Left: Such lesions present as polyps. When the tissue is crushed, as in this example, these lesions are easily confused wi th
well differentiated neuroendocrine (carcinoid) tumors.
Right: This is a chromogranin stain from the lesion seen on the left.

127
Survival Guide to Gastrointestinal Mucosal Biopsies

an individual with affected relatives; or 4) any

Figure 6-10
PEUTZ-JEGHERS POLYPS
This small bowel resection shows some large polyps as well
as some more subtle early ones in the center of the sample.
number of polyps in an individual with promi-
nent mucocutaneous pigmentation.
Mutations or deletions in an involved gene,
LKB/STKll are found in most (80 to 94 percent)
of affected patients (11, 12). · ·
Peutz-Jeghers polyps are often easy to recognize
on large endoscopic biopsies that show the
characteristic branching smooth muscle (figs.
6-10-6-12). When biopsies are superficial or
when ulceration distorts them, the features are
unrecognizable. The polyps display arborizing,
smooth muscle cores from which the mucosa
emanates. These polyps occasionally have asso-
ciated dysplasia or (rarely) invasive carcinoma.
P] polyps may also produce a striking transmural
polyposis cystica profunda ("pseudoinvasion":
in which the glands herniate rather than in-
vade into the small bowel wall [fig. 6-12]) that
is unassociated with pseudomyxoma peritonei.
ADENOCARC INOMA
Small bowel adenocarcinomas account for
about 2 percent of GI tract turners, resulting in
less than 1 percent of GI tract cancer deaths (13) .
Our ability to detect them has improved over
time (14,15). Small bowel adenocarcinomas arise

Figure 6-11
PEUTZ-JEGHERS POLYPS
Left: Note the eosinophilic cords of smooth muscle that partition groups of site specific mucosa. The appearance is that
of disorganized site specific mucosa that has produced a polyp.
Right: This is a higher magnification image of the polyp seen on the left.

128
 Small Bowel Neoplasms

in older adults (median age, 65 to 70 years) with

a male predominance and are over-represented in
African-Americans compared to Caucasians.
They arise in association with adenomatous
polyps. Alcohol consumption, smoking, and di-
ets rich in refined sugar, refined carbohydrates,
red meat, and smoked food are risk factors for
small intestinal adenocarcinoma (14). Small bow-
el adenocarcinoma can also arise in patients with
polyposis syndromes (primarily FAP, MUTYH
polyposis, hereditary nonpolyposis colon car-
cinoma syndrome [HNPCC]/Lynch syndrome,
biallelic mismatch repair deficiency syndrome,
Peutz-Jeghers syndrome, and juvenile polyposis
syndrome) (15, 16). Some are also associated with
Crohn's disease; gluten-sensitive enteropathy
(GSE); ileostomy; and ileal conduits. The relative
risk of duodenal adenocarcinoma is highest in
persons with familial adenomatous polyposis
(relative risk, 330.82) (17); whereas the relative
risk of small intestinal cancer in Crohn's disease
and celiac disease are each about 50- to lOO-fold;
but these are still rare.
Most small intestinal adenocarcinomas arise
in the duodenum, where most (65 percent) are
periampullary, and their prevalence decreases Figure 6-12
distally. The exception to this proximal loca- PEUTZ-JEGHERS POLYPS
tion occurs in patients with Crohn's disease, in This example has h erniated through the muscularis
whom 70 percent of adenocarcinomas are ileal. propria in an enteritis cystica profunda configuration . This
Small bowel adenocarcinomas are similar carries no risk for pseudomyxoma peritonei.
histologically to colorectal adenocarcinomas
and most are moderately differentiated, and
one third is poorly differentiated. Often an the ampulla of Vater but the term ampullary
adenomatous precursor can be detected (fig. 6- carcinoma indicates carcinomas centered at the
13). Unfortunately, adenomatous epithelium is ampulla (figs. 6-14-6-16).
often mimicked by tumors metastatic to the GI Ampullary carcinomas are rare, accounting
mucosa and thus the pathologist should be cau- for less than 1 percent of gastrointestinal ma-
tious about reporting small bowel adenocarci- lignant neoplasms presumably because the area
nomas as primary (18). Immunohistochemistry in which they can arise is small. Most patients
can be helpful to exclude metastatic disease. are in the seventh to ninth decade, and there
In persons with Lynch syndrome or its vari- is a male predominance. Syndromic cases (FAP,
ants, immunolabeling for mismatch repair Lynch syndrome) arise in younger patients.
proteins (MLHl, PMS2, MSH2, MSH6) can be Patients present with jaundice, abdominal pain,
informative. pancreatitis, and weight loss.
Most ampullary carcinomas have an intesti"
AMPULLARY CARCINOMAS nal phenotype versus a pancreatobiliary phe-
Ampullary adenocarcinoma has either in- notype (8). The most critical rule to remember
testinal or pancreatobiliary differentiation and is not to diagnose ampullary adenomas or car-
originates in the ampulla of Vater (8). Carcino- cinomas if there is any degree of uncertainty.
mas from the distal common bile duct, head Pancreatic carcinoma often spreads directly to
of the pancreas, or duodenum can all involve the ampulla (fig. 6-17).

129
 Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 6-13
SMALL BOWEL ADENOCARCINOMA
Left: This small bowel adenocarcinoma (left) arose in association with an adenoma in the duodenum in a patient with
celiac disease.
Right: This is high magnification of the lesion seen on the left.

Figure 6-14
AMPULLARY ADENOMA
Left: The lesion is mostly in the upper right part of the field. There are many ampullary glands in the center. They tend
to be admixed with smooth muscle in this site and are biliary type glands that lack gastric or intestinal type mucin.
Right: This is a higher magnification of the area seen on the left.

130
 Small Bowel Neoplasms

Figure 6-15 Figure 6-16

AMPULLARY ADENOCARCINOMA AMPULLARY ADENOCARCINOMA,
COLONIZING DUODENAL MUCOSA GROSS SPECIMEN
Note the Brunner glands at the lower left. The carcinoma An adenoma is seen to the left of the carcinoma. Small
at the top has colonized the surface at the top thereby intestine and a massively dilated biliary tree appears at
mimicking an in situ component. the top.

Figure 6-17
SUBTLE ADENOCARCINOMA IN AN AMPULLARY BIOPSY
Left: This well differentiated adenocarcinoma is deceptively bland. There is a large malignant gland at 10:00 to 12:00 and
small ampullary glands in the center of the field.
Right: The malignant gland at left center does not match the bland biliary glands at the lower right. A small intestinal
gland at the upper left is partly colonized by carcinoma and a malignant gland is at the upper right.

131
 Survival Guide to Gastrointestinal Mucosal Biopsies
Figure 6-18
SARCOMATOID LUNG CANCER
Top: The lesion from a lung has a "bottom up" growth pattern.
Bottom: This is a CAM5 .2 keratin stain from the lesion seen on the left. The mesothelial cells on the small bowel serosa,
the small bowel epithelium, and the carcinoma are all reactive.
Figure 6-19
SARCOMATOID LUNG CANCER FROM THE LUNG
Pleomorphic sarcomas are rare as primary small bowel
lesions such that this appearance should suggest sarcomatoid
carcinoma or dedifferentiated liposarcoma.
132
. ,(, .
.~f\
~ .
Metastases must always be considered (figs.
6-18, 6-19). Features supporting a metastatic
tumor include the presence of multiple lesions,
the absence of a precursor adenoma, a histologic
appearance of tumor being "bottom heavy,"
and lack of ulceration. Common metastatic
lesions include melanoma, colonic adenocar-
cinoma, renal cell carcinoma, testicular/germ
cell neoplasms, and breast and gynecologic
malignancies.
NEUROENDOCRINE TUMORS
As noted in chapter 5, well differentiated
neuroendocrine (carcinoid) tumors are easy to
overlook in mucosal biopsies but are always
worth looking for in duodenal biopsies from
nodules (fig. 6-20).
Small bowel well-differentiated neuroen-
docrine tumors (WDNETs, carcinoid tumors)
comprise about one third of small intestine
neoplasms. They appear to be over-represented
in African-Americans (19).
Duodenal WDNETs account for approximate-
ly 20 percent of GI tract WDNETs (20) . Overall,
duodenal WDNETs are more common in men
(the male-to-female ratio is 1.5:1), with a me-
dian age of about 60 years. About two thirds of
duodenal WDNETs show G cell differentiation
(by immunolabeling with gastrin antibodies).
They can only be termed gastrinomas (G-cell
 Small Bowel Neoplasms

., .

t I ": •t i'

Figure 6-20
WELL-DIFFERENTIATED NEUROENDOCRINE (CARCINOID) TUMOR
Left: The lesion is present throughout the bottom part of the image but is subtle.
Right: This is a chromogranin stain from the lesion depicted on the left.

tumors) if they are functional and produce
gastrin; only one third of gastrin-labeled tu-
mars is functional and causes Zollinger-Ellison
syndrome (ZES) (see the images in chapter 4).
About a third of somatostatin expressing tumors
is associated with von Recklinghausen disease
(neurofibromatosis, type l/NF1) (fig. 6-21).
Gastrinomas tend to be smaller than so-
matostatinomas, and a minority (15 percent) are
multicentric. They can be associated with MEN1
(multiple endocrine neoplasia, type 1, with
parathyroid lesions, pancreatic endocrine/islet
cell tumors, and pituitary lesions) . They can be
very diminutive and yet produce massive bulky
lymph node metastases (21, with (inaccurate)
reports of "primary lymph node gastrinomas."
The grading system is currently in use for
gastrointestinal neuroendocrine tumors are G 1:
<2 mitoses/10 high power fields or ~2 percent
Ki-67 index (fig. 6-22); and G2: mitotic count
2-20 per 10 high power fields or 3-20 percent
Ki-6 7 index.
Grade 3 tumors are high-grade neuroendonine
carcinomas (large cell or small cell types) and are
characterized by >20 mitoses /10 high power fields
or >20 percent Ki-67 index (fig. 6-23).
WDNETs consist of a monotonous prolifera-
tion of small, bland, polygonal cells with mod-
erate amounts of cytoplasm and round, regular
nuclei with "salt and pepper" chromatin.
Duodenal WDNETs are generally indolent
(overall about 5 percent mortality); however,
two thirds of somatostatinomas and one half
of functional gastrinomas behave aggressively.
Poor outcome in duodenal tumors is best pre-
dicted by invasion beyond the submucosa and
lymph node or distant metastases. Jejunoileal
WDNETs have a worse prognosis than those
of the duodenum, with a 20 percent mortality
rate. Survival has been negatively correlated
with distant metastases (liver), lymph node
metastases, tumor multiplicity, mitotic rate/ki-
67labeling index, invasion beyond submucosa,
and female gender.

133
 Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 6-21
WELL-DIFFERENTIATED NEUROENDOCRINE (CARCINOID) TUMOR
Left: This is a somatostatinoma and it arose in a patient with neurofibromatosis, type 1 (NFl).
Right: Psammoma bodies (lower right) are characteristic of duodenal somatostatinomas.

Figure 6-22
WELL-DIFFERENTIATED NEUROENDOCRINE (CARCINOID) TUMOR
Left: This tumor is centered in the subm ucosa.
Right: This ileal carcinoid shows a very characteristic feature of ileal carcinoids, namely th e presence of reddish cytoplasmic
granules that point towards the outside of the tumor nests, with their contents thus "aimed" at blood vessels. Note the "salt
and pepper" chromatin.

134
 Small Bowel Neoplasms

Figure 6-23
HIGH-GRADE NEUROENDOCRINE CARCINOMA
Left: In this small cell type arising in association with adenoma, the malignant cells at the top show abundant nuclear
molding.
Right: This is a high magnification of the lesion seen on the left.

An occasional pitfall is paraganglia or para- On immunohistochemistry, the tumors

gangliomas, which is more an issue in resection
specimens than in mucosal biopsies (fig. 6-24).
In doubtful cases, keratin staining can be added,
which labels WDNETs but not paraganglia and
paragangliomas.
GANGLIOCYTIC PARAGANGLIOMA
Gangliocytic paragangliomas are essentially al-
ways found in the duodenum in adult patients
with an average age of about 54 years (22- 28) .
Rare examples are found in the jejunum or even
the pylmus. They are usually centered in the sub-
mucosa. Most tumors are 3 to 4 cm, with a soft,
yellowish, cut surface, and infiltrative borders.
These tumors have varying proportions of
three cell types (fig. 6-25): 1) spindled nerve
sheath cells; 2) ganglion-like cells; and 3) epi-
thelioid cells arranged in nests ("endocrine" pat-
tern), and trabeculae or papillary structures.
are reactive with S-100 protein in the spindle
cells and synaptophysin in ganglion-like cells.
About half of the cases display keratin in the
epithelioid cells.
Gangliocytic paragangliomas are usually
benign, but there are rare reports of regional
metastases (28) and a single report of a tumor-
associated death (29).
LYMPHOMAS
Diffuse large B-celllymphomas can arise in
the duodenum, as can mucosa-associated lym-
phoid tissue (MALT) lymphomas, but the ones
that are interesting in the small bowel include
follicular lymphomas, mantle cell lymphomas,
and T-celllymphomas. Large B-celllymphomas
can be evaluated as per those in the stomach.
Lymphoid follicles themselves are common
in the small intestine and ileum and most are

135
Survival Guide to Gastrointestinal Mucosal Biopsies

·,.,.'
.,1.
Figure 6-24
PARAGANGLION
A: This is a normal structure. There is a
nerve coursing through adipose tissue along the
bottom of the image with an adjoining structure
that contains both ganglion cells (center of ..·
image) and paraganglia! cells (top left).
B: This is the paraganglia! component from \~ .
the paraganglion seen in A. The nuclei are \
similar to those of carcinoid tumors but the
cytoplasm is grey. If there is any doubt, keratin
stains are negative in paraganglia.
C: This is the ganglion cell component from
the paraganglion seen in figure A. There are
admixed Schwann cells with spindled nuclei.
The ganglion cells have prominent nucleoli
(upper left and lower right) and abundant
cytoplasm that contains purple Nissl substance
(see best in the cells at the top).

reactive and require no immunolabeling. A lymphoma must be distinguished from mantle

pitfall is that sometimes nonneoplastic B cells
in the terminal ileum eo-label with CD43 (30).
The special lymphoma to recognize in the
duodenum is follicular lymphomas, which is
frequently an indolent process detected in the
evaluation of an unrelated condition such as
gastroesophageal reflux disease. This type of
cell lymphoma, which can be aggressive and
relentless. The key immunostain to use for
mantle cell lymphoma is BCLl/cyclin Dl. A
panel for lymphomas containing small B cells
as detected on CD20 can include BCL2, cyclin
Dl, and CDS (to capture small lymphocytic
lymphoma/leukemia).

136

Follicular Lymphoma
In the absence of concomitant disease else-
where, small intestinal follicular lymphoma can
usually be managed by observation alone. In the
2016 World Health Organization (WHO) clas-
sification, duodenal type follicular lymphoma is
a separate category that is akin so-called in situ
Small Bowel Neoplasms
Figure 6-25
GANGLIOCYTIC PARAGANGLIOMA
A: The tumor is centered in the submucosa.
B: There are three components. Epithelioid
nests of endocrine type cells (lower half of the
image, Schwann cells (top) and ganglion cells
(throughout) comprise the lesion.
C: This image shows Schwann cells and
ganglion cells. In small biopsies that lack all
components, this lesion can be interpreted as a
nerve sheath tumor whereas if only the epithelioid
component is sampled, an interpretation of
carcinoid is likely. .Gangliocytic paragangliomas
have keratin expression in the epithelioid
component in about half of cases in contrast
to paraganglia, which lack keratin expression.
follicular neoplasia (31). Rare cases progress to
diffuse large B cell lymphoma.
At low magnification, prominent lymphoid
follicles are seen but the apparent germinal
centers lack typical tingible body macrophages
(figs. 6-26, 6-27). On immunolabeling, the
tumor cells (the ones inside the prominent fol-
licles) eo-express CD20, CD10, BCL2, and BCL6,
137
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 6-26
FOLLICULAR LYMPHOMA
Left: There is a large follicle at the bottom that lacks tingible body macrophages in its center.
Right: The center of the follicle contains monotonous cells with spaces ("halos" /fried egg appearance) around. The
architecture of the lesion (this is a high magnification of the large follicle on the left) is that of follicular lymphoma, but the
cytologic features overlap with those of mantle cell lymphoma and chronic lymphocytic leukemia/lymphoma, so adding
immunolabeling is sometimes important.

but not CD5 or CD43. Normal cells inside the
follicles are BCL2 negative so the co-labeling
of the cells inside the follicles with BCL2 and
BCL6 is a clue to the diagnosis. CD21 or CD23
can highlight follicular dendritic cells if they are
difficult to discern on routine stains.
Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) is incurable, aris-
ing in older adults (mean age, 55 years) with a
male predominance (of at least 2:1). Extranodal
disease is common, with GI tract involvement
in about one third of MCL patients.
When MCL involves the GI tract, both distal
small bowel and colon involvement are typical
(32). A "lymphomatous polyposis" pattern is
commonly associated with MCL but not specific
for it. Mesenteric node involvement often ac-
companies GI tract disease.
The lymphoma cells are small- to medium-
sized with minimal cytoplasm and there is often a
"fried egg" appearance (fig. 6-28); the nuclei have
irregular outlines and indistinct nucleoli. MCL
has a much more monotonous appearance at low
magnification than other low-grade lymphomas.
Mitotic figures are easily identified. While displace-
ment and/or obliteration of the glands may also
be evident, lymphoepitheliallesions characteristic
of MALT-type lymphomas are absent.
The tumor cells are B-cells that express both
CD19, CD20, and BCL2, and aberrantly express
CD5 and CD43. They lack CDlO and CD23. Cy-
clin D-1 (Bel-l) expression (nuclear) is virtually
always present.
T-Cell Lymphomas
The majority of T-cell primary GI lympho-
mas occur in the setting of gluten-sensitive

138
 Small Bowel Neoplasms

Figure 6-27
FOLLICULAR LYMPHOMA
Left: This BCL6 stain highlights the follicular center areas where aberrant expression of BCL2 can be sought.
Right: This BCL2 stain highlights cells in abnormal follicles.

Figure 6-28
MANTLE CELL LYMPHOMA
Left: Note the similarity of the cytologic features to those of the follicular lymphoma in figures 6-26 and 6-27. This lesion,
however, did not form follicles.
Right: This is a cyclin Dl (BCLl) stain. It labels the nuclei of the lymphoma cells but also the proliferating nuclei of the
reactive enterocytes.

139
Survival Guide to Gastrointestinal Mucosal Biopsies
Figure 6-29
T-CELL LYMPHOMA, ENTEROPATHY-ASSOCIATED
This example is subtle but features enlarged atypical cells
in the lamina propria at the top center of the image.
enteropathy (GSE) and are specifically referred
to as "enteropathy-type T-celllymphoma" (ETL)
but these are rarer than B cell tumors (fig. 6-29).
ETL is rare (about 5 percent of all GI tract lym-
phomas). Refractory GSE and ulcerative enteritis
(jejunitis) are probably represent the first step
toward ETL (33).
The WHO 2016 classification divides intesti-
nal T cell lymphomas into two types (31): 1) En-
teropathy-associated T cell lymphoma (EATL).
This type is associated with celiac disease and
tends have pleomorphic cytologic features and
is likely to be found in persons with Northern
European ancestry. Immunophenotype: CD3+,
CDS-, CD7+, CD8 +/-, CD4-, CD56-; and 2)
Monomorphic epitheliotropic intestinal T cell
lymphoma (termed EATL, type 2 in the past) is
NOT associated with celiac disease and is found
in Asians and Hispanics and has monomorphic
cytologic features. Immunophenotype: CD3+,
CD4-, CD8+, CD56+.
140
MESENCHYMAL TUMORS
Gastrointestinal Stromal Tumors
(GISTs) of the Small Bowel
Small intestinal GISTs are more aggressive
than gastric GISTs (34,35).
Gastrointestinal Tumors of Duodenum
Duodenal GISTs are most common in the
second part of the duodenum and the most
common presenting sign is GI bleeding. Most
have spindled morphology with common focal
nuclear atypia and over 50 percent have skenoid
fibers. Duodenal GISTs are consistently immu-
noreactive with CD117 but S-100 positivity and
focal nuclear palisading in these tumors (20
percent) may raise the possibility of schwan-
noma (fig. 6-30).
Gastrointestinal Tumors of Jejunum and Ileum
Patients most commonly present with GI
bleeding (mostly insidious), but acute abdomen
with obstruction, tumor rupture with intraab-
dominal hemorrhage, and abdominal pain
mimicking appendicitis are all recorded (34).
Most tumors have spindled morphology, but
some may be epithelioid, or mixed (spindled
and epithelioid).
The presence of multiple GISTs, especially
in the small bowel (including the duodenum),
should raise the possibility of neurofibromatosis
1 (NF1) (34,36,37). While NF1-associated GISTs
are immunoreactive with CD 117, they lack KIT
or PDGFRA mutations, in keeping with different
pathogenesis from that of sporadic GISTs (37).
Jejuna-ileal GISTs essentially all express KIT,
sometimes in a dot-like Golgi zone distribution
whereas CD34 is found in only about 40 percent
of cases. Smooth muscle actin expression oc-
curs in about a third and desmin expression is
exceptional and focal. S-1 00 protein expression
is found in about 15 percent.
DOG1 (discovered on GISTs1, also termed
anoctamin 1 or AN01 and ORAOV2 or- over-
expressed in oral carcinoma) is another marker
(38). DOG1 is a chloride channel protein that
was identified in GISTs by gene profiling studies
(3 9-41). DOG 1 is expressed in 3 6 to 9 2 perc:ent
of KIT-negative GISTs (38). KIT is more sensitive
for intestinal GISTs than DOG 1 but the two
markers together (42) mark nearly all GISTs.
 Small Bowel Neoplasms

Figure 6-30
GASTROINTESTINAL STROMAL TUMOR (GIST)
Left: The nuclei are highly monotonous and arranged in palisades that suggest a Schwannoma. Nuclear pleomorphism
is unusual in GISTs.
Right: This is a CD117 /KIT stain, showing strong membranous labeling.

The most common mutations in GISTs are
those of exon 11 of the KIT gene. About 20 per-
cent of GISTs have mutations in exon 9 instead,
and these usually arise in the intestines (small
and large). Tumors with mutations in exons 13,
17, and 8 also tend to affect the small bowel
although there are few data on the latter since
they are rare (38,42). Occasional small intestinal
GISTs have BRAF V600E mutations.
VASCULAR LESIONS
Vascular tumors of the small bowel are uncom-
mon. Lymphangiomas usually arise in children
and can involve any portion of small intestine
including the Ampulla of Vater (43,44). The
tumor is composed of numerous thin-walled
lymphatic spaces filled with proteinaceous ma-
terial (fig. 6-31). The vessel walls may contain
lymphoid aggregates. "Lymphangiomatosis"
has been applied to extensive, diffuse lesions.
Vascular malformations are often best diag-
nosed on imaging studies but finding thick-
walled small caliber vessels in the lamina pro-
pria suggests the diagnosis (45) .
Angiosarcoma may involve the GI tract and
has a tendency to display epithelioid morphol-
ogy. Small bowel angiosarcomas are grossly red,
polypoid mucosal- or serosal-based hemorrhag-
ic, friable lesions. The tumors are infiltrative
and grow as diffuse sheets of epithelioid cells
with areas of clefting. Cytologically the tumors
show uniform, epithelioid cells with eosinophil-
ic cytoplasm and hyperchromatic nuclei with
very prominent nucleoli (figs. 6-32, 6-33). Im-
munohistochemical staining can be misleading
since the epithelioid variant of angiosarcoma
is immunoreactive to AE1/ AE3 and may also
show immunoreactivity to other keratins but
not CK20.

141
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 6-31
LYMPHANGIOMA
Left: Dilated lymphatic spaces contain lymphocytes. Unfortunately it is impossible to know whether a mucosal lesion
found in a small biopsy such as this is a small isolated lesion or the "tip of the iceberg" of lymphangiomatosis/lymphatic
malformation, especially in biopsies from children.
Right: This is a high magnification of the lesion seen on the left.

Figure 6-32
ANGIOSARCOMA
Note the epithelioid and spindle cell
appearance at the left.

142
 Small Bowel Neoplasms

Figure 6-33
ANGIOSARCOMA
Left: The malignant cells feature prominent nucleoli. Often immunolabeling is needed to confirm the interpretation;
many express keratins such that carcinoma is considered.
Right: This is a CD31 stain from the tumor seen in figure 6-32 and on the left.

REFERENCES

1. Rosty C, Campbell C, Clendenning M, Betting-
ton M, Buchanan DD, Brown IS. Do serrated
neoplasms of the small intestine represent a dis-
tinct entity? Pathological findings and molecular
alterations in a series of 13 cases. Histopathology
2015;66:333-342.
2. Genta RM, Feagins LA. Advanced precancerous
lesions in the small bowel mucosa. Best Pract Res
Clin Gastroenterol 2013;27:225-233.
3. Genta RM, Hurrell]M, Sonnenberg A. Duodenal
adenomas coincide with colorectal neoplasia.
Dig Dis Sci 2014;59:2249-2254.
4. Shih IM, Wang TL, Traverso G, et al. Top-down
morphogenesis of colorectal tumors. Proc Natl
Acad Sci US A 2001;98:2640-2645.
5. Vieth M, Montgomery EA. Some observations on
pyloric gland adenoma: an uncommon and long
ignored entity!] Clin Pathol2014;67:883-890.
6. Kim I<, ]ang S], Song H], Yu E. Clinicopatho-
logic characteristics and mucin expression in
Brunner's gland proliferating lesions. Dig Dis Sci
2013;58:194-201.
7. Vieth M, Kushima R, Bm·chard F, Stolte M. Pyloric
gland adenoma: a clinico-pathological analysis
of 90 cases. Virchows Arch 2003;442:317-321.
8. Bosman F, Carneiro F, Hruban R, Theise N, eds.
WHO Classification of tumours of the digestive
system. In: Bosman F, ]affee E, Lakhani S, Ohgaki
H, eds. World Health Organization Classification
of tumours. Lyon: IARC; 2010.
9. Giardiello FM, Brensinger]D, Tersmette AC, et al.
Very high risk of cancer in familial Peutz-Jeghers
syndrome. Gastroenterology 2000;119:1447-
1453.
10. van Lier MG, Wagner A, Mathus-Vliegen EM,
Kuipers EJ, Steyerberg EW, van Leerdam ME.
High cancer risk in Peutz-Jeghers syndrome: a
systematic review and surveillance recommenda-
tions. Am] Gastroenterol 2010;105:1258-1264;
author reply 1265.
11. Aretz S, Stienen D, Uhlhaas S, et al. High proportion
of large genomic STK11 deletions in Peutz-]eghers
syndrome. Hum Mutat 2005;26:513-519.
12. Volikos E, Robinson ], Aittomaki I<, et al. LKB1
exonic and whole gene deletions are a common
cause of Peutz-Jeghers syndrome. ] Med Genet
2006;43:e18.
13. Siegel RL, Miller KD, ]emal A. Cancer statistics,
2016. CA Cancer] Clin. 2016;66:7-30.
14. Aparicio T, Zaanan A, Svrcek M, et al. Small
bowel adenocarcinoma: epidemiology, risk
factors, diagnosis and treatment. Dig Liver Dis
2014;46:97-104.
15. Pounnand I<, Itzkowitz SH. Small bowel neoplasms
and polyps. CurT Gastroenterol Rep 2016; 18:23.
16. Durno CA, Sherman PM, Aronson M, et al.
Phenotypic and genotypic characterisation of
biallelic mismatch repair deficiency (BMMR-D)
syndrome. Eur] Cancer 2015;51:977-983.

143
Survival Guide to Gastrointestinal Mucosal Biopsies
17. Offerhaus G], Giardiello FM, Krush A], et al. The
risk of upper gastrointestinal cancer in famil-
ial adenomatous polyposis. Gastroenterology
1992;102:1980-1982 ..
18. Estrella]S, Wu TT, Rashid A, Abraham SC. Mucosal
colonization by metastatic carcinoma in the gas-
trointestinal tract: a potential mimic of primary
neoplasia. Am] Surg Pathol 2011;35 :563-5 72.
19. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of
13,715 carcinoid tumors. Cancer 2003;97:934-959.
20. Burke AP, Federspiel BH, Sobin LH, Shekitka
KM, Helwig EB. Carcinoids of th e duodenum. A
histologic and immunohistochemical study of
65 tumors . Am] Surg Pathol 1989;13:828-837.
21. Anlauf M, Enosawa T, Henopp T, et al. Primary
lymph node gastrinoma or occult duodenal
microgastrinoma with lymph node metastases
in a MEN1 patient: the need for a systematic
search for the primary tumor. Am] Surg Pathol
2008;32:1101-1105.
22. Burke AP, Helwig EB. Gangliocytic paraganglia-
ma. Am J Clin Pathol 1989;92:1-9.
23. Hashimoto S, Kawasaki S, Matsuzawa K, Harada
H, Makuuchi M. Gangliocytic paraganglioma of
the papilla of Vater with regional lymph node me-
tastasis. Am] Gastroenterol1992;87:1216-1218.
24. Inai K, Kobuke T, Yonehara S, Tokuoka S. Duo-
denal gangliocytic paraganglioma with lymph
node metastasis in a 17-year-old boy. Cancer
1989;63:2540-2545.
25. Perrone T, Sibley RI<, Rosai]. Duodenal gangliocyt-
ic paraganglioma. An immunohistochemical and
ultrastructural study and a hypothesis concerning
its origin. Am] Surg Pathol1985;9:31-41.
26. Reed R], Caroca PJ Jr, HarkinJC. Gangliocytic para-
ganglioma. Am] Surg Pathol1977;1:207-216.
27. Scheithauer BW, Nora FE, LeChago ], et al.
Duodenal gangliocytic paraganglioma. Clinico-
pathologic and immunocytochemical study of
11 cases. Am] Clin Pathol 1986;86:559-565 .
28. Witkiewicz A, Galler A, Yeo C], Gross SD. Ganglia-
cytic paraganglioma: case repmt and review of the
literature. J Gastrointest Surg 2007;11:1351-1354.
29. LiB, Li Y, Tian XY, Luo BN, Li Z. Malignant gan-
gliocytic paraganglioma of the duodenum with
distant metastases and a lethal course. World J
Gastroenterol 2014;20:15454-15461.
30. Mojtahed A, Pai RI<, Anderson MW, Arber DA,
Longacre TA. Reactive lymphoid hyperplasia of
the terminal ileum: a benign (lymphoma-like)
condition that may harbor aberrant immunohis-
tochemical patterns or clonal immunoglobulin
heavy chain gene rearrangements. Appl immu-
nohistochem Mol Morphol 2014;22:585-592.
31. Swerdlow SH, Campo E, Pileri SA, et al. The
2016 revision of the World Health Organization
classification of lymphoid neoplasms . Blood
2016;127:2375-2390.
32. RomagueraJE, Medeiros LJ, Hagemeister FB, et al.
Frequency of gastrointestinal involvement and
144
its clinical significance in mantle cell lymphoma.
Cancer 2003;97:586-591.
33. Daum S, Weiss D, Hummel M, et al. Frequency
of clonal intraepithelial T lymphocyte prolif-
erations in enteropathy-type intestinal T cell
lymphoma, coeliac disease, and refractory sprue.
Gut 2001;49:804-812.
34. Miettinen M, Makhlouf H, Sobin LH, Lasota ].
Gastrointestinal stromal tumors of the jejunum
and ileum: a clinicopathologic, immunohisto-
chemical, and molecular genetic study of 906
cases before imatinib with long-term follow-up.
Am] Surg Pathol2006;30:477-489 .
35. Miettinen M, Sobin LH, Lasota]. Gastrointestinal
stromal tumors of the stomach: a clinicopath-
ologic, immunohistochemical, and molecular
genetic study of 1765 cases with long-term fol-
low-up. Am J Surg Pathol 2005;29:52-68.
36. Hirashima K, Takamori H, Hirota M, et al. Mu!-
tiple gastrointestinal stromal tumors in neuro-
fibromatosis type 1: report of a case. Surg Today
2009;39 :979-983.
37. Miettinen M, Fetsch ]F, So bin LH, Lasota]. Gas-
trointestinal stromal tumors in patients with
neurofibromatosis 1: a clinicopathologic and
molecular genetic study of 45 cases. Am J Surg
Pathol 2006;30:90-96.
38. Doyle LA, Hornick JL. Gastrointestinal stromal
tumours: from KIT to succinate dehydrogenase .
Histopathology 2014;64:53-67.
39. Espinosa I, Lee CH, Kim MK, et al. A novel
monoclonal antibody against DOG 1 is a sensitive
and specific marker for gastrointestinal stromal
tumors. Am J Surg Pathol 2008;32:210-218.
40. Gomez-Pinilla P] , Gibbons SJ, Bardsley MR, et al.
Ano1 is a selective marker of interstitial cells of
Cajal in the human and mouse gastrointestinal
tract. Am J Physiol Gastrointest Liver Physiol
2009;296:G 13 70-1381.
41. West RB, Corless CL, Chen X, et al. The novel mark-
er, DOG 1, is expressed ubiquitously in gastmintes-
tinal stromal tumors irrespective of KIT or PDGFRA
mutation status. Am] Pathol2004;165:107-113.
42. Miettinen M, Lasota ]. Gastrointestinal stromal
tumors. Gastroenterol Clin North Am 2013;42:
399-415.
43. Artaza T, Potenciano ]M, Legaz M, Munoz C,
Talavera A, Sanchez E. Lymphangioma of Vater's
ampulla: a rare cause of obstructive jaundice.
Endoscopic therapy. Scand J Gastroenterol
1995;30:804-806.
44. Elliott RL, Williams RD, Bayles D, Griffin] .
Lymphangioma of the duodenum: case report
with light and electron microscopic observation.
Ann Surg 1966;163:86-92.
45 . Handra-Luca A, Montgomery E. Vascular mal-
formations and hemangiolymphangiomas of
the gastrointestinal tract: morphological fea -
tures and clinical impact. Int] Clin Exp Pathol
2011 ;4:430-443.
 7 NON -NEOPlASTIC COlON
Like the small intestine, the colon has a lim-
ited set of responses to injuries that can be di-
vided into a few general patterns. These include
acute colitis, an ischemic pattern, active chronic
colitis, lymphocytic colitis, collagenous colitis,
and apoptotic colopathy with or without any
of the other patterns! These patterns and some
of the entities associated with them appear in
Table 7-1. Once these patterns are recognized,
Table 7-1
PATTERNS OF NON-NEOPLASTIC DISEASE
Pattern Description
Pure acute colitis Neutrophils in crypts and lamina
propria; no crypt distortion, no
basal plasmacytosis
Ischemic colitis Hyalinized ("collapsed") lamina
propria, atrophic crypts, surface
erosions, reactive changes;
overall intact crypt architecture
Active chronic colitis Cryptitis, crypt abscesses, crypt
distortion, basal plasmacytosis,
Paneth cell metaplasia in distal
colon, pyloric metaplasia
Lymphocytic colitis Intraepitheliallymphocytosis
with or without prominent
crypt apoptosis
Collagenous colitis Intraepitheliallymphocytosis
with or without prominent
crypt apoptosis and abnormal
thickened subepithelial collagen
table
Apoptotic colopathy Prominent crypt apoptosis
(surface apoptosis is normal)
with or without inflammation
it is not difficult to develop a differential diag-
nosis. In addition to recognizing the patterns
and some of the associations, there are a few
infections that are important to recognize and
those are discussed initially, followed by discus-
sion of the patterns. Some infections can affect
both the small intestine and colon and have
been discussed in chapter 5 (strongyloidiasis,
Mycobacterium avium complex).
Associations
Bacterial infections
Chemical injuries
Phosphosoda bowel preparations (seldom used)
Vascular insufficiency
Infections (C. difficile, enterohemorrhagic E. coli,
cytomegalovirus)
Drugs (sometimes drugs of abuse such as cocaine but
also decongestants, oral contraceptives)
Vasculitis
Ulcerative colitis
Crohn's disease
Diverticular disease
Some infections (histoplasmosis, amebic colitis)
Idiopathic
Celiac disease
Autoimmune conditions
Common variable immunodeficiency
Medications (proton pump inhibitors, angiotensin II
receptor antagonists such as losartan and olmesartan)
Idiopathic
Autoimmune conditions
Common variable immunodeficiency
Medications (proton pump inhibitors, angiotensin Il
receptor antagonists such as losartan and olmesartan)
Graft versus host disease
Medications (mycophenolate, angiotensin II receptor
antagonists such as losartan and olmesartan, idelalisib,
PDLl blockade drugs and other monoclonal antibodies)
Common variable immunodeficiency
Autoimmune enterocolopathy
Infections (cytomegalovirus)
145
 Survival Guide to Gastrointestinal Mucosal Biopsies
Figure 7-1
NORMAL COLONIC MUCOSA
The top etypt shows Paneth cells (one is indicated), which
contain plump pink granules that contain lysozyme. The
cytoplasm points towards the lumen so that the granules can
release their contents to protect the body. Ail endocrine cell
is indicated in the lower crypt and features tiny red granules
pointed towards the lamina propria and thus the circulation.
Paneth cells are normally found in the right colon but not
the left colon. Their presence in the left colon is metaplastic.
Figure 7-2
RIGHT COLON
It is easy to spot inflammatory cells in the lamina
propria, a mixture of plasma cells, lymphocytes, and
eosinophils. A few intraepithelial eosinophils are normal
in the right colon, and can be dismissed.
146
..
'·..
(
•(
/
' ·- .
Figure 7-3
LEFT COLON
There are far fewer inflammatory cells in the lamina propria
of the left colon, than in that of the right colon.
NORMAL COLONIC MUCOSA
As seen in chapter 5, the colonic crypts can
be compared to test tubes lined up in a test tube
rack (see figs. 5-1, 5-2). This basic architecture
is preserved in some abnormal conditions and
deranged in others. Paneth cells are normally
found in the cecum and ascending colon and
even sometimes the transverse colon but should
be absent in the left colon and also need to be
distinguished from neuroendocrine cells (fig.
7-1). There are more lamina propria inflamma-
tory cells in the right colon than the left colon
(figs. 7-2, 7-3). Lymphoid aggregates are also
normal and it is normal to encounter a break
in the muscularis mucosae in the area of the
lymphoid aggregates (fig. 7-4). This becomes an
important issue in assessing early carcinomas
and adenomas, shown in chapter 8. Remember
that patients with irritable bowel syndrome have
normal microscopic anatomy. Because of this, it
can be important to report normal to establish
this diagnosis. Many rectal biopsies contain mu-
ciphages (fig. 7-5), which have a very different
appearance from cells infected with Whipple
bacillus and are an incidental finding.
 Non-Neoplastic Colon

:...
- ·C\
Figure 7-4
LYMPHOID AGGREGATE
A: Note that there is a break in the muscularis mucosae at the site of the lymphoid aggregate. This is an entirely normal
finding. Note also that the nonneoplastic epithelium has herniated a bit into the aggregate. It is important to be aware of
this since adenomatous epithelium can do the same, and this does not indicate invasive carcinoma.
B: In this example, the epithelium is seen right in the gap in the muscularis mucosae and the lymphoid aggregate has
a germinal center.
C: This example produced a polyp.
D: Note the appearance of the surface epithelium over the lymphoid aggregate seen in "C." The presence of many
intraepithelial lymphocytes is entirely normal. However, finding neutrophils atop lymphoid aggregates is not normal and
can be the earliest sign of Crohn's disease in mucosal biopsies, especially those from children.

147
Survival Guide to Gastrointestinal Mucosal Biopsies
Figure 7-5
MUCIPHAGES
These are very common in rectal biopsies. When they
contain pigment (lipofuscin), the term melanosis coli can
be invoked. The latter is associated with overuse of laxatives.
Rectal muciphages are found in the deep lamina propria.
INFECTIONS W ITH
CHARACTERISTIC FEATURES
Colonic spirochetosis is associated with ab-
dominal pain, appendicitis, chronic diarrhea,
and rectal bleeding but is often is an inciden-
tal finding with no clear clinical correlates.
The mucosa may appear entirely normal to
the endoscopist or may show areas of ulcer-
ation, erosion, edema, and/or erythema (1-3) .
Brachyspira aalborgi and Brachyspira pilosicoli,
anaerobic bacteria, seem to be responsible for
most cases of spirochetosis. The organism was
found in 0.7 percent of patients with chronic
watery diarrhea (4). On histologic examination
the organism produces a fuzzy pattern on the
surface of the colon (fig. 7-6). Symptomatic pa-
tients are typically treated with metronidazole,
while antibiotics are not typically administered
to asymptomatic individuals.
148
Cytomegalovirus is associated with immuno-
suppression, including that intrinsic to old age.
The viral cytopathic inclusions preferentially
affect endothelial cells but can be found in ep-
ithelial cells and stromal cells (fig. 7-7).
ACUTE COLITIS
Acute colitis essentially means finding neu-
trophils in colon crypts. It can be very focal (fig.
7-8), which can raise the possibility of Crohn's
disease in children whereas focal acute colitis
in adults can be essentially regarded as an inci-
dental finding (5,6) sometimes associated with
self-limiting infection and drugs (e.g., NSAIDs).
Campylobacter jejuni can sometimes be invoked
(7) . In children, about a quarter with focal acute
colitis are later shown to have Crohn's disease
(8). In Greenson's studies, no adult patient with
FAC developed Crohn's disease (5). In general,
infections such as Campylobacter jejuni pro-
duce an acute colitis picture with neutrophils
in crypts and in the lamina propria (fig. 7-9).
The important thing is that the basic mucosal
architecture remains intact.
ISCHEMIC COLITIS PATTERN
The pattern of injury associated with isch-
emic colitis includes marked surface injury, mu-
cin loss in crypts, "atrophic microcrypts", and
the hyalinization of the lamina propria, wherein
the normal loose connective tissue (dotted with
plasma cells, lymphocytes, and eosinophils) is
replaced with a dense eosinophilic matrix, and
the residual glands become more closely spaced
(lamina propria "collapse") (fig. 7-10) (9). Cyto-
logic atypia can even include abnormal mitoses
and pseudomembranes.
Ischemic colitis can be associated with both
legal and illegal drugs (prescribed and "over-
the-counter") (10), as well as hypertension, dia-
betes, chronic obstructive pulmonary disease,
coronary artery disease, abdominal surgery,
use of opioids, antihypertensives, hormone
replacement therapy, performance-enhancing
supplements, kayexalate (as seen in chapter 5),
and immunomodulators (10-12).
The infectious agents that can produce an
ischemic colitis pattern include enterohemor-
rhagic (verotoxin-producing) E. coli and Clos-
n·idium dif(icile. Stool studies are required to
confirm the diagnosis.
 Non-Neoplastic Colon

Figure 7-6
INTESTINAL SPIROCHETOSIS
A: At first glance, the sample appears entirely normal with preserved crypt architecture.
B: At high magnification, the surface appears "fuzzy."
C: This is an immunostain for syphilis but the organisms of intestinal spirochetosis cross react with the antibody. Finding
intestinal spirochetosis in a sample from a child does not indicate child abuse.
D: High magnification of the immunostain.

Radiation colitis has overlapping features with
ischemic colitis. It can be acute or chronic. In acute
radiation colitis, crypts are dilated and lined by
"flattened" atypical epithelial cells showing large
irregular nuclei with prominent nucleoli but a low
nuclear to cytoplasmic ratio . Intracytoplasmic
vacuoles and/or neutrophils, as well as eosinophil-
rich crypt abscesses may be seen (13) . Chronic ra-
diation colitis features hyalinized vessel walls that
tend to be aligned parallel to the surface epithelial
basement membrane (fig. 7-11). Amyloidosis can
have similar appearances (figs. 7-12, 7-13).

149
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 7-7
CYTOMEGALOVIRUS COLITIS
Left: The viral cytopathic effect is typically seen in the endothelial cells. Accompanying features can include hemorrhage,
acute inflammation and prominent crypt apoptosis. There is an enlarged infected cell in the center of the field.
Right: Two endothelial cells in the center of the image show cytoplasmic inclusions and the nuclei are smudged. Other
stromal cells in the field show smudged nuclei (Cowdry type B inclusions).

Figure 7-8
FOCAL ACUTE COLITIS
There .are a few neutrophils
in the crypt epithelium at center
right. In adults this is generally
an incidental findings akin to a
"pimple" of the colon whereas
in children it is a harbinger of
inflammatory bowel disease in 20
to 25 percent of patients.

150
 Non-Neoplastic Colon

Figure 7-9
ACUTE BACTERIAL COLITIS
Left: In this acute bacterial colitis (such as from Campylobacter sp) the crypts are basically arranged in "their normal
configuration but they contain neutrophils, as does the lamina propria.
Right: In this case, the crypts are cut tangentially but they appear as evenly spaced tubules that contain neutrophils (acute
colitis); the crypts are stuffed with neutrophils so the term "crypt abscess" is used.

Figure 7-10
ISCHEMIC COLITIS
Left: The lamina propria is hyalinized compared to the looser appearance in figures 7-2 and 7-3. The number of goblet
cells is reduced.
Right: There is goblet cell loss and striking reactive change. The cells have prominent nucleoli, and an atypical mitosis
is present.

151
Swvival Guide to Gastrointestinal Mucosal Biopsies

Figure 7-11
RADIATION COLITIS
Left: The fragmented portion at the upper right has hyalinized lamina propria but note the dilated lamina propria vessels
that are oriented parallel to the surface.
Right: The lamina propria capillaries have thicker walls than the normally essentially invisible lamina propria
capillaries.

Figure 7-12
AMYLOIDOSIS
Consider amyloidosis whenever
hemorrhagic colorectal samples are
encountered. The tissue is friable/
crumbly in amyloidosis and bleeds
readily on manipulation.

152
 Non-Neoplastic Colon

Figure 7-13
AMYLOIDOSIS
Left: The amyloid is deposited in the muscularis mucosae, imparting a waxy appearance.
Right: This high magnification images shows the amyloid deposition in the muscularis mucosae.

sociated with exacerbations and remissions of

ACTIVE CHRONIC COLITIS
Active chronic colitis is the key pattern for di-
agnosing inflammatory bowel disease. In other
words, there is evidence of ongoing damage to
the mucosa as well as acute damage (figs. 7-14,
7-15). Some observers prefer the term chronic
active colitis. This does not matter, but the
concept does. Acute injury is characterized by
neutrophils, but chronic injury is characterized
not only by prominent chronic inflammation
but also by crypt distortion and crypt atrophy
and various metaplasias. In crypt atrophy, the
crypts do not extend all the way to the basement
membrane and that space may be stuffed with
plasma cells (basal plasmacytosis).
Ulcerative colitis, the prototype for active
chronic inflammatory disease, is a chronic
inflammatory process that results from altered
immune function, characterized by a predomi-
nantly mucosal-based disease and clinically as-
hemorrhagic diarrhea (14). Disease presents at
all ages but the peak age at presentation in the
15- to 25-year age range and a minor peak in
the seventh decade. Children are often brought
for medical attention before these features are
fully developed (whereas adults wait before seek-
ing evaluation) (8,15-17). Biopsies show crypt
architectural distortion and increased mucosal
inflammatory cells. Neutrophils are located
within crypt epithelium (cryptitis) and crypt
lumina (crypt abscesses), with fewer within the
lamina propria around the crypts. Architectural
distortion refers to decreased numbers of crypts
("crypt drop-out") and shortened, branched,
malformed, regenerated crypts
Biopsy fragments from the same area often
show the same degree of inflammation and in-
jury. Granulomas are absent, but occasionally,
a foreign body response to a ruptured crypt
may be found. Paneth cell metaplasia is much

153
 Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 7-14
ULCERATIVE COLITIS
A: The appendiceal orifice can be seen in the lower left side of the image and the entire colon is severely damaged. This is a
sample from the 1970s, when treatments were less effective than modern ones, and such colectomies are seldom seen more recently.
B: This is a so-called cecal patch, an acceptable skip area in patients with ulcerative colitis. The opening of the ileum is
in the center. A nodular red patch is present at the right in otherwise normal-appearing cecal mucosa. The patient also had
disease from the descending colon to the distal rectum.
C: The lamina propria is expanded and some crypts are missing at the bottom. There is band-like inflammation along
the muscularis mucosae and there is chronic inflammation between the bottoms of the crypts and the top of the muscularis
mucosae (basal plasmacytosis). Note that the entire tissue fragment is affected.
D: This image shows both basal plasmacytosis and Paneth cell metaplasia (the sample was from the rectum, where Paneth
cells are not normally found).

154
 Non-Neoplastic Colon

Figure 7-15
CROHN'S DISEASE
A: Note that the tissue at the bottom of the image appears normal whereas the tissue at the top is damaged. In an untreated
patient, this is a clue to a diagnosis of Crohn's disease. However, once patients are treated, the disease distribution can be altered.
B: There is tremendous crypt distortion and basal plasmacytosis at the top part of the sample whereas the bottom part
is unaffected .
C: The pyloric gland metaplasia in the center is characteristic. Pyloric metaplasia is a common finding in ileal Crohn's
disease but is occasionally seen in the colon.
D: There is a granuloma at th e right of th e image and mild acute colitis in the crypt at the left. Granulomas are a marker
for Crohn's disease but not an indication of acute disease. This example shows minimal crypt distortion. In general the
degree of crypt distortion is less prominent than that in ulcerative colitis.

155
Survival Guide to Gastrointestinal Mucosal Biopsies
Figure 7-16
DIVERSION COLITIS
Left: The numerous red nodules are lymphoid
aggregates.
Below: Lymphoid aggregates are striking. At higher
magnification, cryptiti s was prominent but crypt
distortion is mild.
more common than pyloric gland metaplasia.
Upper tract findings (duodenitis, gastritis) are
sometimes reported in patients who otherwise
have classic ulcerative colitis (18-20). Overall,
however, most ulcerative colitis patients have
no or minimal nonspecific upper GI inflamma-
tion in biopsies (20).
Crohn disease (regional enteritis, granulo-
matous enterocolitis, and terminal ileitis) is a
chronic, relapsing, and remitting inflammato-
ry disease of unknown etiology that is often
multifocal and can affect any portion of the GI
tract. Its features focally distributed glandular
destruction, aphthous erosions, and serpiginous
ulcers, as well as transmural inflammation,
fibrosis, and sometimes granulomas. Because
of its transmural nature, fissures, sinuses, and
fistulas may develop. It has an equal gender
incidence and occurs at all ages, with the major
peak incidence between 20 and 30 years of age.
On mucosal biopsies, several biopsies from
the same general site often show a different
156
degree of inflammation and some might be
completely uninflamed. Discrete foci of in-
flammation adjacent to histologically normal
crypts are common. Aphthous erosions or
ulcers, characterized by focal surface epithelial
necrosis atop lymphoid aggregates, are typical
early lesions.
ACTIVE CHRONIC COLITIS MIMICKERS
OF INFLAMMATORY BOWEL DISEASE
Diversion colitis is sometimes encountered. In
some situations, a segment of bowel is resected,
but the surgeon is forced to create an ileostomy
or colostomy because there is simply too much
inflammation (or tumor) to reanastomose the
remaining bowel without clinical compromise.
The remaining bowel (often the rectum) has
no passing fecal stream which can result in so-
called diversion colitis (fig. 7-16) . If the rectum
is left as a blind opening, continuous with the
anus, it is called a "Hartmann pouch," and the
pathologist should consider that there might

,v ,·
' I
~:
i"'
. '
Figure 7-17
DIVERTICULITIS
Note the prominent inflammation in the diverticulum.
Such inflammation can also be prominent at the surface and
mimic inflammatory bowel disease on mucosal samples.
be diversion colitis. The features can perfectly
mimic both ulcerative colitis and Crohn colitis.
Regression of the colitis generally follows res-
toration of the normal continuity of the fecal
stream (21). The colitis is believed to result
from absence of luminal, short-chain fatty acids
(the preferred metabolic substrate of colonic
epithelium) from a change in the bacterial mi-
lieu (21,22). The key feature is the presence of
striking numbers of lymphoid aggregates.
Diverticular disease-associated colitis can also
mimic inflammatory bowel disease (figs. 7-17,
7-18). The inflammatory process is restricted to
the segment of the colon containing diverticula,
which is usually the sigmoid colon, and the rec-
tum and proximal colon are not involved (23) .
The histologic findings can closely mimic those
of ulcerative colitis (24) or Crohn disease (25).
Basal plasmacytosis and lymphoid aggregates
may be present but acute inflammation is usually
mild. Some cases of diverticular disease even have
granulomas, which may also be found in resected
lymph nodes (25). It is important to hesitate in
Non-Neoplastic Colon
Figure 7-18
DIVERTICULAR DISEASE-ASSOCIATED COLITIS
This condition tends to mimic Crohn's disease but
Crohn 's disease restricted to the sigmoid colon is distinctly
unusual. This example shows basaLplasmacytosis and mild
crypt distortion.
diagnosing IBD affecting only the sigmoid colon
in patients with diverticular disease.
There are also a few infections that can
produce features that mimic Crohn's disease.
These include yersiniosis and histoplasmosis
and sexually transmitted proctitides (syphilis
and lymphogranuloma venereum) proctitis. The
latter should be considered in rectal samples in
which the degree of architectural distortion does
not match the degree of chronic inflammation
(figs. 7-19, 7-20). Invariably the patients prove
to be men who have sex with men who are HIV
positive, but this history is not always provided.
LYMPHOCYTIC AND COLLAGENOUS COLITIS
Lymphocytic and collagenous colitis (figs.
7-21-7-23) have been considered patterns of
colitis unified by being forms of "microscopic
colitis." This term has been used to describe
biopsies taken from patients with symptomatic
colitis in whom (usually) there are no endo-
scopic (gross) anomalies, but in which specific
microscopic features are found. Neither seems
157
Swvival Guide to Gastrointestinal Mucosal Biopsies

Figure 7-19
SYPHILIS PROCTITIS
Left: There is massive chronic inflammation out of proportion to the modest degree of crypt distortion. The inflammation
is also prominent in the superficial submucosa.
Right: This is a syphilis immunostain, which highlights the organisms. Unfortunately, most examples of syphilis proctitis
are nonreactive using the syphilis immunostain so correlation with serology is required for diagnosis. Also, lymphogranuloma
venereum proctitis has the same appearances and must be confirmed by rectal swab studies.

Figure 7-20
LYMPHOGRANULOMA
VENEREUM PROCTITIS
Note that most of the inflammation
is submucosal and there is minimal
crypt distortion.

158
 Non-Neoplastic Colon

Figure 7-21
LYMPHOCYTIC COLITIS PATTERN
Left: This pattern can be idiopathic but can be associated with celiac disease and a number of medications. The crypt
architecture is intact but there is prominent intraepitheliallymphocytosis in both the surface epithelium and crypt epithelium.
Right: There is no need to count to see that there are too many lymphocytes in the epithelium. There are also a few
subepithelial macrophages, which is an unremarkable finding.

Figure 7-22
COLLAGENOUS COLITIS PATTERN
Left: There is mild surface intraepithelial lymphocytosis but not much crypt lymphocytosis . No te the subepithelial
collagen that encircles capillaries and traps fibroblast nuclei. It is the quality of this collagen rather than the quantity that
matters for diagnosis. There are prominent eosinophils.
Right: This example features an expanded lamina propria. Collagenous colitis is usually most prominent in the right and
transverse colon and can be missed if only the left colon is biopsied.

159
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 7-23
EROSION IN COLLAGENOUS COLITIS
Left: Erosion is an area of damage that involves only the mucosa and does not involve the full mucosal thickness.
Right: Note the reactive stromal cells.

to impart an increased risk for development of
malignancy or chronic inflammatory bowel dis-
ease such as Crohn disease or ulcerative colitis
but these patterns of injury have associations
with several medications (26).
Collagenous colitis is usually associated with
a normal endoscopic appearance, although
some cases of collagenous colitis may feature
linear mucosal tears or defects, especially those
associated with the use of the proton pump
inhibitor lansoprazole (27-29). Collagenous
colitis has a female-to-male ratio of 6 to 8:1
and a median age at diagnosis of SS years. As-
sociated diseases include rheumatoid arthritis,
thyroid disorders, celiac disease, and diabetes
mellitus. Since the latter conditions are treated
with medications that further alter the immune
system, some examples of collagenous colitis are
undoubtedly medication-associated.
Patients with lymphocytic colitis have chron-
ic watery diarrhea and normal colonoscopy
(30). There is a broad age range at diagnosis, the
mean is in the sixth to seventh decades. Men
and women are equally affected. Some patients
report abdominal pain and/or weight loss. Lym-
phocytic colitis has a stronger association with
celiac disease than collagenous colitis. As with
collagenous colitis, there is be an association
with medication use (e.g., NSAIDs, PPis).
Collagenous and lymphocytic patterns both
feature increased lamina propria cellularity,
which is primarily attributable to plasma cells,
but also lymphocytes and eosinophils. The
crypts are nondistorted or minimally distorted.
There is surface epithelial injury and infiltration
by lymphocytes with loss of mucin, nuclear
irregularity, pyknosis, and flattening of the
surface epithelium. Collagenous colitis, in ad-
dition to the lymphocytosis shows deposition
of an abnormal, irregular layer of collagen un-
derneath the surface epithelium. It tends to be
more pronounced in the proximal colon and

160
 Non-Neoplastic Colon

Figure 7-24
GRAFT VERSUS HOST DISEASE
A: There is crypt dropout and some of the crypts are
tiny and atrophic. There is a loss of inflammation in the
lamina propria.
B: The crypt in the center shows several apoptotic
bodies and the crypt at the left is nearly destroyed and
all that remains is a few endocrine cells with the granules
pointed to the lamina propria. These endocrine nests are
very characteristic of graft versus host disease.
C: The large center crypt shows an apoptotic body at
the lower left and there is an atrophic gland with residual
endocrine cells. The lamina propria lacks eosinophils. Some
patients who have had bone marrow transplants are also
taking mycophenolate, which can produce crypt apoptosis
but it is usually associated with eosinophils and few
endocrine cell nests. It is also always important to search for
cytomegalovirus before diagnosing graft versus host disease.

I
.
I
...
•I •
~
•

••
.• " •• -· ...
;
-'
•

less so in the rectosigmoid. Scattered neutro-
phils are often found in collagenous colitis but
are not a feature of lymphocytic colitis. When
neutrophils are prominent, it suggests superim-
posed infectious colitis. The surface epithelium
tends to separate from the basement membrane
beneath, leaving zones in which abnormal
collagen is exposed on the surface. The surface
lymphocytosis is usually more prominent in
lymphocytic colitis, eosinophils are less com-
mon, and prominent crypt-epithelial lympho-
cytosis is often a feature . It is not necessary to
count lymphocytes.
APOPTOTIC COLOPATHY
Prominent crypt apoptosis can accompany
the patterns noted previously but itself refines
the differential diagnosis (figs. 7-24-7-29) . There
are a few points to note when an apoptotic
colopathy pattern is seen: 1) If the patient is
asymptomatic and crypt apoptotic bodies are
prominent (such is in samples performed at the
time of polypectomies in asymptomatic patients
undergoing colorectal carcinoma screening),
consider the possibility of bowel preparation
artifact; 2) See if plasma cells are present! If
they are absent, consider common variable

161
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 7-25
CHRONIC MYCOPHENOLATE-ASSOCIATED INJURY
Left: There is crypt distortion but the sample lacks the prominent inflammation seen in inflammatory bowel disease.
Mycophenolate is administered to solid organ transplant patients to maintain their grafts (usually kidney) but is used for a
number of autoimmune conditions as well. Even at low magnification, eosinophils are notable in the center of the image.
Right: Eosinophils are readily apparent in contrast to in graft versus host disease as seen in figure 7-24.

Figure 7-26
CHRON IC MYCOPHENOLATE-
ASSOCIATED INJURY
Crypt apoptosis is striking in
this field.

162
 Non-Neoplastic Colon

Figure 7-27
COLITIS ASSOCIATED WITH PEMBROLIZUMAB
Left: There is nothing specific about the findings in this image. Pembrolizumab interferes with the mechanism that allows cells
to be recognized as self to avoid destruction by our immune system. Some tu m or cells acquire "self" antigens to evade immune
surveillance and pembrolizumab and other such preparations block this system thereby creating an iatrogenic autoimmune
diathesis in the patient. There is intraepitheliallymphocytosis, prominent crypt apoptosis, and variable acute inflammation.
Right: Note the crypt apoptosis. The only way to diagnose this condition is by knowing the history, but the apoptosis
is a clue to seek it.

Table 7-2
DECODING THE NAMES OF SOME MONOCLONAL ANTIBODY DRUGS ( - mab)

Type of drug "Code" Examples

Human antiboclies -limu- Ada-limu-mab, lpi-limu-mab
Murine antibodies -Iima- Afe-limo-mab
Chimeric antibodies -lixi- Inf-lixi-mab
Humanized -lizu- Pembro-lizu-mab
Chimeric and humanized -lixizu- Ote-lixizu-mab
Interleukin -kinu- Cana-kinu-mab
Inflammatory lesion -leso- Su-leso-mab

immunodeficiency (31); 3) See if goblet cells nolate (CellCept, Myofortic); 2) Colchicine; 3)

are present. If they are absent, consider auto-
immune enterocolopathy; and 4) Search for
cytomegalovirus and cryptosporidium.
Learn the history. If the patient has had a
solid organ transplant, consider mycopheno-
late-associated injury. Study the medication
list and learn if the patient is taking any of
the following medications (32): 1) mycophe-
Idelalisib; 4) PD-1 inhibitors (pembrolizumab,
nivolumab); 5) Anti CTLA4 medications (ipili-
mumab); 6) -"Sartans": Olmesartan and other
angiotensin II receptor antagonists
Any of the monoclonal antibodies can re-
sult in an apoptotic colopathy pattern. Some
of the monoclonal antibody preparations are
described in Table 7-2.

163
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 7-28
COLITIS IN A PATIENT TAKING BOTH IPILIMUMAB AND NIVOLUMAB
A: Since both dmgs have the same associated alterations, there is no way to know which is responsible for the findings. Ipilimumab
is a CTLA4 inhibitor. This is the arm of the T cells that controls attack on self antigens to augment tumor attack by T cells.
B: There is striking intraepitheliallymphocytosis, and a few intraepithelial neutrophils are also seen.
C: There is prominent crypt apoptosis.

164
 Non-Neoplastic Colon

Figure 7-29
COLITIS IN A PATIENT WITH A MUTATION IN THE GENE THAT ENCODES FOR CTLA4
Left: This patient's immune system is therefore continually activated in an autoimmune fashion. The crypt architecture
is intact. The features are essentially identical to those in persons taking anti-CTLA4 medications (ipilimumab).
Right: This is a high magnification image.

REFERENCES

1. Khashab M, Wilson S, Cho WK. Image of the
month. Intestinal spirochetosis: an unusual
cause of asymptomatic colonic ulceration. Clin
Gastroenterol Hepatol 2010;8:A22.
2. Tsuzawa K, Fujisawa N, Sekino Y, et al. Educa-
tion and imaging. Gastrointestinal: colonic
spirochetosis. J Gastroenterol Hepatol2008;23(Pt
1):1160.
3. UmenoJ, Matsumoto T, Nakamura S, et al. Intes-
tinal spirochetosis due to Brachyspira pilosicoli:
endoscopic and radiographic features. J Gastro-
enterol 2007;42:253-256.
4. Esteve M, Salas A, Fernandez-Banares F, et al.
Intestinal spirochetosis and chronic watery diar-
rhea: clinical and histological response to treat-
ment and long-term follow up. J Gastroenterol
Hepatol2006;21:1326-1333.
5. GreensonJK, Stern RA, Carpenter SL, BarnettJL.
The clinical significance of focal active colitis.
Hum Pathol 1997;28:729-733.
6. Volk EE, Shapiro BD, Easley KA, GoldblumJR. The
clinical significance of a biopsy-based diagnosis
of focal active colitis: a clinicopathologic study
of 31 cases. Mod Pathol1998;11:789-794.
7. Schneider EN, Havens JM, Scott MA, et al. Molec-
ular diagnosis of Campylobacter jejuni infection
in cases of focal active colitis. Am J Surg Pathol
2006;30: 782-785.
8. Xin W, Brown PI, Greenson JK. The clinical
significance of focal active colitis in pediatric
patients. AmJ Surg Pathol2003;27:1134-1138.
9. Dignan CR, Greenson JK. Can ischemic colitis
be differentiated from C difficile colitis in biopsy
specimens? AmJ Surg Pathol1997;21:706-710.

165
Survival Guide to Gastrointestinal Mucosal Biopsies
10. Longstreth GF, Yao ]F. Diseases and drugs that
increase risk of acute large bowel ischemia. Clin
Gastroenterol Hepatol 2010;8:49-54.
11. Magee CD, Moawad F], Moses F. NO-Xplode: a
case of supplement-associated ischemic colitis.
Mil Med 2010;175:202-205.
12. Zou X, Cao ], Yao Y, Liu W, Chen L. Endoscopic
findings and clinicopathologic characteristics of
ischemic colitis: a report of 85 cases. Dig Dis Sci
2009;54:2009-2015.
13. Leupin N, CurschmannJ, Kranzbuhler H, Maurer
CA, Laissue ]A, Mazzucchelli L. Acute radiation
colitis in patients treated with short-term preop-
erative radiotherapy for rectal cancer. Am] Surg
Pathol 2002;26:498-504.
14. Tsang P, Rotterdam H. Biopsy diagnosis of coli-
tis: possibilities and pitfalls. Am ] Surg Pathol
1999;23:423-430.
15. Glickman ]N, Bousvaros A, Farraye FA, et al. Pe-
diatric patients with untreated ulcerative colitis
may present initially with unusual morphologic
findings. Am] Surg Pathol 2004;28:190-197.
16. Washington K, Greenson JK, Montgomery E, et
al. Histopathology of ulcerative colitis in ini-
tial rectal biopsy in children. Am ] Surg Pathol
2002;26:1441-1449.
17. Robert ME, Tang L, Hao LM, Reyes-Mugica M.
Patterns of inflammation in mucosal biopsies of
ulcerative colitis: perceived differences in pediatric
populations are limited to children younger than
10 years. Am] Surg Pathol2004;28:183-189.
18. Rubenstein ], Sherif A, Appelman H, Chey WD.
Ulcerative colitis associated enteritis: is ulcerative
colitis always confined to the colon?] Clin Gas-
troenterol 2004;38(1):46-51.
19. Valdez R, Appelman HD, Bronner MP, Greenson
JK. Diffuse duodenitis associated with ulcerative
colitis. Am] Surg Pathol 2000;24:1407-1413.
20. LinJ, McKenna B], Appelman HD. Morphologic
findings in upper gastrointestinal biopsies of pa-
tients with ulcerative colitis: a controlled study.
Am] Surg Pathol2010;34:1672-1677.
21. Pal K, Tinalal S, AI Buainain H, Singh VP. Diver-
sion proctocolitis and response to treatment
with short-chain fatty acids--a clinicopatho-
166
logical study in children. Indian] Gastroenterol
2015;34:292-299.
22. Harig]M, Soergel KH, Komorowski RA, Wood CM.
Treatment of diversion colitis with shmt-chain-fatty
acid irrigation. N Engl] Med 1989;320:23-28.
23. Tursi A, Elisei W, Brandimarte G, et al. The endo-
scopic spectrum of segmental colitis associated with
diverticulosis. Colorectal Dis 2010; 12:464-470.
24. Makapugay LM, Dean P]. Diverticular disease-
associated chronic colitis. Am ] Surg Pathol
1996;20:94-102.
25. Goldstein NS, Leon-Armin C, Mani A. Crohn's
colitis-like changes in sigmoid diverticulitis speci-
mens is usually an idiosyncratic inflammatory
response to the diverticulosis rather than Crohn's
colitis. Am] Surg Pathol 2000;24:668-675.
26. Kao KT, Pedraza BA, McClune AC, et al. Micro-
scopic colitis: a large retrospective analysis from
a health maintenance organization experience.
World] Gastroenterol2009;15:3122-3127.
27. Nomura E, Kagaya H, Uchimi K, et al. Linear
mucosal defects: a characteristic endoscopic
finding of lansoprazole-associated collagenous
colitis. Endoscopy 2010;42(Suppl2):E9-10.
28. Umeno ], Matsumoto T, Nakamura S, et al. Linear
mucosal defect may be characteristic of lansopra-
zole-associated collagenous colitis. Gastrointest
Endosc 2008;67:1185-1191.
29. Yusuke H, Jun T, Naotaka M, Yuichi T, Yutaka E,
Kazuaki I. Lansoprazole-associated collagenous
colitis: unique presentation, similar to ischemic
colitis. Endoscopy 2009;41(Suppl 2):E281-282.
30. ]essurun], Yardley ]H, Lee EL, Vendrell DD, Schil-
ler LR, Fordtran]S. Microscopic and collagenous
colitis: different names for the same condition?
Gastroenterology 1986;91:1583-1584.
31. Daniels]A, Lederman HM, Maitra A, Montgom-
ery EA. Gastrointestinal tract pathology in pa-
tients with common variable immunodeficiency
(CVID): a clinicopathologic study and review. Am
] Surg Pathol2007;31:1800-1812.
32. Vieth M, Montgomery E. Medication-associ-
ated gastrointestinal tract injury. Virchows Arch
2017;470:245-266.
 COLON POLYPS
8 AND NEOPLASMS
As in the stomach, in the colon, any process
that produces a protuberance creates a clinical
polyp, and some polyps are incidental benign
lesions and some are clinically significant. Most
polyps are readily managed by endoscopic pol-
ypectomy. Of course it is well-established that
removing colorectal adenomas prevents their
progressing to adenocarcinomas .
BENIGN FINDINGS THAT CAN MIMIC
NEOPLASMS OR OTHER DISEASES
Sometimes lymphoid aggregates result in
a clinical polyp. Remember that epithelium
can herniate through breaks in the muscularis
mucosae associated with lymphoid aggregates
(fig. 8-1). Knowing this becomes especially
important when adenomatous epithelium
involves the mucosa that has herniated into
the lymphoid aggregates. It is also common to
encounter air that has entered the tissue in the
area of lymphoid aggregates (fig. 8-2). The air is
introduced into the colon during colonoscopy
(air insufflation) to stretch the mucosa and al-
low the colonoscopist to search for lesions and
some of it seeps into the mucosa, often in areas
of lymphoid aggregates, where it resembles adi-
pose tissue. Generally it is an incidental finding,
but it can sometimes produce a nodule.
Vegetable matter, especially pulses (beans,
chickpeas, lentils) can become lodged in the
mucosa, especially in or around diverticula (and
thus in the sigmoid colon), where it can result
in granulomas, so-called pulse granulomas
(fig. 8-3) that have appearances reminiscent of
parasitic ova!
Occasionally, heterotopic gastric mucosa can
be found in the rectum and form a polyp; such
polyps can result in localized erosions because
they are formed by oxyntic mucosa, which
produces acid (fig. 8-4). If the patient has had
an appendectomy, the stump can occasionally
invert and present as a polyp. When this is
biopsied, the distorted muscularis propria can
mimic a mesenchymal lesion. As a general rule,
it is prudent to inform colonoscopy colleagues
when muscularis propria is present in the
Figure 8-1
NORMAL COLON
Notice that there is a small lymphoid
aggregate tucked just under the muscularis
mucosae . A few benign glands have
herniated into it, h aving extended through
a break in th e muscularis mucosae. Please
compare this image to figure 7-4A,B. The
colon glands (crypts) are obviously benign
in this image but it is important to be aware
of this phenomenon when adenomas
involve such glands.
167
 Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 8-2
PSEUDOLIPOMATOSIS (AIR INSUFFLATION ARTIFACT)
Left: Note the bubbles in the lymphoid aggregate and deep lamina propria. These are composed of air rather than adipose tissue.
Right: There is no tissue response to the air that forms the cleared spaces.

Figure 8-3
PULSE GRANULOMA
Left: This biopsy was from a nodule in the sigmoid colon in a patient with diverticula. There is partially mineralized
vegetable material embedded in the tissue. The mineralization suggests that the foreign material has been lodged in the
tissue for a prolonged period.
Right: The appearance can suggest a parasitic organism, but the material shows varying sizes and shapes.

168
 Colon Polyps and Neoplasms

Figure 8-4
RECTAL GASTRIC HETEROTOPIA
Left: There is oxyntic mucosa (with parietal cells) at one end of the sample but the normal colorectal type mucosa is at
the other end. This lesion presented as a polyp.
Right: This image shows adjoining gastric and colonic type mucosa in rectal gastric heterotopia.

sample, since finding it often indicates that an
iatrogenic perforation has occurred at the time
of colonoscopy (fig. 8-5).
As in any other part of the gastrointestinal
tract mucosa (or in any organ with glands), isch-
emic damage or ulcers can result in sloughing
of the epithelium into the lumen. This benign
mimicker of carcinoma is termed signet ring cell
change (1,2). It mimics signet ring cell carcino-
ma but there are differences. Figures 8-6 and 8-7
shows signet ring cell change, whereas figure 8-8
shows a signet ring cell carcinoma in the lamina
propria of the colon. The "imposter" is found in
the lumen of the glands and has degenerative
cytologic features. The signet ring cell carcinoma
is found in viable lamina propria. The nuclei are
larger as well. Figures 8-7, left (imposter) and 8-8,
right (carcinoma) were taken at the same magni-
fication. Compare the appearance of signet ring
cell change also to the in situ signet ring cell car-
cinoma of the stomach (chapter 4, figure 4-12).
A mimicker of sarcoma in polyps and ulcers
in the GI tract is pseudosarcomatous change,
which is seen in hypoxic fibroblasts at the
interface between viable and nonviable zones
(figs . 8-9) (3,4). These lesions are diagnosed by
morphology; immunolabeling is typically a
meaningless expensive exercise.
MUCOSAL PROLAPSE POLYPS
There are certain histologic features that are
associated with mucosal prolapse (fig. 8-10), and
chronic mucosal prolapse can result in ulcers and
polyps. Solitary rectal ulcer syndrome is a term
used to denote a pattern of mucosal prolapse
changes (encompassing polyps that lack ulcer-
ation) of the rectum. The classic history is of a
young woman with constipation and straining.
At endoscopy, ulcers are seen in up to 70 percent
of patients, usually on the anterior or anterolateral
rectal wall, but a mass-like lesion can also be pres-
ent. These patients are believed to have difficulty

169
Survival Guide to Gastrointestinal Mucosa l Biopsies

Figure 8-5
INVERTED APPENDICEAL STUMP
PRESENTING AS A POLYP
A: The center has the appearance of a mesenchymal
neoplasm but consists of muscularis propria, which
indicated that the patient has undergone an iatrogenic
perforation from the biopsy of a "polyp." When such
cases are encountered, it is good practice to contact
the colonoscopist to suggest monitoring the patient
for bowel perforation. Note that the base of the lesion
has curled such that the latera l (mucosal) margin has
the appearance of a deep m argin .
B: This is a desmin stain, which highlights the
muscularis propria.
C: This is an S-100 protein stain, which highlights
nerves a nd Auerbach's plexus in the m uscularis
propria from the same sample as that seen in A and B.

Figure 8-6
SIGNET RING CELL CHANGE IN
COLORECTAL MUCOSA ADJOINING
THE ANAL SQUAMOUS MUCOSA
This area was from a hemorrhoidectomy
specimen and there was a nearby ulcer.
These entrapped colorectal type glands show
sloughing of the epithelium and the sloughed
cells have pooled in the lumina together with
entrapped mucin. Each distended glan d is
encircled by basement membrane and well-
demarcated from the lam ina propria.

170
 Colon Polyps and Neoplasms

Figure 8-7
SIGNET RING CELL CHANGE IN COLORECTAL MUCOSA ADJOINING THE ANAL SQUAMOUS MUCOSA
Left: The sloughed cells have rounded up, imparting an alarming appearance reminiscent of that of signet ring cell
carcinoma, but the cells in question are restricted to the lumen.
Right: The cells have signet ring shapes such that the nucleus has the appearance of the jewel and the outlines of the
cytoplasm the appearance of the bad portion of the ring, but the nuclei have a degenerated appearance.

Figure 8-8
COLORECTAL SIGN ET RING CELL CARCINOMA
Left: The cells have invaded the mucosa and are an integral component of the tissue rather than restricted to the lumen
of a gland.
Right: The nuclei are far larger than those of the "imposter" benign sloughed cells in figure 8-6C. Compare their size to
that of the endothelial cell in the right center portion of the image.

171
Survival Guide to Gastrointestinal Mucosal Biopsies

..
r.·.
. \r 1

.
••

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.. .

' ; ......... ]. -·
·.; ~·

,.
.,.
'!. .... '
..
Figure 8-9
PSEUDOSARCOMATOUS CELLS IN AN ULCER
Left: The surface of the image shows ulcer exudate (neutrophils and fibrin) whereas the base shows ingrowth of capillaries and
fibroblasts attempting to repair the ulcer. Note the enlarged atypical fibroblasts at the interface. These cells are entirely benign.
Right: At high magnification, the cell il} the center of the image is enlarged but has a low nucleus to cytoplasmic ratio.

Figure 8-10
MUCOSAL PROLAPSE CHANGE
Left: This is a rectal biopsy from a male patient who reported men who have sex with men (MSM) sexual practices. In
mucosal prolapse, individual strands of smooth muscle separate the crypts, replacing the lamina propria and imparting a
pink appearance in the tissue. This muscle replacement of the lamina propria also can be seen in association with neoplasms,
especially those in the sigmoid colon.
Right: This very high magnification image shows the smooth muscle that has replaced the lamina propria. Smooth muscle
features brightly eosinophilic cytoplasm and delicate longitudinal cytoplasmic striations.

172

coordinating smooth muscle functions during
the defecation process, such that the puborec-
talis sling fails to relax at the proper time.
The lesions can have a "polypoid phase" or
an ulcerated phase. Crypts become angulated;
some have used the term "diamond-shaped"
(fig. 8-11) (5,6). Frequently such polyps have
serrated features, which has resulted in confu-
sion with sessile serrated adenomas/polyps (SSA;
discussed below) but sessile serrated adenomas/
polyps lack smooth muscle proliferation in the
lamina propria. However, some hyperplastic pol-
Colon Polyps and Neoplasms
Figure 8-ll
MUCOSAL PROLAPSE POLYP OF THE RECTUM
A: Note that the crypts have serrated contours (like the
business side of a steak knife or bread knife) and the lamina
propria between the crypts is replaced by smooth muscle.
The surface of the polyp is eroded (such lesions are also
termed "solitary rectal ulcer" when they arise in the rectum).
B: At high magnification, the lamina propria smooth
muscle is readily apparent by its eosinophilic (pink)
appearance.
C: Note the delicate longitudinal striations in the smooth
muscle cells.
yps or sessile serrated adenomas have associated
perineuriomas/benign fibroblastic polyps in their
lamina propria (fig. 8-12) (7-12) .
A pitfall in diagnosing mucosal prolapse pol-
yps is that mucosal prolapse changes adjacent
to carcinomas have identical appearances to
those of isolated mucosal prolapse, so multiple
biopsies of large "solitary rectal ulcers" can be
suggested to exclude sampling error (13). "Coli-
tis cystica profunda" is part of the same process
and indicates that glands have prolapsed into
the submucosa or muscularis propria.
173
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 8-12
HYPERPLASTIC POLYP WITH
ASSOCIATED PERINEURIOMA
A: The lamina propria is replaced by
a proliferation that is less eosinophilic
than the smooth muscle seen in figures
8-10, 8-11 .
B: This image shows the bubbly micro-
vesicular cytoplasm in the serrated portion
of the hyperplastic polyp at the upper left
and a nodule of the perineurioma. The
latter is essentially a benign incidental
finding that can present as a polyp or in
association with serrated polyps.
C: The stromal proliferation is far less
eosinophilic than the lamina propria
smooth muscle seen in figures 8-10, 8-11.

POLYPS: CONVENTIONAL ADENOMAS, matic than those of normal colonic epithelial

HYPERPLASTIC POLYPS, AND
. OTHER SERRATED POLYPS
Colorectal polyps are an important compo-
nent of gastrointestinal pathology, and most
can be easily diagnosed, using a few simple
concepts as seen in Table 8-1.
Tubular Adenomas
About half of Western people are believed to
be destined to develop a colorectal adenoma
(14). Adenomas have dysplasia by definition,
meaning that their nuclei are more hyperchro-
cells (fig. 8-13). The dysplasia is usually low-
grade with regular nuclei showing maintained
nuclear polarity (their long axes are perpendic-
ular to the basement membrane) and the nuclei
are elongated rather than round. Generally
when there is only low-grade dysplasia, pathol-
ogists diagnose "adenoma" without mention
of dysplasia, which is only mentioned if there
is high grade dysplasia. Apoptotic bodies are
usually easily found in sporadic adenomas.
Some variant features include finding clear
cell change (fig. 8-14) (15), squamous-like

174
 Colon Polyps and Neoplasms

Figure 8-13
TUBULAR ADENOMA
A: The adenoma is composed of tubules and is on a long stalk. The tubules have lost their orientation with respect to th e
surface of the polyp and with respect to the muscularis mucosae.
B: Colorectal adenomas originate near the surface and, as they grow, the adenoma cells fill in the mucosa below the
surface. This early lesion shows only sur face involvement, but th e adenomatous glands have already lost their orientation
with th e surface and begin to grow la terally. Their nuclei are larger and more elongated than those of the crypts below.
C: These polyps have a "top-down" growth pattern. At this stage, the la mina propria appears relatively unremarkable.
D: Thi s example shows nonneoplastic crypts between the adenomatous ones. The neoplastic nuclei are elongated but
oriented with their long axes perpendicular to the basemen t membranes.

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Survival Guide to Gastrointestinal Mucosal Biopsies

Table 8-1
CHARACTERISTICS OF CONVENTIONAL ADENOMAS AND SERRATED POLYPS
Polyp Type · Description Illustration
Tubular Tubular adenomas have their growth
Adenoma initiation at the surface and begin to
form tubules that lose their orientation
to the surface; the adenomatous nuclei
towards the surface are larger than the
nuclei at the base; as the adenoma
grows, the base fills in with the lesion.
The architecture of tubular adenomas
is abnormal.
The cytology is dysplastic.

Hyperplastic Hyperplastic polyps essentially have

Polyp the same architecture as colorectal
mucosa such that there is a connection
between the lumen and the base of
each crypt, which lands on the
muscularis mucosae.
A line can be drawn that communicates
from the lumen to the muscularis
mucosae (see arrow).
The architecture of hyperplastic polyps
is normal.
The surface shows serrations with
"bubbly" microvesicular cytoplasm; the
bases of the crypts are narrow and have
the appearance of normal crypts.
The cytology is nondysplastic.

morules that have varying amounts of neuro-
endocrine differentiation (figs. 8-15, 8-16) (16),
and Paneth cell differentiation. Sometimes these
variant patterns are seen in invasive carcinomas
that arise in association with the adenomas (15) .
Some reports have noted some degree of endo-
crine differentiation in the squamous morules
and referred to them as "microcarcinoids" (17).
Such squamous morules are often found in large
adenomas with high grade dysplasia.
Adenomas originate near the surface of the
mucosa; early adenomas only affect the upper
half of the mucosa and grow in a "top-down"
fashion (18) . The adenoma cells in the superfi-
cial portions of the mucosa spread laterally and
downward to form new crypts that first connect
to pre-existing normal crypts, eventually over-
taking them.
High-Grade Dysplasia and
Villous Features in Adenomas
High-grade dysplasia (fig. 8-17) is equiva-
lent to Tis but in the colon, invasion into the
lamina propria is also considered as Tis (19).
Validated criteria to diagnose high-grade dys-
plasia in colon adenomas are not established
even though finding it places the patient into
a more intensified surveillance protocol (20).
The 2012 American Gastroenterological As-
sociation (AGA) guidelines for management
after diagnosis of adenomas: persons with 3 to
10 adenomas detected at initial colonoscopy,

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 Colon Polyps and Neoplasms

Table 8-1, continued

Polyp Type Description Illustration
Sessile Sessile serrated adenomas have essentially
Serrated the same architecture as colorectal mucosa . • .......
Adenoma such that there is a connection between
the lumen and the base of each crypt,
which lands on the muscularis mucosae.
A line can be drawn that communicates
from the lumen to the muscularis mucosae
(see arrow).
The overall architecture of sessile serrated
adenomas is close to normal.
There are serrations that extend all the way
to the bases and some of the crypts branch
laterally at the bases to form L or inverted
T shaped crypts.
The cytology is nondysplastic.

Traditional Traditional serrated adenomas have a dis-

Serrated organized growth pattern such that the
Adenoma lesion loses its orientation to the mus-
cularis mucosae; no line can be drawn
as for the hyperplastic polyp and sessile
serrated adenoma.
The architecture of traditional serrated
adenomas is abnormal.
There are serrations throughout; the
glands have small outpouchings that
are indicated by stars.
The cytology is dysplastic but the
nuclei are smaller than those seen in
conventional tubular adenomas.

persons with adenomas more than 10 mm (1 In general, however, high-grade dysplasia

cm), villous adenomas, or adenomas with high and large adenoma size generally go hand in
grade dysplasia should have surveillance at 3 hand so unvalidated diagnostic thresholds for
years rather than the 5 to 10 years suggested for high-grade dysplasia are less important than
1 or 2 small typical adenomas (20) . they might seem. However, high-grade dysplasia

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Survival Guide to Gastrointestinal Mucosal Biopsies

in colorectal adenomas can be diagnosed in

adenomas with cribriform architecture and/or
loss of nuclear polarity (figs. 8-35, 8-36). When
carcinomas arise in adenomas of the colon, lam-
ina propria invasion is considered biologically
equivalent to high-grade dysplasia.
The question of separating tubular versus tu-
bulovillous versus villous adenoma is subjective
and usually does not matter on clinical grounds.
Adenomas with "villous features" are said to
warrant closer surveillance than those without
but there are no real criteria for when an ade-
noma has "villous features," however, villous
features tend to correlate with large size-often
the adenoma size is not known when the ade-
noma is reviewed (21). If the lesion has plentiful
structures that resemble small bowel villi but
are clearly neoplastic, this can be reported as
villous adenoma (fig. 8-17).
Pseudoinvasion (Mucosal
Prolapse Change) in Adenomas
Figure 8-14
Adenomas can have striking mucosal pro-
lapse changes, especially those in .the sigmoid TUBULAR ADENOMA WITH CLEAR CELL CHANGE
colon. The neoplastic glands prolapse through This example shows prominent clear cell change. This is
essentially a histologic curiosity but sometimes carcinomas
the muscularis mucosae, often through small arise in association with adenomas with this appearance and
breaks in areas with lymphoid aggregates. This these carcinomas have a clear cell appearance.

Figure 8-15
TUBULAR ADENOMA WITH SQUAMOUS MORULES
Left: Note the more solid nests in the low magnification image.
Right: The nests in question have a slightly infiltrative appearance but the cells have bland cytologic fea tures.

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 Colon Polyps and Neoplasms

Figure 8-16
TUBULAR ADENOMA WITH SQUAMOUS MORULES
Left: Sometimes these lesion display neuroendocrine differentiation and some observers have used the term
"microcarcinoids" to describe them. Overall they are an incidental finding, but they are usually encountered in large adenomas.
Right: Note the cytologic feature compared to those of the conventional adenoma component.

Figure 8-17
HIGH DYSPLASIA IN TUBULAR ADENOMA
Left: The glands have complex cribriform (sieve-like) contours and some have luminal necrosis. The lamina propria can
be seen between them
Right: Note the luminal necrotic debris.

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Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 8-18
COLORECTAL TUBULOVILLOUS ADENOMA
Left: In this resection specimen the lesion has arisen in otherwise normal mucosa.
Right: The adenoma has prominent structures reminiscent of small intestinal villi coated by dysplastic (adenomatous)
epithelium.

Evaluation of Adenomas that Contain

is concerning for invasion into the submucosa
(Tl), especially if the glands become obstructed
and inspissated mucus dissects into the sur-
rounding connective tissue (figs. 8-19, 8-20)
(22). The prolapsed glands often carry their
lamina propria but in distal polyps (sigmoid),
the investing lamina propria can be replaced by
smooth muscle from mucosal prolapse.
Some clues for separating invasive carcino-
ma from pseudoinvasion are: 1) in "pseudoin-
vasion," lamina propria is "pulled" with the
neoplastic glands into the submucosa and thus
invests the misplaced glands; 2) accompanying
hemosiderin in often present in pseudoinva-
sion; 3) prolapsed (pseudoinvading) glands
tend to be rounded (gland angulation is more
commonly seen in carcinoma); and 4) the sub-
mucosal component has the same appearance
as the adenoma that is clearly in the mucosa-
sometimes there is even high-grade dysplasia.
Carcinomas in Polypectomy Specimens
("Malignant Polyp")
Carcinomas develop in about one in 25 ade-
nomas left in situ. When an invasive carcinoma
is found in an endoscopically removed polyps
(defined as invading into the submucosa; T1),
a decision concerning whether to perform a
follow-up colectomy is made and the pathologic
evaluation is the key factor. To justify offering
the patient a colectomy, the risk of the patient
having a metastasis must be higher than the risk
of the patient undergoing surgery to remove a
segment of the colon. Polyps containing invasive
carcinoma (figs. 8-21, 8-22) account for about
5 percent of all adenomas. The likelihood of
finding an invasive component increases with
polyp size, and the incidence of invasive carci-
noma in adenomas more than 2 cm ranges from
35 to 53 percent. When technically feasible, it

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 Colon Polyps and Neoplasms

Figure 8-19
ADENOMA WITH PSEUDOINVASION
(MUCOSAL PROLAPSE INTO THE SUBMUCOSA)
A: The polypectomy margin at the right has been painted
with blue ink and the adenoma can be seen coating the
surface at the left of the image. The adenoma has prolapsed
into the submucosa. At the left it has obviously brought the
lamina propria with it. Some of the glands have lost their
connection to the surface but continued to secrete mucin
which has accumulated and extruded into the surrounding
tissue. This is not an indication of a mucinous carcinoma.
B: The adenoma at the top has extended into a lymphoid
aggregate akin to the normal epithelium in figure 8-1.
C: This is a higher magnification of B. The adenoma
glands appear angulated suggestive of carcinoma but several
of the lamina propria glands have the same appearance. It
is important to realize that high grade dysplasia can also
undergo pseudoinvasion.

is recommended that these polyps be removed
intact, rather than in fragments, with as great a
margin as possible at the base or stalk. Identifica-
tion of the resection margin allows determina-
tion of both the adequacy of the excision and
the closest approach of the tumor, a parameter
that predicts the risk of tumor recurrence.
Many malignant polyps often constitute a
form of early carcinoma (pathologic T category
pTl) can be managed adequately by endoscopic
polypectomy alone but he incidence of an un-
favorable outcome (i.e., lymph node metastasis
or local recurrence from residual malignancy)
for malignant polyps treated by polypectomy
alone varies from 0 percent to about 20 percent
in the literature. The following risk factors must
be assessed (23- 28): 1) Is there a poorly differen-
tiated component? 2) Is the tumor excised and
at least 1 mm from the margin (some authors
suggest 2 mm)? This can be assessed by making
two small dots (one at the leading edge of the
tumor and the other at the nearest cauterized
margin) and measuring the distance between
them with a ruler; 3) Is there vascular space
invasion? (figs. 8-21, right and 8-22, right) and
4) Is there tumor budding? (fig. 8-23).
Tumor budding simply means single cells
invading into the stroma at the invasive front of
the carcinoma. In some ways this is equivalent
to a poorly differentiated component. There

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 Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 8-20
ADENOMA WITH PSEUDOINVASION (MUCOSAL PROLAPSE INTO THE SUBMUCOSA)
A: Note that the surface contains an adenoma and part of it has herniated into the submucosa. The entrapped glands
continue to produce mucin but have lost their connection with the lumen such that the mucin is extruded into the submucosal
tissue, sometimes with a few adenoma cells. However, the low magnification appearance is especially important, since there
is a lobular configuration.
B: This is a higher magnification image of the lesion seen in A. There is lamina propria associated with the glands at the
top of the mucus pool, a clue that this is a benign process, but the mucin in the center of the image has burst into the tissue
and elicited an inflammatory response.
C: This is a very high magnification image of the mucin pool seen in A. In the context of the overall architecture, the
glands can be regarded as sloughed rounded up adenomatous tissue.
D: There is prominent hemosiderin deposition in an area of pseudoinvasion, and the glands in the area have associated
lamina propria even though they are in the submucosa.

182
 Colon Polyps and Neoplasms

Figure 8-21
ADENOCARCINOMA ARISING IN A TUBULAR ADENOMA
Left: The adenoma can be seen at the upper left and lower right and the adenocarcinoma, characterized by glands
containing abundant necrotic debris, appears at the right. The carcinoma invades the submucosa very superficially and is
present on a long stalk.
Right: The presence of vascular space invasion in the early carcinoma shown on the left is an indication for an operation
to recover lymph nodes in many cases.

are many complicated definitions for tumor
budding but Irish colleagues reported that as-
sessing this "by eyeball" at low magnification
correlated with poor outcome (29,30). If these
colleagues noted budding at 4X magnification
and confirmed it at 10X, the tumor is designat-
ed as having budding. The 8th edition of the
A] CC staging manual did not suggest reporting
budding (19) for cancers in polyps but it can be
subsumed in a high grade component if it is a
prominent feature to achieve the same outcome.
If one or more of the above features is pres-
ent, the risk of an adverse outcome following
polypectomy is estimated to be about 10 to 25
percent. Management is decided on an individ-
ual case basis, but segmental resection of the
involved colonic segment, local excision (e.g.,
transanal disk excision for a low rectal lesion),
or radiation therapy may be considered. In the
absence of high-risk features, the chance of ad-
verse outcome is very low such that polypecto-
my alone is considered curative. Some societies
have begun to advocate measuring the depth
of invasion from the bottom of the muscularis
mucosae (27) but this has not been consistently
advocated in the US (probably because most
colleagues require a 2 mm margin rather than
a 1 mm margin.
Serrated Polyps
Serrated polyps can be divided into several
types: 1) hype1plastic polyps (HPs) (fig. 8-24); 2)
sessile serrated adenomas (SSAs, the term sessile
serrated polyp is equally acceptable) (fig. 8-25)
traditional serrated adenomas (TSAs) (fig. 8-26);
and 4) sessile serrated adenomas with cytological
dysplasia (formerly termed mixed hyperplastic/
adenomatous polyps [MHAPs]) (fig. 8-27).

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Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 8-22
ADENOCARCINOMA ARISING IN A TUBULAR ADENOMA
Left: Note the complex architecture of the glands and effacement of the normal loose lamina propria.
Right: There is subtle vascular space invasion in this image, taken from the same lesion as that shown on the left.

Figure 8-23
ADENOCARCINOMA
Left: This example shows prominent stromal desmoplasia and highly angulated glands.
Right: This image is from the leading edge of the invasive front of the tumor. There are single malignant cells "sprayed"
into the stroma at the right side of the image, an appearance termed "tumor budding," which is associated with a host of
adverse factors .

184
 Colon Polyps and Neoplasms

Figure 8-24
HYPERPLASTIC POLYP
Left: There are open serrated glands towards the lumen but the bases of the crypts are slender. The basement membrane
at the top is somewhat thickened such that the surface epithelium has partly "chipped off" in processing. The serrations,
associated with eosinophilic bubbly cytoplasm, extend only about halfway down the crypts. The essential architecture of
the colon is maintained in that the glands communicate between the lumen and the muscularis mucosae.
Right: This example has numerous endocrine cells in the bases of the crypts. Endocrine cells are typically lacking in
sessile serrated adenomas.

It had been well recognized that classic ade-
nomatous polyps are premalignant lesions (31),
but the importance of serrated lesions was not
recognized until much later.
Hyperplastic polyps comprise about 75
percent of all serrated polyps. They are an inci-
dental finding during screening colonoscopy.
They may arise singly or multiply, typically in
the rectosigmoid colon, and are small(< 5mm).
The serrated architecture is limited to the up-
per crypt with glands that become slender at
the base and have prominent neuroendocrine
cells. The cytoplasm has a bubbly appearance
(microvesicular). Microvesicular hyperplastic
polyps have frequent BRAF mutations while
KRAS mutations are identified more frequently
in the goblet cell-rich type (32). Rarer types are
the goblet cell and mucin poor types, which
are uncommon.
Sessile serrated adenomas account for 15 to
20 percent of colorectal polyps (33,34) using the
criterion of accepting them as such with only a
single aberrant crypt, in line with the frequency
of MSI-H colorectal cancer. SSAs usually arise
in the right colon, are broad-based, and may
become large (several centimeters) . The endo-
scopic appearance is often subtle. These polyps
are characterized by serrated crypt architecture
that extends to the deep crypts, and dilated
crypt bases oriented parallel to the muscularis
mucosae. Although the 2010 World Health Or-
ganization (WHO) initially arbitrarily suggested
that three "boot shaped" or "L shaped" or "T
shaped crypts were required for a diagnosis (32),
a single altered crypt suffices (33,34). We have
also encountered peculiar oncocytic changes
in SSAs. As they progress, some of these polyps
may develop conventional-appearing low-grade

185
 Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 8-25
SESSILE SERRATED ADENOMA (POLYP)
A: The essential colorectal architecture is maintained in that the lumina of the glands communicate with the muscularis
mucosae but the crypts themselves have sideways extensions. Serrations extend to the bottoms of the crypts. However, note
also that some of the crypts have slender bases, such as those at the right of the image. If a scant biopsy fails to demonstrate
the unusual crypt contours, this does not exclude sessile serrated adenoma. Because of such issues, many colleagues regard
essentially any right sided serrated polyp as a potential sessile serrated adenoma.
B: One of the crypts has a shape reminiscent of that of a sail boat and another like a boot or sock. Regardless, these crypts
communicate between the lumen and the muscularis mucosae.
C: The nuclei Jack the conventional dysplasia appearance seen in tubular adenomas.
D: This is the base of an oddly shaped crypt. There are no endocrine cells. ·

186
 Colon Polyps and Neoplasms

Figure 8-26

TRADITIONAL SERRATED ADENOMA

A: These lesions usually arise in the left colon. Note the disorganized architecture. The adenoma cells are dysplastic but
their cytoplasm is far more eosinophilic and their nuclei far less basophilic than those of typical adenomas.
B: Note the eosinophilic cytoplasm and the outpouchings from the gland in the center.
C: This example shows especially prominent tiny crypt-like outpouchings from the main glands. These outpouchings
have been termed ectopic crypt formations and are characteristic of traditional serrated adenoma.
D: This is a very high magnification image of some ectopic crypt formations.

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Survival Guide to Gastroin.testinal Mucosal Biopsies

Figure 8-27
SESSILE SERRATED ADENOMA WITH CYTOLOGIC DYSPLASIA
Left: The lesion is tangentially embedded so the architecture is subtle but there is a sessile serrated adenoma in the lesion
lacking dysplasia and a dysplastic component on the bottom, which resembles a typical tubular adenoma. Such lesions were
termed "mixed hyperplastic polyps/adenomas" in the past but they are simply sessile serrated adenomas in the process of
progressing to adenocarcinoma .
Right: This is a high magnification image from the dysplastic component of the polyp seen on the left. It is essentially
indistinguishable from a conventional adenoma.

dysplasia (previously termed mixed hyperplastic
adenomatous polyps [MHAPs]), characterized
on immunohistochemistry by loss of expression
of mismatch repair proteins (MLH1) in about
half of cases. Remember that loss of MLH1
expression at the surface of a nondysplastic
serrated polyp of colon mucosa is meaningless;
the surface cells are not engaging in mismatch
repair because they are not dividing so nega-
tive surface nuclei is normal. SSAs often have
activating mutations in the BRAF gene, which
interferes with cellular apoptosis and, as a con-
sequence, epithelial cells "pile up," producing
serrated areas characteristic of these polyps.
Traditional serrated adenomas (TSAs, also
known in the literature as "serrated adenomas")
usually arise in the distal colon. They feature
complex villiform architecture with crypts
that lose their orientation to the muscularis
mucosae. Small outpouchings from these al-
ready disorganized crypts are termed "ectopic
crypt formations" (ECF) and they define the
entity. TSAs are composed of by epithelial cells
with abundant, eosinophilic cytoplasm and
cigar-shaped nuclei that are paler than the
dysplastic nuclei characteristic of tubular ade-
nomas and they lack significant enlargement,
prominent nucleoli, and apoptosis.
Some polyps are difficult to classify but some
comments follow: 1) If the overall morphology
is that of a hyperplastic polyp but the lesion
is located on the right or transverse colon, err
on the side of diagnosing SSA; 2) Although
SSAs can be encountered on the left, they are
uncommon in that site. Some hyperplastic
polyps may display reactive epithelial changes
and mild, uniform crypt dilation but finding
neuroendocrine cells is a clue to a diagnosis of
hyperplastic polyp; and 3) Some observers use
the term "serrated polyp with features of SSA"

188

or "serrated polyp, not further classified" for
examples that do not entirely fulfill SSA criteria.
Guidelines exist for the management of
adenomatous polyps, but guidelines for the
serrated family of polyps are less established
(20): 1) Small (<1 cm), banal-appearing HPs:
Next colonoscopy in 10 years; 2) SSA, <10 mm
(1 cm): Complete polypectomy; follow-up in 5
years; 3) Large (:2:10 mm (1 cm) SSAs or SSAs with
cytological dysplasia: Complete endoscopic pol-
ypectomy is desirable, but often the adequacy of
excision is uncertain endoscopically because of
frequent poor demarcation of these lesions and
uncertain histology, due to the sessile nature of
these polyps. If incompletely excised, follow-up
with endoscopic debulking seems reasonable,
but segmental resection can be considered. For
Colon Polyps and Neoplasms
Figure 8-28
ADENOCARCINOMA ARISING IN ASSOCIATION
WITH A SESSILE SERRATED ADENOMA
A: The sessile serrated adenoma component is
on the left and a dysplastic component can be seen
on the right whereas the invasive carcinoma is in
the center.
B: This is a high grade dysplasia component of the
lesion shown A. Note that this component has many
lymphocytes in the epithelium. This is a feature
associated with mismatch repair defects.
C: This is the adenocarcinoma component from
the lesion seen in A.. Note all the tu m or infiltrating
lymphocytes.
endoscopically worrisome lesions, segmental
resection could be justified in some cases; 4) Tra-
ditional SAs: complete polypectomy; follow-up
in 3 years; and 5) Serrated polyposis: annual
colonoscopy with polypectomies
COLORECTAL CANCER
Colorectal carcinomas are usually not difficult
to recognize on colon mucosal biopsies (figs.
8-28-8-31). Invasive carcinoma shows angulat-
ed glands and single cells set in a desmoplastic
stroma. The key issue is that mucosal biopsies
are-biopsies of the mucosa. Colorectal carcino-
ma is not regarded as invasive (Tl) unless there
is submucosal invasion resulting in occasional
doubt in samples that do not contain submucosa.
As such, if well-developed desmoplasia can be
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Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 8-29
ADENOCARCINOMA
ARISING IN THE CECUM
The appendix and ileum
can be seen at the right side
of the image.

Figure 8-30
POORLY-DIFFERENTIATED ADENOCARCINOMA ARISING IN
ASSOCIATION WITH COLITIS-ASSOCIATED LOW-GRADE DYSPLASIA
Left: The carcinoma is present in the center of the image.
Right: This is a cytokeratin immunostain.

190
 Colon Polyps and Neoplasms

identified, even in the lamina propria, there is

nearly always an underlying invasive carcinoma
(into at least submucosa); in this situation it is
impmtant to correlate with the endoscopic ap-
pearance of the lesion. It is also important to
report whether there is an associated adenoma
component to help affirm that the lesion is
primary (associated with a precursor).
COLITIS-ASSOCIATED NEOPLASIA
Dysplasia in ulcerative colitis (figs. 8-32, 8-33)
is separated into low and high grades, and cases
in which the findings are unclear are diagnosed
as "indefinite for dysplasia ." A diagnosis of
low-grade dysplasia requires nuclear alterations
(adenoma-like) that extend onto the mucosal
surface without loss of nuclear polarity; in
contrast, high-grade dysplasia displays surface
loss of nuclear polarity. There are also unusual
cases of serrated colitis-associated dysplasia and
serrated polyps in patients with inflammatory
bowel disease. Patients with inflammatory
bowel disease can also develop adenomas and
serrated polyps that are genetically the same as Figure 8-31
sporadic adenomas. There are no perfect criteria ADENOCARCINOMA
to separate sporadic adenomas from colitis-as- This example has a micropapillary pattern, a pattern
sociated polypoid dysplasia, but if there is no that is associated with aggressive behavior. There is also
flat dysplasia, polypoid dysplasia can generally abundant necrosis, a general feature of colorectal carcinoma.

Figure 8-32
COLITIS-ASSOCIATED LOW-GRADE DYSPLASIA (LEFT) AND SERRATED EPITHELIAL
CHANGE OF THE TYPE SEEN IN LONG-STANDING INFLAMMATORY BOWEL DISEASE
The lesion at the left is essentially indistinguishable from a sporadic adenoma, but in the context of the fragment at the right,
which is damaged and highly abnormal, it can be assumed to be a colitis-associated process. The epithelium in the fragment at
the right appears similar to that of a hyperplastic polyp or sessile serrated adenoma but differs by featuring marked architechtral
distortion. Slight serration is common in colonoscopic biopsies from asymptomatic persons and should not be reported but
the findings in the fragment to the right are worth reporting as they can be regarded as equivalent to "indefinite for dysplasia."

191
SwYival Guide to Gastrointestinal Mucosal Biopsies
Figure 8-33
COLITIS-ASSOCIATED LOW-GRADE DYSPLASIA
This focus is indistinguishable from a sporadic adenoma
and can be diagnosed as such only in context of the sur-
rounding mucosal findings. If adjoining mucosa has features
of inflammatory bowel disease, colitis-associated dysplasia
can be diagnosed. When a lesion such as this is polypoid and
there is no flat dysplasia in a person with inflammatory bowel
disease, management by polypectomy is safe.
be managed as per sporadic adenomas in both
ulcerative colitis and Crohn's disease, with
polypectomy (35,36) . Some colitis patients
have serrated changes in their colonic mucosa
reminiscent of hyperplastic polyps but no polyp
is seen and there is striking architectural distor-
tion. Serrated epithlelial change without overt
dysplasia probably merits intensified follow-up
similar to that for dysplasia although our patient
base is enriched for high-risk persons (37).
JUVENILE POLYPS
Juvenile polyps are the most common col-
orectal polyps in children, and up to half of the
time, more than one juvenile polyp is found.
Most sporadic juvenile polyps have a spherical
lobulated surface, often with erosions (fig. 8-34).
192
These polyps are hamartomatous so, in the
colon, they display colonic type mucosa. They
are formed by irregularly shaped and dilated
glands, accompanied by lamina propria that is
expanded with edematou·s granulation tissue.
Dysplasia is rare in sporadic juvenile polyps.
On the other hand, juvenile polyposis is
essentially a cancer syndrome. Diagnostic cri-
teriainclude finding: 1) more than five juvenile
polyps of the colorectum; 2) juvenile polyps
throughout the GI tract; or 3) any number of
juvenile polyps in a patient with a family histo-
ry of juvenile polyposis. Small juvenile polyps
from syndromic patients have appearances that
are identical to those of typical sporadic ones
but larger ones have an increase in the relative
amount of epithelium compared to stroma, are
are multilobulated with projecting rounded or
elongated lobes, and are more likely to have
dysplasia. The dysplasia in juvenile polyps re-
sults in an appearance indistinguishable from
that of sporadic adenomas.
NEUROENDOCRINE TUMORS
Neuroendocrine tumors of the colon and
rectum appear to be increasingly detected; they
are essentially limited the rectum (38). Neuro-
endocrine tumors of the colon and rectum have
been divided into well- differentiated (carcinoid
tumor) and high grade categories. Well-differen-
tiated tumors are further divided into low (G1,
previously known as "carcinoids") and intermedi-
ate (G2, previously known as "well differentiated
endocrine carcinoma") grades based on their pro-
liferative rate. High grade (G3) neuroendocrine
carcinomas are aggressive and include tumors
with small and large cell type morphology. The
WHO grading system (32) is as follows: 1) G1 =
<2 mitoses/10 high power fields or <2 percent
Ki-67 index; 2) G2 = mitotic count 2-20 per 10
high power fields or 3 to 20 percent Ki-67 index;
and 3) Grade 3 tumors are high-grade neuroen-
docrine carcinomas (large cell or small cell types)
and are characterized by >20 mitoses/10 high
power fields or >20 percent Ki-67 index.
WDNETs of the colorectum (fig. 8-35) have a
spectrum of appearances, but these are unified
by cells that contain small round nuclei with
"salt and pepper" chromatin. An important pit-
fall is that they express PSAP (prostate-specific
acid phosphatase) (39) and this can lead to an
 Colon Polyps and Neoplasms

Figure 8-34
JUVENILE POLYP
A: Note the flat surface and the prominent dilation of the glands.
B: These polyps often have an eroded surface.
C: Note the lamina propria expansion and cystically dilated nondysplastic glands.
D: There is prominent reactive surface change. Several neutrophils are present in the surface epithelium.

193
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure8-35
RECTAL WELL-DIFFERENTIATED
NEUROENDOCRINE (CARCINOID) TUMOR
A: The lesion shows no surface component, consisting
of cells with small round nuclei.
B: The nuclei are rounded with dappled ("salt and
pepper") chromatin. A mitosis is shown in the center right.
Most such tumors are Grade 1 with rare mitoses but this
one is a Grade 2 lesion.
C: This is a ki-67 immunostain. Labeled nuclei are easy
to identify.

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erroneous diagnosis of spread from prostate can-
cer in both low-grade tumors (carcinoids) and
high grade ones. Most rectal WO NETs are small
and most are indolent with a 5-year survival rate
of nearly 90 percent. They are only rarely asso-
ciated with adenomas (fig. 8-36) (whereas high
grade neuroendocrine carcinomas are associated
with adenomas; fig. 8-37). Tumor size and mus-
cularis propria invasion are the key predictors of
malignant behavior in well differentiated neu-
roendocrine (carcinoid) tumors. Rectal WO NETs
larger than 2.0 cm or with locoregionallymph
node involvement are managed as per rectal
adenocarcinomas whereas small tumors (1 to
2 cm) confined to the mucosa and submucosa
are safely managed by endoscopic polypectomy.
Patients with small tumors (1 to 2 cm) showing
muscularis propria invasion and without lymph
node metastases on endoscopic ultrasound, may
be managed with transanal excision. A small
percentage (12 percent) of GI tract neuroendo-
crine tumors is reported in the proximal colon
(mostly the cecum), and these tend to be larger
more aggressive lesions (38,40).
Neuroendocrine carcinomas (G3) (fig. 8-38)
are highly aggressive tumors with small cell
or large cell histology characterized by a high
mitotic rate (>20 mitoses/10 high power fields,
usually much higher) and extensive necrosis.
Median survival time after diagnosis is 1 to 2

194
 Colon Polyps and Neoplasms

Figure 8-36
WELL-DIFFERENTIATED NEUROENDOCRINE (CARCINOID) TUMOR
Left: It is unusual for these tumors to arise in association with adenomas, so this is an exceptional case. The area in
question is subtle on hematoxylin and eosin (H&E) staining.
Right: This is a chromogranin immunostain showing the lesion depicted on the left.

Figure 8-37
HIGH-GRADE NEUROENDOCRINE CARCINOMA ARISING IN ASSOCIATION WITH AN ADENOMA
Left: The malignant cells feature nucleoli in keeping with large cell type.
Right: This is a synaptophysin stain. The expression is weaker in the carcinoma than in the endocrine cells in the adenoma
component at the right.

195
Swvival Guide to Gastrointestinal Mucosal Biopsies

Figure 8-38
NEUROENDOCRINE CARCINOMA, SMALL CELL TYPE, IN COLONIC MUCOSA
A: The lesion is in the center of the image.
B: The malignant nuclei are crushed against one another and compress one another (nuclear molding).
C: The malignant cells have colonized a pre-existing crypt and are seen in the space between the basement membrane
and the row of nuclei.
0: This is a synaptophysin stain from the carcinoma seen in figures A through C.

196
 Colon Polyps and Neoplasms

Figure 8-39
DIFFUSE LARGE B-CELL LYMPHOMA IN COLONIC MUCOSA
Left: This is the most common type of lymphoma to involve the colon .
Right: Diffuse large B cell lymphoma in colonic mucosa. This is a CDZO stain.

years with no significant differences between
large cell and small cell subtypes (41).
OTHER COLORECTAL TUMORS
Any of the lymphomas can be encountered
in the colon, but the most common type is
diffuse large B cell lymphoma (fig. 8-39). Simi-
larly, gastrointestinal stromal tumors (fig. 8-40),
leiomyomas (fig. 8-41), leiomyosarcomas (figs.
8-42, 8-43), and granular cell tumors (figs. 8-44)
(42) can be encountered but they are all uncom-
mon. Vascular malformations and angiomas can
also be seen (fig. 8-45). Lastly, it is important to
always consider endometriosis (which has been
shown to harbor mutations usually associated
with cancer even though it is not a form of
cancer) (fig. 8-46) (43), as it can be a pitfall.

197
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 8-40
COLORECTAL GASTROINTESTINAL STROMAL TUMOR (GIST)
Left: Such tumors are more likely to behave in a malignant fashion than gastric GISTs. Note the relatively monotonous
cytologic features.
Right: This is a DOG 1 stain.

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,;c-:.·~
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:i
.
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-·
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,,·
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Figure 8-41
COLORECTAL LEIOMYOMA
Left: These benign lesions arise in association with the muscularis mucosae and are composed of cells with brightly
eosinophilic cytoplasm. They are usually found in the rectum.
Right: The lesion is quite hypocellular.

198
 Colon Polyps and Neoplasms

Figure 8-42
COLORECTAL
LEIOMYOSARCOMA
The lesion is brightly eosin-
ophilic but far more cellular
than the leiomyoma seen in
figure 8-41.

Figure 8-43
COLORECTAL LEIOMYOSARCOMA
Left: Atypical nuclei are present.
Right: The fascicles of tumor cells are oriented perfectly perpendicularly to one another. Some of the cells featur e
paranuclear vacuoles.

199
Survival Guide to Gastrointestinal Mucosal Biopsies

#
. (
(

~~

Figure 8-44
COLONIC GRANULAR CELL TUMOR
A: The esophagus is the most common gastrointestinal site for these. They tend to be detected in the right colon and can
feature enlarged nuclei along with their granular cytoplasm.
B: This image highlights the nuclear enlargement of the granular cells .
C: An S-100 protein stain is strongly reactive, labeling both the nuclei and the cytoplasm.

200
 Colon Polyps and Neoplasms

Figure 8-45
DIEULAFOY LESION OF THE COLON
There is a large abnormal artery extending into
the submucosa just beneath the surface. This lesion
was an incidental finding in a resection performed
for another indication but such lesions, which are
essentially vascular malformations, can lead to massive
hemorrhage if they become eroded. Most such lesions
are encountered in the stomach, where they were first
described.

Figure 8-46
VASCULAR MALFORMATION, COLON
Left: It is impossible to determine whether a lesion such as this is a small angioma or the "tip of the iceberg" from a large
vascular malformation. In general, however, large vessels are not normally encountered in the colorectal lamina propria.
When reporting such lesions it is important to point out the need for imaging to determine whether the process in small
and incidental or part of an expansive process.
Right: Vessels this thick are abnormal in the colorectal mucosa. Radiation and amyloidosis can result in thickened vessels
but in a sample such as this, which was from a child, the likely choice is a vascular malformation.

201
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 8-47
ENDOMETRIOSIS
A: This example mimics a neoplasm.
B: The endometriotic glands appear dysplastic but the
nuclei are smaller than those of adenomas.
C: This is a CDlO stain from the area seen in A and B. It
highlights abundant endometrial stroma. In endometriosis
in which the glands are sparse, it is easy to consider a
sarcoma.

REFERENCES

1. Cameselle-Teijeiro ], Abdulkader I, Forteza ]. in inflammatory pseudopolyps of the colon. Arch

Signet-ring cell change in pseudomembranous
colitis versus signet-ring cell carcinoma. Am ]
Surg Pathol 2004;28: 1111.
2. Wang K, Weinrach D, La! A, et al. Signet-ring cell
change versus signet-ring cell carcinoma: a com-
parative analysis. Am] Surg Pathol2003;27:1429-
1433.
3. ]essurun], Paplanus SH, Nagle RB, Hamilton SR,
Yardley ]H, Tripp M. Pseudosarcomatous changes
Pathol Lab Med 1986;110:833-836.
4. Shekitka KM, He! wig EB. Deceptive bizarre stro-
mal cells in polyps and ulcers of the gastrointes-
tinal tract. Cancer 1991;67:2111-2117.
5. Warren BF, Dankwa EK, Davies ]D. 'Dia-
mond-shaped' crypts and mucosal elastin:
helpful diagnostic features in biopsies of rectal
prolapse. Histopathology 1990;17:129-134.

202

6. Warren BF, Davies ]D . Prolapse-induced inflam-
matory polyps of the colorectum and anal tran-
sition zone. Histopathology 1994;24:201-202.
7. Agalmy A, Stoehr R, Vieth M, Hartmann A.
Benign serrated colorectal fibroblastic polyps/
intramucosal perineuriomas are true mixed epi-
thelial-stromal polyps (hybrid hyperplastic pol-
yp/mucosal perineurioma) with frequent BRAF
mutations. Am] Surg Pathol2010;34:1663-1671.
8 . Eslami-Varzaneh F, Washington K, Robert ME,
. Kashgarian M, Goldblum ]R, ]ain D. Benign
fibroblastic polyps of the colon: a histologic, im-
munohistochemical, and ultrastructural study.
Am J Surg Pathol 2004;28:3 74-3 78.
9. Groisman G, Amar M, Alona M. Early colonic
perineurioma: a report of 11 cases. Int ] Surg
Pathol 2010;18:292-297.
10. Groisman GM, Polak-Charcon S. Fibroblastic
polyp of the colon and colonic perineurioma:
2 names for a single entity? Am ] Surg Pathol
2008;32:1088-1094.
11. Groisman GM, Polak-Charcon S, Appelman HD.
Fibroblastic polyp of the colon: clinicopatho-
logical analysis of 10 cases with emphasis on
its common association with serrated crypts.
Histopathology 2006;48:431-43 7.
12. Hornick JL, Fletcher CD. Intestinal perineuri-
omas: clinicopathologic definition of a new
anatomic subset in a series of 10 cases. Am] Surg
Pathol 2005;29:859-865.
13. Li SC, Hamilton SR. Malignant tumors in the rec-
turn simulating solitary rectal ulcer syndrome in
endoscopic biopsy specimens. Am J Surg Pathol
1998;22:106-112.
14. Kinzler KW, Vogelstein B. Lessons from heredi-
tary colorectal cancer. Cell1996;87:159-170.
15. Shi C, Scudiere JR, Cornish TC, et al. Clear cell
change in colonic tubular adenoma and corre-
sponding colonic clear cell adenocarcinoma is
associated with an altered mucin core protein
profile. Am] Surg Pathol 2010;34:1344-1350.
16. Sarlin JG, Mori K. Morules in epithelial tumors
of the colon and rectum. Am J Surg Pathol
1984;8:281-285.
17. Salaria SN, Abu Alfa AK, Alsaigh NY, Montgomery
E, Arnold CA. Composite intestinal adenoma-ml-
crocarcinoid clues to diagnosing an under-rec-
ognised mimic of invasive adenocarcinoma. ]
Clin Pathol 2013;66:302-306.
18. Shih IM, Wang TL, Traverso G, et al. Top-down
morphogenesis of colorectal tumors. Proc Natl
Acad Sci US A 2001;98:2640-2645.
19. Amin M, EdgeS, Greene F, Byrd DR, Brookland
RK, Washington MK. A] CC Cancer Staging Man-
ual. 8th ed: Switzerland: Springer; 2016.
20. Lieberman DA, Rex DK, Winawer SJ, et al. Guide-
lines for colonoscopy surveillance after screening
Colon Polyps and Neoplasms
and polypectomy: a consensus update by the US
Multi-Society Task Force on Colm·ectal Cancer.
Gastroenterology 2012;143:844-857.
21. Appelman HD. Con: High-grade dysplasia and
villous features should not be part of the routine
diagnosis of colorectal adenomas. Am] Gastro-
enterol2008;103:1329-1331.
22. Pascal RR, Hertzler G, HunterS, Goldschmid S.
Pseudoinvasion with high-grade dysplasia in a
colonic adenoma. Distinction from adenocarci-
noma. Am] Surg Pathol1990;14:694-697.
23. Cooper HS. Surgical pathology of endoscopically
removed malignant polyps of the colon and
rectum. Am J Surg Pathol 1983;7:613-623.
24. Cooper HS. Pathologi.c issues in the treatment
of endoscopically removed malignant colorectal
polyps.] Natl Compr Cane Netw 2007;5:991-996.
25. Hassan C, Zullo A, Risio M, Rossini FP, Morini
S. Histologic risk factors and clinical outcome
in colorectal malignant polyp: a pooled-data
analysis. Dis Colon Rectum 2005;48:1588-1596.
26. Muller S, Chesner IM, Egan M], et al. Signif-
icance of venous and lymphatic invasion in
malignant polyps of the colon and rectum. Gut
1989;30: 1385-1391.
27. Quirke P, Risio M, Lambert R, von Karsa L, Vi-
eth M, International Agency for Research on
C. European guidelines for quality assurance
in colorectal cancer screening and diagnosis.
First Edition-Quality assurance in pathology
in colorectal cancer screening and diagnosis .
Endoscopy 2012;44(Suppl 3):SE116-130.
28. Wilcox GM, Beck JR. Early invasive cancer in
adenomatous colonic polyps ("malignant pol-
yps"). Evaluation of the therapeutic options by
decision analysis . Gastroenterology 198 7;92(Pt
1):1159-1168.
29. Rogers AC, Gibbons D, Hanly AM, et al. Prognos-
tic significance of turn or budding in rectal cancer
biopsies before neoadjuvant therapy. Mod Pathol
2014;27:156-162.
30. Rogers AC, Winter DC, Heeney A, et al. System-
atic review and meta-analysis of the impact of
tumour budding in colorectal cancer. Br J Cancer
2016;115:831-840.
31. Vogelstein B, Fearon ER, Hamilton SR, et al.
Genetic alterations during colorectal-tumor
development. N Engl J Med 1988;319:525-532.
32. Bosman FT, World Health Organization, Inter-
national Agency for Research on Cancer. WHO
classification of tumours of the digestive system,
4th ed. Lyon: IARC Press; 2010.
33. Bettington M, Walker N, Rahman T, et al. High
prevalence of sessile serrated adenomas in con-
temporary outpatient colonoscopy practice.
Intern MedJ 2017;47:318-323.
203
Survival Guide to Gastrointestinal Mucosal Biopsies
34. Bettington M, Walker N, Rosty C, et al. Critical
appraisal of the diagnosis of the sessile serrated
adenoma. Am] Surg Pathol2014;38:158-166.
35. Odze RD, Far-raye FA, Hecht]L, HornickJL. Long-
term follow-up after polypectomy treatment for
adenoma-like dysplastic lesions in ulcerative coli-
tis. Clin Gastroenterol Hepatol2004;2:534-541.
36. Quinn AM, Farraye FA, Naini BV, et al. Polyp-
ectomy is adequate treatment for adenoma-like
dysplastic lesions (DALMs) in Crohn's disease.
Inflamm Bowel Dis 2013;19:1186-1193.
37. Parian A, Koh], Limketkai BN, et al. Association
between serrated epithelial changes and colorec-
tal dysplasia in inflammatory bowel disease.
Gastrointest Endosc 2016;84:87-95 e81.
38. Modlin IM, Lye KD, Kidd M. A 5-decade analysis
of 13,715 carcinoid tumors. Cancer 2003;97:934-
959.
204
39. Kimura N, Sasano N. Prostate-specific acid phos-
phatase in carcinoid tumors. Virchows Arch A
Pathol Anat Histopathol 1986;41 0:24 7-251.
40. Saha S, Hoda S, Godfrey R, Sutherland C, Raybon
K. Carcinoid tumors of the gastrointestinal tract: a
44-year experience. South MedJ 1989;82: 1501-1505.
41. Shia ], Tang LH, Weiser MR, et al. Is nonsmall
cell type high-grade neuroendocrine carcinoma
of the tubular gastrointestinal tract a distinct
disease entity? Am] Surg Pathol 2008;32:719-
731.
42. Singhi AD, Montgomery EA. Colorectal granular
cell tumor: a clinicopathologic study of 26 cases.
Am] Surg Pathol2010;34:1186-1192.
43. Anglesio MS, Papadopoulos N, Ayhan A, et al.
Cancer-Associated Mutations in Endometriosis
without Cancer. N Engl J Med 2017;376:1835-
1848.
 9 NON-NEOPLASTIC ANUS

The length of the anus is short, such that a
biopsy from the anatomic (clinical) anus might
contain glandular, transitional, or squamous
mucosa. A biopsy labeled "anus," can show
colonic-type mucosa and be correctly labeled!
Anatomically, the anal canal begins as the rec-
tum enters the puborectalis sling (palpated as
the anorectal ring on a digital exam), ending
at the squamous mucocutaneous junction with
the perianal skin. The upper two thirds are
endoderm-derived, and the lower one third is
ectodermally derived. The dentate, or pectinate
line, is where the two zones meet.
Most of the anal canal is lined by squamous
mucosa. The adjoining nonsquamous lining can
consist of either transitional (urothelium-like) or
rectal glandular mucosa and there are anal ducts
and glands at the transition zone (figs. 9-1-9-3).
HEMORRHOIDS
Hemorrhoids are common (1,2). They have
been viewed as varicosities of submucosal
veins but current belief is that they result from
sagging or slippage of normal structures that
is exacerbated by straining at defecation. The
hemorrhoids are normal anatomic structures lo-
cated in the subepithelial space (1-3), consisting
of connective tissue cushions surrounding the
direct arteriovenous communications between
the terminal branches of the superior rectal
arteries and the superior, inferior, and middle
rectal veins. The hemorrhoidal cushions are

Figure 9-1
ANAL TRANSITIONAL MUCOSA
Left: Note that th e basal cells are similar to those of squamous epithelium whereas the superficial cells contain mucin
droplets.
Right: This is a high magnification image. Note the cytologic features of the basal layers and the sizes of the nuclei
compared to those of the stromal cells beneath the basement membrane.

205
Survival Guide to Gastrointestinal Mucosal Biopsies
Figure 9-2
HIGH-GRADE ANAL INTRAEPITHELIAL NEOPLASIA
This is a beautiful image to contrast with the transitional
epithelium in figure 9-1, right. These images were obtained
at the same magnification. Compare the nuclear features
and sizes.
essentially a "stopper" that allows the anal canal
to fully close.
Hemorrhoidal vessels are usually above the
dentate line on the left lateral, right anterior,
and right posterior aspects of the anal canal.
Symptomatic hemorrhoids can be found above
(internal) or below (external) the dentate line.
Hemorrhoids are reported to affect about 4
percent of persons in the United States; most pa-
tients are between 45 and 65 years of age. While
there is rio overall gender predilection, symptom-
atic hemorrhoids are frequent during pregnancy.
Surgical treatment ofhemorrhoids is suggest-
ed for only a subset of patients, including those
who: 1) fail medical and nonoperative therapy;
2) have symptomatic severe hemorrhoids; 3)
have symptomatic hemorrhoids in the presence
of a separate anorectal condition that requires
surgery; and 4) patient desire (1) .
Microscopically, hemorrhoids demonstrate
large ectatic vessels, and the associated mucosa
206
Figure 9-3
ANAL DUCTS/GLANDS
These are small tubules that tend to be surrounded by
a cuff of lymphoplasmacytic cells akin to a lamina propria
as in the colon.
typically displays prolapse changes (4) . Epithe-
lial changes overlying the hemorrhoids can be
strikingly reactive and have the appearance of
"Pagetoid dyskeratosis" (5) which is illustrated
in chapter 10 as a finding in so-called anal tags
(fibroepithelial polyps). It is important not to
diagnose this reactive process as human papil-
loma virus- associated viral cytopathic effect.
If course, sometimes squamous dysplasia can
be found in association with hemorrhoids so
vigilance is always indicated (figs. 9-4, 9-5).
PAPILLARY ENDOTHELIAL HYPERPLASIA
(VEGETANT INTRAVASCULAR
H EMANG IOEN DOTH ELIOMA)
Papillary endothelial hyperplasia was first
reported in hemorrhoidal vessels, producing a
gross appearance that reminded Pierre Masson of
a cherry (6). The condition is wholly benign itself
but the terminology coined over a century ago at
the time of the original description is alarming.
 Non-Neoplastic Anus

Figure 9-4
HEMORRHOIDECTOMY SPECIMEN
Left: Large ectatic blood vessels are present, some stuffed with erythrocytes . This is an internal hemorrhoid sample
because there is both colorectal type mucosa and squamous mucosa. It is important to study such samples carefully; note
the squamous findings indicated by the arrow.
Right: There is high grade squamous dysplasia (anal intraepithelial neoplasia/AIN). This is a high magnification image
of the focus indicated on the left.

Figure 9-5
HEMORRHOIDECTOMY SPECIMEN
Left: This sample is from the anal transitional zone. There is a colorectal type crypt an the left but the top of the image
shows squamous epithelium. A thrombosed hemorrhoidal vessel is seen at the bottom of the image. There is papillary
endothelial hyperplasia in the thrombus towards the top of it.
Right: This is a high magnification of papillary endothelial hyperplasia, a wholly benign finding. Sometimes, however, it
raises the possibility of angiosarcoma . What is now known as papillary endothelial hyperplasia was initially termed vegetant
hemangioendothelioma, a tetm that is no longer used. Hemangioendothelioma is currently used to desGibed a group of vascular neoplasms
that have low grade malignant behavior. In contrast, the lesion depicted is simply a dramatic form of organizing thrombus. Note
that small endothelial cell nuclei form a coating around cores of fibrin and the lesion is restricted to a vessel lumen.

207
Survival Guide to Gastrointestinal Mucosal Biopsies

. .. ..
''
I! -. ·- - ..
~~· ~
. .'•:• ..... ..... ·'
...... -
• •• ; : - :. , ·

':..
--~ ·~·.~
. • • j

•.f - -•
•. .

Figure 9-6
RADIATION PROCTITIS
Left: There is squamous epithelium at the right and colorectal mucosa at the left. The arrow indicates a thickened lamina
propria vessel that is oriented parallel to the surface; the vascular orientation and thickness is typical of the vascular changes
in radiation proctitis. These samples were from a man who had been radiated for prostate carcinoma.
Right: Note the ectatic thick capillaries just under the surface.

This benign reactive process is simply a form else. For all practical purposes, only squamous
of organizing vascular thrombus. It may occur epithelium is affected. It is associated with genital
at any age and involve any vessel, including lesions and penoanal intercourse (7-10). Biopsies
those of neoplasms and vascular malformations. show characteristic multinucleated cells, with
Histologically, the lesion is usually within a smudged intranuclear inclusions in squamous
vessel or area of thrombus and consists of pap- epithelial cells at the edge of ulcers (fig. 9-7).
illary fronds with cores of fibrin or hyalinized
Cytomegalovirus
collagen, lined by a single layer of endothelial
cells. The endothelial cells may have a hobnail Cytomegalovirus (CMV) proctitis is typically
appearance (be plump and protrude a bit) but an infection of HIVI AIDS patients but it should
lack significant atypia or mitotic activity (fig. also be sought in individuals with inflamma-
9-5). Occasionally, the fronds appear to be tory bowel disease taking immunomodulation
"free-floating" within the vessel lumen. Extra- therapy (11). It can manifest as ulcers, polyps,
vascular extension may occasionally be seen, or a mass. The viral cytopathic effect in CMV
although it is usually not extensive. proctitis is identical to that in other sites with
Remember also that radiation proctitis can re- both nuclear and cytoplasmic inclusions that
sult in vascular changes, a possibility to consider enlarge the infected cells (fig. 9-8).
in men with a history of prostate carcinoma and
Syphilis
women with lower genital tract neoplasms such
as cervical carcinoma (fig. 9-6). Syphilis, caused by Treponema pallidum is a
sexually transmitted disease characterized by
INFECTIOUS PROCTITIS primary, secondary, and tertiary stages. The
primary stage features a chancre, a painless firm,
Herpes Simplex Virus
red lesion at the site of inoculation, which heals
He1pes simplex virus (HSV) proctitis has the after 3 to 6 weeks . Of course, in the rectum or
same appearance as HSV infection anywhere anal canal, this lesion is wholly inapparent to

208
 Non-Neoplastic Anus

Figure 9-7
ANAL BIOPSY FROM A PATIENT WITH SYPHILIS AND HERPES SIMPLEX VIRUS PROCTITIS
Left: The sample is from the edge of an ulcer. The lymphoplasmacytosis at the left is a feature of syphilis proctitis but the
multinucleated cell at th e center of the image is a clue to consider herpes simplex virus.
Right: Note the multinucleation of th e cell at the upper left. The nuclei have a smudged appearance (ground glass
appearance).

Figure 9-8
CYTOMEGALOVIRUS PROCTITIS
This is a sample from an HIV infected
man who has sex with men (MSM). The
infected cell is an endothelial cells and
it has both cytoplasmic inclusions and
a nuclear inclusion. It is very large
compared to the other endothelial
cells in the image.

209
Survival Guide to Gastrointestinal Mucosal Biopsies
Figure 9-9
SYPHILIS PROCTITIS WITH CONDYLOMA LATUM
At low magnification, the eye-catching feature is
the dense band-like plasmacytic inflammation and the
cauliflower-like appearance of the squamous proliferation.
The appearance if very much like that of a genital wart
(condyloma) but the dense inflammation is very different.
Note that the vessels at the bottom of the image are also
cuffed by plasma cells.
the patient or anyone else. The secondary stage
is characterized by a maculopapular rash and
that results from spirochete multiplication with-
in the skin and mucous membranes and occurs
2 to 10 weeks after the initial stage. Condyloma
lata (raised, broad-based plaques) may be seen
during this stage and may produce lesions that
clinically masquerade as HPV infection or ma-
lignancy. Condyloma lata shows acanthosis,
surface erosion, broadening and elongation of
rete ridges, exocytosis and neutrophils in the
most superficial layers, and spongiosis (fig. 9-9)
(12). Vessels may show endothelial swelling and
proliferation and may be encased by plasma
cells (fig. 9-10) (12).
Tertiary syphilis is now rare since antibiot-
ics are readily available but manifests aortitis,
210
Figure 9-10
SYPHILIS PROCTITIS WITH CONDYLOMA LATUM
This is a high magnification showing the dense plasma
cell rind encircling the vessels.
tabes dorsalis, and gummas (rubbery nodules
composed of a necrotic center with surrounding
macrophages, fibroblasts, lymphocytes, and
plasma cells).
Endoscopically, syphilitic proctitis may show
granular, friable, erythematous, or ulcerated
mucosa (13-15) or even a mass clinically con-
cerning for malignancy (16,17).
Biopsies show squamous epithelial hyperpla-
sia with or without ulceration, granulation tis-
sue, and striking, band-like lymphoplasmacytic
infiltrate underlying the squamous epithelium
that is at least focally angiocentric (16). Defin-
itive diagnosis requires serologic confirmation
with rapid plasma reagin (RPR), fluorescent
treponema! antibody-absorption test (FTA), or
immunolabeling (fig. 9-11) but it is important
to know that a negative immunostain does not
exclude the diagnosis.
 Non-Neoplastic Anus

Figure 9-11
SYPHILIS IMMUNOSTAIN
Left: When using this preparation in perianal skin and anal orifice biopsies, it is unwise to use DAB (3,3' Diaminobenzidine)
as the indicator of a positive test as this leads to brown staining, which appears similar to normal melanocytic processes. As
such, it is prudent to use AEC (3-Amino-9-Ethylcarbazole) which results in red staining of the organisms. In this case, the
red colored structures are syphilis organisms whereas the delicate brown ones are melanocytic processes.
Right: This is a negative area and the brown structures are melanocytic processes. There are publications that depict such
an appearance and tout a positive immunostain. This image is from the same case as that shown on the left 16 in a focus
that lacked organisms. It is important to realize that a negative immunostain does not exclude an infection with syphilis
and that lymphogranuloma venereum proctitis has essentially identical feature.

Lymphogranuloma Venereum
Lymphogranuloma venereum (LGV) is caused
by Chlamydia trachomatis, serotypes Ll, L2, and
L3. Other subtypes of this organism can cause
cervicitis, endometritis, urethritis, and trachoma
(18) . Outbreaks are repmted in men who have sex
with men (MSM) (18) . The classically described
presentation of LGV consists of a penile papule
followed by a secondary stage characterized by
tender inguinal lymphadenitis (Bubos). How-
ever, in MSM patients, the presentation may
include rectal discharge and proctitis with a
tertiary stage of anorectal strictures, perirectal
abscesses, genital elephantiasis, penile defor-
mities, and esthiomene (a chronic ulcer), all of
which mimics inflammatory bowel disease (18).
The diagnosis is established by serology or PCR
and the infection is treated with doxycycline.
The histologic findings in LGV are nonspe-
cific and often indistinguishable from those of
syphilis proctitis (fig. 9-12) and thus the diag-
nosis must be confirmed by laboratory testing.
Crohn's Disease
Patients with Crohn's disease may have ana-
genital skin lesions (anal sldn tags, hemorrhoids,
tumor-like lesions [rare]) (19), anal canal mani-
festations (anal fissures, anal ulcers, and anorectal
strictures), perianal fistulas and abscesses, rectovag-
inal fistulas, and cancer (20) . However, the risk of
anal cancers is minimally elevated over that of
controls if there is indeed an increased risk (21).

211
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 9-12
CHLAMYDIA (LYMPHOGRANULOMA VENEREUM) PROCTITIS
Left: The findings are similar to those seen with syphilis proctitis. The degree of chronic inflammation of out of proportion
to the degree of acute inflammation and the degree of crypt distortion (in the colonic type component of the mucosa).
Right: There is dense chronic inflammation but scant acute inflammation. There are a few neutrophils in the crypt at the
left but abundant lamina propria inflammation.

In patients with ulcerative colitis, involve-
ment of the anal canal is typically nonspecific
and unrelated to the inflammatory disease
whereas patients with Crohn disease have anal
involvement about 25 percent of the time if
they have classic small intestinal disease and up
to 80 percent of the time if they have colonic
involvement. Biopsies may show patchy, active
chronic inflammation or fissures, fistulas, and
striking chronic inflammatory infiltrates can be
encountered (fig. 9-13). Unfortunately, unless
granulomas are seen, the biopsy features are
not specific and must be correlated with clini-
cal ones. Additionally, many colleagues prefer
not to obtain anal canal biopsies since they are
uncomfortable for the patient.

212

REFERENCES
1. Clinical Practice Committee, American Gastro-
enterological Association. American Gastroenter-
ological Association medical position statement:
diagnosis and treatment of hemorrhoids. Gastro-
enterology. 2004;126:1461-2.
2. Madoff RD, Fleshman JW, Clinical Practice
Committee, American Gastroenterological
Association. American Gastroenterological As-
sociation technical review on the diagnosis and
treatment of hemorrhoids. Gastroenterology
2004;126:1463-73.
Non-Neoplastic Anus
Figure 9-13
CROHN'S DISEASE PROCTITIS
A: This is seldom biopsies but note that there is dense
inflammation at the right of the image and minimal
inflammation at the left. This biopsy is from the anal
opening since skin structures can be seen at the left. The
inflammation at the right is granulomatous.
B: A granuloma showing a multinucleated giant cell
with numero us nuclei.
C: This granuloma shows multinucleated giant cells but
also epithelioid histiocytes with reniform (kidney-shaped)
nuclei.
3. Hulme-Moir M, Bartolo DC. Hemorrhoids. Gas-
troenterol Clin North Am 2001;30:183-97.
4. Kaftan SM, Haboubi NY. Histopathological
changes in haemorrhoid associated mucosa and
submucosa. IntJ Colorectal Dis 1995;10:15-8.
5. Val-Bernal JF, Pinto ]. Pagetoid dyskeratosis is
a frequent incidental finding in hemorrhoidal
disease. Arch Pathol Lab Med 2001;125:1058-62.
6. Masson P. Hemangioendotheliome vegetant in-
travasculaire. Bull Soc Anat Paris 1923;93:517-23.
213
Survival Guide to Gastrointestinal Mucosal Biopsies
7. Evans BA, Kell PD, Bond RA, MacRae KD, Slomka
M], Brown DW. Predictors of seropositivity to
herpes simplex virus type 2 in women. IntJ STD
AIDS 2003;14:30-6.
8. ]acobs E. Anal infections caused by herpes sim-
plex virus. Dis Colon Rectum 1976;19:151 -7.
9. Krone MR, Tabet SR,Paradise M, Wald A, Corey
L, Celum CL. Herpes simplex virus shedding
among human immunodeficiency virus-negative
men who have sex with men: site and frequency
of shedding.] Infect Dis 1998;178:978-82.
10. van de Laar M], Termorshuizen F, Slomka M], et
al. Prevalence and correlates of herpes simplex
virus type 2 infection: evaluation of behavioural
risk factors. IntJ Epidemiol 1998;27:127-34.
11. Alam I, Shanoon D, Alhamdani A, Boyd A, Grif-
fiths AP, Baxter ]N. Severe proctitis, perforation,
and fatal rectal bleeding secondary to cytomega-
lovirus in an immunocompetent patient: report
of a case. Surg Today 2007;37:66-9 .
12. Pandhi RI<, Singh N, Ramam M. Secondary syph-
ilis: a clinicopathologic study. Int ] Dermatol
1995;34:240-3.
13. Furman DL, Patel SI<, Arluk GM. Endoscopic and
histologic appearance of rectal syphilis. Gastro-
intest Endosc 2008;67:161; commentary 161-2.
14. Nazemi MM, Musher DM, Schell· RF, Milo S.
Syphilitic proctitis in a homosexual. ]AMA
1975;231:389.
214
15. Teitelman M, Wilson ]A, Guy CD. Image of the
month. Syphilitic proctitis. Clin Gastroenterol
Hepatol 2008;6:xxvi.
16. Gopal P, Shah RB . Primary anal canal syphilis
in men: the clinicopathologic spectrum of an
easily overlooked diagnosis. Arch Pathol Lab
Med 2015;139 :1156-60.
17. Bender Ignacio RA, Koch LL, Dhanireddy S,
Charmie Godorrtes B, Lukehart SA, Marrazzo ]M .
Syphilis? An unusual cause of surgical emergency
in a human immunodeficiency virus-infected
man. Open Forum Infect Dis 2015;2:ofv094.
18. Kapoor S. Re-emergence oflymphogramiloma ve-
nereum. ] Eur Acad Dermatol Venereol2008;22:
409-16.
19. Kim BS, Kim HS, Kim MB, Oh CK, Kwon KS.
Perianal Crohn's disease with a clenched fist-like
appearance.] Eur Acad Dennatol Venereol2009;
23:1197-8.
20. Sandborn WJ, Fazio VW, Feagan BG, Hanauer
SB, American Gastroenterological Association
Clinical Practice C. AGA technical review on
perianal Crohn's disease . Gastroenterology
2003;125:1508-30.
21. Ryan DP, Compton CC, Mayer R]. Carcinoma of
the anal canal. N Engl] Med. 2000;342:792-800.
 10 ANAL POLYPS AND NEOPLASMS
Anal neoplastic pathology mostly concerns
squamous carcinoma and its precursors, even
though such tumors are relatively rare. Most
cancers are treated with radiation and chemo-
therapy so resections are not very common and
biopsy pathology is key. An important issue
in anal pathology is that it is the size, rather
than the depth, that determines the T stage in
anal cancers (T1 is Q cm, T2 is >2 to 5 cm, T3
is >5 cm, and T4 encompasses invasion into
adjacent organs regardless of the size) (1) . A few
skin lesions can be encountered in the skin just
adjacent to the anus.
HIDRADENOMA PAPILLIFERUM
This benign apocrine neoplasm arises in the
perianal skin and vulva and is almost always
a lesion of women over the age of 30. Most
examples involve the labia majora, perineum,
and perianal skin (2- 4) .
Lesions are composed of epithelial-lined cysts
in the mid-dermis with intricate papillary in-
foldings that are formed by fibrovascular cores,
lined by two layers of cuboidal epithelium with
foci of bridging and tuft formation (figs . 10-1,
10-2). These tumors express CK5/6, which is
helpful in excluding an adenocarcinoma, as
well as express estrogen receptor (ER.
POLYPS
Inflammatory Cloacogenic Polyp
Inflammatory cloacogenic polyp is a mucosal
prolapse polyp arising at the anorectal transi-
tion, thus having both squamous and columnar
mucosa but it is essentially the same process as
solitary rectal ulcer and mucosal prolapse as seen
in chapter 8 (figs. 10-3,10-4) (5,6). Patients com-
plain of hematochezia, and the polyps generally
arise on the anterior wall of the anal canal.
Fibroepithelial Polyps
Fibroepithelial polyps are also termed anal
tags and excising them is generally not per-
formed unless they interfere with personal
hygiene. Removal may be painful and, in the
case of those associated with Crohn's disease,
may result in additional morbidity. They are
Figure 10-1
HIDRADENOMA PAPILLIFERUM
These benign lesions are skin appendage
tumors that arise in the perineum and are
almost always lesions of adult women.
The lesion is well marginated but the
complex low magnification architecture is
concerning for adenocarcinoma.
215
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 10-2
HIDRADENOMA PAPILLIFERUM
Left: These tumors are composed of complex tubules that each have two cell layers (an outer myoepitheliallayer and an
inner epithelial layer).
Right: This high magnification image emphasizes the dual layer of cells encircling each tubule. The tubules are sectioned
longitudinally in this image.

Figure 10-3
INFLAMMATORY
CLOACOGENIC POLYP
This is a mucosal prolapse
polyp at the anal transition zone
so there are both squamous and
columnar components. At this
magnification the replacement
of the lamina propria by strands
of smooth muscle imparts a pink
rather than blue appearance to
the lamina propria .

216
 Anal Polyps and Neoplasms

Figure 10-4
INFLAMMATORY CLOACOGENIC POLYP
Left: The colorectal type glands are angulated ("diamond shaped") and separated by strands of smooth muscle. In areas
they herniate beneath th e squamous epithelium.
Right: Note the elongated strands of smooth muscle between colorectal type glands. They seem to mold to one another.

often submitted to the pathologist as though
they are hemorrhoids. They are essentially the
same as skin tags (acrochordons).
Fibroepithelial polyps consist of myxoid or
collagenous stroma covered by squamous epi-
thelium (fig. 10-5). Some larger ones contain
atypical but reactive stromal cells There is oc-
casionally epidermoid metaplasia (squamous
epithelium with a granular layer in non-skin
anal mucosa).
ANAL SQUAMOUS
INTRAEPITHELIAL NEOPLASIA
Anal squamous intraepithelial neoplastic le-
sions, like those in the uterine cervix, are related
to sexually transmitted human papillomavirus
(HPV) infections, and these are regarded as the
precursors to invasive anal squamous cell car-
cinomas. HPV infections are very common but
only about 8,000 estimated new cases of anal
cancers and about 12,900 new cervical cancers
were estimated for 2016 (7), which suggests a
very low progression rate for HPV infection. The
total number of infected persons is believed to
be on the order of 80 to 110 million (see http:/ I
www.cdc.gov/std/hpv/). In human immunode-
ficiency virus (HIV)-infected men who have sex
with men (MSM), individuals at nearly 40 fold
the risk for anal squamous carcinoma over the
general population, the data support vaccinat-
ing against HPV as a cost effective policy (8).
Endorsement of HPV vaccination in both young
men and young women was offered by the Cen-
ter for Disease Control (CDC) in 2013 (9).
The anal canal has a transformation zone
akin to that in the uterine cervix, and this is
where many precursor lesions are detected .
The HPV-associated lesions had been classified
as anal intraepithelial neoplasia (AIN) I, AIN
II, and AIN Ill, but now, as for the cervix, most

217
Survival Guide to Gastrointestinal Mucosal Biopsies

. A '
.
~:· ,·

Figure 10-5
ANAL FIBROEPITHELIAL POLYP (ANAL TAG)
A: The surface has a peculiar reactive appearance from
local trauma.
B: Note the unusual reactive appearance of the surface.
This appearance has been termed "Pagetoid dyskeratosis"
when it is found in prolapsed uterine cervical mucosa and
it can mimic squamous dysplasia or Paget disease but it is
a purely reactive finding.
C: The stromal cells within the subepithelial tissue of the
polyp frequently display degenerative atypia.

observers prefer to separate low- and high-
grade lesions, with the AIN II subsumed under
high-grade. Increasing degree of loss of nuclear
stratification and polarity, nuclear pleomor-
phism and hyperchromatism (with or without
keratinization or HPV viral cytopathic changes),
and increased mitoses high in the epithelium
are the findings used to grade dysplasia/intra-
epithelial neoplasia (figs. 10-6, 10-7). As in the
uterine cervix, dysplasia may be seen extend-
ing into colonic glands but not penetrating
the basement membranes; this should not be
mistaken for carcinoma (fig. 10-8).
c
Immunolabeling with Ki-67 and p16 antibod-
ies can be helpful in confirming and grading
dysplasia but it has limitations (10). Ki-67 is a
sensitive marker (when used as validated) for
dysplasia in mature squamous epithelium and
is therefore helpful for confirmation of AIN1
and condyloma (figs. 10-6A,B, 10-7B,C). Ki-67
labeling does not distinguish reparative changes
from dysplasia/intraepithelial neoplasia.
A positive Ki-67 stain, for the purposes of
grading dysplasia, can be defined as the pres-
ence of a group of at least two strongly labeled
epithelial nuclei in the upper two-thirds of

218
 Anal Polyps and Neoplasms

Figure 10-6
LOW-GRADE ANAL INTRAEPITHELIAL NEOPLASIA
A: The cytologic features are similar to those of a
condyloma except that the lesion is flat and found in the
anal transitional mucosa (the area where the squamous and
columnar epithelium meet). There is koilocytotic atypia at
the surface with large nuclei surrounded by paranuclear
cavities but mitotic activity is found in the basal half of
the epithelium.
B: This is a Ki-67. It shows some collections of nuclei
in the upper half of the epithelium. Of course, this pattern
can also be encountered in reparative conditions, so Ki-67
labeling is interpreted in the ·context of the morphologic
features on hematoxylin and eosin (H&E) staining.
C: This p16 preparation is nonreactive .

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the epithelial thickness. This labeling pattern of the squamous epithelium, with or without
is that is it not useful for separating low- and superficial staining.
high-grade dysplasia/intra-epithelial neoplasia P16 labeling is an excellent marker of high-
and does not separate low-risk from high-risk grade AIN but has only limited value in confirm-
HPV type lesions. ing a diagnosis of low-grade AIN.
Ki-67 labeling is combined with p16 immu- Bowen disease, an eponymous term, indicates
nolabeling: squamous carcinoma in situ at the anal margin
1) absent or discontinuous, patchy nuclear (the outside part that can be seen on clinical
and cytoplasmic staining pattern is a negative examination, in contrast to lesions seen at the
p16 result. transition zone, inside the canal, at the dentate
2) A positive p16 result is diffuse and strong line, which are seen by anoscopy) where it
staining of cells of the basal and parabasal layers presents macroscopically as a brownish plaque.

219
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 10-7 .
HIGH-GRADE ANAL
INTRAEPITHELIAL NEOPLASIA
A: Hyperchromatic nuclei extend to the
surface and the nuclei are oriented with their
long axes perpendicular to the basement
membrane and surface until about two thirds
of the way to the surface, when they become
oriented with their long axes parallel to the
surface (AIN2 of 3). There is a mitosis about
two thirds of the way to the surface on the
upper right of the image. Note that in this type
of dysplasia nucleoli are inconspicuous.
B: This Ki-67 stain labels numerous nuclei.
C: There is prominent labeling with this
p16 antibody.

Bowen's disease is essentially an AIN lesion that
arises in the perianal skin (11). Bowenoid papu-
losis was first described in the penis (12) and is
a clinicopathologic diagnosis. The patients have
multiple papules, each with features of in situ
carcinoma, but these essentially never progress
to invasive carcinoma and sometimes they
resolve. These, too, are HPV-associated lesions.
ANAL SQUAMOUS CELL CARCINOMA
Carcinoma of the anal canal is uncommon,
accounting for only 1 to 2 percent of gastro-
intestinal tract cancers in the United States,
with an estimated 8,080 new cases in 2016 and
about 1,080 disease-associated deaths (7). Years
ago, anal cancer was regarded as an inflamma-
tion-related neoplasm and treatment was an
abdominoperineal resection with permanent
colostomy. Now most patients have small pro-
cedures and chemoradiation.
Most tumors arising within the anal canal
distal to the dentate line are keratinizing squa-
mous cell carcinomas, whereas proximal ones
are nonkeratinizing squamous cell carcinomas.
The nonkeratinizing subtypes were referred to
as transitional cell or cloacogenic carcinomas

220

Figure 10-8
HIGH-GRADE ANAL INTRAEPITHELIAL NEOPLASIA EXTENDING INTO COLORECTAL TYPE GLANDS
Left: This is not an indication of invasive carcinoma.
Right: Note the mitotic activity.
in the past; however, they are now recognized
as variants of squamous cell carcinoma. One
type is composed of large cells, and the other
is characterized by small cells. Many tumors
show more than one morphologic subtype but
the majority of these neoplasms are diagnosed
on small biopsies, which are likely not repre-
sentative of the entire tumor morphology. The
bladder and anus share a common embryo logic
origin, thus giving rise to the similar (i.e., transi-
tional or cloacogenic) morphology. The biology
and prognosis of keratinizing and nonkeratiniz-
ing tumors of the anal canal are essentially the
same, so prior concern about subclassification of
anal tumors is probably not warranted. Tumor
differentiation, however, should be included in
the report as poorly differentiated neoplasms
are associated with a higher risk of death than
well to moderately differentiated examples
(13). It is also important to separate high-grade
neuroendocrine (small cell and large cell) carci-
nomas from squamous cell carcinomas of the
anus. Adenocarcinomas of the anal canal are
clinicopathologically like rectal cancer and are
treated as such.
Anal squamous carcinoma was historically
classified into several types (Table 10-1) (14).
Anal Polyps and Neoplasms
Table 10-1
HISTORIC CLASSIFICATION OF
ANAL SQUAMOUS CARCINOMA-
Squamous cell (cloacogenic)
Large cell keratinizing
Large cell nonkeratinizing (transitional)
Basaloid
Giant condyloma (verrucous carcinoma)
' Data from reference 14.
In this classification, nonkeratinizing car-
cinomas were believed to resemble urothelial
carcinomas, and basaloid carcinoma was com-
posed of solid sheets of small cells, often with
peripheral palisading (fig. 10-9). Overall, most
anal squamous cell carcinomas have the features
of squamous carcinoma in other anatomic sites
with striking nuclear alterations with nuclear
pleomorphism, prominent mitotic activity, and
scattered squamous intercellular bridges (figs. 10-
10-10-12). An exception to the usual epithelial
changes is the rare verrucous carcinoma, which
consists of broad-based squamous papillae that
are sheet-like in a sclerotic background (fig. 10-
13). Verrucous carcinoma has also been termed
221
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 10-9
SQUAMOUS CELL CARCINOMA, BASALOID TYPE
Left: This type was called "cloacogenic" carcinoma in the past. Some examples can be difficult to diagnose and require
an immunolabeling panel to exclude neuroendocrine (small cell) carcinoma and even mesenchymal tumors.
Right: Squamous cell carcinoma, basaloid type. The individual cells have scant cytoplasm.

Figure 10-10
SQUAMOUS CELL CARCINOMA
Left: The appearance of anal squamous cell carcinoma is similar to that of squamous cell carcinoma in other anatomic sites.
Right: The tumor is eosinophilic and nests of tumor are invested in desmoplastic stroma.

222
 Anal Polyps and Neoplasms

Figure 10-11
SQUAMOUS CELL CARCINOMA
A: This example is highly differentiated with a pushing border but the cytologic features are more atypical than those
of so-called verrucous carcinoma.
B: Despite the pushing growth pattern, this example is associated with vascular space invasion as seen at the left of the
image.
C: The vascular invasion in this lesion (same case as that depicted in B) shows "paradoxical maturation in which keratinization
becomes more prominent as the lesion invades. Note the dense keratinization (eosinophilia) at the periphery ofthis lymphatic
space deposit of carcinoma.

223
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 10-12
SQUAMOUS CELL CARCINOMA
Left: This is a subtle example of early (superficial) invasion in high grade dysplasia/intraepithelial neoplasia. The brightly
eosinophilic extension from the bottom center portion of the lesion is the clue that this lesion is invading.
Right: This is a high magnification showing the pocket of paradoxical maturation in a focus of invasion. Note that the
high grade dysplasia from which the invasioh takes off is more atypical than the invasive tongue.

Figure 10-13
VERRUCOUS CARCINOMA
Left: Such lesions are impossible to diagnose on superficial biopsies but the massive thickness and pushing front are the
clues to diagnosis.
Right: Note the bland cytologic features at the base of the lesion.

224
 Anal Polyps and Neoplasms

)
'

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...
..
'

Figure 10-14
COLORECTAL TYPE ADENOCARCINOMA DIAGNOSED ON AN ANAL BIOPSY
Left: Such tumors have the characteristic of colorectal carcinomas from the rest of the colon . Note the "dirty" necrosis.
Right: A sizable minority of these tumors express CKS/6 as per the internal control (overlying squamous epithelium).
This finding is not relevant to diagnosing these lesions as colorectal type adenocarcinomas.

the "giant condyloma of Buschke-Lbwenstein"

and may involve the external genitalia and
perianal skin. It resembles a condyloma, but is, if
anything, cytologically blander with less striking
viral cytopathic changes. Koilocytes with nuclear
cavities are not seen. Sometimes lesions that
otherwise have the appearance of verrucous car-
cinomas display zones of more typical invasive,
well-differentiated squamous cell carcinoma, a
feature which should also prompt a diagnosis of
conventional squamous cell carcinoma.
Recognizing the subtypes is not really im-
portant and they have no impact on outcome
with the exception of verrucous carcinoma and
poorly differentiated carcinomas. Providing a di-
agnosis of invasive carcinoma is all that is clini-
cally relevant. Ordinary colorectal carcinoma
can also be found on biopsies of the anus and
can express CK5/6 in a subset of cases, which
can be ignored (fig. 10-14).
PAGET D ISEASE
Extramammary Paget disease affects apocrine
gland-rich sites, including the perianal zone.
It grows slowly, consisting of an erythematous
eczematoid plaque that may extend internally
to the dentate line. It is essentially a sweat type
carcinoma with an intraepithelial growth pat-
tern. Histologically, the squamous epithelium is
infiltrated by large pale cells, some of which may
have signet cell features, and some of which
may be large and pink (fig. 10-15). A pitfall is
that when epithelium is crushed, it can be dif-
ficult to separate the Paget cells from atypical
keratinocytes of AIN, or even from melanoma.
Immunohistochemistry can resolve most cases.
Anal Paget disease is a lesion with apocrine cell
differentiation, so the cells express CAM 5.2,
carcinoembryonic antigen (CEA), gross cystic
disease fluid protein (GCDFP), and CK7, and

225
Swvival Guide to Gastrointestinal Mucosal Biopsies

Figure 10-15
ANAL/PERIANAL PAGET DISEASE
A: This biopsy was taken from the anal canal so the
granular layer is metaplastic. There are plump intra epithelial
malignant columnar cells. Paget disease is essentially an
intraepithelial carcinoma that differentiated along the lines
of skin appendages.
B: This is a CK7 stain, which labels the malignant cells
but not the squamous epithelium
C: This is a p16 stain. The significance of this labeling
is not clear but this image is included to point out that
immunolabeling is used to confirm interpretations rather
than to make them in the first place. This staining is
irrelevant to evaluation of Paget's disease.

they contain mucin (15). Nonneoplastic so-
called Taker cells in skin can also express CK7,
a feature the pathologist must consider when
evaluating these stains. Additionally, nonneo-
plastic Merkel cells can express CK20.
The key issue is to separate cases showing
adenocarcinoma cells in anal squamous mu-
cosa that reflect Pagetoid extension of a nearby
colorectal cancer into squamous epithelium
(figs . 10-16, 10-17). These lesions lack GCDFP
and are often CK20+, CK7-, and CDX2+. Occa-
sional microsatellite unstable colorectal carci-
noma, however, may lack CK20 (16). Therefore,
the way to determine whether any given case
of anal Paget disease is associated with an inva-
sive cancer is by a careful clinical examination.
Rarely this type of lesion is associated only with
a colorectal adenoma! The "tlue" Paget disease
cases that are epidermotrophic skin append-
age type neoplasms have a proclivity for local
recurrence and can eventually become inva-
sive. Those that result from epidermotropism
of "ordinary" adenocarcinomas behave as the
associated cancers.

226
 Anal Polyps and Neop lasms

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Figure 10-16
PAGETO ID EXTENSION OF COLORECTAL CARCINOMA INTO ANAL SQUAMOUS EPITHELIUM
A: This pattern is indistinguishable from that of true Paget's disease but accounts for about half of cases of anal intra epithelial
carcinoma. The malignant cells are plump and mucinous.
B: This CDX2 preparation highlights the malignant colorectal carcinoma cells that have spread into the squamous
epithelium.
C: This high magnification shows the cytoplasmic mucin of the malignant cells.
D: An adenomatous precursor is seen in the colorectal mucosa at the right side of the image. In rare cases, no invasive
colorectal carcinoma is seen but colorectal type cells are found in the squamous epithelium in a Pagetoid pattern. In fact
the squamous epithelium at the left harbors intraepithelial malignant cells but, in this case there was also an associated
invasive colorectal adenocarcinoma.

227
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 10-17
PAGETOID EXTENSION OF COLORECTAL CARCINOMA INTO ANAL SQUAMOUS EPITHELIUM
Left: This is an invasive colorectal adenocarcinoma that produced Pagetoid invasion into squamous epithelium.
Right: At first glance, this process has an appearance of squamous dysplasia, but note the cytoplasmic mucin in the cell
in the center.

ADENOCARCINOMA AND ANAL
GLAND ADENOCARCINOMAS
Adenocarcinomas arising in the anus are usu-
ally of the rectal type and arise in the upper zone
of the anus (which is lined by columnar mucosa).
These are identical to rectal carcinomas and are
managed as such. On biopsies, they are also
identical to rectal adenocarcinomas, and their
immunohistochemical profile is identical (CK20+,
CK7 usually negative; note the pitfall with CKS/6
seen in figure 10-14). Anal adenocarcinomas are
usually easy to diagnose, although the differen-
tial diagnosis is with mucosal prolapse polyps
(inflammatory cloacogenic polyps), which have
diamond-shaped glands, fibromuscular mucosal
stranding, and bland cytology.
A rare subset of anal canal adenocarcinomas
shows differentiation towards, anal ducts/anal
glands (fig. 10-18) . These are called anal gland
(duct) carcinomas. They are composed of tu-
bules originating from ducts that open onto
the mucosal surface. They lack a luminal in situ
component but some show Pagetoid spread into
the squamous epithelium. They are typically
CK7+ and CK20-, as per anal glands and ducts.
Anal gland carcinoma lacks immunoreactivity
with CKS/6 and P63 (17). However, some cases
can express CDX2. Anal duct/gland carcinomas
have lacked prostate-specific antigen (PSA) and
prostatic acid phosphatase (18) and have also
lacked hormone receptor expression and HPV
by in situ hybridization (19). Many have be-
haved aggressively (19).
A general caveat to remember is that typical
colorectal (and some colorectal neuroendocrine
neoplasms) cancer can display PAP expression.

228

..()
.I#
OTHER TUMORS
Granular Cell Tumor
Most gastrointestinal granular cell tumors
arise in the esophagus, followed by the anus.
There is a female predominance and most affect-
ed individuals are adults. Granular cell tumors
generally arise at the anocutaneous junction as
a nodule but they are sometimes found within
the anal canal. These infiltrative lesions consist
of uniform cells with abundant pink granular
cytoplasm, just like those of other sites (fig.
Anal Polyps and Neoplasms
Figure 10-18
ANAL DUCT/GLAND CARCINOMA
A: There are numerous malignant tubules in the
subepithelial tissue but no surface component.
B: Note the malignant glands beneath the squamous
epithelium.
C: This is a CK7 preparation .
10-19). They may induce overlying squamous
pseudoepitheliomatous hyperplasia that can
mimic invasive squamous cell carcinoma. They
express CD68 and S-100 protein.
Melanoma and Nevi
Melanocytes are normal constituents of the
anal canal and anal verge, so both melanomas
and nevi can be encountered. In this location,
melanomas are more common than nevi and
usually affect white adults. However, as is the
case with subungual and esophageal lesions,
individuals with pigmented skin can also be
229
Survival Guide to Gastrointestinal Mucosal Biopsies

Figure 10-19
GRANULAR CELL TUMOR
A: The lesion is at the bottom of the field but the eye-
catching feature is the pseudoepitheliomatous hyperplasia
at the top and left of the image, which can mimic squamous
cell carcinoma.
B: The tumor is composed of eosinophilic cells with
ample cytoplasm.
C: This high magnification image highlights the granular
cytoplasmic appearance.

affected. When patients present with a mass
or often rectal bleeding, it is often initially
attributed to hemorrhoids (20) . Since anal
melanomas often lack pigment, a panel immu-
nohistochemical approach is often required to
exclude carcinomas and lymphomas. Assuring
that the lesion is primary is best accomplished
by the identification of an in situ component.
Anal melanomas often are CD117 /KIT+ on
immunohistochemistry, which does not always
correlate with KIT mutations. Some mucosal
melanomas (about 20 to 30 percent) do have
J(]T mutations (21) and can respond to imati-
nib (22). BRAF mutations are rare in mucosal
melanomas but common in cutaneous ones but
treatment with vemurafenib has been useful
in rare persons harboring such mutations (23).
There are few data on response to PD1-related
(programmed death 1) targeted immunotherapy
(24) in anal melanoma at this writing, but in
theory anal melanomas should be amenable to
this treatment
Anal melanomas can be difficult to diagnose
if an in situ component is not seen. Melanomas
can be pleomorphic and sarcomatoid as well as
epithelioid (fig. 10-20).

230
 Anal Polyps and Neoplasms

Figure 10-20
MELANOMA
A: This highly malignant appearing neoplasm has
spindle cell features and cannot be readily diagnosed as
melanoma on the H&E stain. Usually no in situ component
is detected so immunolabeling is needed to confirm the
diagnosis.
B: Prominent nucleoli are a clue to the diagnosis but
immunolabeling was required.
C: This is an S-100 protein stain.

Melanocytic nevi are rare in this area and the body with collections of bland melanocytes
only sporadic examples are reported in the lit- that show maturation towards the deep aspect
erature. They appear similar to nevi elsewhere in of the lesion (figs. 10-21, 10-22).

231
Survival Guide to Gastrointestinal Mucosal Biopsies

-V
•"'*

Figure 10-21
COMPOUND NEVUS WITH CONGENITAL FEATURES
Left: Anal and perianal nevi are uncommon but occasionally encountered.
Right: Compound nevus with congenital features. Finding the nevus extending along skin appendages (a hair shaft in
this example) suggests that it could be congenital.

Figure 10-22
INTRADERMAL NEVUS WITH CONGENITAL FEATURES
Left: This nevus is highly pigmented.
Right: Intradermal nevus with congenital features. This lesion arose in pigmented perianal skin.

232

REFERENCES
1. Amin M, EdgeS, Greene F, et al. A]CC Cancer
Staging Manual, 8th ed. Switzerland: Springer
International Publishing; 2017.
2. Goette DK. Hidradenoma papilliferum. ] Am
Acad Dermatol 1988;19(Pt 1):133-135.
3. Handa Y, Yamanaka N, Inagaki H, Tomita Y. Large
. ulcerated perianal hidradenoma papilliferum in a
young female. Dermatol Surg 2003;29:790-792.
4. Loane ], Kealy WF, Mulcahy G. Perianal hidrad-
enoma papilliferum occurring in a male: a case
report. Ir] Med Sci 1998;167:26-27.
5. Lobert PF, Appelman HD. Inflammatory cloaco-
genic polyp. A unique inflammatory lesion of
the anal transitional zone. Am ] Surg Pathol
1981;5:761-766.
6. Saul SH. Inflammatory cloacogenic polyp: rela-
tionship to solitary rectal ulcer syndrome/mu-
cosal prolapse and other bowel disorders . Hum
Pathol1987;18:1120-1125.
7. Siegel RL, Miller KD, ]emal A. Cancer statistics,
2016. CA Cancer] Clin 2016;66:7-30.
8. Deshmukh AA, Chhatwal ], Chiao EY, Nyitray
AG, Das P, Cantor SB. Long-term outcomes of
adding hpv vaccine to the anal intraepithelial
neoplasia treatment regimen in HIV-positive
men who have sex with men . Clin Infect Dis
2015;61:1527 -1535.
9. Advisory Committee on Immunization Prac-
tices. Recommend ed adult immunization
schedule: United States, 2013*. Ann Intern Med
2013;158:191-199.
10. Patil DT, Yang B. Utility of human papilloma virus
capsid protein L1 and p16 in the assessment and ac-
curate classification of anal squamous int:raepithe-
liallesions. Am] Clin Pathol2015;144:113-121.
11. Bosman F, Carneiro F, Hruban R, Theise N, eds.
WHO classification of tumours of the digestive
system. In: Bosman F, ]affee E, Lakhani S, Ohgaki
H, eds. World Health Organization classification
of tumours. Lyon: IARC Press; 2010.
12. Wade TR, Kopf AW, Ackerman AB. Bowenoid papu-
losis of the penis. Cancer. 1978;42:1890-1903.
13. Bilimoria KY, Bentrem DJ, Rock CE, Stewart
AI<, Ko CY, Halverson A. Outcomes and prog-
nostic factors for squamous-cell carcinoma of
Anal Polyps and Neoplasms
the anal canal: analysis of patients from the
National Cancer Data Base. Dis Colon Rectum
2009;52:624-631.
14. ]ass], Sobin L. Histological Typing of intestinal tu-
mours, 2nd ed. New York: Springer; 1989:10-11.
15. Goldblum]R, Hart WR. Perianal Paget's disease: a
histologic and immunohistochemical study of 11
cases with and without associated rectal adeno-
carcinoma. Am J Surg Pathol 1998;22: 170-179.
16. McGregor DK, Wu TT, Rashid A, Luthra R,
Hamilton SR. Reduced expression of cytokeratin
20 in colorectal carcinomas with high levels
of microsatellite instability. Am ] Surg Pathol
2004;28:712-718.
17. Lisovsky M, Patel K, Cymes K, Chase D, Bhuiya
T, Morgenstern N. Immunophenotypic char-
acterization of anal gland carcinoma: loss of
p63 and cytokeratin 5/6. Arch Pathol Lab Med
2007; 131:1304-1311.
18. Ballo MT, Gershenwald ]E, Zagars GK, et al.
Sphincter-sparing local excision and adjuvant
radiation for anal-rectal melanoma.] Clin On col
2002;20) :4555-4558.
19. Meriden Z, Montgomery EA. Anal duct carcinoma:
a report of 5 cases. Hum Pathol2012;43:216-220.
20. Felz MW, Winburn GB, Kallab AM, Lee JR. Anal
melanoma: an aggressive malignancy masquer-
acting as hemorrhoids. South MedJ 2001;94:880-
885.
21. Antonescu CR, Busam I<], Francone TD, et al.
L576P KIT mutation in anal melanomas cor-
relates with KIT protein expression and is sensi-
tive to specific kinase inhibition. Int] Cancer
2007;121:257-264.
22. Carvajal RD, Antonescu CR, Wolchok ]D, et al.
KIT as a therapeutic target in metastatic mela-
noma. JAMA 2011;305:2327-2334.
23. Martinez-Cadenas C, Bosch N, Penas L, et al.
Malignant melanoma arising from a perianal
fistula and harbouring a BRAF gene mutation: a
case report. BMC Cancer 2011;11:343.
24. Topalian SL, Hodi FS, Brahmer ]R, et al. Safety, activ-
ity, and immune correlates of anti-PD-1 antibody
in cancer. N Engl] Med 2012;366:2443-2454.
233
 Index*

endoscopic mucosal resection, 36

A
goblet cells, 23
Active chronic colitis, 153 granular cell tumor, 39
ulcerative colitis, 153 intramucosal carcinoma, 31
Acute colitis, 148 leiomyoma, 40
Adenocarcinoma, 74, 128, 189, 228 multilayered epithelium, 21
anal, 228 nondysplastic Barrett's esophagus, 24
colon, 189 squamous cell carcinoma, 37, see also Squamous
gastric, 74 cell carcinoma in Barrett's esophagus
small intestine, 128 treatment issues, 34
Adenoma, 70, 121, 174 Bowen disease, 219
colon, 174 Brunner gland lesions, small intestine, 124
high-grade dysplasia, 176
pseudoinvasion, 178
malignant polyp, 180
c
sessile serrated adenoma, 177 Carcinoid tumors, 83, 132
traditional serrated adenoma, 177 gastric, 83
tubular, 17 4 small bowel, 132
gastric, 70 Celiac disease, 107
intestinal, 73 Chemical gastropathy, 48
pyloric, 73 nonsteroidal anti-inflammatory drug use, 48
small intestine, 121 Crohn's disease, 64, 129, 156, 191
pyloric, 124 and adenocarcinoma, small bowel, 129
tubular/tubulovillous, 121 andcolitis,156,191
Adenomatous polyps, 129 gastric, 64
Ampullary carcinoma, small bowel, 129 Colitis, 148, 191
Anal biopsy, 205 active chronic, 153
hemorrhoids, 205 acute, 148
infectious proctitis, 208 associated neoplasia, 191
normal mucosa, 205 collagenous colitis, 15 7
Anal gland carcinomas, 228 diverticular-associated, 15 7
Anal intraepithelial neoplasia, 206 ischemic, 148
Angiosarcoma, small bowel, 141 lymphocytic colitis, 157
Apoptotic colopathy, 161 radiation, 149
Apoptotic esophageal injury, 14 ulcerative colitis, 153
Autoimmune enteropathy, 111 Colitis-associated neoplasia, 191
Autoimmune gastritis, 55 Collagenous colitis, 15 7
Autoimmune metaplastic atrophic gastritis, 55 Collagenous gastritis, 62
Colon biopsy, 145
active chronic colitis, 153
B
acute colitis, 145
Barrett's esophagus, 21 apoptotic colopathy, 161
adenocarcinoma, 37 collagenous colitis, 15 7
dysplasia, 23 infectious organisms, 148
high-grade dysplasia, 25 ischemic colitis, 148
indefinite for dysplasia, 25 lymphocytic colitis, 157
low-grade dysplasia, 25 normal mucosa, 146

235
Survival Guide to Gastrointestinal Mucosal Biopsies
patterns of disease, 145
radiation colitis, 149
Colorectal cancer, 189
colitis-associated neoplasia, 191
juvenile polyps, 192
neuroendocrine tumors, 192
Common variable immunodeficiency, small
intestine, 110
Crohn's disease, anal, 211
Cytomegalovirus, 61, 101, 148, 208
anus, 208
colon, 148
small intestine, 101
stomach, 61
Cytomegalovirus enteritis, small intestine, 103
Cytomegalovirus proctitis, 218
D H
Diffuse large B-celllymphoma, colon, 197
E
Endometriosis, colon, 197
Endoscopic mucosal resection, 36
Eosinophilic esophagitis, 5
Eosinophilic gastritis, 61
Epidermoid metaplasia, esophagus, 18
Erosions, esophagus, 10
Esophageal biopsy, 1
apoptotic injury, 14
biopsy evaluation, 1
epidermoid metaplasia, 18
esophagitis dissecans pattern, 15
granulomas, 15
hyperkeratosis, 16
intraepithelial eosinophils, 5
intraepitheliallymphocytes, 8
reactive epithelial changes, 2
ulcers and erosions, 10
Esophagitis dissecans, 15
Extranodal marginal zone lymphoma, gastric, 85
F Intraepitheliallymphocytes, 8
Familial adenomatous polyposis, 69, 126
and fundic gland polyps, 69
and Peutz-]eghers polyps, 126
Fibroepithelial polyps, anal, 215
Follicular lymphoma, small intestine, 137
Fundic gland polyps, 69
236
G
Gangliocytic paraganglioma, small bowel, 135
Gastric antral vascular ectasia, 50
Gastric cardia, 3
Gastric siderosis, 51
Gastrointestinal stromal tumor, 88, 140
small bowel, 140
stomach, 88
Giardia Iamblia, small intestine, 102
Giardiasis, small intestine, 102
Goblet cells 23
Granular cell tumor, 39, 229
anus, 229
esophagus, 39
Granuloma, esophagus, 15
Helicobactor pylori, 50, 70, 85
gastric polyps, 70
gastritis, 50
mucosa-associated lymphoid tissue lymphomas, 85
Helicobactor pylori gastritis, 50
Hemorrhoids, 205
Herpes simplex proctitis, 208
Hidradenoma papilliferum, anal, 215
Human papillomavirus, 38, 217
in Barrett's esophagus, 38
Human papillomavirus-associated neoplasia, 217
Hyperkeratosis, esophagus, 16
Hyperplastic polyps, 70, 176
colon, 176
gastric, 70
Hyperplastic serrated polyps, colon, 183
Infectious proctitis, see Proctitis, infectious
Inflammatory cloacogenic polyp, 215
Inflammatory fibroid polyp, gastric, 88
Intestinal adenoma, 73
Intraepithelial eosinophils, 5
Intramucosal carcinoma, 31
Iron pill gastritis, 52
Ischemic colitis, 148
Juvenile polyps, colon, 192
 Index

L Peutz-Jeghers polyps, 72, 126

gastric, 72
Leiomyoma, esophagus, 40 small intestine, 126
Lichen planus esophagitis, 9 Pit apoptosis, gastric, 60
Lymphangioma, small bowel, 141 Polyps, 69, 167, 215
Lymphocytic colitis, 15 7 anal, 215
Lymphocytic gastritis, 60 fibroepithelial polyps, 215
Lymphogranuloma venereum, 211 inflam matory cloacogenic polyp, 215
Lymphomas, 85, 135 colon, 167
. gastric, 85 hyperplastic polyps, 176
mucosa-associated lymphoid tissue tumors, 85 malignant polyp, 180
small bowel, 135 mucosal prolapse polyps, 169
follicular lymphoma, 13 7 serrated polyps, 183, see also Serrated polyps,
mantle cell lymphoma, 138 colon
T-celllymphoma, 138 tubular adenoma, 17 4
gastric, 69
M adenomas, 70
Malignant polyp, colon, 180 fundic gland polyps, 69
MALT lymphoma, 85 familial adenomatous polyposis associated, 69
Mantle cell lymphoma, small intestine, 138 sporadic, 69
Melanoma, anal, 229 hyperplastic polyps, 70
Mesenchymal tumors, small intestine, 140 juvenile polyp, 71
gastrointestinal stromal tumors, 140 Peutz-Jeghers polyp, 72
Metastatic carcinoma, gastric, 77 small intestine, 121
Mucosa-associated lymphoid tissue tumors, 85 Brunner gland lesions, 124
Mucosal prolapse polyps, colon, 169 pancreatic heterotopia, 124
M)'cobacterium avium, small intestine, 105 Peutz-Jeghers polyp, 126
Mycobacterium avium enteritis, small intestine, 105 pyloric gland adenoma, 124
tubular/tubulovillous adenoma, 121
N Papillary endothelial hyperplasia, anal, 206
Neoplasms, 69, 121, 167, see also individual Portal gastropathy, 49
neoplasms Proctitis, infectious, 208
anal, 217 Crohn's disease, 211
colon, 167 cytomegalovirus, 208
normal colon and carcinoma mimics, 167 herpes simplex virus, 208
small bowel, 121 lymphogranuloma venereum, 211
stomach, 69 syph ilis, 208
Neuroendocrine tumors, 81, 132, 192, see also Pseudomelanosis, 101
individual twnors Pyloric adenoma, 73, 124
colon, 192 Pyloric gland adenoma, small intestinal, 124
gastric, 81
sma ll bowel, 132 R
Nevus, anal, 231 Radiation colitis, 149
Nodular duodenitis, 101 Reflux esophagitis, 3, 5
Nonsteroidal anti-inflammatory drugs, 48 Russell bodies, 64

p s
Paget disease, anal, 225 Sessile serrated adenoma, colon, 177, 183
Pancreatic heterotopia, small intestine, 124 Sessile serrated polyps, colon, 183

237
Swvival Guide to Gastrointestinal Mucosal Biopsies

Serrated polyps, colon, 183 Stongyloides stercora/is, small intestine, 102

hyperplastic polyps, 183 Strongyloidiasis, small intestine, 104
sessile serrated adenoma with cytological ·squamous cell carcinoma, anal, 220
dysplasia, 183 classification, 221
sessile serrated polyps, 183 Squamous cell carcinom'a in Barrett's esophagus, 37
traditional serrated polyps, 183 biopsy findings, 39
Small intestinal biopsy, 95 human papillomavirus, 38
autoimmune enteropathy, 111 precursor lesions, 37
common variable immunodeficiency, 110 Syphilis, anal, 208
infectious organisms, 101
cytomegalovirus enteritis, 103 T
giardiasis, 102
T-celllymphoma, small intestine, 138
Mycobacterium avium enteritis, 105 Traditional serrated adenoma, colon, 177
strongyloidiasis, 104
Traditional serrated polyp, colon, 183
Whipple disease, 106
Trophe1yma whippleii, small intestine, 106
medication-associated injury, 111
Tubular/tubulovillous adenoma, 121, 174
neoplasms, see Neoplasms, small bowel
colon, 174
nodular duodenitis, 101
small intestine, 121
normal mucosa, 96
patterns of injury, 95 u
pseudomelanosis, 101
Spirochetosis, colon, 148 Ulcerative colitis, 153, 191, 212
Squamous intraepithelial neoplasia, anal, 217 Ulcers, esophagus, 10
human papillomavirus, 217
in situ, 219 V
Stomach biopsy, 45 Vascular lesions, small intestine, 141
autoimmune gastritis, 55 angiosarcoma, 141
chemical gastropathy, 48 lymphangioma, 141
Crohn's disease, 64 malformations, 141
eosinophils, 61 Vascular malformations, small bowel, 141
Helicobactor pylori, 50 Vegetant intravascular hemangioendothelioma, 206
inflamed mucosa, 50 Verrucous carcinoma, anal, 221
lymphocytic gastritis, 60
nonsteroidal anti-inflammatory drug use, 48 w
pit apoptosis, 60
Well-differentiated neuroendocrine tumors, 81,
portal gastropathy, 49
132, 192
Russell bodies, 64
colon, 192
type of gastric mucosa, 45
gastric, 81
antral, 45
small bowel, 132
oxyntic, 46
Whipple disease, small intestine, 106
transitional, 47
uninflamed mucosa, 46

238