CD Case33 Der Ma To Pathology

DERMATOPATHOLOGY
Common Problems in Diagnosis of Pigmented Lesions

Zembowicz, Flotte, Mihm, Murphy & Tahan
CASES IN
Knowledge Books and Software
Acknowledgements Publisher Rob Watts Layout design John Faulds Graphics Dean Maynard Knowledge Books and Software, Brisbane, QLD 2006 Knowledge Books and Software All rights reserved. Published 2006. This book is copyright. Apart from any fair dealing for the purposes of private study, research, criticism and classroom use, as permitted under the Copyright Act, no part may be reproduced by any process without written permission. Inquiries should be addressed to the publisher. Knowledge Books and Software ABN 75003053316 PO Box 50, Sandgate, Queensland, 4017, Australia Telephone (07) 3869 0994; 1-800-773353 Facsimile (07) 3269 6444 Email: orders@kbs.com.au Website: www.kbs.com.au Printed in China ISBN: 1741620 88-0 Product code: SA28
Contents
Introduction About the Authors Contributors Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 Case 9 Case 10 Case 11 Case 12 Case 13 Melanoacanthoma
Jong Min Park and Thomas J. Flotte
iii v ix 1 7 17 23 27 31 37 43 53 57 63 73 81
Large spindle and/or epithelioid cell nevus (Spitz nevus)

Mohammad Tawara and Thomas J. Flotte
Pigmented spindle cell nevus of Reed

Madhu Dahiya and Artur Zembowicz
Recurrent melanocytic nevus (at site of prior biopsy)

Steven R. Tahan
Irritated melanocytic nevus

Steven R. Tahan
Inverted type A nevus

Sam Dadras and Artur Zembowicz
Conjunctival compound nevus

Pitipol Choopong and Artur Zembowicz
Atypical genital nevus

Briana C. Gleason and Phillip H. McKee
Nevus of Ito
Adriano Piris, Artur Zembowicz, Martin C. Mihm Jr.
Amelanotic cellular blue nevus

Mitsuhiro Sugiura and Artur Zembowicz
Junctional dysplastic melanocytic nevus with moderate cytologic atypia

Elsa F. Velazquez
Melanocytic tumor of uncertain malignant potential (MELTUMP)

George F. Murphy
Superficial atypical melanocytic proliferation of uncertain significance (SAMPUS)

George F. Murphy
Case 14 Case 15
Pigmented epithelioid melanocytoma

89 97
Severely atypical proliferative nodule (borderline lesion) arising in a congenital nevus

Norma Rodriguez, Zeina Tannous and Artur Zembowicz
Case 16
Combined melanocytic lesion with a predominant component of atypical deep penetrating nevus associated with nodal metastases
Richard A. Scolyer, Rajmohan Murali and Stanley W. McCarthy
105
Case 17
Tumoral melanosis
Walter Klein and Artur Zembowicz
125
Cases in Dermatopathology
Case 18
Micrometastatic melanoma, with prominent involvement of lymph node capsule mimicking nevus cell rest
George F. Murphy
131
Case 19 Case 20 Case 21 Case 22 Case 23 Case 24 Case 25
Lentiginous melanoma
Tracy L. Davis and Artur Zembowicz
139 145 153 157 171 177 189
Malignant melanoma in situ, lentigo maligna type

Gabriela Rolz-Cruz and Thomas J. Flotte
Malignant blue nevus

Scott Granter
Nevoid melanoma
Phillip H McKee
Desmoplastic melanoma
Adriano Piris and Martin C. Mihm Jr.
Pleomorphic melanoma with osteoclast-like giant cells

Rosalynn M. Nazarian and Lyn M. Duncan
Conjunctival melanoma in situ (conjunctival primary acquired melanosis with atypia, high-risk)
Case 26 Case 27 Case 28 Case 29 Case 30 Case 31 Case 32 Case 33 Case 34 Case 35
Conjunctival malignant melanoma

193 199 213 221 227 233 235 237 247 249
Pigmented dermatofibrosarcoma protuberans (Bednar tumor)

Rajmohan Murali and Richard A. Scolyer
Cellular neurothekeoma
Jason L. Hornick
Cutaneous myoepithelioma
Thomas Brenn
Argyria (silver deposition)

Ruth Holzmann and Thomas J. Flotte
Exogenous ochronosis
Alison Z. Young
Tinea nigra
Alison Z. Young
Minocycline-induced cutaneous pigmentation

Arni K. Kristjansson, Kirsten Bellucci, Mark Harbeck, and Vincent Liu
Manus (talon) noir

Aaron Caplan and Artur Zembowicz
Iron hyperpigmentation
ii
Introduction
Dear Colleague,
his is the second book in a series of Cases in Dermatopathology resulting from collaboration of Dermatopathology Faculty of Harvard-Affiliated Hospitals in Boston including Beth Israel Hospital, Brigham and Womens Hospital and Massachusetts General Hospital. It presents 35 cases discussed during the Slide Seminar on Pigmented Lesions at the Harvard Dermatopathology Update CME Course held in Boston on October 21, 2006. This book offers pathologists, dermatopathologists and dermatologists who could not attend the course the opportunity to learn from this teaching exercise. The current volume discusses the most common difficult problems in diagnosis of pigmented lesions. The cases include melanocytic nevi, variants of malignant melanoma and emerging category of borderline melanocytic tumors. Some cases represent non-melanocytic mimics of melanocytic tumors and medical conditions which result in pigmented lesions of the skin. The book would not be possible without the enthusiasm, expertise and love of dermatopathology by contributing current and former members of our Faculty, Residents and Fellows of Harvard Combined Dermatopathology Training Program. It is a testimony to the tradition of collegiality, commitment to teaching and advancement of the field, and depth of experience passed on from generation to generation at Harvard dermatopathology community. We have also been very fortunate this year to have contributions from Dr. Phillip H. McKee, whom we miss dearly in Boston, and Drs. Richard A Scolyer, Stanley W. McCarthy and Rajmohan Murali, our friends and supporters of the course from Sydney Melanoma Unit and Royal Prince Alfred Hospital in Sydney, Australia. I would also thank our publisher, Rob Watts and his team from Knowledge Books and Software in Brisbane, Australia for their outstanding work during the entire project. Finally, I would like to express my gratitude for Trestle Corporation who hosted virtual slides discussed at the seminar. I hope that you will enjoy the cases. Artur Zembowicz, M.D., Ph.D.
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About the Authors

Dr. Artur Zembowicz
r. Zembowicz received his MD and PhD (Pharmacology) degrees from Copernicus Academy of Medicine in Cracow, Poland. His Ph.D. work included studies on inflammation and vascular homeostasis under direction of Nobel Prize Winner, Sir John R. Vane at the William Harvey Institute in London, UK. He trained in Anatomic Pathology at the Brigham and Womens Hospital and completed the Harvard Dermatopathology Fellowship. He is presently Assistant Professor of Pathology at Harvard Medical School and serves as Staff Pathologist at Massachusetts General Hospital and Associate Pathologist in Ophthalmic Pathology at Massachusetts Eye and Ear Infirmary. Dr. Zembowiczs first real dermatopathology job was in Martin C. Mihms consultation practice. After six years, sharing time and work with Dr. Mihm still remains the most exciting and inspiring part of his diverse activities at the MGH. His busy practice also includes oral, eyelid and general head and neck pathology including frozen sections. His wife Margaret is a Pediatric Anesthesiologist at the Childrens Hospital in Boston. They have two sons, Filip and Thomas, who keep them busy off the campus as they try to keep up with them playing, skiing, swimming, bicycling or playing soccer.
Dr. Thomas J. Flotte

r. Flotte received a combined undergraduate degree from Rensselaer Polytechnic Institute and medical degree from Albany Medical College. He did an Anatomical Pathology Residency at New York University Medical Center and a Dermatopathology fellowship at the Massachusetts General Hospital. He went on the staff of the Dermatopathology Unit at MGH. He is the Director of the Dermatopathology Unit at MGH and an Associate Professor of Dermatology. In addition to his responsibilities for the Dermatopathology Unit at MGH, Dr. Flotte has a federally funded research lab studying basic biology and translational opportunities of melanoma as well as novel optical imaging devices and approaches. When he is not at the hospital, he enjoys spending time with his family and their interests in figure skating and model rocketry. Rocketry is a very Zen sport. You put all your effort and time in making a rocket thats strong, functional, cool and pretty. Then you slap in an explosive and hope it all comes back in one piece. Dave Urbanek
Knowledge Books and Software v
Dr. Martin C. Mihm

r. Mihm received his MD degree from the University of Pittsburgh Medical School. After the internship at Mount Sinai Hospital in New York and period of practice of internal medicine, he trained in Dermatology and Pathology at the Massachusetts General Hospital and Harvard Medical School. He mentions establishing Dermatopathology Training Program at Massachusetts General Hospital (1976) which was later extended to other Harvard Institutions (Beth Israel Hospital, Brigham and Women's Hospital, and Children's Hospital), opening of Photopathology Laboratory (in 1982, with Dr. John Parrish), co-directorship of WHO Melanoma Program (with Claudio Clemente), establishing Rare Tumors Institute of the WHO, establishing Dermatology and Dermatopathology Training Programs at the Albany Medical College, and opening Vascular Malformations Clinic at Massachusetts General Hospital as highlights of his professional career. He is currently Senior Dermatopathologist at Massachusetts General Hospital and Clinical Professor of Pathology and Dermatology at Harvard Medical School. Dr. Mihms research, educational and clinical contributions to the fields of dermatology, pathology and dermatopathology are well known and speak for themselves. Through his teaching and mentoring he continues to touch lives of students, residents, fellows and young physicians from all over the world, including the authors of this book. In addition to clinical activities in pathology, which include routine and consultative service at MGH, he sees general dermatology and melanoma patients, attends Vascular Malformation Clinics in Boston, Athens (Greece) and Pamplona (Spain). Between work and constant travel, he always finds time for his great passion for the opera and classical music. He is a frequent guest in concert halls all over the world and in Boston, where he volunteers his time as a member of Boston Symphony Orchestra Board of Overseers.
Dr. George F. Murphy

r. Murphy received his undergraduate degree from the University of Pennsylvania, his medical degree from the University of Vermont, and his post-doctoral training at the Massachusetts General Hospital, Harvard Medical School. He has served as Director of Dermatopathology at the University of Pennsylvania and founded the Center for Dermatopathology in the Department of Pathology at Jefferson Medical College. He has served as a former president of the American Society of Dermatopathology, holder of Penns first Herman Beerman Endowed Professorship, and as an elected member of the American Society for Clinical Research. He presently is Professor of Pathology at the Harvard Medical School and Chief of the Dermatopathology Service at the Brigham and Womens Hospital.
vi Knowledge Books and Software
Dr. Murphy stays busy attending to daily responsibilities for the dermpath service, his consultation practice, and the Brighams Program in Dermatopathology research laboratory, as well as sharing experiences in the art and science of skin pathology with students of all ages and backgrounds. Inspired by the philosophy of his friend and mentor, Martin Mihm, he regards the discipline of dermatopathology as a symbiotic mix of translationally-relevant discovery and diagnostic adventure. When not looking down a microscope, he reveres spending time with his wife and daughters, sharing in his wifes passion for art history, and indulging in his own for the history of printing. In recent years he has taken up golf, and while agreeing with Samuel Clemens that the game too often represents a good walk spoiled, Dr. Murphy would add that it remains a good walk, nonetheless.
Dr. Steven R. Tahan
r. Tahan received his undergraduate degree from the Harvard College, medical degree from the Yale University, and post-doctoral training at the New England Deaconess and Massachusetts General Hospitals, Harvard Medical School. He is presently Associate Professor of Pathology at Harvard Medical School and serves as Director of Dermatopathology at the Beth Israel Deaconess Medical Center, Boston, and Program Director of the Harvard Dermatopathology Fellowship. Diagnostic responsibilities in Dermatopathology and Pathology, consultations from outside pathologists and risk management groups, and mentoring fellows and residents in diagnostic Dermatopathology and translational research create a full plate of daily activities for Dr. Tahan. In order to preserve a broader view, he ensures that there is at least some time each week to pursue other interests. Boston friends refer to him as an ahmchair ahchitect in recognition of his abiding interest in structural and landscape design. This dovetails perfectly with the talents of his wife, whose insights into plant diversity and growth characteristics help to frame what is achievable in their own gardens. He is, of course, not adverse to sitting back and enjoying the view at the end of the day.
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Contributors
Kirsten S. W. Bellucci, M.D. Clinical Assistant Professor of Pathology, Penn State College of Medicine Staff Pathologist/Dermatopathologist Health Network Laboratories and Lehigh Valley Hospital Allentown, PA, USA Email: Kirsten.Bellucci@ healthnetworklabs.com (Formerly: Clinical Fellow in Dermatopathology, Harvard Combined Dermatopathology Program, Boston, MA) Thomas Brenn, M.D., Ph.D. Consultant Dermatopathologist Salford Royal Hospital Trust and University of Manchester Manchester, United Kingdom Email: Thomas. Brenn@srht.nhs.uk Sam S. Dadras, M.D., Ph.D. Assistant Professor, Departments of Pathology and Dermatology Stanford University School of Medicine Stanford, CA, USA Email: sdadras@stanford.edu
Madhu Dahiya, M.D. Instructor in Pathology, Harvard Medical School Staff Dermatopathologist Beth Israel Deaconess Medical Center Boston, MA, USA Email: mdahiya@bidmc.harvard.edu
Tracy L. Davis, M.D., Ph.D. Clinical Fellow in Dermatopathology Massachusetts General Hospital and Harvard Medical School Boston, MA, USA Email: tdavis3@partners.org
Aaron P. Caplan, M.D. Staff Dermatopathologist CBLPath Mamaroneck, NY, USA Email: acaplan@cblpath.com (Formerly: Clinical Fellow in Dermatopathology, Harvard Combined Dermatopathology Program, Boston, MA)
Lyn M. Duncan, M.D. Associate Professor of Dermatology, Harvard Medical School Staff Dermatopathologist Massachusetts General Hospital Boston, MA, USA Email: lduncan@partners.org
Pitipol Choopong, M.D. Research Fellow in Pathology, Harvard Medical School Cogan Eye Pathology Laboratory, Department of Ophthalmology Massachusetts Eye and Ear Infirmary Boston, MA, USA Email: pitipol@hotmail.com
Thomas J. Flotte, M.D. Associate Professor of Dermatology Harvard Medical School Director, Dermatopathology Unit Massachusetts General Hospital Boston, MA, USA Email: tflotte@partners.org
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Briana C. Gleason, M.D. Clinical Fellow, Harvard Medical School Resident in Pathology Brigham and Womens Hospital Boston, MA, USA Email: bgleason@partners.org
Scott Granter Associate Professor of Pathology, Harvard Medical School Staff Dermatopathologist Brigham and Women's Hospital Boston, MA, USA Email: sgranter@partners.org
Walter Klein, M.D. Staff Pathologist, Department of Pathology Bryn Mawr Hospital Bryn Mawr, PA, USA Email: wm_klein@hotmail.com (Formerly: Clinical Fellow in Dermatopathology, Harvard Combined Dermatopathology Program, Boston, MA)
Mark J. Harbeck, M.D. Resident Physician, Department of Dermatology University of Iowa Hospitals and Clinics Iowa City, IA, USA Email: mark-harbeck@uiowa.edu
Arni K. Kristjansson Resident Physician, Department of Dermatology University of Iowa Hospitals and Clinics Iowa City, IA, USA Email: arni-kristjansson@hotmail.com
Ruth Holzmann, M.D. Fellow, International Training Program in Dermatology Massachusetts General Hospital and Harvard Medical School 15 Fruit Street Boston, MA, USA Email: rholzmann@partners.org
Vincent Liu, M.D. Clinical Assistant Professor of Dermatology and Dermatopathology University of Iowa Hospitals and Clinics Iowa City, IA, USA Email: vincent-liu@uiowa.edu
Jason L. Hornick, M.D., Ph.D. Assistant Professor, Harvard Medical School Staff Pathologist Brigham and Womens Hospital Boston, MA, USA Email: jhornick@partners.org
Stanley W. McCarthy, M.B.B.S., F.R.C.P.A. Department of Anatomical Pathology, Sydney Melanoma Unit and the Melanoma and Skin Cancer Research Institute Royal Prince Alfred Hospital Sydney, NSW, Australia Email: stanley.mccarthy@ email.cs.nsw.gov.au
Phillip H McKee M.B., M.D., F.R.C.Path 185 Topkie Drive, Sedona, AZ, USA Email: phmckee1948@msn.com (Formerly: Associate Professor of Pathology, Harvard Medical School Chief of Dermatopathology Brigham and Womens Hospital Boston, MA, USA)
Martin C. Mihm Jr., M.D., F.A.C.P., F.R.C.P.I. Clinical Professor of Pathology and Dermatology, Harvard Medical School Senior Dermatopathologist Massachusetts General Hospital Boston, MA, USA Email: mmihm@partners.org
Adriano Piris, M.D. Clinical Fellow in Dermatopathology Harvard Medical School and Massachusetts General Hospital Boston, MA, USA Associate Pathologist Instituto de Patologia e Investigacion, Asuncion, Paraguay Email: apiris@partners.org
Rajmohan Murali, M.B.B.S., F.R.C.P.A. Clinical Fellow, Cancer Institute New South Wales Department of Anatomical Pathology and Sydney Melanoma Unit, Royal Prince Alfred Hospital, Sydney, NSW, Australia Email: rajmohan.murali@ email.cs.nsw.gov.au
Norma Rodriguez, M.D. Clinical Fellow in Pathology, Harvard Medical School Resident in Pathology, Massachusetts General Hospital Boston, MA, USA Email: parisgorrillablack@yahoo.com
George F. Murphy, M.D. Professor of Pathology, Harvard Medical School Chief of Dermatopathology Brigham and Womens Hospital Boston, MA, USA Email: gmurphy@rics.bwh.harvard.edu
Gabriela Rolz-Cruz, M.D. Fellow, International Training Program in Dermatology Massachusetts General Hospital and Harvard Medical School Boston, MA, USA Email: grolzcruz@partners.org
Rosalynn M. Nazarian, M.D. Clinical Fellow in Pathology, Harvard Medical School Resident in Pathology, Massachusetts General Hospital, Boston, MA, USA Email: rmnazarian@partners.org
Jongmin Park, M.D. Fellow, International Training Program in Dermatology Massachusetts General Hospital and Harvard Medical School Boston, MA, USA Email: jpark15@partners.org
Dr Richard A. Scolyer, M.B.B.S., M.D., F.R.C.P.A. Department of Anatomical Pathology, Sydney Melanoma Unit and the Melanoma and Skin Cancer Research Institute Royal Prince Alfred Hospital Sydney, NSW, Australia Email: richard.scolyer@ email.cs.nsw.gov.au
Mitsuhiro Sugiura, M.D. Research Fellow in Dermatopathology, Department of Pathology Massachusetts General Hospital and Harvard Medical School Boston, MA, USA Email: msugiura@partners.org
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Steven R. Tahan, M.D. Associate Professor of Pathology, Harvard Medical School Program Director, Harvard Dermatopathology Fellowship Program Director of Dermatopathology and Staff Pathologist Beth Israel Deaconess Medical Center Boston, MA, USA Email: stahan@bidmc.harvard.edu
Elsa F. Velazquez, M.D. Assistant Professor of Pathology, Harvard Medical School Staff Dermatopathologist Brigham and Women's Hospital Boston, MA, USA Email: evelazquez@partners.org
Zeina Tannous, M.D. Instructor in Dermatology and Faculty Director for Resident Training in Dermatopathology, Department of Dermatology, Harvard Medical School Director, Mohs/Dermatologic Surgery, VA Medical Center and Staff Physician, Dermatology, Laser and Cosmetic Surgery, Massachusetts General Hospital Boston, MA, USA Email: ztannous1@hotmail.com
Alison Z. Young, M.D. Staff Dermatologist, Virginia Mason Medical Center Seattle, WA, USA Email: alison.z.young@gmail.com (Formerly: Clinical Fellow in Dermatopathology, Harvard Combined Dermatopathology Program, Boston, MA)
Mohammad Tawara, M.D. Fellow, International Training Program in Dermatology Massachusetts General Hospital and Harvard Medical School Boston, MA, USA Email: mtawara@partners.org
Artur Zembowicz, M.D., Ph.D. Assistant Professor of Pathology, Harvard Medical School Staff Pathologist (Dermatopathology and Head and Neck Pathology Service) Massachusetts General and Massachusetts Eye and Ear Infirmary Hospitals, Boston, MA, USA Email: dr.zembowicz@gmail.com
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CASE 1
Case History
56-year-old woman presents with a 7 x 4 mm raised pigmented lesion that is clinically consistent with an irritated seborrheic keratosis.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 1: Figure 2: Figure 3:
Figure 4:
Scanning magnification showing a lesion characterized by epidermal hyperplasia and hyperkeratosis/parakeratosis. Intermediate magnification illustrating that the lesion shows benign cytological features and contains substantial amount of melanin pigment. High magnification showing that there are many pigmented dendritic melanocytes interspersed between the keratinocytes. Note that the pigment is predominantly in the melanocytes. High magnification showing that there are many pigmented dendritic melanocytes interspersed between the keratinocytes. Note that the pigment is predominantly in the melanocytes.
Diagnosis
Melanoacanthoma.
Commentary
Melanoacanthoma is a rare, cutaneous and mucosal benign neoplasm characterized histologically by proliferation of epidermal keratinocytes and pigment-forming dendritic melanocytes. The two types of Blochs original benign non-nevoid melanoepithelioma1 are now recognized as separate entities; type I melanoepithelioma as melanoacanthoma (Figs. 1-4) and type II melanoepithelioma as ordinary, pigmented seborrheic keratosis (Figs. 5-7). The clinical characteristics of melanoacanthoma are not as specific as the histologic findings. It presents clinically as an asymptomatic solitary or infrequently multiple elevated, deeply hyperpigmented nodular lesion.2-4 Therefore, the clinical differential diagnosis includes seborrheic keratosis, malignant melanoma, nevus, melanocytic nevus and pigmented basal cell carcinoma (Figs. 8-10). Most lesions are found among those over the age of 55-65 years. There is no preponderance in either sex, although the majority of cases were reported in whites. Most lesions have been present at least five years before histologic examination, with the head and neck region the most common anatomic location. Oral melanoacanthoma is a rare, benign mucosal lesion probably due to a reactive process resulting from local trauma rather than a neoplastic process.5,6 Cutaneous and mucosal melanoacanthoma differ in terms of patient age, patient race, and site. Melanoacanthoma is histologically distinguished by the presence of numerous relatively well-defined islands of small basaloid cells and numerous large dendritic melanocytes with abundant melanin granules within an acanthotic epidermis (Figs. 1-4). Many melanocytes are scattered throughout the tumor lobules of a melanoacanthoma rather than localized to the basal layer. The keratinocytes contain little or no melanin. Cytologic atypia is not a feature of the melanocytes or keratinocytes in a melanoacanthoma. There is some controversy over whether or not melanoacanthomas are actually different from irritated seborrheic keratoses. Suprabasal dendritic melanocytes may be seen in every type of seborrheic keratosis except the reticulated type. The tumor islands are not sharply defined in seborrheic keratosis. They are made up of small basaloid cells that may show a variable amount of pigmentation. Melanosome transfer from melanocytes to tumor keratinocytes is not blocked and therefore keratinocytes contain a large number of melanosomes. A study in which seborrheic keratoses were irritated by croton oil or surgical trauma failed to demonstrate any changes characteristic of melanoacanthomas.7
Case 1
Therefore it appears that melanoacanthoma is a distinct entity that should be considered in the differential diagnosis of any rapidly growing, pigmented lesion on the skin or mucous membranes. Secondary colonization by dendritic melanocytic cells, with dendritic melanocytic cells at all levels of the epidermis or epithelium, should be distinguished from the much more common hypertrophy and hyperplasia of these cells in which they remain at the dermal-epidermal junction. Both, however, can cause a problem in differential diagnosis of melanoma, especially since the lesion may not be colonized uniformly and since the colonized lesion may arise rapidly, a characteristic feature of acral-lentiginous melanoma. Squamous cell carcinomas, verruca vulgaris and lichen simplex chronicus can show colonization of such nonmelanocytic processes. Blue nevus, even ordinary nevocellular nevi may, especially in the epidermis, show extensive dendritic differentiation. This is particularly likely to occur in nevi of the distal aspect of the lower extremities and in subungual nevi. A small minority, probably less than 5%, of dermatofibrosarcoma protuberans shows a proliferation within the neoplasm of dendritic, heavily pigmented cells, a phenomenon originally noted by Bednar (Figs. 11-13).
Figure 5
Figure 6
Figure 5: Figure 6:
Seborrheic Keratosis. Scanning magnification illustrates an exophytic epidermal hyperplasia with pseudohorn cysts and sharp demarcation. Seborrheic Keratosis. Intermediate magnification shows prominent melanin within the majority of the keratinocytes.
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11
Figure 12
Case 1
Figure 13
Figure 7:
Figure 8:
Figure 9:
Figure 10: Figure 11:
Figure 12:
Figure 13:
Seborrheic Keratosis. High magnification confirms the presence of the melanin in the keratinocytes and does not show an increased number of melanocytes nor dendritic melanocytes. Pigmented Basal Cell Carcinoma. Scanning magnification showing islands of epithelial cells in the dermis. Note the pigment present in many areas of the tumor. Pigmented Basal Cell Carcinoma. Intermediate magnification showing basaloid tumor cells with a peripheral palisade and brown pigment in the center of the nodule. Pigmented Basal Cell Carcinoma. High magnification showing brown pigment consistent with melanin in many of the cells in the tumor. Dermatofibrosarcoma protuberans with melanin pigment (Bednar tumor). Scanning magnification showing a spindle cell tumor filling the entire dermis and extending into the subcutaneous tissue. Dermatofibrosarcoma protuberans with melanin pigment (Bednar tumor). Intermediate magnification showing the tumor composed of short intersecting fascicles of spindle cells. Note the presence of pigment in the tumor. Dermatofibrosarcoma protuberans with melanin pigment (Bednar tumor). High magnification showing the spindle shaped tumor cells and thee presence of many pigmented epithelioid cells in the tumor. The pigment is consistent with melanin.
References
1. 2. 3. 4. 5. 6. 7. Bloch B. ber benigne, nicht naevoide melanoepitheliome der haut nebst bemerkungen ber das wesen und die genese der dendritenzellen. Arch Dermatol Syphilol 1927; 153:20-40. Mishima Y, Pinkus H. Benign mixed tumor of melanocytes and malpighian cells. Arch Dermatol 1960; 81:539-50. Prince C, Mehregan H, Hashimoto K, Plotnick H. Large melanoacanthomas: a report of five cases. J Cut Pathol 1984; 11:309-17. Schlappner OLA, Rowden G, Phillips TM, Rahim Z. Melanoacanthoma: ultrastructural and immunological studies. J Cut Pathol 1978; 5:127-41. Sexton FM, Maize JC. Melanotic macules and melanoacanthomas of the lip. Am J Dermatopathol 1987; 9:438-44. Andrews BT, Trask DK. Oral melanoacanthoma: A case report, a review of the literature and a new treatment option. Annals Otol Rhinol Laryngol 2005; 114:677-80. Mevorah B, Mishima Y. Cellular response of seborrheic keratosis following croton oil irritation and surgical trauma. Dermatologica 1965; 131:452-64.
Jong Min Park and Thomas J. Flotte
CASE 2
Case History
4-year-old boy who has had a nevus on his right forearm which recently has become raised, deeply pigmented with variegated borders. It measures 3 x 5 mm.
Figure 1
Figure 2
Figure 1:
Figure 2:
Scanning magnification showing a symmetrical, well-circumscribed pigmented lesion. Note that the majority of nevomelanocytes are in nests at the dermoepidermal junction with occasional cells at varying levels of the epidermis (pagetoid spread). Intermediate magnification showing nests of melanocytes in the epidermis and dermis. Note the vertical orientation of the spindle cells in the epidermal nests on both the left and right sides of the lesion (the so-called raining down pattern). In the center, the cells are oriented horizontally (the so-called school of fish pattern). Also note the occasional nevomelanocyte at varying levels of the epidermis.
Figure 3
Figure 4
Figure 3:
Figure 4:
Intermediate magnification showing the presence of melanin in many of the nevomelanocytes as well as the presence of melanophages in the dermis. Note the uniformity of the nuclei and that the nuclei of the nevomelanocytes are larger than those of the keratinocytes. High magnification illustrating the morphology of the cells. Note the predominance of spindle cells and the presence of melanin. The nuclei show an even distribution of chromatin with a single eosinophilic nucleolus.
Diagnosis
Large spindle and/or epithelioid cell nevus (Spitz nevus).
Commentary
The Spitz nevus, named after Sophia Spitz, who first described it in 1948 as Juvenile melanoma in her historic article entitled Melanomas of childhood. But Darier and Civatte, in 1910, described an unusual (Spitzoid) melanocytic tumor developing rapidly on the nose of a young child, and they were completely thwarted in their efforts to decipher whether the lesion was benign or malignant. This benign melanocytic proliferation is also known as large spindle and/or epithelioid cell nevus to reflect its histological features. Spitz nevi occur most often during the first two decades of life. However, they can arise at any age.1 Rarely, it may be congenital or emerge in a congenital nevus.2 They occur predominantly in the white population. Spitz nevi occur anywhere in the body; the cheeks and ears are favored sites in children while the limbs and trunk are the most common in adults.1,2 Typically, the lesion is a solitary, pink, red or slightly pigmented nodule, usually of less than 1 cm in size. Generally, pigmentation of Spitz nevus is more common in adolescence and adulthood. Occasionally, multiple Spitz nevi could exist either agminated or widely disseminated.
Case 2
Epiluminescence microscopy slightly enhances the diagnostic accuracy but, generally, the findings remain inconclusive.2 Although most Spitz nevi are diagnosed with confidence and can be differentiated easily from melanoma, equivocal lesions are among the most problematic entities in diagnostic dermatopathology. The diagnosis of Spitz nevus requires examination of the whole lesion and careful assessment of a range of architectural and cytological features. Most Spitz nevi are compound lesions, but some are entirely junctional or intradermal. The architectural features include: Symmetry, sharp lateral demarcation, zonation, maturation (diminution with depth in cell size, cellularity, loss of pigmentation and loss of proliferative activity), and regular pattern of epidermal hyperplasia. The epidermal component tends to be arranged in a vertically oriented nests that usually not extending beyond the dermal component. The architecture of the deep dermal part of the Spitz nevi is infiltrating rather than pushing.2 Pagetoid melanocytosis, if present, is generally only focal, relatively slight and usually limited to the lower half of the epidermis. An additional diagnostic clue is the Kamino bodies; an amorphous, PAS-positive, eosinophilic globules found at, or immediately subjacent to, the dermoepidermal junction in 60% of cases where they often aggregate in clumps. The finding of artifactual semilunar clefts separating the nests from the overlying epidermis is a useful diagnostic feature in Spitz nevi with junctional activity. The most important common denominator is the large size of the melanocytes; these may be epithelioid and/or spindled with abundant amphophilic cytoplasm. In early childhood, the Spitz nevi are often composed wholly or largely of epithelioid cells with scarce or absent melanin pigment, while those in adults are significantly more likely to be intradermal, composed largely of spindle cells and are often pigmented.2,3 The nuclei are large, with pale, delicate chromatin pattern and uniform nucleoli. Mitoses are absent in about half of the cases. Atypical mitoses, dermal mitotic rate more than two mitoses in square millimeter or mitoses within the lower half of the lesion should be interpreted with great caution. Melanin pigment is often scarce or absent; when present, there are no substantial variations in degree or quality of pigmentation between areas at the same level of the lesion. Multinucleated epithelioid giant melanocytes may be present and numerous in some cases. Histopathological variants of Spitz nevi include: desmoplastic, halo, angiomatoid, pagetoid, hyalinizing, combined, plexiform, tubular, polypoidal and dysplastic.2,4 A subset of Spitz nevi poses substantial diagnostic difficulty, even among experts, due to inadequate guidelines for the dichotomous distinction from malignant melanoma. Atypical Spitz nevi considered by most of the dermatopathologists as distinct lesions with borderline behavior residing between Spitz nevi and malignant melanoma.3 These lesions may display architectural and cytological atypia to a degree beyond what is accepted in a benign Spitz nevus, but the atypical features are not sufficient for a histological diagnosis of
melanoma. Others believe its nondiagnosis and stressing that the lesions must be signed out either Spitz nevus, melanoma, or I dont know when it must be subjected for another opinion from a respected colleague.5 Lesions reported to have features of atypical Spitz nevus have spread to regional lymph nodes without subsequent disease progression, but some metastasized to distant organs and resulted in death.2,5,6 Therefore, it has been recommended that such atypical Spitz tumors should be categorized into risk categories for aggressive behavior. Spatz et al. have attempted to develop a scoring system for risk stratification based on age of the patient age, diameter of the lesion, involvement of subcutaneous fat, ulceration and mitotic activity. This permits grading of the lesions into low, intermediate and high risk categories.7 Spitzoid melanoma is a subtype of melanoma that clinically and histopathologically resembles Spitz nevus. While Spitz nevus can be usually be confidently diagnosed by experienced dermatopathologists, the current histological criteria do not allow distinguishing Spitz nevus from spitzoid melanomas in all cases. However, the features, which assist in this differential diagnosis from the literatures and experience of the authors, are summarized in Table 1. Ancillary immunohistochemical stains studied in the literature including HMB-45, Ki67, Mart-1, fatty acid synthetase, MIB-1, cyclin D-1 and p53 are rarely helpful in the real life cases.2,3,6 Recent progress in molecular characterization of melanocytic proliferations holds some promise for development of molecular diagnostic tests. Mutations in the BRAF gene (53-80%) and N-RAS gene (~10%) that lead to activation of the mitogen-activated protein kinase (MAPK) pathway play a role in the pathogenesis of many conventional melanomas.8 Similarly, a high rate of activating mutations in B-RAF is found in benign melanocytic nevi (70-90%), suggesting a role for B-RAF in both benign and malignant melanocytic tumors.6,8 In contrast, activating hot spot mutations in B-RAF or N-RAS are not found in Spitz nevi. Unfortunately, this features is not helpful in differential diagnosis between Spitz nevus and spitzoid melanoma as a recent study demonstrated only one mutation in B-RAF (of 33 case) and no mutations in N-RAS in spitzoid melanoma.8 The most useful currently available molecular diagnostic test appears to be comparative genomic hybridization (CGH) which shows normal chromosomal complement or gains of chromosome 11p in Spitz nevus, which contrasts with complex chromosomal aberrations seen in melanoma.9 However, CGH is expensive and has limited sensitivity. There is no consensus concerning management of Spitz nevi. The lack of consensus in the medical literature reflects to some extent the lack of certainty in the histological differentiation of Spitz nevi from melanomas. These lesions are at the top of malpractice claims for misdiagnosed lesions in surgical pathology. Generally speaking, atypical Spitz nevi and spitzoid melanoma need inter-expert dermatopathologists consultation before a report is issued. Ideally, all Spitz nevi
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Case 2
should be completely excised for further histopathological study and all the cases should be followed up clinically. To date, for frankly atypical spitzoid melanocytic neoplasms it is not possible to predict the biological behavior with certainty. The grading system for risk stratification and mutation analysis can providing useful but not definitive information for the management of atypical nevi, though, the safest course of action for these lesions is undoubtedly to perform local treatment as for a melanoma of equivalent depth with interpretation of a positive sentinel lymph node biopsy as evidence of a malignant potential of the tumor.4
Criteria Size Involvement of subcutaneous fat Symmetry Atraumatic ulceration Circumscription Pagetoid melanocytosis Absent Present Absent Sharp Focal, and in lower half of epidermis Low Present Present with aggregates < 2/ mm Absent Rare < 10% Regular Ground glass Few or absent Absent
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Spitz nevus <10 mm
Atypical/Malignant >10 mm Present Absent Present Poor Over a large zone and in the upper half of the epidermis High Absent Few or none > 2-6/ mm2 Present Common > 10% High Irregular Granular Present Present
Cellular density Zonation and maturation Kamino bodies Mitotic rate Deep/ marginal mitoses Atypical Mitoses Ki-67 expression Nuclear membrane Cytoplasm Hyperchromasia Large nucleoli
Nuclear/cytoplasmic ratio Low
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Figure 5
Figure 6
Figure 7
Figure 8
Figure 5:
Atypical Spitz Nevus. At scanning magnification, note the presence of nests of varying sizes present mostly at the dermoepidermal junction with occasional spread of predominantly individual cells higher in the epidermis. The lesion is sharply demarcated on the left side but trails off on the right side. In addition to the nevomelanocytic proliferation, there is epidermal hyperplasia. Atypical Spitz Nevus. At high magnification, note the variation in the size of the nuclei and that they are larger than the mid-level keratinocytic nuclei. Atypical Spitz Nevus. At scanning magnification, note the symmetrical spindle cell nevomelanocytic proliferation with epidermal hyperplasia. Atypical Spitz Nevus. At higher magnification, the nuclei show mostly even distribution of chromatin although occasional cells show clumping. Note the occasional dermal mitosis.
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Case 2
Figure 9
Figure 10
Figure 11
Figure 12
Figure 9:
Figure 10:
Atypical Spitz Nevus. At scanning magnification, there is a polypoid dermal nevomelanocytic proliferation. The nests are small but having an infiltrating pattern at the deep margin. Atypical Spitz Nevus. Higher magnification showing variation in the size of the nuclei, including some very large lesions. Some of the nuclei show clumping of their chromatin. Spitzoid Melanoma. Intermediate magnification showing variation in the size and level of nests of the nevomelanocytes. Spitzoid Melanoma. At high magnification, note the variation in size of the nests and nuclei. Many of the cells have hyperchromatic nuclei.
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Figure 13
Figure 14
Figure 15
Figure 16
Spitzoid Melanoma. Note the large asymmetrical dermal proliferation that approaches the subcutaneous tissue. Spitzoid Melanoma. The cytoplasm is amphophilic. The nuclei are large with prominent irregularly shaped nucleoli. There is peripheral condensation of the nuclear chromatin with occasional clearing. Mitotic figures are easily identified. Spitzoid Melanoma. There is an asymmetrical compound melanocytic proliferation with irregularly-shaped, large dermal masses. Spitzoid Melanoma. The cells are both epithelioid and spindle shaped. The nuclei are large. The nucleoli show irregular size and shape.
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Case 2
Figure 17
Figure 18
Figure 17:
Figure 18:
Malignant Melanoma arising in association with an Atypical Spitz Nevus. At scanning magnification, there is dramatic asymmetry of the lesion. In the center and the left side, there is spindle cell proliferation with little pigment. On the right side, there are small pigmented hyperchromatic cells. Malignant Melanoma arising in association with an Atypical Spitz Nevus. Intermediate magnification showing the junction of the two cell types. In the left lower corner, there is a proliferation of spindle cells characterized by amphophilic cytoplasm and large nuclei. At the dermoepidermal junction and to the right, there is a proliferation of pigmented, small epithelioid cells, consistent with malignant melanoma. This is an interesting pattern of a superficial spreading type melanoma arising in association with an atypical Spitz nevus.
References
1. 2. 3. Casso EM, Grin-Jorgensen CM, Grant-Kels JM. Spitz nevi. J Am Acad Dermatol 1993 Oct; 29(4):667-8. Mooi, Wolter J. Spitz nevus and its histologic simulators. Adv Anat Pathol 2002; 9(4):209-221. Kapur P Selim MA, Roy LC, Yegappan M, Weinberg AG, Hoang MP , .Spitz nevi and atypical Spitz nevi/tumors: a histological and immunohistochemicl analysis. Modern pathology 2005; 18:197-204. Dahlstrom JE, Scolyer RA, Thompson JF, Jain. S. Spitz naevus: diagnostic problems and their management implications. Pathology 2004 Oct; 36(5):452-7. Mones JM, Ackerman AB. "Atypical" Spitzs nevus, "malignant" Spitzs nevus, and "metastasizing" Spitzs nevus: A critique in historical perspective of three concepts flawed fatally. Am J Dermatopathol 2004; 26:310-333. Raymond L Barnhill. The spitzoid lesion: rethinking Spitz tumors, atypical variations, "Spitzoid melanoma" and risk assessment. Modern pathology 2006; 19, S21-S33. Spatz A, Calonje E, Handfield-Jones S, Barnhill RL. Spitz tumors in children: a grading system for risk stratification. Arch Dermatol 1999 Mar; 135(3):282-5. Lee DA, Cohen JA, Twaddell WS, Palacios G, Gill M, Levit E, Halperin AJ, Mones J, Busam KJ, Silvers DN, Celebi JT. Are all melanomas the same? Spitzoid melanoma is a distinct subtype of melanoma. Cancer 2006 Feb 15; 106(4):907-13. Bastian BC, Wesselman U, Pinkel D, Leboit PE. Molecular cytogenetic analysis of Spitz nevi shows clear differences to melanoma. J Invest Dermatol 1999; 113:1065-1069.
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6. 7. 8.
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Mohammad Tawara and Thomas J. Flotte

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Notes
CASE 3
Case History
29-year-old male with a darkly pigmented 5 mm macule on the right shoulder, clinically suspicious for melanoma.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 1:
Figure 2:
Figures 3 & 4:
Scanning magnification reveals a sharply circumscribed and symmetrical compound melanocytic proliferation which is superficial, with little extension into the reticular dermis. The base of this lesion is relatively flat, and the melanocytic proliferation forms a superficial plaque-like growth, contrasting to the wedge-shaped dermal growth pattern of a classic Spitz nevus. Spindled to ovoid melanocytes are arrayed predominantly as junctional nests whose long axis is roughly perpendicular to the overlying epidermis. At the tips of elongate epidermal rete, the melanocyte nests fuse with one another and are arrayed in parallel to the epidermal surface, in similar fashion to the horizontally oriented junctional melanocyte nests of a dysplastic nevus.
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Figure 5
Figure 6
Figure 7
Figure 8
Figure 5:
Figure 6:
Figure 7:
Figure 8:
Epidermal hyperplasia is commonly described in pigmented spindle cell nevus and in this example adjacent elongate epidermal rete are fused with one another, and the nests of lightly pigmented melanocytes are present at the base and sides of the rete. The majority of melanocytes comprising the lesion are spindled to ovoid, lightly pigmented, and are interspersed with variable numbers of more epithelioid cells with small, but prominent nucleoli and eosinophilic cytoplasms. Dermal maturation is present and consists of banal melanocytes that are smaller toward the base of the lesion with smooth contoured nuclei containing evenly dispersed chromatin. This field shows some epithelioid cells with small but prominent nucleoli, however, the majority of melanocytes are small and regular with uniformly dispersed chromatin and smooth nuclear contours. Notice similarity between the nuclei of the nevus and those of epidermal keratinocytes. High magnification view showing junctional nest and adjacent eosinophilic globules.
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Case 3
Diagnosis
Pigmented spindle cell nevus of Reed.
Commentary
Pigmented spindle cell nevus (PSCN) is a benign, acquired melanocytic nevus with unique clinical presentation, demographics and histopathological features. Among the unusual variants of melanocytic nevus, PSCN is one of the least controversial entities. It usually presents as a well-demarcated and heavily pigmented, black or dark brown and rarely gray or gray/blue, papule or plaque. Clinical appearance of PSCN is usually worrisome and it is biopsied to rule out melanoma. However, in contrast to melanoma, it rarely exceeds the size of 6 mm and is usually symmetrical. The most common sites of occurrence are the proximal arm and leg, followed by the lower trunk. Elbows and knees are frequently involved in children.1-4 The women are affected twice as commonly as men. PSCN nevus is a lesion of young adults with the most lesions occurring in the third and fourth decade of life (the average age is about 25 years old). PSCN is not uncommon in routine practice. Initial series included close to 100 cases each.2-4 Histological features are very characteristic. At low power, PSCN is usually a sharply circumscribed and symmetrical proliferation of variably pigmented melanocytes. The epidermis may be acanthotic and often shows increased pigmentation. Most lesions are compound, but the dermal component is often inconspicuous and frequently limited to the papillary dermis. Thus, the first impression may be that of a junctional melanocytic proliferation. The dermal component is usually located in the center of the lesion. Dermal melanocytic nests are frequently surrounded by heavily pigmented melanophages. There may also be associated lymphocytic host response. The junctional nests are typically elongated with vertical, oblique or sometimes horizontal orientation. There is often sharp crescent-like clefting between the nested melanocytes and the adjacent epidermis. Junctional nests extending along eccrine ducts or the infundibular portion of hair follicle can be identified in one third of cases. The junctional nests are formed by spindled melanocytes forming short fascicles. They are characterized by monotonous small to medium size elongated nuclei with bland cytological features including vesicular nuclei and inconspicuous amphophilic nucleoli. The chromatin pattern is very fine and granular. In most cases there is minimal nuclear pleomorphism and hyperchromasia. It is often remarkable how similar the nuclei of PSCN cells are to each other and to those of the surrounding keratinocytes in terms of chromatin pattern, nucleoli and staining properties. The nuclei often have a see through semi-transparent appearance. Cytoplasm is usually moderately abundant with very fine pigmentation. In the areas of the most active junctional
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activity there is often pagetoid spread of individual cells or small nests. Transepidermal elimination of nests can be seen. The dermal component has similar cytological features. In most cases with a prominent dermal component, evidence of maturation with depth can be observed. PSCN may show some histological features typically associated with Spitz nevus. In rare cases the overlap may prevent unequivocal separation of the two entities. Therefore, it has been postulated that PSCN may be a variant of Spitz nevus. The spitzoid features in PSCN include Kamino bodies/eosinophilic globules, focal upward pagetoid spread, and supra-apical clefting of junctional melanocyte nests.5,6 In some instances, PSCN may show some overlap with dysplastic nevus. The most important differential diagnosis of PSCN is superficial spreading melanoma. The key differentiating points include small size, sharp lateral circumscription, symmetry, low-level pagetoid spread generally confined to the center of the lesion, and maturation of the dermal component of PSCN.7 Probably the most useful are cytological features and observation of bland see through monotonous spindled to oval nuclei with small amphophilic nucleoli, which are very characteristic of PSCN. Comparing nuclei of PSCN to those of adjacent keratinocytes is a very helpful exercise. In contrast to classic PSCN, nuclei of superficial spreading melanoma are distinctly different from those of epidermal keratinocytes. With hundreds of reported cases and many more cases encountered in routine and consultation practice, it is safe to say that PSCN is a benign lesion and that a simple excision with uninvolved margins is curative. At the present time, there is no evidence that PSCN can metastasize. Rarely, an incompletely excised PSCN can recur. The illustrated case is a good example of the entity. It has more dermal component then most cases. Figures 9-14 illustrate another classic example of PSCN.
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Case 3
Figure 9
Figure 10
Figure 11
Figure 12
Figures 11 & 12:
Scanning magnification. The key diagnostic features are: (1) predominantly junctional proliferation, (2) sharp circumscription and (3) symmetry. The edge of the lesion. The key diagnostic features are: (1) sharp border without significant lateral spread beyond the last junctional nest, (2) mild pagetoid spread, (3) dermal melanophages. Central portion of the lesion. The key diagnostic features are: (1) fascicular streamlined arrangement of cells in junctional nests with lateral semiulnar clefts between the cells and the epidermis, (2) epidermal pigmentation, (3) transepidermal elimination of junctional nests.
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Figure 13
Figure 14
Figures 13 & 14:
Cytological features. The key diagnostic points are: (1) Predominatly spindle cell morphology, (2) vesicular, see through nuclei with very similar staining properties to the nuclei of adjacent keratinocytes, (3) amphophilic pigmented moderately abundant cytoplasm.
References
1. Requena L, Sanchez YE. Pigmented spindle cell naevus. Br J Dermatol 1990; 123:757763 2. Sau P Graham JH, Helwig EB. Pigmented spindle cell nevus: a clinicopathologic analy, sis of ninety-five cases. J Am Acad Dermatol 1993; 28:565-571. 3. Sagebiel RW, Chinn EK, Egbert BM. Pigmented spindle cell nevus. Clinical and histologic review of 90 cases. Am J Surg Pathol 1984; 8:645-653 4. Barnhill RL, Barnhill MA, Berwick M, Mihm MC Jr. The histologic spectrum of pigmented spindle cell nevus: a review of 120 cases with emphasis on atypical variants. Hum Pathol 1991; 22:52-58. 5. Smith NP The pigmented spindle cell tumor of Reed: an underdiagnosed lesion. . Semin Diagn Pathol 1987; 4:75-87. 6. Wistuba I, Gonzalez S. Eosinophilic globules in pigmented spindle cell nevus. Am J Dermatopathol 1990; 12:268-271. 7. Barnhill RL, Mihm MC Jr. Pigmented spindle cell naevus and its variants: distinction from melanoma. Br J Dermatol 1989; 121:717-725.
Madhu Dahiya and Artur Zembowicz
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CASE 4
Case History
30-year-old woman had a nevus removed from her left abdomen. Histology revealed a congenital pattern nevus with focal slight atypia of the intraepidermal component and focal extension to the specimen margin. The nevus rapidly regrew at the site of the scar and was re-excised six weeks later.
Figure 1
Figure 2
Figure 3a
Figure 3b
Figure 1:
Figure 2:
Figures 3a & 3b:
Original nevus: Architectural symmetry with predominantly dermal population of small nevomelanocytes exhibiting diminution in nest and cell size tapering towards the center in deeper aspects. There is extension into adventitia of appendages and blood vessels consistent with congenital onset. Nevic cells focally reach deep margin (40x). Original nevus: Dermal population of small banal nevomelanocytes. Fibrotic superficial focus with dropout of melanocytes suggests prior remote trauma (100x). Original nevus: A few junctional nevic nests extend peripherally beyond the dermal component (a 100x) with slight cytologic atypia (b 200x).
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 4: Figure 5:
Recurrence at site of biopsy: Regrowth of junctional epidermis over scar, six weeks after near- complete excision (40x). Recurrence at site of biopsy: Higher magnification showing variably single cell and confluent junctional nests of melanocytes with irregularity in size and shape (100x).
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Case 4
Figure 10
Figure 6: Figures 7-9: Figure 10:
Recurrence at site of biopsy: Cells are large with small hyperchromatic nuclei and dusty finely melanized cytoplasm (400x). Melanoma-in-situ with dermal regression (200x, 400x, 400x). Similar histology of recurrent nevus with dermal component and invasive melanoma with partial regression (200x).
Diagnosis
Recurrent melanocytic nevus (at site of prior biopsy).
Commentary
Recurrent nevus refers to a nevus that regrows at the site of prior removal of a benign nevus. Some authors draw a distinction between recurrent and persistent nevus, with recurrent nevus developing at the site of seemingly complete removal of a nevus and persistent nevus having residual and regenerating components. In the former instance it is most likely that the nevus repopulates the epidermis from an appendage not completely removed. In both cases, clinically an area of pigmentation develops in a scar, sometimes with irregular borders and variegated brown color. Histologically, the growth pattern and appearance of cytologic atypia can mimic melanoma, a phenomenon that some observers have referred to as pseudomelanoma. The typical patient is a young adult, often female, who had a raised banal nevus removed several weeks before. An incompletely removed dysplastic nevus generally regrows much slower, in the range of months to two years, and melanomas even longer. Generally after initial rapid regrowth, recurrent benign nevi tend to stabilize, and if not originally atypical, pose little risk for malignant transformation. Histologically at low magnification, there are a minimum of two zones, junctional melanocytes and upper dermal healing reaction/ early scar formation, and in cases that had been grossly transected, three zones, with a deeper area of the residual original nevus (Figs. 1 Knowledge Books and Software 25
4). The striking component lies within the epidermis, showing a hybrid single cell and confluent growth pattern with variably large melanocytes exhibiting hyperchromatic, sometimes pleomorphic nuclei (Figs. 5- 6). This component can closely simulate melanoma-insitu (Figs. 7-9). Key to the recognition of a recurrent nevus in contradistinction from melanoma in situ is that the junctional component is sharply demarcated and does not extend beyond the scar. In some lesions, particularly after months, atypical cells can also be found in the upper dermal scarred area. These cases this can be very difficult to distinguish from melanoma without review of the histology of the original lesion (Fig. 10). Recurrent Spitz nevi are particularly challenging, as these can exhibit marked cytologic atypia.
References
1. 2. Massi G and Leboit PE. Histologic Diagnosis of Nevi and Melanoma. Steinkopff Verlag Darmstadt, Springer 2004, pp. 379-384. Park HK, Leonard DD, Arrington JH 3rd, Lund HZ. Recurrent melanocytic nevi: clinical and histologic review of 175 cases. J Am Acad Dermatol 1987 Aug;17(2 Pt 1):28592. Kornberg R, Ackerman AB. Pseudomelanoma: recurrent melanocytic nevus following partial surgical removal. Arch Dermatol 1975;111:1588-1590. Sexton M, Sexton CW. Recurrent pigmented melanocytic nevus. A benign lesion, not to be mistaken for malignant melanoma. Arch Pathol Lab Med 1991 Feb;115(2):1226.
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Steven R. Tahan
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CASE 5
Case History
17-year-old female had a 5 mm polypoid nevus excised from the right buttock, which was being chafed by a pant elastic strap. It was submitted to Pathology to rule out atypical nevus.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 1: Figure 2:
Figure 3: Figures 4 & 5:
Low magnification view of nevus showing a polypoid symmetric compound melanocytic nevus extending into the reticular dermis (40x). Central most exophytic area of the nevus with loss of rete ridges, single and variably sized nests of melanocytes irregularly disposed along the junctional epidermis, superficial dermal fibrosis, and upper dermal melanophages (100x). Absence of changes at edge of nevus (100x). Higher power view of central area showing large melanocytes along the junctional epidermis, abundant upper dermal melanophages, and fibrosis (200x). These features are not seen at the periphery of the lesion.
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Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figures 6 & 7: Figure 8: Figure 9:
Junctional melanocytes are commonly hypermelanotic with some enlargement of the nuclei (400x). Another example of an irritated nevus. Note changes in the most exophytic central area (right side of photograph) (40x). Central area showing focal parakeratosis, variable epidermal hyperplasia and atrophy, and thin zone of superficial dermal fibrosis (100x).
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Case 5
Figure 11
Figure 12
Figure 13
Figure 10: Figures 11 & 12: Figure 13:
Peripheral area lacking the central changes. Note absence of centripetal extension of the intraepidermal component (100x). Melanocytes can become epithelioid and monotypic, some with upward scatter within the epidermis (200x). The monotypic cytomorphology and single cell pattern with upward scatter can mimic melanoma-in-situ, if viewed at high magnification out of context of the entire nevus (400x).
Diagnosis
Irritated melanocytic nevus.
Commentary
Nevi in locations subject to repeated chaffing such as bra-straps, elastic bands, belt lines, neck collar areas, and facial sites accessible to rubbing can develop atypical morphologic changes that can sometimes mimic melanoma in situ.
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In a series of 100 nevi removed from sites of irritation, defined as repeated physical trauma or chaffing, we observed several distinctive characteristics illustrated by this case (manuscript in preparation). Symmetry is maintained (Fig. 1), but the following changes involve the dome of nevus (Figs. 2-13): 1. Focal hyper- and/or parakeratosis. 2. Loss of epidermal rete ridges and sometimes focal epidermal hyperplasia. 3. Single cell array and occasional variably sized nests of enlarged hypermelanotic epithelioid melanocytes disposed along the junctional epidermis with focal upward scatter. Melanocytes have hyperchromatic or enlarged nuclei with occasionally prominent nucleoli and ample cytoplasm with abundant melanin granules, sometimes coarse. Enlarged atypical appearing melanocytes can extend in single cell pattern down appendages. 4. Thin zone of fibrosis in superficial dermis, sometimes with telangiectasias. 5. Melanophages, occasionally aggregated, in upper dermis. 6. Banal subjacent dermal nevomelanocytic component. Many of these features resemble those of the recurrent nevus, however there is no developed scar or history of prior biopsy. A key feature is that the changes are most pronounced over the highest, most exposed, part of the nevus and do not involve its edges or extend peripherally beyond the dermal component. If nevomelanocytes extend within the epidermis beyond the dermal component with associated fibrosis and melanophages, this should not be ascribed to irritation effect. Difficulty in interpretation can be encountered in partial shave biopsies that do not allow for examination of the periphery of the nevus.
References
McCarthy SW, Scolyer RA. Melanocytic lesions of the face: diagnostic pitfalls. Ann Acad Med Singapore 2004 Jul; 33(4 Suppl):3-14.
Steven R. Tahan
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CASE 6
Case History
30-year-old woman, eight months pregnant, presented to her ophthalmologist with a rapidly growing brown spot on her eyelid. A biopsy was performed to rule out suspected malignant melanoma.
Figure 1
Figure 2
Figure 1: Figure 2:
Clinical appearance of a 3 mm brown papule with an eccentrically placed blueblack focus on the right lower eyelid. Scanning magnification shows a symmetrical and wedge-shaped intradermal melanocytic proliferation with a distinct darkly pigmented focus involving skeletal muscle.
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Figure 3
Figure 4
Figure 5
Superficial aspect of the lesion shows banal intradermal nevus, which matures with increasing dermal depth. The pigmented focus is formed by a distinct clone of epithelioid cells associated with melanophages. These cells show cytological features similar to those of type A melanocytes in common compound nevus.
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Case 6
Diagnosis
Inverted type A nevus.
Commentary
We use the term inverted type A nevus to a group of nevi, which are characterized by preservation of type A melanocyte morphology in the deep dermal component. The presented case shows an excellent example of inverted type A nevus and illustrates terminological difficulties in classification of similar lesions. The sections show a combined melanocytic proliferation with wedge shape architecture. The superficial portion of the lesion is essentially indistinguishable for a common nevus. The deep portion of the lesion shows a focus of distinct cellular proliferation associated with pigmented melanophages. This focus extends into subcutaneous tissue and involves superficially located eyelid skeletal muscle in a manner similar to deep penetrating nevus. Examination at higher magnification reveals that the cells in the pigmented focus have distinct cytological features from the surrounding nevus cells. They show epithelioid features and are similar to type A melanocytes which usually are found in the junctional or superficial dermal component of a common nevus. In contrast, to the common nevus, in this lesion type A cells are found in the deep portion of the lesion, so the architecture of this lesion in upside down, or inverted. Hence, the designation inverted type A nevus. As the inverted type A cells appear to represent a distinct clone of cells this lesion could also be classified as a clonal nevus. In the above passage, we described this lesion using adjectives, which were used in the literature to describe different subsets of problematic but benign melanocytic nevi. Accordingly, this lesion could be described as inverted type A, clonal, combined and deep penetrating nevus. The number of adjectives used for similar lesions is due to morphological complexity of this type of lesions and importance of recognizing them as benign even though they may have some features frequently observed in melanomas. The categories of clonal, combined, and deep penetrating and inverted type A nevus are distinct at the ends of their spectra but show significant histological overlap in many cases. In our practice, we find that cytological features of these lesions are as, if not more, important than architecture in their differentiation from melanoma. Therefore, we always scrutinize them paying attention to cytological characteristics. We find that identification of cytological similarities of the clonal, deep penetrating, or combined nevus to type A cells in the common nevus is the most reassuring feature in this group of lesions. Hence we often use the term inverted type A nevus for the lesions like the one illustrated above. We learned the concept of inverted type A nevus from Dr. Mihm, who credits Dr. Richard Reed with introducing this term, which he used frequently in his consultation reports.
We recently characterized the clinicopathologic features of a 102 ITANs and found that they are frequently (5%) of misdiagnosed as malignant melanoma.1 The typical clinical appearance of this nevus is a tan to light brown macule with an eccentrically placed blue-black focus.2 ITAN is most common in young women (female to male ratio = 1.5) with the median age of 32 years. The most common locations are face, back and upper extremity. The history of recent change within a preexisting nevus brings the lesion to medical attention in many of the cases. The histology of this benign melanocytic nevus is characterized by the presence of epithelioid (type A) nevus cells, usually identified in the superficial dermis of common acquired nevi, located deep in the dermal component. This histologic hallmark defies the orderly transition or "maturation" between type A, type B and type C melanocytes. The impression of upside-down maturation has invoked the name inverted. The presence of large epithelioid focus deep in the dermis is the feature that causes the most difficulty, as it can resemble cutaneous melanoma, in vertical growth phase, arising within a preexisting nevus. Histologic hallmark of these lesions is the presence of round to oval, often pigmented epithelioid melanocytes, resembling type-A nevus cells of common nevi, in the deep dermal component. This architectural arrangement defies the rules of maturation seen in benign nevi. Surrounded by heavily pigmented melanophages, nested inverted type A nevus cells show ample cytoplasm with dusty pigmentation and medium sized round to oval regular nuclei with conspicuous nucleoli and fine chromatin. In contrast to malignant melanoma, only a few cases of the inverted type A nevus cells show scattered mild to moderately epithelioid cytological atypia, within the nests, and never form confluent nodules or sheets. Mitotic activity is infrequent (less than 1-2 mitoses/mm2) but it can be identified in as many as 12% of the lesions. As discussed above many of inverted type A nevi are combined nevi showing features overlapping with deep penetrating nevus, when they extend into deep reticular dermis3, and clonal nevus4, if the inverted type A cells are limited to the superficial dermis. However, a number of inverted type A nevi are composed of pure type A nevus cells showing no maturation with depth. Such lesions are neither combined, clonal or deep penetrating. Clinical follow-up in our cohort (42-79 months, mean 68.1 months) showed no evidence of recurrence or metastases in lesions with clear margins. We recommend conservative re-excision of ITANs. Finally, some inverted type A nevi may show moderate to severe degree of cytological atypia. These lesions may raise concern of evolving melanoma. It would be reasonable to consider ITANs showing focal severe cytological atypia as borderline melanocytic tumors or put them into the category of melanocytic tumor of unknown malignant potential.
34
Case 6
Acknowledgements
The author thanks Dr. Arthur Grove, M.D., Boston, MA for providing the clinical picture.
References
1. 2. 3. 4. Dadras S, Zembowicz A, Flotte TJ, Duncan LM, Mihm MC. manuscript in preparation. Huynh PM, Glusac EJ, Bolognia JL: The clinical appearance of clonal nevi (inverted type A nevi). Int J Dermatol 2004; 43:882-885. Seab JA, Jr., Graham JH, Helwig EB: Deep penetrating nevus. Am J Surg Pathol 1989; 13:39-44. Ball NJ, Golitz LE: Melanocytic nevi with focal atypical epithelioid cell components: a review of seventy-three cases. J Am Acad Dermatol 1994; 30:724-729.
Sam Dadras and Artur Zembowicz
35
Notes
CASE 7
Case History
12-year-old boy presented with a pigmented conjunctival lesion. The lesion was first noticed nine months before. It caused irritation and foreign body sensation in the left eye.
Figure 1
Figure 2
Figure 3
Figure 4
Figures 1-4:
Low magnification views showing rather symmetrical compound melanocytic proliferation. Of note is presence of small subepithelial glandular cysts and maturation with depth.
37
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figures 5-9: Figures 10-14:
Intermediate magnifications show nested junctional component, maturation with depth and detailed view of conjunctival cysts, which contain goblet cells. Cytological details. Junctional melanocytes show epithelioid type A morphology with small bland nuclei and minimal nuclear atypia. One can appreciate lack of hyperchromasia or pleomorphism by comparing the nuclei of the melanocytes to those of adjacent epithelial cells.
38
Case 7
Figure 11
Figure 12
Figure 13
Figure 14
Diagnosis
Conjunctival compound nevus.
Commentary
Conjunctival melanocytic nevus is the most common benign tumor of the conjunctiva. It is frequently diagnosed during childhood and teenage years and rarely occurs after the age of 50. The nevi in children are often lighter then in adults. As many as thirty percent of conjunctival nevi may be amelanotic.1 There is usually progression of pigmentation with age, especially during puberty. Limbus and bulbar conjunctiva are the most common locations. Conjunctival nevi are less common in the caruncle.2 Nevi on palpebral conjunctiva are exceptionally rare, but can occur. Malignant melanoma should be first suspected when nevus-like lesion is found on palpebral conjunctiva, unless it is proven otherwise by biopsy. Conjunctival nevi occurring at the limbus tend to be flat. They typically do not extend to the corneal region. Those appearing elsewhere tend to be elevated and diffuse. Nevi
occurring on the bulbar conjunctiva, but not those located at the limbus, should be freely moveable over the underlying sclera. Malignant melanoma can resemble or rarely arise from a conjunctival nevus. There are no reliable clinical signs, which distinguish melanoma from a nevus or predict the risk of its malignant transformation. Many authors2-4 advocate high level of suspicion in recurrent nevi. Concerning features also include large size, multiple feeder vessels, rapid growth, and significant recent color change. Palpebral and forniceal conjunctiva are also uncommon location for conjunctival nevi. Histologically, conjunctival nevi share many morphological features with cutaneous nevi. However, they occur in a unique anatomical context and may be very challenging even to experienced pathologists not familiar with this specific location. They are divided into junctional, compound, and subepithelial nevi. If two different nevus types are present, they are referred to as combined nevi. The most common second component is blue nevus. The intraepithelial (junctional) component of a conjunctival nevus shows usually nested and less frequently lentiginous growth pattern. In most lesions, the junctional melanocytes display epithelioid features with moderately abundant cytoplasm, small round to oval nuclei containing tiny nucleoli and are essentially indistinguishable from type A nevus cells in the skin. Purely junctional nevi are rare. In the absence of any subepithelial component, many ophthalmic pathologists erroneously interpret junctional nevi as primary acquired melanosis with atypia,2,3 a concept discussed elsewhere in this book. However, junctional nevi can be easily distinguished from primary acquired melanosis on clinical grounds. They are small, well circumscribed lesions. It is also helpful to be aware of the age of the patient. Most junctional conjunctival nevi occur in children and young adults, whereas primary acquired melanosis is a disease of adults and older people. Compound nevi are by far the most common type comprising 70-78% of all conjunctival nevi.3,4 They demonstrate both intraepithelial and subepithelial type A nevus cells. Sometimes, large epithelioid and multinucleated giant nevus cells can be found within or near the epithelium. The subepithelial component of the compound nevus is usually nested but single cell growth can be seen in many cases. It is not unusual for the junctional nests in conjunctival nevi to coalesce and give impression of confluent growth. As confluent growth pattern is concerning in skin lesions, one should not over interpret this finding. Significant nuclear pleomorphism is usually absent, but rare isolated atypical cells can be identified. Pigmentation varies from case to case. In adults, the junctional component is usually mitotically inactive and does not extend beyond the lateral edge of the subepithelial component. Mitoses are sometimes identified in children. Smaller cuboidal, lymphocytoid (type B) nevus cells form deeper dermal component. In many lesions, amelanotic spindle-shaped cells resembling type C nevus cells populate the base. These morphological changes
40
Case 7
representing progressive maturation with depth are very reassuring in the context of differential diagnosis with melanoma. One of very characteristic and diagnostically useful features of conjunctival nevi is their ability to induce downward migration of small pegs or buds of the surface epithelium and formation of conjunctival cysts. (Fig. 15) The cysts often have goblet cells. They are present in 50% or more of conjunctival nevi.1 In contrast, melanomas almost never induce significant epithelial hyperplasia and cyst formation. Conjunctival cysts are less common in children, where they are usually small. They become larger and more prominent with age. In some cases, the cysts are the major component of the lesion. It may be difficult to recognize the lesion as a nevus, as the melanocytes may be rare and may be interpreted as inflammatory cells. We are aware of cases where nevi with prominent cyst formation were diagnosed as cystadenomas. Subepithelial nevi are quite rare. They usually show orderly maturation with depth. They often contain epithelial cysts. They may in fact be the end-stage in evolution of nevi, as they are usually found in older individuals. Most conjunctival nevi do not require treatment, especially if the lesion has been stable for many years. Simple excision is almost always curative and is a treatment of choice. Since the risk of malignant melanoma supervening in a nevus is low, excision is only recommended in lesions with suspicious features. Conjunctival nevi are also removed for cosmetic reasons.
Figure 15
Figure 16
Figure 15: Figures 16-18:
An example of a conjunctival nevus with large epithelial cysts. (a different case). A different conjunctival nevus from a young child. The lesion is compound and quite resembles the cutaneous counterpart. Note that the junctional nests show confluent growth pattern which taken out of anatomical context may be concerning. However, it is not an uncommon feature in the conjunctiva.
41
Figure 17
Figure 18
References
1. Jay B. Naevi and melanomata of the conjunctiva. Br J Ophthalmol 1965; 49:169-204. 2. Folberg R, Jakobiec FA, Bernardino VB, Iwamoto T. Benign Conjunctival Melanocytic Lesions. Clinicopathologic Features. Ophthalmology 1989; 96(4):436-61. 3. Grossniklaus HE, Green WR, Luckenbach M, Chan CC. Conjunctival Lesions in Adults. A Clinical and Histopathologic Review. Cornea 1987; 6(2):78-116. 4. Shields CL, Fasiuddin AF, Mashayekhi A, Shields JA. Conjunctival Nevi: Clinical Features and Natural Course in 410 Consecutive Patients. Arch Ophthalmol 2004; 122(2):167-75.
42
CASE 8
Case History
27-year-old pregnant woman was found to have a 1.1 x 1.0 cm brown papule on her left labium majus during a prenatal gynecologic examination. The lesion was excised by her obstetrician at the time of Cesarean section.
Figure 1
Figure 2a
Figure 2b
Figure 3a
Figure 1: Figures 2a & 2b:
Figures 3a & 3b:
Low power demonstrates a broad lesion with contiguous large nests along the dermoepidermal junction. The nests are composed of dyscohesive melanocytes with well developed retraction artifact between the nevus cells and the overlying epidermis. Mild cytological atypia is present in the junctional component. The dermal component shows no significant cytological atypia.
43
Figure 3b
Figure 4
Figure 5a
Figure 5b
Figure 6a
Figure 6b
Figure 4: Figures 5a & 5b: Figures 6a & 6b:
Focally, nests of banal nevus cells can be seen in the dermis underlying the florid epidermal melanocytic proliferation. In areas, the nests are poorly defined and appear to efface the epidermis. Mild to moderate cytological atypia is present. Rare suprabasilar pagetoid spread is seen in traumatized areas (note parakeratosis with intracorneal neutrophils).
44
Case 8
Figure 7
Figure 8
Figure 7: Figure 8:
Adnexal spread is present. The periphery of the lesion shows areas of typical genital nevus with round, discrete nests of dyscohesive cells.
Diagnosis
Atypical genital nevus.
Commentary
Vulvar nevi are uncommon, occurring in only 2.3% of patients screened at their routine gynecologic exam in one prospective study.1 Banal, congenital, dysplastic, common blue and Spitz nevi may all be encountered. While the majority of vulvar nevi are histologically unremarkable,2 a subset in young women shows unusual and characteristic histologic features. These lesions were first described in a series of seven cases by Friedman and Ackerman.3 In 1998, Clark et al. reported 36 additional cases, 13 of which were originally diagnosed as melanoma by the consulting pathologist, and proposed the name atypical melanocytic nevi of the genital type.4 Commonly this is abbreviated to atypical genital nevi (AGN). The synonyms flexural nevi and milk-line nevi are also sometimes applied. AGN most commonly present in premenopausal women (range 1440 years of age).2,3 Younger children may also rarely be affected. The nevi are usually found on the vulva, with roughly equal involvement of the mucosal and glabrous surfaces, but have also been described on the perineum, mons pubis, scrotum, umbilicus, axillae, areola and the flexures.4-7 They may be elevated or flat and are often larger than typical acquired nevi (up to 24 mm).3,4 Histologically, AGN have a distinctive melanocytic proliferation at the dermoepidermal junction (DEJ) characterized by large, often confluent, nests of variable size and shape with diminished intercellular cohesion. Although most lesions that are encountered are compound
in type, sometimes, particularly in teenagers, junctional variants may be seen (Figs. 9a & 9b). Clark et al. described three patterns that may occur individually or in combination at the DEJ: (1) a predominance of variably sized but typically large nests, often oval and oriented perpendicular or parallel to the DEJ (the nested pattern); (2) nearly contiguous intraepidermal nests composed of large, dyscohesive cells, forming a band that separates the epidermis from the underlying mature dermal melanocytes (the dyshesive nest pattern); or (3) closely apposed ill-defined nests and single cells obscuring the dermoepidermal junction (DEJ) (the crowded pattern). Of these, the nested and dyshesive patterns are most commonly seen4 (Figs. 10a10c). In approximately 50% of cases, a banal dermal nevus is present beneath the melanocytic proliferation at the DEJ. The associated dermal nevus is often large and may have a mushroom-cap shape (Figs. 11a & 11b); the epidermal component of AGN covers the surface and rarely extends laterally beyond the intradermal component. In addition to the unusual melanocytic proliferation at the DEJ, AGN may show one or more worrisome histologic features that prompt consideration of melanoma. The intraepidermal cells are usually epithelioid and dyscohesive, with abundant eosinophilic cytoplasm and vesicular or hyperchromatic nuclei generally containing small basophilic nucleoli.6 Multinucleate cells are also present in some cases (Fig. 12). Dusty cytoplasmic pigmentation is commonly evident and heavily pigment-laden melanophages may be seen in both the junctional and dermal components. Mild to moderate cytological atypia is common in the epidermis and may be seen in the superficial dermal component, but maturation is always present in the deep portion of the lesion. Infrequently (three of the 36 cases in Clarks report4), AGN show marked cytologic atypia. Adnexal involvement is common3 (Fig. 13), and pagetoid spread has been noted in a variable percentage of cases (ranging from 16-80%).8 However, the pagetoid cells are usually found only in the central part of the lesion, and rarely extend into the granular layer9,10 (Figs. 14 & 15). Rare mitoses may be present in the epidermis3 and, in our experience, isolated mitotic figures may be found in the superficial dermal component (Fig. 16). The differential diagnosis includes dysplastic nevi (DN) and melanoma. DN may occur on the vulva as on any other site11 but in contrast to AGN, they appear to preferentially involve the labia majora over the labia minora or clitoris.4 Histologically, DN typically show a lentiginous proliferation of single cells and small nests with random cytologic atypia, whereas AGN are dominated by large nests with generally uniform, mild cytologic atypia. Some AGN may have a lentiginous single-cell pattern, but this is usually only focal and found at the periphery of the lesion. Dense, patchy lymphocytic infiltrates are more common in DN than AGN (40% vs 16% in one study4), and the two patterns of stromal fibrosis characteristically seen in DN concentric eosinophilic fibroplasia and lamellar fibroplasia are not a
46
Case 8
feature of AGN.4 In rare cases however, there is extensive overlap between the histologic features of AGN and DN,4 and a definitive distinction may be impossible. Vulvar melanoma is a disease of postmenopausal usually elderly women, in contrast to the younger age group presenting with AGN. Childhood vulvar melanoma however has been very rarely documented, generally arising in a background of lichen sclerosus.12,13 In contrast to the predominantly nested pattern of AGN, most vulvar melanomas are of mucosal lentiginous type14 and show a predominance of single cells over nests. Melanoma also typically has greater cytologic atypia and lacks the symmetry, sharp lateral circumscription, and maturation seen in AGN. Although melanoma may uncommonly arise in a banal dermal nevus, the malignant component in such cases typically develops at one edge of the pre-existing benign lesion and grows asymmetrically, in contrast to the pattern seen in AGN associated with common dermal nevi. Despite the often worrisome histologic appearance of AGN, the limited clinical follow-up available to date suggests that these lesions probably have no risk of progression. In Ackermans seven cases and Clarks study of 36 AMNGT, no recurrences or metastases occurred, although the length of follow-up was not detailed in either report.3,4 Accurate diagnosis of these lesions is critical for treatment purposes. Most authors recommend complete excision of AGN, but wide excision should be vigorously discouraged.4,15 Overdiagnosis of AGN inevitably leads to unnecessary wide excision or vulvectomy with or without sentinel lymph node biopsy. In addition, severe psychological issues are raised for the patient and the pathologist may be liable for litigation.
Figure 9a
Figure 9b
Figure 9a: Figure 9b:
Typical nested pattern of a junctional genital nevus, with large discrete nests at the dermoepidermal junction. The nests are composed of dyscohesive epithelioid melanocytes with abundant finely pigmented cytoplasm and hyperchromatic nuclei. Note the welldeveloped retraction artifact.
Figure 10a
Figure 10b
Figure 10c
Figure 11a
Figure 11b
Figure 12
Compound variant showing contiguous junctional nests and a dermal component composed of banal nevus cells. There is a dense lymphocytic infiltrate. Figures 10b&10c: The melanocytic nuclei are variably hyperchromatic or vesicular. There is mild cytological atypia. In addition to a background of fine cytoplasmic pigmentation, coarse melanin granules are also apparent. Figures 11a&11b: Atypical genital nevus associated with a large, mushroom-shaped, banal dermal nevus. Note the dyscohesive, junctional component with well developed retraction artifact. Figure 12: Multinucleate cells are prominent in this case. Figure 10a:
48
Case 8
Figure 13
Figure 14a
Figure 14b
Figure 14c
Figure 15a
Figure 15b
Figure 13: Figures 14a-14c:
Extension of nests and single melanocytes into adnexal structures is common. Focal suprabasilar pagetoid spread may be present in genital nevi. Note the nevus cell in the mid-prickle cell layer (b) and mild cytological atypia (c). The dermal component shows maturation. Figures 15a&15b: In contrast, prominent pagetoid spread at all levels of the epidermis is seen in this vulvar melanoma. There is diffuse cytological atypia.
49
Figure 16a
Figure 16b
Figure 16c
Figure 16d
Figures 16a-16d:
Scanning view of small heavily pigmented nevus (a). There is a characteristic dyscohesive junctional component (b). A mitotic figure is present in the dermal component (c & d).
References
1. Rock B, Hood AF, Rock JA. Prospective study of vulvar nevi. J Am Acad Dermatol 1990; 22:104-106. 2. Christensen WN, Friedman KJ, Woodruff JD, et al. Histologic characteristics of vulvar nevocellular nevi. J Cutan Pathol 1987; 14:87-91. 3. Friedman RJ, Ackerman AB. Difficulties in the histologic diagnosis of melanocytic nevi on the vulvae of premenopausal women. In, Ackerman AB, ed. Pathology of malignant melanoma. New York, NY: Masson, 1981:119-127. 4. Clark WH, Jr., Hood AF, Tucker MA, et al. Atypical melanocytic nevi of the genital type with a discussion of reciprocal parenchymal-stromal interactions in the biology of neoplasia. Hum Pathol 1998; 29:S1-24. 5. Barnhill RL. Pathology of melanocytic nevi and malignant melanoma. Boston, MA: Butterworth-Heinemann, 1995:59-63. 6. Massi G, LeBoit PE. Nevi on genital skin. In: Massi G, LeBoit PE, Histological diagnosis of nevi and melanoma. Springer, 2004:303-314. 7. Rongioletti F, Ball RA, Marcus R, et al. Histopathological features of flexural melanocytic nevi: a study of 40 cases. J Cutan Pathol 2000; 27:215-217.
50 Knowledge Books and Software
Case 8
8. 9. 10. 11. 12. 13. 14.
15.
Haupt HM, Stern JB. Pagetoid melanocytosis. Histologic features in benign and malignant lesions. Am J Surg Pathol 1995; 19:792-797. Stern JB, Haupt HM. Pagetoid melanocytosis: tease or tocsin? Semin Diagn Pathol 1998; 15:225-229. Crowson AN, Magro CM, Mihm MC. The melanocytic proliferations. New York, NY: Wiley-Liss, 2001:257-265. Blickstein I, Feldberg E, Dgani R, et al. Dysplastic vulvar nevi. Obstet Gynecol 1991; 78:968-970. Egan CA, Bradley RR, Logsdon VK, et al. Vulvar melanoma in childhood. Arch Dermatol 1997; 133:345-348. Hassanein AM, Mrstik ME, Hardt NS, et al. Malignant melanoma associated with lichen sclerosus in the vulva of a 10-year-old. Pediatr Dermatol 2004; 21:473-476 Ragnarsson-Olding BK, Kanter-Lewensohn LR, Lagerlof B, et al. Malignant melanoma of the vulva nationwide, 25-year study of 219 Swedish females: clinical observations and histopathologic features. Cancer 1999; 86:1273-1284. Elder DE. Precursors to melanoma and their mimics: nevi of special sites. Mod Pathol 2006; 19 Suppl 2:S4-20.
Briana C. Gleason and Phillip H. McKee
51
Notes
CASE 9
Case History
n 18-year-old Asian American girl came to the doctor because she wanted the blue spot in her left shoulder removed. She did not remember how long she had it for. The clinical appearance of the lesion was that of a poorly circumscribed bluish-gray area over the left deltoid area.
Figure 1
Figure 2
Figure 3
Figure 1: Figure 2:
Figure 3:
Low power picture reveals dermal pigmented lesion involving the papillary and upper reticular dermis. Higher power reveals many of the melanin-laden cells to have a dendritic appearance with minimal fibrosis in the background. Many dendritic cells and their dendritic extensions lie parallel to surface of epidermis superficially. The cellular proliferation spares the periadventitial dermis. Note occasional pigmented dendritic cells in the reticular dermis. In this profile one can appreciate the scattered dendritic cells in the reticular dermis, and again the sparing of the adventitial dermis of the eccrine glands.
53
Figure 4a
Figure 4b
Figures 4a & 4b:
The dense concentration of cells in the upper dermis easily reveals the difference between the delicate dendritic melanocytes with fine melanin granules as opposed to the coarsely granulated melanophages with almost stellate shapes (a). In the deep dermis the same cellular characteristics are evident (b).
Diagnosis
Nevus of Ito.
Commentary
The hamartomatous proliferations of dermal dendritic melanocytes (dermal melanocytoses) can present clinically as four distinct entities: nevus of Ota, nevus of Ito, Mongolian spot, and dermal melanocyte hamartoma.1,2 In some cases, the hamartomatous melanocytic component is associated with a vascular proliferation.3,4 Such cases are designated as phakomatosis pigmentovascularis or nevus pigmentovascularis. The common feature of all these entities is the presence of dendritic melanocytes, which are diffusely scattered throughout the dermis and, sometimes, subcutaneous tissue. They are believed to be the result of incomplete or aberrant migration of embryonic melanocytes from the neural crest toward the epidermis during the development. Dermal melanocytoses are usually congenital or appear in the early childhood, but in rare cases they are acquired with the onset in the adulthood. Clinically, they present as poorly delineated bluish macules or patches. According to the location, dermal melanocytoses are classified into the following categories: Nevus of Ota is located in the face along the distribution of the trigeminal nerve. It affects predominantly the ophthalmic and maxillary branches. It can also involve the eye and the oral mucosa.5
54
Case 9
Nevus of Ito is located in the shoulder along the distribution of the acromioclavicular nerve.6 Mongolian spot is present in the lower back and sacrum Dermal melanocyte hamartoma is present in different anatomical locations, usually in dermatomal distribution.7 Rarely, identical lesions can occur in the mucosa of the oral, sinonasal or genital regions (Fig. 5). The nevus of Ota can be associated with a number of developmental conditions including nevus of Ito, phakomatosis pigmentovascularis, leptomeningeal melanosis, pigmentation of the sclera, cornea, retina, and optic disc, glaucoma, neurofibromatosis, and SturgeWeber syndrome.
Histology
All clinical subtypes of dermal melanocytoses show similar histological features. The histological hallmark of these lesions is the presence of pigmented dendritic melanocytes. The dendritic cells are indistinguishable from those of blue nevus, which is the main histological differential diagnosis of the nevus of Ito and related conditions. The histological differentiation between dermal melanocytoma and blue nevus requires analysis of the architectural features and cellular composition of a lesion, and is rarely difficult. Blue nevi are typically wedge-shaped with frequently asymmetrical extension into deep reticular dermis and subcutaneous tissue along the adnexal structures. Essentially, all blue nevi induce dermal fibrosis and are relatively well demarcated. Importantly, in blue nevi the dendritic cells are accompanied by varying number of ovoid or spindled melanocytes resembling type B and type C melanocytes of common nevus. In fact, the non-dendritic cells are the predominant cell type in the majority of cases. In contrast, dermal melanocytoses are diffuse poorly demarcated dermal proliferations. They often involve the subcutaneous tissue, deep soft tissue and even bone. Fibrosis is absent or, if present in the nevus of Ota or Ito, it is mild. Dendritic cells are the only melanocytic cells present, but they can be accompanied by occasional melanophages in some cases. In the superficial reticular dermis, the melanocytes form a linear array parallel to the epidermal surface and distribution of dermal collage fibers. Quite characteristically, they outline the contours of the adnexal structures without involvement of the adventitial dermis. In phakomatosis pigmentovascularis, in addition to the dermal melanocytes there is a hamartomatous vascular proliferation. In most cases, it has features of a capillary hemangioma.
Prognosis and treatment

The nevi of Ota, Ito and related conditions are permanent benign lesions, which require no surgical treatment. The development of malignant melanoma in their context is extremely rare, but has been described. In patients with nevus of Ota an ophthalmologic evaluation
should be performed to rule out glaucoma and ocular involvement by the melanocytic hamartoma. The management is usually medical with makeup to camouflage the pigmentation in cosmetic sensitive areas. Laser treatments available include Pulsed Q-switched laser surgery with alexandrite and Nd:YAG lasers. Other options include cryotherapy, microsurgery and dermabrasion.
Figure 5
Figure 5:
Melanocytic hamartoma (ectopic mongolian spot) of the palate. This palatal pigmented lesion exhibited dendritic melanocytes scattered among collagen fibers with no evidence of fibrosis or melanophages, all characteristics of a melanocytic hamartoma. This patient had the classical Mongolian spot in her buttock area.
References
1. Zembowicz A, Mihm MC. Dermal dendritic melanocytic proliferations: an update. Histopathology 2004 Nov; 45(5):433-51. 2. McKee PH, Calonje E, Granter SR. in Pathology of the Skin, Third Edition. Elsevier Mosby, London 2005. 3. Vidaurrri-de IC, Tamayo-Sanchez L, Duran Mckinster C, et al. Phakomatosis pigmentovascularis IIA and IIB: clinical findings in 24 patients. J Dermatol 2003; 30:381-388. 4. Sawada Y, Iwata M, Mitsuhashi Y. Nevus pigmentovascularis. Ann Plast Surg 1990; 25:142-145. 5. Ota M, Tanino H. Nevus fusco-caeruleus ophthalmomaxillaris and melanosis bulbi. Tokyo Iji Shinshi 1939; 63:1243-1245. 6. Ito M. Nevus fusco-caeruleous acromio-deltoideus. Tohoku Exp Med 1954; 60:10-12. 7. Buckhart CG, Gohara A. Dermal melanocytic hamartoma. A distinctive new form of drmal melanocytosis. Arch Dermatol 1981; 117:102-104.
Adriano Piris, Artur Zembowicz, Martin C. Mihm Jr.
56
CASE 10
Case History
lowly-growing skin-colored tumor on the lower back in a 38-yearold female.
Figure 1
Figure 2
Figure 3
Figure 4
Figures 1 & 2:
Figures 3 & 4:
Low magnification view showing amelanotic dermal spindle cell proliferation with desmoplastic stroma. Deep portion of the lesion extends into subcutaneous tissue along adnexal structures and neurovascular bundles. The subepidermal zone showing spindle cells reminiscent of type B nevus cells set in desmoplastic stroma. There is no epidermal hyperplasia. In the deeper portion of the lesion there are areas of increased cellularity.
57
Figure 5
Figure 6
Figure 7
Figure 8
Figures 5 & 6: Figures 7 & 8:
Cellular areas in deep reticular dermis. Cytological detail of cellular areas. The melanocytes have uniform rounded to oval nuclei with small amphophilic nucleoli and lightly staining bluish cytoplasm. There is no significant cytological atypia.
Diagnosis
Amelanotic cellular blue nevus.
Commentary
Amelanotic cellular blue nevus (ACBN) is not a distinct clinicopathological entity but merely a histological variant of cellular blue nevus (CBN)1-3 with very little or no melanin pigmentation. Yet it is an important lesion to be aware of as lack of expected pigmentation often leads to misdiagnosis of ACBN as a soft tissue tumor. In our series of 20 ACBNs4 clinical diagnosis of blue nevus was not suspected in any of the cases; only eight out of 19 cases submitted for the second opinion
58
Case 10
were correctly diagnosed as a variant of cellular blue nevus.4 The most common tumors confused with ACBN are melanoma, deep penetrating nevus, desmoplastic melanoma, malignant blue nevus, clear cell sarcoma, dermatofibroma, cellular neurothekoma and myoepithelioma. Some of these entities are discussed elsewhere in this volume. Histological differential diagnosis of ACBN is also discussed in great detail in a recent review.5 Current experience with ACBN indicates that it has similar demographics to common CBN. The buttocks, head and neck and extremities are the most common sites. The lesions present clinically as skin-colored firm deep dermal nodules or tumors ranging in size from a few centimeters to giant size; sometimes exceeding 10 cm. Involvement of the subcutaneous and soft tissue such as skeletal muscle, tendon or the bone of the scalp may occur. Ulceration is rare. The prototypical ACBN is usually an amelanotic dermal or subcutaneous tumor with a zonal appearance at scanning magnification (Figs. 1 & 2). The superficial zone is indistinguishable from amelanotic blue nevus (Fig. 3). As in amelanocytic blue nevus, correct diagnosis has to be suspected on architectural grounds, as dendritic blue nevus cells cannot be appreciated without help of immunohistochemical stains. Helpful features include mild dermal fibrosis, nesting and spindle cells with hyperchromatic nuclei. In contrast to a much more common dermatofibroma, superficial portion of the ACBN is often wedgeshaped and the lesion is not associated with epidermal hyperplasia. Diagnostic cellular areas of ACBN are present within the blue component or at the deep edge of the tumor in reticular dermis or subcutaneous tissue. In occasional tumors only the cellular component can be identified. In many cases cellular areas are sharply demarcated from the area of conventional blue nevus and form discrete expansive nodules. In other cases, cellular areas merge imperceptibly with surrounding blue nevus or have an infiltrative border. Cellular nodules often extend as bulbous or hour-glass-like aggregates into the subcutaneous tissue along adnexal structures or neurovascular bundles. They are divided by fibrous septae into nests, cohesive sheets or alveoli6 (Figs. 4-6). This outline of superficial and deep nodules has also been referred to as a dumbbell shaped. Melanocytes in cellular areas have rounded to oval nuclei with small amphophilic nucleoli and lightly eosinophilic cytoplasm (Figs. 7 & 8). Cytological atypia is usually absent or mild. Multinucleated wreath-like cells can be encountered in cases with an alveolar growth pattern. ACBN does not show coarse granular melanin pigment, which is usually present in melanophages occupying fibrous septae surrounding cellular nodules in classic CBN. However, careful inspection of many levels may reveal rare dermal spindle and dendritic cells showing cytoplasmic pigmentation. Hemorrhage and hemosiderin deposition may be present in larger tumors. Mitotic activity can be identified in most, if not all cases, but is rarely higher than 3 mitoses/mm2. Tumor necrosis is very rare and if present should raise
59
a possibility of malignant blue nevus. It is well known that classic CBN found in areas of pressure such as the scalp on the back of the head or buttocks may show areas of cystic degeneration with nevus cells or nests lying free in tumor clefts. This phenomenon can also be found in ACBN and has to be distinguished from tumor necrosis in order to avoid consideration of malignant blue nevus. Immunohistochemical studies are rarely needed in adequately sampled lesions. However, in small biopsies they may be helpful. As all blue nevi, ACBN invariably shows expression of HMB-45 in addition to S100 and Mart-1. In summary, the key to diagnosis of ACBN is recognition of the biphasic nature of the tumor with classic blue nevus-like spindle and dendritic cell proliferation in the superficial dermis and cellular expansive nodules or sheets of round to oval cells with oval nuclei, inconspicuous nucleoli and clear to lightly eosinophilic cytoplasm in the deep portion of the lesion. Figures 9-14 illustrate histological features of another example of ACBN.
Figure 9
Figure 10
Figure 11
Figure 12
60
Case 10
Figure 13
Figure 14
Figures 9 & 10:
Figures 11-14:
Low magnification view of a different example of amelanotic cellular blue nevus. The sections show characteristic dumbbell shaped architecture and zonal appearance with cellular areas extending into deep dermis along adnexal structures and neurovascular bundles. Cytological detail from other examples of amelanotic cellular blue nevus.
References
1. 2. 3. 4. Rodriguez HA, Ackerman LV. Cellular blue nevus. Clinicopathologic study of forty-five cases. Cancer 1968; 21:393-405. Leopold JG, Richards DB. Cellular blue naevi. J Pathol Bacteriol 1967; 94:247-255 Allen AC, Spitz S. Malignant melanoma. A clinicopathological analysis of criteria for diagnosis and prognosis. Cancer 1953; 6:1-45. Zembowicz A, Granter SR, McKee PH, Mihm MC. Amelanotic cellular blue nevus: a hypopigmented variant of the cellular blue nevus: clinicopathologic analysis of 20 cases. Am J Surg Pathol 2002; 26:1493-1500. Zembowicz A, Mihm MC. Dermal dendritic melanocytic proliferations: an update. Histopathology 2004; 45:433-51. Review. Michal M. Cellular blue naevi with microalveolar pattern a type of naevus frequently confused with melanoma. Pathol Res Pract 1998; 194:83-86.
5. 6.
61
Notes
CASE 11
Case History
23-year-old female presented to her dermatologist for evaluation of a 6 mm pigmented lesion will ill-defined border that was located on her right inner arm. A biopsy was performed to rule out an atypical melanocytic lesion.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 1: Figure 2:
Figure 3: Figure 4:
At scanning magnification, the lesion is broad and slightly asymmetrical. There is a lentiginous proliferation of single and nested melanocytes at the dermoepidermal junction. Nests of melanocytes vary in size and tend to be oriented parallel to the surface and to bridge between elongated rete ridges. There is mild lamellar fibroplasia of the papillary dermis and a moderate lymphocytic infiltrate. A few melanocytes are seen above the basal layer.
63
Figure 5
Figure 5:
The melanocytes are slightly enlarged with moderate (discontinuous) cytologic atypia.
Diagnosis
Junctional dysplastic melanocytic nevus with moderate cytologic atypia.
Commentary
In 1978 Clark and co-workers characterized the dysplastic nevus as a defining element of the familial multiple atypical mole melanoma syndrome The B-K mole syndrome.1 Dysplastic nevus, also referred to as atypical nevus or Clarks nevus, is an acquired mole that may be solitary or multiple. The incidence of dysplastic nevi is about 5-10% in Caucasians.2 They are significant because of their inherent risk of transformation to malignant melanoma and also because someone with a dysplastic nevus is considered to have an increased lifetime risk for melanoma at other sites (the magnitude of which is related to total number of moles and family history among other factors).3 Clinically and histologically, dysplastic nevi show intermediate features between common nevi and malignant melanoma. Histologically, there is a spectrum ranging from lesions that show mild and incomplete dysplastic changes and are difficult to separate from banal nevi to lesions with severe atypia that are hard to differentiate from melanomas. Most dysplastic nevi, however, can be reliably differentiated from banal nevi and from melanoma with current pathologic criteria. Molecular studies suggest that dysplastic nevi represent intermediate lesional steps in the progression to melanoma.4
Clinical features
Dysplastic nevi usually appear in adolescence, most commonly on the back, chest, abdomen, buttocks, and scalp. They tend to be larger
Case 11
than ordinary nevi, usually measuring from 5-12 mm.3 Patients with familial dysplastic nevus syndrome often have smaller lesions showing the classic dysplastic histology. Dysplastic nevi display a macular component with ill defined, irregular border, sometimes surrounding an elevated darker papular center; they often reveal a pebbled surface. Unlike common nevi, they are colored in varying shades of tan and brown.3 With dermoscopy (epiluminiscence microscopy), dysplastic nevi usually show a broken network, a pattern characterized by patchy interruptions in the pigment network.
Histopathological features
Dysplastic nevi reveal a reproducible histology with a characteristic pattern on scanning magnification. The constellation of histologic features in dysplastic nevi, encompasses two basic components: architecture and cytology. A panel of experts agreed upon a set of criteria for the diagnosis of dysplastic melanocytic nevi. Two major and four minor criteria were defined. They proposed that both major criteria and at least two minor criteria should be required for the diagnosis.5 The major criteria are 1) basilar proliferation of atypical melanocytes (that in compound lesions extends at least three rete ridges beyond a dermal component) (Fig. 9), and 2) organization of this proliferation in a lentiginous or epithelioid-cell pattern (Figs. 6-8). Minor criteria are 1) the presence of lamellar fibrosis or concentric eosinophilic fibrosis, 2) telangiectasia and/or vascular proliferation, 3) lymphocytic infiltrates in the papillary dermis, and 4) fusion of rete ridges by confluence of melanocytes nests (Figs. 1-3). The junctional component is usually asymmetrical. The nests of melanocytes at the dermoepidermal junction tend to vary in size, and they are often larger than in banal nevi.6 It is noteworthy to mention that even though bridging of rete ridges is a minor criteria for the diagnosis of dysplastic nevi, confluent bridging involving three or more rete ridges and/or erosion of the dermoepidermal junction are worrisome for melanoma.7 Most authors consider a fundamental criterion the presence of some degree of cytologic atypia in dysplastic nevus.3,6,7 This feature is usually discontinuous and random.3,6,9 The predominant background cell type in most lesions is similar to that of banal nevi (Fig. 9-11).3,6 A two or a three grade system can be used to evaluate cytologic atypia in dysplastic nevi. In the three grade system, cytologic atypia can be classified in mild, moderate and severe (see table) (Figs. 11-15). The two grade system considers low-grade and high-grade dysplasia; moderate and severe cytologic atypia are considered high grade dysplasia.
65
Grading of dysplastic nevi

Parameter Mild Moderate Double the size Severe Double the size or greater Severe Vesicular or less often hyperchromatic Prominent and enlarged Nuclear size Same size compared to keratinocyte nucleus Nuclear pleomorphism Chromatin Mild Hyperchromatic
Moderate Hyperchromatic or vesicular Absent or small
Nucleolus Cytoplasm
Absent or small Usually little but sometimes abundant with dusty pigmentation
Usually little but Often abundant sometimes abundant with dusty pigmentation
Modified from Culpepper et al.7 Although this grading system is mainly cytomorphologic, the architecture of the lesion contributes to the overall assessment of a nevus.7,9 It appears to be a significant correlation between the degree of architectural and cytologic atypia.9 It has been shown that using predetermined criteria, melanocytic dysplasia can be reproducibly graded among diverse general dermatopathologists.8 Some lesions show the full spectrum from mild to severe atypia suggesting a step progression of these lesions. The end point is a monotonous population of atypical melanocytes (uniform cytologic atypia) in one area or throughout the lesion, marking the development of melanoma.3 Pagetoid spread is not a characteristic of dysplastic nevi; however, it may be acceptable when focal and limited to the lower levels of the epidermis (as in the case we chose for this exercise) (Fig. 4). The presence of numerous melanocytes, or the extension into the upper spinous layer, should raise suspicion for melanoma.3,6,7
Differential diagnosis
There are some nevi that show one or a few of the features of dysplastic nevi (e.g. superficial epithelioid cell changes in a younger person, or flexural architecture without the other stromal changes and without cytologic atypia). These lesions may be diagnosed as lentiginous (non-dysplastic) nevi. Lesions that present unusual features and cannot be placed on a specific category, should be managed on an individual basis.3 It is important to keep in mind that congenital nevi and other nevi on special locations (e.g. acral nevi, nevi of genital skin, breast, flexural sites etc.) may show some level of architectural (and sometimes even stromal) overlap with dysplastic nevi without representing true dysplastic nevi. Other differential diagnoses include pigmented and spindle cell variant of Spitzs nevus (Figs. 16-19), recurrent nevus and malignant melanoma (superficial spreading, lentigo maligna and acral melanoma types) (Figs. 20-22).
Case 11
In summary, we have illustrated a case of junctional dysplastic melanocytic nevus showing all the key features of a dysplastic nevus (major and minor criteria). Because the lesion showed moderate cytologic atypia and a few melanocytes above the basal layer, its complete conservative excision was suggested. Usually, we do not include treatment recommendations for mildly atypical dysplastic nevi that focally extend to the margins. For severely dysplastic nevi, we recommend a complete removal with 5 mm margin.
Acknowledgement
Dr Zembowicz supplied the original material upon which this exercise was based.
Figure 6
Figure 7
Figure 6: Figure 7:
Juntional dysplastic melanocytic nevus with a predominant lentiginous pattern. Higher magnification of the lentiginous junctional dysplastic melanocytic nevus illustrating variation in size and shape of melanocytes at the dermoepidermal junction. Lentiginous dysplastic nevi reveal a predominance of single melanocytes randomly disposed along the dermoepidermal junction that shows elongated rete ridges. Melanocytes usually have angulated, hyperchromatic nuclei.
67
Figure 8
Figure 9
Figure 10
Figure 11
Figure 8:
Figure 11:
Junctional dysplastic melanocytic nevus, epithelioid cell variant. Medium power view illustrates the abundant dusty cytoplasm of the epithelioid melanocytes. Epithelioid dysplastic nevi display epithelioid melanocytes arranged as variably sized nests at the dermoepidermal junction. The epidermis may be normal or slightly hyperplastic. The melanocytes have round to oval nuclei and often a variably abundant dusty pale cytoplasm. Compound dysplastic nevus showing a shoulder on the left side. In the garden variety dysplastic nevus, the majority of melanocytes are small and uniform, similar to those seen in banal nevi. There are scattered, mildly atypical melanocytes (discontinuous atypia). Higher power view highlights the presence of a few enlarged melanocytes in the junctional component on this case.
68
Case 11
Figure 12
Figure 13
Figure 14
Figure 15
Dysplastic nevus with moderate cytologic atypia. Some melanocytes with enlarged hyperchromatic nuclei double the size of the keratinocytes. Dysplastic nevus with severe cytologic atypia with a predominant nested pattern. Both, the cytological and architectural parameters show severe atypia. There is confluence of several rete ridges and the lesion is very cellular. The limits with an evolving melanoma in situ can be difficult to demarcate. Even though the high cellularity, no pagetoid spread is seen in this case. Higher power view illustrating the melanocytes with enlarged vesicular nuclei with evident nucleoli. High power of severely atypical melanocytes in a junctional dysplastic nevus. Severely atypical melanocytes are predominantly arranged as single units at the dermoepidermal junction. Juntional dysplastic nevi with severe atypia in which an evolving melanoma in situ is difficult or impossible to rule out can be categorized as SAMPUS or superficial atypical melanocytic proliferations of uncertain significance. If completely excised, the prognosis of these lesions is excellent.
69
Figure 16
Figure 17
Figure 18
Figure 19
Figure 16:
Figure 17:
Pigmented and spindle cell variant of Spitzs nevus (PSCN) can be confused with dysplastic nevi. PSCN tend to be more symmetrical with more uniform melanocytes. In compound lesions, the junctional component is wider than the dermal component, similarly to the shoulders of dysplastic nevi. In addition, PSCN may show patchy lymphocytic infiltrate and some bridging of junctional nests. Unlike dysplastic nevi, nests of melanocytes tend to be vertically oriented. Melanocytes are slightly enlarged and spindle shaped. However, they tend to be more uniform than in dysplastic nevus. Dysplastic nevi may sometimes show spindle shaped melanocytes, especially when showing moderate to severe dysplasia. In dysplastic nevi, this is most likely secondary to prominent bridging and fibroplasia. This example of PSCN nevus has prominent eosinophilic globoid Kamino bodies. Clefting artifact between nests and adjacent keratinocytes tend to be less prominent than in classical Spitzs nevi; however, they may be present as illustrated in this picture.
70
Case 11
Figure 20
Figure 21
Figure 22
Figure 20:
Low power view of a lentigo maligna (melanoma in situ). These lesions can histologically simulate dysplastic nevi. However, they are usually larger and more asymmetrical and atypical. There is confluence of atypical melanocytes at the dermoepidermal junction that follows the epithelium of adnexal structures in this case. Dysplastic nevi can also follow the epithelium of adnexal structures, this feature however, tend to be more prominent in lentigo maligna. Lentigo maligna almost always occur in sun-damaged skin; note the solar elastosis in the dermis. The rete ridges pattern is usually effaced in lentigo maligna. Lentigo maligna with some melanocytes above the basal layer. Pagetoid spread tend to be less prominent in this melanoma than in other melanoma variants. Severely atypical melanocytes are present in this case of lentigo maligna.
71
References
1. Clark WH Jr, Reimer RR, Greene M, et al. Origin of familial malignant melanomas from heritable melanocytic lesions. The B-K mole syndrome. Arch Dermatol 1978; 114:732-8. Nordlund JJ, Kirkwood J, Forget BM, et al. Demographic study of clinically atypical (dysplastic) nevi in patients with melanoma and comparison subjects. Cancer Res 1985; 45:1855-61. Elder DE, Murphy GF. Melanocytic tumors of the skin. Atlas of Tumor Pathology AFIP. Third Series, 1991. Hussein MR, Wood GS. Molecular aspects of melanocytic dysplastic nevi. J Mol Diagn 2002; 4:71-80. Clemente C, Cochran AJ, Elder DE, et al. Histopathologic diagnosis of dysplastic nevi: concordance among pathologists convened by the World Health Organization Melanoma Programme. Hum Pathol 1991; 22:313-9. Murphy GF, Mihm MC Jr. Recognition and evaluation of cytological dysplasia in acquired melanocytic nevi. Hum Pathol 1999; 30:506-12. Culpepper KS, Granter SR, McKee PH. My approach to atypical melanocytic lesions. J Clin Pathol 2004; 57:1121-31. Weinstock MA, Barnhill RL, Rhodes AR, et al. Reliability of the histopathologic diagnosis of melanocytic dysplasia. The Dysplastic Nevus Panel. Arch Dermatol 1997; 133:953-8. Shea CR, Vollmer RT, Prieto VG. Correlating architectural disorder and cytologic atypia in Clark (dysplastic) melanocytic nevi. Hum Pathol 1999; 30:500-5.
2.
3. 4. 5.
6. 7. 8.
9.
Elsa F. Velazquez
72
CASE 12
Case History
54-year-old woman presented with a small brown slowly-enlarging papule on abdominal skin. A sister had developed a malignant melanoma at age 38.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 1: Figure 2:
Figure 3:
Figure 4:
At scanning magnification, the lesion is relatively symmetrical and predominantly intradermal. Higher magnification of the more superficial portion of the lesion reveals the majority of cells to be epithelioid, with admixed pigmented cells. Nucleoli are focally observed. The deeper portion of the lesion is also composed predominantly of epithelioid cells, although there is the impression of focal maturation at the base. The epithelioid component, however, shows considerable nuclear pleomorphism, with occasional enlarged and hyperchromatic forms. The pigmented cells are interspersed among the dominant epithelioid cell population and are consistent with melanophages.
73
Figure 5
Figure 5:
While focally dramatic atypia is present, mitotic activity is not prominent.
Diagnosis
Melanocytic tumor of uncertain malignant potential (MELTUMP).
Commentary
Melanocytic tumor of uncertain malignant potential (MELTUMP) is a descriptive term for an ill-defined group of predominantly dermal melanocytic tumors that exhibit one or several features indicative of possible malignancy, such as nuclear atypia, macronucleoli, mitotic activity, necrosis, or rarely ulceration, but exhibit these features in number or degree insufficient to justify an outright malignant diagnosis.1-3 Accordingly, one might view this category as having hybrid features between a banal nevus and a vertical growth phase (tumorigenic) melanoma. This is clearly a heterogeneous group of lesions, and accordingly it may include cellular blue nevus with atypia, deep penetrating nevus with atypia, certain combined nevi with atypia, pigmented epithelioid melanocytoma4, atypical Spitz tumors, and any congenital or acquired nevus variant with significant intradermal atypia. Most of the lesions qualifying for a designation of MELTUMP have been seen in consultation, often with a history of slow growth of a blue-black pigmented nodule. The clearest example of a lesion with an uncertain diagnosis is one that has been reviewed by a panel of experts, with equal numbers favoring either a benign or a malignant diagnosis. For such a difficult or impossible diagnostic problem (based upon diligent application of existing criteria by eminently qualified observers), the descriptive diagnosis of uncertain is clearly the only correct interpretation. In this regard, Cerroni and Kerl5 have published an important study wherein six experts reviewed 71 cases of mostly difficult melanocytic tumors, many of which were thick,
74
Case 12
tumorigenic lesions. Although the overall agreement for these difficult cases was approximately 80%, there was substantial disagreement. Ostensibly benign nevi in general, and in particular Spitz nevus variants in adults and nevoid/Spitzean melanomas, accounted for the majority of the disagreement. The existence of cases that elicit balanced disagreement (i.e. three observers with a malignant and three with a benign diagnosis) clearly indicates that the state of the art in histological diagnosis still leaves room for uncertainty in diagnosis. Indeed, in such cases, the only authentic and clinically responsible diagnosis is a descriptive diagnosis, namely melanocytic tumor of uncertain malignant potential. Tumors that we initially have placed in the MELTUMP category had tended to be bulky neoplasms of the order of several millimeters in diameter and thickness, composed of pigmented often spindleshaped cells that have abundant cytoplasm containing relatively finely particulate but sometimes coarse melanin pigment.2 The cells may be arranged in nested clusters, the overall cellularity being relatively low compared to ordinary malignant melanomas. In some lesions, there may be attributes of schwannian differentiation, such as spindle cells surrounding clusters of plumper more epithelioid cells in a pattern reminiscent of neuro-sustentacular cells, or wavy spindle cell fiber bundles similar to patterns observed in neurofibromas. Melanocytic cells may be seen in peripheral nerves, a finding that may also be seen in benign blue nevi and in some Spitz nevi and is not automatically indicative of malignancy. The nuclei are often relatively large and may contain visible eosinophilic or amphophilic nucleoli. There also may be occasional mitoses, but not more than one or a few per section plane. If the rate is greater than 2 mm2, in our experience the diagnosis will usually be melanoma. Moreover, abnormal mitoses are not typically observed (if so, the lesion would likely be termed malignant melanoma). Focal areas of individual-cell necrosis may be present, although there are no areas of confluent geographic necrosis, and most lesions do not spontaneously ulcerate. Although there may be a few enlarged melanocytes or occasional nests in the epidermis, there is no atypical intra-epidermal component that can be construed as a radial growth phase of malignant melanoma of any of the common types. The example presented herein (depicted in Figs. 1-5) is a relatively small lesion. In addition to its size, it also shares with a banal nevus bilateral architectural symmetry. However, cytologically it is composed of variably and highly atypical epithelioid melanocytes. Accordingly, it is best classified as a melanocytic tumor of uncertain malignant potential. By comparison, the lesion depicted in Figures 6-9 is also symmetrical, although it exhibits architectural atypia in the form of an expansile, finger-like projection at its base (as also may cellular blue and deep penetrating nevi). As with the case under discussion, it too shows significant cytologic atypia, including occasional intradermal mitoses (Fig. 9). Other lesions (Figs. 10-14; Fig. 17) may
initially resemble lentiginous compound nevi, replete with cytologic maturation at the base (Fig. 11). Closer inspection, however, will reveal both architectural (Fig. 12) and cytologic abnormalities, even in the small cell deep component, consisting of cellular atypia and mitotic activity (Figs. 13 & 14). Occasionally, ordinary nevi will show only focal areas of intradermal atypia, as depicted in Figures 15 & 16. Because it is not possible to definitively exclude the emergence of a malignant clone within the dermal component of such lesions, they are best regarded in the MELTUMP category. The descriptive diagnosis of MELTUMP is one of exclusion. One must first determine whether a lesion clearly qualifies for a specific designation of one of the many benign melanocytic nevus variants. Next, upon recognition of intradermal atypia that precludes such a wholly benign designation, it must be determined whether a lesion qualifies as one of the recognized subtypes of malignant melanoma. If neither is possible, the designation of MELTUMP should be seriously considered. The concept of MELTUMP allows for patient safety because the recommended therapy for this diagnosis is to apply minimal treatment for melanoma, based on the putative microstage of the tumor (i.e., the microstaging attributes that would have been applied if the lesion had been interpreted as a melanoma). Sentinel node sampling also should be discussed with the patient. This approach has been offered to patients with atypical or biologically uncertain melanocytic tumors in a number of centers6, 7, and some such cases have proven to be associated with lymph node metastases. However, long-term follow-up will be required to determine whether nodal involvement for tumor in the MELTUMP category has the same prognostic implications as for conventional melanoma.
Acknowledgement
I am indebted to Dr. David Elder, whose pioneering work in melanocytic biology has contributed significantly many of the conceptual advances contained herein.
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Case 12
Figure 6
Figure 7
Figure 8
Figure 9
Figure 6: Figure 7:
Figure 8: Figure 9:
This lesion also has a symmetric cross-sectional profile, with a prominent fingerlike endophytic component at the base. Superficial portion of lesion depicted in Figure 6, showing a cellular epithelioid melanocytic neoplasm with foci of nest formation along the dermal-epidermal interface. Scattered melanophages are also present. Variable cytologic atypia is noted at higher magnification, with nuclear enlargement, contour angulation, hyperchromasia, and visible nucleoli. Mitiotic activity (center of the field) is also easily detected.
77
Figure 10
Figure 11
Figure 12
Figure 13
Figure 12:
Figure 13:
This more superficial lesion also gives the initial impression of symmetry, perhaps correlating with an ordinary lentiginous compound nevus. Examination if the superficial component of the lesion depicted in Figure 10 at intermediate magnification reveals apparent maturation from a more epithelioid component to a smaller cell component at the base. While some regions of the dermal-epidermal interface contain irregular nests composed of epithelioid nevic cells, significant high level pagetoid spread or contiguous and continuous lentiginous replacement of the basal cell layer are lacking. Mitotic activity (center of the field), however, is present even in the smaller cell component of the lesion.
78
Case 12
Figure 14
Figure 15
Figure 16
Figure 16:
Here a mitotic figure (slightly to left of center) is detected near the base of the lesion. An epithelioid nodule that formed within an ordinary exophytic dermal nevus from a 48-year-old woman. The cells show nuclear pleomorphism and prominent nucleoli, and occasional mitotic figures were noted. Mib-1 stain from epithelioid nodule depicted in Figure 15. Although the proportion of positive cells is lower than in many melanomas, the number of cells engaged in non-resting phases of the division cycle is more than the cells forming less atypical regions of this nevus.
79
Figure 17: Composite of a melanocytic proliferation regarded as a MELTUMP The top panel shows . overall symmetry, and the middle left, middle central, and lowermost panels at varying magnifications suggest maturation. However, although there is overall symmetry, the individual nests are enlarged and irregular in shape (middle panels to left and center). In addition, the epithelioid compoment is mitotically active (lower panel to left), and shows considerable HMB-45 expression (middle panel to right).
Figure 17
References
1. Elder DE, Elelitsas R, Murphy GF, Xu X: Benign pigmented lesions and malignant melanoma, in Levers Histopathology of the Skin, 9th edition (DE Elder, R Elenitsas, BL Johnson, and GF Murphy, eds.), Philadelphia, Lippincott William & Wilkins, 2005, pp. 785-786. 2. Elder DE and Murphy GF. Atlas of Tumor Pathology: Melanocytic Tumors of the Skin, AFIP Fascicle Series (volume 2, series 3), Armed Forces Institute of Pathology and Universities Associated for Research in Pathology, Washington, D.C., 1991. (Portions of the commentary presented herein was developed in collaboration with Dr. David Elder, and will appear in the forthcoming edition [series 4] of Melanocytic Tumors of the Skin [Elder and Murphy, in press]). 3. Elder DE and Xu X. The approach to the patient with a difficult melanocytic lesion. Pathology 2004; 36:428-434. 4. Zembowicz A, Carney JA, and Mihm MC. Pigmented Epithelioid Melanocytoma: A Low-grade Melanocytic Tumor With Metastatic Potential Indistinguishable From Animaltype Melanoma and Epithelioid Blue Nevus. Am J Surg Pathol 2004; 28:31-40. 5. Cerroni L and Kerl H: Tutorial on melanocytic lesions. Am J Dermatopathol 2001; 23:237-241. 6. Su LD, Fullen DR, Sondak VK, et al. Sentinel lymph node biopsy for patients with problematic Spitzoid melanocytic lesions: a report on 18 patients. Cancer 2003; 97:499507. 7. Kelley SW, Cockerell CJ. Sentinel lymph node biopsy as an adjunct to management of histologically difficult to diagnose melanocytic lesions: a proposal. J Am Acad Dermatol 2000; 42:527-530.
George F. Murphy
80
CASE 13
Case History
46-year-old male presented with an enlarging brown macule involving skin overlying the left shoulder. The patient first became aware of the lesion six months earlier. Clinically, there was a slightly variegated 8 mm brown macule with an irregular border. An excisional biopsy was performed.
Figure 1
Figure 2
Figure 3
At scanning magnification, it is difficult to appreciate a well-defined or potentially atypical lesion. At intermediate magnification, severely atypical epithelioid melanocytes are present singly within the lowermost two-thirds of the epidermal layer. High magnification reveals melanocytes exhibiting variable high-grade atypia scattered singly within the epidermis; contiguous and continuous lentiginous replacement of the basal cell layer, and/or high-level pagetoid spread involving the stratum granulosum, are lacking.
81
Diagnosis
Superficial atypical melanocytic proliferation of uncertain significance (SAMPUS).
Commentary
The need for a gray zone category to designate superficial melanocytic proliferations for which current diagnostic criteria are presently insufficient for outright diagnosis of wholly benign nevus or melanoma is essentially the same as for tumorigenic (vertical growth phase equivalent) melanocytic proliferations (see Case 12 dealing with the concept of MELTUMP). Depending on which criteria are emphasized by different observers, disagreement may emerge as to the precise diagnosis, resulting in uncertainty as to biological behavior of the lesion. Stated differently, melanocytic proliferations that according to present criteria express hybrid features between a wholly benign superficial nevus and a superficial (non-tumorigenic) evolutionary phase of melanoma must be regarded as having uncertain biological potential. This uncertainty is not because the possibility of metastases after complete local excision cannot be ruled out (as is the case for the MELTUMP category), but because the potential for further local growth and progression upon incomplete excision cannot be excluded. Such uncertainty should be communicated clearly and directly to physicians and their patients, and patients should be offered appropriate management options with truly informed consent.1 Accordingly, Superficial Atypical Melanocytic Proliferation of Uncertain Significance (SAMPUS)2 represents the category of nontumorigenic melanocytic proliferations that present superficially (i.e. within the epidermis or in the epidermis and superficial dermis), thus correlating with a worst possible biological scenario of radial growth phase melanoma. Operationally, the term SAMPUS broadly encompasses all significantly atypical melanocytic proliferations that are predominantly junctional or intradermal (usually papillary dermal) without evidence of tumorigenic growth. It should be recognized that such a classification has its detractors, primarily based on the objections that the SAMPUS category is 1) a description, not a precise diagnosis; 2) an acknowledgement of doubt concerning biological behavior; and 3) a descriptor that fails to add to overall understanding of pathogenesis.3 We agree with these comments, although cannot fathom how recognition of a category of lesions that minimizes potential for both overand underdiagnosis, optimizes preventative patient care, and sequesters lesions in a category that facilitates further clinicopathological study is objectionable. Many proliferations in the SAMPUS category are typically lesions where the differential diagnosis lies between melanoma in situ or microinvasive radial-growth-phase melanoma, and a benign simulant such as a junctional or superficial compound dysplastic nevus, a
Case 13
pigmented spindle cell nevus of Reed, a superficial Spitz nevus, or an atypical lentigo. In these situations, tumorigenic proliferation in the dermis is not present, and the prognosis is most favorable, with an exceedingly low (some studies suggesting non-existent) probability of metastatic disease, as long as local control can be achieved. If not excised, however, some such proliferations may persist at the local site and then may have a propensity regrow or recur, and perhaps in time to progress to a more fully malignant stage of melanocytic neoplasia. Until such progression (i.e., to vertical growth phase) occurs, these recurrences (or persistences followed by regrowth) are not associated with competence for metastasis, and are amenable to local control by excision with clear margins.4 Melanocytic lesions in the SAMPUS category are not infrequently signed out as atypical intraepidermal or superficial melanocytic proliferation. However, this term does not adequately convey the potential significance of a differential diagnosis that may include a melanoma. The lesions depicted in Figures 4-6 provide specific examples where the term SAMPUS may be effective. Figure 4, for example, shows a compound nevoid melanocytic proliferation with an infiltrative lymphoid response consistent with halo-like regression. The nested junctional component, however, is characterized by moderate to severe architectural and cytologic atypia, with dyshesive growth and extension down a follicular infundibulum. The lesion shown in Figure 5 is also nevoid, with severe architectural atypia in the form of irregular and expansile junctional nests formed by small nevomelanocytes containing hyperchromatic nuclei. Finally, Figure 6 depicts a predominantly lentiginous proliferation of atypical melanocytes that approach continuous and contiguous replacement of the basal cell layer. All of these lesions are regarded as high-grade dysplasias, and all should be completely excised in a manner to insure against local recurrence and the possibility of further progression. All therefore qualify in the SAMPUS category. Figure 7 consists of a predominantly junctional dysplastic nevus. However, the bordering epidermal layer (Fig. 8) shows single cell proliferation in lentiginous and lowlevel pagetoid array by melanocytic cells exhibiting high-grade cytologic atypia. Occasionally the architectural pattern of such single cell and sometimes nested melanocytic proliferations is even better appreciated by the use of correlative MART-1 immunohistochemistry (Figs. 9a & 9b). In such dysplastic nevi, if there is no high-level (involving stratum granulosum) and/or extensive (i.e., > approximately 1 high-power field or greater in width) pagetoid proliferation, no extensive continuous/contiguous basal proliferation, no high-grade and uniform cytologic atypia, and no mitotic activity in these foci, such lesions may be interpreted descriptively as Superficial atypical melanocytic proliferation of uncertain significance, see note. In a note one could add that while a diagnosis of a junctional nevus with moderate to focally severe melanocytic dysplasia is favored, there are focal changes suggestive of evolving melanoma in situ, and this diagnosis
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cannot be ruled out. In addition, sometimes the SAMPUS category may be appropriate to use for an inadequate biopsy, with a recommendation for complete excision to obtain additional diagnostic material. The existence of this uncertainty should be communicated to the patient and treatment options should be discussed with the differential diagnosis taken into consideration. For SAMPUS lesions when the pathologist cannot be entirely certain of adequacy of excision based on the specimen at hand, we recommend re-excision, aiming at a minimum for a clear margin of normal skin around the scar of the biopsy and any residual portion of the lesion. However, many clinicians may choose to apply minimal treatment for melanoma in situ, i.e., a clinical measured margin of 3-5 mm, with clear margins histologically.5,6 This approach should minimize the possibility of under-treatment of an in situ melanoma, which might then recur locally as unequivocal in situ melanoma, or as a more advanced lesion. The concept that melanocytic lesions with hybrid or intermediate histologic features between nevi and melanoma is not new (recall the misunderstood categories of borderline and minimal deviation melanoma) or even unique to skin pathology (consider borderline ovarian neoplasia, for example). In 2000, the notion was formally advanced7 that some melanocytic lesions with significant junctional atypia, albeit dysplastic nevus-like, may be prone to progression to more aggressive forms, and that not all markedly atypical (melanoma-like) melanocytic proliferations conform to the prognostic attributes of conventional melanomas, hence establishing a basis for recognition of biological uncertainty in both tumorigenic and nontumorigenic lesions. Utilization of this concept for gray-zone proliferations, here described under the descriptive category of SAMPUS for superficial non-tumorigenic lesions, as well the related term of MELTUMP (melanocytic tumors of uncertain biological potential) to describe deeper tumorigenic lesions, should permit most accurate physician and patient education within the limits of diagnostic certainty. Such approaches should maximize appropriate therapy, and provide descriptors that will facilitate better understanding of how these lesions may be more precisely described in the context of their specific clinicopathological attributes.
Acknowledgement
I am indebted to Dr. David Elder, whose pioneering work in melanocytic biology has contributed significantly to many of the conceptual advances contained herein.
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Figure 4
Figure 5
Figure 6
Figure 7
Figure 4:
Figure 5:
Figure 6:
Figure 7:
Compound nevoid melanocytic proliferation with halo-like infiltrative lymphoid response. Nested junctional melanocytes show moderate to severe cytologic atypia and marked architectural abnormalities, including dyshesive growth and extension within a follicular infundibulum (extreme right of field). Predominantly junctional melanocytic proliferation from truncal skin of an elderly male. The nevoid architecture is complicated by expansile and somewhat dyshesive nests of small nevomelanocytes exhibiting densely hyperchromatic nuclei. Significant pagetoid spread, and/or contiguous and continuous lentiginous melanocytic proliferation, however, are lacking. Predominantly junctional nevoid melanocytic proliferation from truncal skin of a 35-year-old male. While there are features suggestive of an evolving dysplastic nevus, the atypical junctional melanocytes are focally approaching contiguous/continuous replacement of the epidermal basal cell layer. Predominantly junctional dysplastic nevus, with architecturally irregular nest formation, foci of low-grade cytologic atypia, and characteristic stromal alterations. Close inspection of the adjacent epidermis, however, revealed additional changes (see Fig. 8).
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Figure 8
Figure 9a
Figure 9b
Figure 8:
Figures 9a & 9b:
Epidermis adjacent to lesion described in Figure 7. The single cell proliferation is in lentiginous and low-level pagetoid array and involves foci of high-grade cytologic atypia that extended to the side margins. (a) poorly-formed small nests and low-level pagetoid melanocytes (sparing the stratum granulosum) exhibiting high-grade atypia are observed. MART-1 staining of a deeper level; (b) confirms this profoundly atypical architecture.
References
1. Elder DE and Murphy GF. Atlas of Tumor Pathology: Melanocytic Tumors of the Skin, AFIP Fascicle Series (volume 2, series 3), Armed Forces Institute of Pathology and Universities Associated for Research in Pathology, Washington, D.C., 1991. (Portions of the commentary presented herein was developed in collaboration with Dr. David Elder, and will appear in the forthcoming edition [series 4] of Melanocytic Tumors of the Skin [Elder and Murphy, in press]). 2. Elder DE and Xu X. The approach to the patient with a difficult melanocytic lesion. Pathology 2004; 36:428-434. 3. Ackerman AB, Elish D, Shami S. Spitz nevus: Reassessment critical, revision radical. New York: New York: Ardor Scribendi, 2005. 4. Yu LL and Heenan PJ. The morphological features of locally recurrent melanoma and cutaneous metastases of melanoma. Hum Pathol 1999; 30:551-555. 5. Thorn M, Ponten F, Johansson AM, and Bergstrom R. Rapid increase in diagnosis of cutaneous melanoma in situ in Sweden, 1968-1992. Cancer Detect Prev 1998; 22:430-437. 6. National Institutes of Health: National Institutes of Health Consensus Development Conference Statement on Diagnosis and Treatment of Early Melanoma, January 27-29, 1992. Am J Dermatopathol 1993; 15:34-43.
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7.
Kim JC and Murphy GF. Dysplastic melanocytic nevi and prognostically indeterminate nevomelanomatoid proliferations. Clin Lab Med 2000; 20:691-712.
George F. Murphy
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Notes
CASE 14
Case History
12-year-old boy presented with a darkly pigmented lesion on the arm. Clinical considerations included melanoma and blue nevus. The case was sent for the second opinion consultation.
Figure 1
Figure 2
Figure 3
Figure 4
Figures 1-4:
Darkly pigmented dermal melanocytic tumor associated with epidermal hyperplasia. It is difficult to appreciate cellular detail at low magnification. The center of the lesion is highly cellular. The borders are infiltrative.
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Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figures 5-10:
Higher magnification reveals mixed cellular composition of the lesion. There are blue nevus-like dendritic cells with long cytoplasmic processes but epithelioid nuclei, polygonal darkly pigmented cells and large epithelioid cells with vesicular nuclei, prominent nucleoli and more ample and less pigmented cytoplasm.
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Case 14
Diagnosis
Pigmented epithelioid melanocytoma.
Commentary
Clinical follow-up
The patient underwent wide local excision and sentinel lymph node sampling. Sentinel lymph node contained metastatic deposits (Figs. 11 & 12). Completion lymphadenectomy was performed.
Pigmented epithelioid melanocytoma

We recently proposed the term pigmented epithelioid melanocytoma (PEM)13 for a spectrum of melanocytic tumors previously diagnosed as human animal-type melanoma3,4,7,10 and epithelioid blue nevus (EBN).2 This proposal was based on prospective analysis and follow-up of 41 cases of lesions of suspected animal type melanoma and their comparison to 11 examples of EBN from the original series of Dr Carney.2,15 We concluded that both groups of lesions were either histologically indistinguishable or had considerable histological overlap. PEM is a distinct clinicopathological entity with unique clinical presentation, demographics and histological features. PEM presents as a slowly growing or recently changing pigmented lesion or dermal tumor with blue or blue/gray hue. Some lesions may be ulcerated or associated with epidermal hyperplasia and hyperkeratosis. Clinical differential diagnosis often includes blue nevus, combined nevus or melanoma. It shows a predilection for children, adolescents and young adults but occurs over a broad age range. It frequently occurs in races less susceptible to sun-induced melanoma including Hispanic, African-American, Asian and Persian. PEM has a wide site distribution with occasional involvement of genital and mucosal sites. The current follow-up is still too short to make definitive statement about the long-term prognosis in PEM, but the experience thus far indicates that it has more favorable prognosis than conventional melanoma. PEM is associated lymph node metastases in up to 46% of cases.15 However, distant metastases are rare. Only one patient in our initial cohort experienced distant metastasis to the liver. Remarkably, this patient is doing well more than 3.5 years after resection of the liver tumor.11,15 Importantly, none of Carney complex-associated PEM had clinically aggressive course and 41 sporadic epithelioid blue nevi5,8,9 have not shown aggressive clinical behavior. On the other hand, PEM is not a benign tumor as they can cause the patients death.4 Moreover, several case reports of probable lethal PEM have been reported under names such as pilar neurocristic hamartoma,10 disseminated dermal melanocytosis7 and malignant cellular blue nevus.6 Thus, current experience indicates that PEM is best classified as a low-grade melanoma or borderline melanocytic tumor with metastatic potential.
Most PEMs arise de novo but occasional tumors arise in association with a common compound, dermal or congenital nevus. An example of PEM arising in a nevus is illustrated in Figures 13-20. They are darkly pigmented deep dermal tumors with frequent involvement of subcutis. They tend to be more cellular in the center and show infiltrating growth pattern at the periphery. Similarly to Jadassohn-Tiechetype blue nevi they sometimes extend into deep reticular tissue or subcutaneous fat along adnexal structures or neurovascular bundles. Many lesions abut the epidermis and are associated with epidermal hyperplasia; however some are separated from the epidermis by a Grenz zone of uninvolved papillary dermis. Epithelioid blue nevi are composed of three principal cell types with many intermediate forms. The most abundant are spindled blue nevus-like cells with small to medium sized vesicular nuclei and variably prominent amphophilic or eosinophilic nucleoli. The second cell type has epithelioid features with heavily pigmented cytoplasm, which may obscure nuclei and small to medium-sized nuclei with small eosinophilic nucleoli. It is not clear if these cells are all melanocytic in nature as some have features reminiscent of tumor infiltrating macrophages. The third, less common but the most specific, cell type is a large epithelioid cell that has large vesicular nuclei with prominent nuclear membrane, large eosinophilic macronucleoli and abundant cytoplasm with frequent perinuclear clearing. Melanin granules tend to aggregate at the periphery of the cells sometimes forming a ring at the periphery of the cell. Some large epithelioid cells are multinucleated. PEM vary in degree of cytological atypia. However, at present our experience is insufficient to establish meaningful prognostic indicators or definitive criteria separating metastasizing from benign tumors.13 The difficulty of separating metastasizing from non-metastasizing tumors stems from the fact that we have seen lymph node metastases in cases on the bland end of the spectrum of cytological atypia with no mitotic activity and thickness of only 1.2 mm. Based on our analysis, we suggested that animal-type melanoma and EBN should, at least for the time being, be combined under the same nosological entity of pigmented epithelioid melanocytoma (PEM).13,14 As in other tumors, it is likely that experience with larger number of cases and longer clinical follow-up will eventually enable us to correlate histological features with risk of metastases and further tumor progression or, perhaps, even define malignant and benign PEM as separate entities. Recently, 14 cases of PEM were reported by Antony et al.1 Scolyer et al., also reported experience with 50 cases of PEM from Sydney Melanoma Unit.12 Their experience further supports the idea that PEM is a distinct clinicopathological entity and is best considered as a low-grade melanoma or borderline melanocytic tumor.
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Figure 11
Figure 12
Figure 13
Figure 14
Figure 15
Figure 16
Figures 11 & 12: Figures 13-16:
Sentinel lymph node metastases. Scanning view showing PEM (on the left) arising in association with a compound nevus (on the right) which occurred on the scalp of 27 years old male (a different case). Figure 16 shows high magnification of the area of transition between the nevus and pigmented epithelioid melanocytoma. Arrow points to large epithelioid cell of PEM.
Figure 17
Figure 18
Figure 19
Figure 20
Figures 17-20:
High magnification views of PEM illustrated in Figures 13-16. Figure 17 shows infiltrating periphery of the lesion. Figures 18-20 show cytological features of the lesion. In addition to dendritic and darkly pigmented polygonal cells, there are numerous large epithelioid cells. As in many cases of PEM, large epithelioid cells are multinucleated. They often have little cytoplasmic pigmentation.
References
1. Anthony FC, Sanclemente G, Shaikh H, Telles AS, Calonje E. Animal type melanoma a clinicopathological study of 14 cases.[Article]. Histopathology 2006; 48:754-62. 2. Carney JA, Ferreiro JA. The epithelioid blue nevus. A multicentric familial tumor with important associations, including cardiac myxoma and psammomatous melanotic schwannoma. Am J Surg Pathol 1996; 20:259-72. 3. Crowson AN, Magro CM, Mihm MC. The melanocytic proliferations. Willey-Liss, 2001. 4. Crowson AN, Magro CM, Mihm MC. Malignant melanoma with prominent pigment synthesis: animal type melanoma a clinical and histological study of six cases with a consideration of other melanocytic neoplasms with prominent pigment synthesis. Hum Pathol 1999; 30:543-50. 5. Groben PA, Harvell JD, White WL. Epithelioid blue nevus: neoplasm Sui generis or variation on a theme? Am J Dermatopathol 2000; 22:473-88.
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6. 7. 8.
9. 10.
11.
12. 13.
14. 15.
Hendrickson MR, Ross JC. Neoplasms arising in congenital giant nevi: morphologic study of seven cases and a review of the literature. Am J Surg Pathol 1981; 5:109-35. Levene A. Disseminated mermal melanocytosis terminating in melanoma. A human condition resembling equine melanotic disease. Br J Dermatol 1979; 101:197-205. Moreno C, Requena L, Kutzner H, de la Cruz A, Jaqueti G, Yus ES. Epithelioid blue nevus: a rare variant of blue nevus not always associated with the Carney complex. J Cutan Pathol 2000; 27:218-23. OGrady TC, Barr RJ, Billman G, Cunningham BB. Epithelioid blue nevus occurring in children with no evidence of Carney complex. Am J Dermatopathol 1999; 21:483-6. Pathy AL, Helm TN, Elston D, Bergfeld WF, Tuthill RJ. Malignant melanoma arising in a blue nevus with features of pilar neurocristic hamartoma. J Cutan Pathol 1993; 20:459-64. Richardson SK, Tannous ZS, Mihm MC. Congenital and infantile melanoma: review of the literature and report of an uncommon variant, pigment-synthesizing melanoma. J Am Acad Dermatol 2002; 47:77-90. Scolyer RA, Thompson JF, Warnke K, McCarthy SW. Pigmented epithelioid melanocytoma. Am J Surg Pathol 2004; 28:1114-5. Zembowicz A, Carney JA, Mihm MC. Pigmented epithelioid melanocytoma, a low grade melanoma indistinguishable from animal type melanoma and epithelioid blue nevus. Am J Surg Pathol 2004; 28:31-40. Zembowicz A. What is Pigmented Epithelioid Melanocytoma? [Letter]. Am J Surg Pathol 2005; 29:1119. Zembowicz A, Mihm MC. Dermal dendritic melanocytic proliferations: an update. Histopathology 2004; 45(5):433-51. Review.
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Notes
CASE 15
Case History
he patient was a seven-month-old male born with a giant congenital nevus involving the lower back and buttock area. Within the nevus there was an irregular tan-gray to black nodular area measuring 1.4 cm in greatest dimension. This nodular area was excised to reveal on gross examination a 0.8 x 0.5 x 0.4 cm tan-gray subcutaneous nodule. During the procedure, two enlarged and pigmented groin lymph nodes were also excised.
Figure 1
Figure 2
Figure 3
Figure 4
Figures 1-4:
Scanning magnification view of dermal nodule arising in giant congenital nevus. The nodule is well-demarcated from the surrounding nevus and extends into the subcutaneous tissue.
97
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figures 5-7: Figures 8 & 9:
Intermediate magnification view showing moderate cellularity of the nodule with hyper and hypocellular areas and thick fibrous capsule. High magnification view showing cytological detail of the epithelioid melanocytes forming the nodule. The cells show moderate nuclear pleomorphism, abundant cytoplasm and coarse chromatin. Some cells are multinucleated, with irregular nuclear contours and macronucleoli. There is no mitotic activity.
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Figure 11
Figure 12
Figure 13
Figure 14
The nodule shows more intense staining with MART-1 than the surrounding nevus. Similar results were obtained with HMB-45. Metastatic deposits in a lymph node. The distribution of deposits in the lymph node is indistinguishable from the metastases of a common melanoma with involvement of subcapsular sinuses and interstitium (best visualized on immunohistochemical stains). The melanocytic deposits show limited degree of cytological atypia and are similar to those of the dermal nodule.
Diagnosis
Severely atypical proliferative nodule (borderline lesion) arising in a congenital nevus.
Commentary
This is a very challenging case. Clearly, the main diagnostic issue is whether the lesion represents an atypical proliferating nodule or malignant melanoma arising in a giant congenital nevus. Proliferative nodules, a term used by Reed8, or dermal melanocytic
99
proliferations, a term used by Clark9, are distinct nodular proliferations composed of epithelioid or rarely spindle melanocytes arising in congenital nevi. They may present at birth or develop in early childhood. They can also occur in adults, but in older patients nodular proliferations developing in congenital nevi should always raise suspicion of melanoma. Clinically, proliferative nodules present as black or brown nodules with a usually smooth surface. Ulceration is rare. Sometimes, they can appear polypoid. Palpation may be needed to detect deeply seated nodules. Histologically, proliferative nodules are easy to recognize at low magnification as distinct areas or nodules within or at the periphery of congenital nevi. They tend to be more cellular than the surrounding nevus and, in most cases, the cells forming the nodules are cytologically different from the surrounding nevus cells. Melanocytes forming proliferative nodules can show a spectrum of cytological atypia. They tend to be larger and show more epithelioid features with larger, often vesicular, nuclei and more abundant cytoplasm than the surrounding nevus. However, nodules composed of predominantly small cells can also occur. Reassuring features in proliferative nodules include small size, gradual blending or merging into the surrounding nevus, lack of significant cytological atypia, no or low mitotic activity (less than 2 mitoses per mm2), absence of necrosis and non-destructive growth pattern.1,2 About 20-30 % of proliferative nodules show nuclear hyperchromasia and/or polymorphism and focally increased mitotic activity. These nodules, especially when large in size or sharply demarcated from the surrounding nevus are referred to as atypical and raise histological differential diagnosis of melanoma arising in congenital nevus. Our case falls into this category. The sections show a congenital nevus containing a well circumscribed nodule (Figs. 1-4). The nodule is sharply demarcated from the surrounding nevus by a thick fibrous capsule (Figs. 1-5). The nodule consists of large nests of atypical epithelioid melanocytes within a focally edematous stroma (Figs. 6-9). The worrisome features include diffuse cytologic atypia and pleomorphism (Figs. 7-9), lack of maturation towards the periphery of the nodule and sharp demarcation between the proliferative nodule and the surrounding nevus (Figs. 25). Yet the atypia appears insufficient for an outright diagnosis of melanoma. Reassuring features include modest size of the nodule, pushing rather than expansile growth pattern, moderate cellularity without crowding with hypo and hyper cellular areas; as well as lack of mitoses, tumor necrosis or inflammatory host response. Immunohistochemical stains are not particularly helpful in distinguishing between atypical proliferative nodules and melanoma. Proliferative nodules often stain more strongly with melanocytic differentiation markers such as HMB45, Mart1 and S100 (Fig. 10) than the surrounding nevus. Strong staining with HMB45 can be observed in some melanomas. We would also caution against relying too much on proliferating markers such as Ki67, as both proliferative nodules
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Case 15
and melanoma can show increased nuclear staining with Ki67. In summary, the histological features of this skin biopsy were most consistent with atypical proliferative nodule. When this case presented in 2000, the surgeon noticed pigmentation in inguinal lymph nodes and two lymph nodes were sampled. One of them contained microscopic subcapsular and parenchymal deposits of melanocytes with cytological appearance and immunohistochemical profile similar to those in the dermal proliferative nodule (Figs. 1114).6 While the lymph node deposits show a histological pattern consistent with metastases rather than that of a capsular nevus, there is increasing awareness that in some atypical melanocytic proliferations, such as Spitz tumors11 or pigmented epithelioid melanocytoma,12 regional lymph node deposits may not have as negative prognostic implications as in conventional melanoma. Therefore, given the histological features of the dermal nodule, we were reluctant to designate this lesion as an outright melanoma. The case was signed out as congenital dermal nevus with severely atypical proliferative nodule, borderline lesion with a node indicating that in spite of lymph node deposits, the atypia appears insufficient for an outright diagnosis of melanoma and that it is difficult to make a definitive statement regarding prognosis in this case. No additional surgical treatment was performed at the time of diagnosis. Since then, the child had two more partial excisions of the congenital nevus and has been developing normally without evidence of metastases. Molecular studies indicate that atypical proliferative nodules arising in congenital nevi show frequent numerical chromosomal aberrations and are probably best considered to be clonal neoplasms with genetic instability.13 The pattern of chromosomal abnormalities in atypical proliferative nodules is different from common melanoma or melanoma arising in congenital nevus. Consistent with this idea are studies by Mancianti et al. who cultured cells derived from two atypical proliferative nodules within congenital nevi of two newborn infants. His group showed that when the cells from the atypical proliferative nodules where injected into nude mice, these cells remained viable at the injection site for months, but without tumor production.10 Immunohistochemical study by Herron et al.7 of 30 proliferative nodules from 10 large congenital nevi revealed that atypical proliferative nodules show increased proliferative index with Mib-1 and are associated with higher expression of p53 and bcl-2 proteins, while expression of p21 is reduced. Proliferative nodules also express c-kit. These results give additional support to the idea that atypical proliferative nodules can be considered as distinct low-grade neoplastic proliferations. Xu et al. observed no evidence of malignant behavior in 16 patients with proliferative nodules, including atypical ones, arising in large congenital nevi followed for 11 years.2 While these findings are reassuring, they can not be directly extrapolated in our case, as the lymph
101
nodes in Xu el al. studies were not sampled. Thus, we still remain cautious regarding the long-term prognosis in our patient. In summary, the present data seems to favor a benign course for atypical proliferative nodules arising in congenital nevi. The prognostic significance of lymph node metastasis in atypical proliferative nodules is unknown at the present time. Therefore, lesions like the one described here should be approached with great caution. Yet, it seems unjustified to re-classify the atypical proliferative nodules as an outright melanoma, because of finding of regional lymph node deposits. For comparison, Figures 15-22 show histological sections from a melanoma arising in a congenital nevus in a seven-year-old girl.
Figure 15
Figure 16
Figure 17
Figure 18
Figures 15:
Figures 16: Figures 17 & 18:
Scanning magnification view showing a large expansive infiltrating nodule arising in the deep portion of a congenital nevus. The tumor involves subcutaneous tissue and approaches fascia. Transition between the congenital nevus and melanoma. Superficial portion of the lesion showing small cells of congenital nevus.
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Case 15
Figure 19
Figure 20
Figure 21
Figure 22
Figures 19 & 20:
Figures 21 & 22:
Transition between the nevus (right) and melanoma (left). The melanoma cells are larger than those of the nevus. Figure 20 shows cytological detail of melanoma cells. Melanoma cells show high cellularity and crowding, severe nuclear pleomorphism, hyperchromasia and frequent mitotic activity.
References
1. Tannous ZS, Mihm MC, Sober JA, Duncan LM. Congenital Melanocytic nevi: Clinical and histopathologic features, risk of melanoma, and clinical management. J Am Acad Dermatol 2005; 52(2):197-203. Xu X, Bellucci KSW, Elenitsas R, Elder DE. Cellular nodules in congenital pattern nevi. J Cutan Pathol 2004; 31:153-159. Crowson NA, Magro CM, Mihm MC. The melanocytic proliferations. Canada:WileyLiss Inc., 2001; pp. 209-223. Fontaine D, Parkhill W, Greer W, Walsh. Nevus cells in lymph nodes. Am J Dermatopathol 2002; 24(1):1-5. Holt JB, Sangueza OP Levine EA, Shen P Bergman S, Geisinger KR, Creager AJ. Nodal , , melanocytic nevi in sentinel lymph nodes. Am J Clin Pathol 2004; 121:58-63. Lohmann CM, Iversen K, Jungbluth AA, Berwick M, Busam KJ. Expression of melanocyte differentiation antigens and ki-67 in nodal nevi and comparison of ki-67 expression with metastatic melanoma. Am J Surg Pathol 2002; 26(10):1351-1357.
2. 3. 4. 5. 6.
Herron MD, Vanderhooft SL, Smock K, Zhou H, Leachman SA, Coffin C. Proliferative nodules in congenital melanocytic nevi: a clinicopathologic and immunohistochemical analysis. Am J Surg Pathol 2004; 28(8):1017-1025. 8. Reed RJ, Ichinose H, Clark WH, Mihm MC. Common and uncommon melanocytic nevi and borderline melanomas. Semin Oncol 1975; 2:119-147. 9. Clark WH, Elder DE, Guerry D. The pathogenesis and pathology of dysplastic naevi and malignant melanoma. In Farmer E.R. Hood A.F., eds. Pathology of the skin. East Norwalk, Connecticut: Appleton and Lange, 1990; 684-756. 10. Mancianti ML, Clark WH, Hayes FA, Herlyn M. Malignant melanoma simulants arising in congenital melanocytic nevi do not show experimental evidence for a malignant phenotype. Am J Pathol 1990; 136:817-829.
7.
Norma Rodriguez, Zeina Tannous and Artur Zembowicz
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CASE 16
Case History
n 11-year-old girl presented with a pigmented lesion on her left thigh. A punch biopsy was performed.
Figure 1
Figure 2
Figure 3
Figure 4
Figures 1-3: Figure 4:
Punch biopsy of skin with a dermal melanocytic tumor. There is surface parakeratotic hyperkeratosis and acanthosis probably related to trauma or irritation.
105
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figures 5-7: Figure 8: Figures 9-14:
The lesion consists predominantly of epithelioid cells with admixed more heavily pigmented melanophages. It extends deeply into the dermis around adnexal structures. The lesion consists predominantly of epithelioid cells with admixed more heavily pigmented melanophages.
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Case 16
Figure 11
Figure 12
Figure 13
Figure 14
Figure 15
Figure 16
Figure 16: Figs. 15, 17&18:
There is a minor component of dermal naevus cells of common acquired type. Some cells have smudged degenerate looking nuclei and other cells include intranuclear pseudoinclusions. Some cells have a more elongated appearance. A small amount of pigment is present in a few scattered tumor cells.
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Figure 17
Figure 18
Figure 19
Figure 20
Figure 21
Figure 22
Figures 19 & 20: Figures 21 & 22:
Immunohistochemical staining for S100 shows positivity in the tumor cells. Immunohistochemical staining for HMB45 shows positivity in the tumor cells.
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Case 16
Diagnosis
A diagnosis of combined melanocytic nevus composed predominantly of a deep penetrating nevus with a very small second component of dermal nevus cells was favored. However, in view of the presence of occasional dermal mitoses and the fact that the biopsy did not include the whole lesion, complete excision and reassessment was recommended.
Commentary
Histologic findings
The specimen consisted of a punch biopsy of skin and superficial subcutis. It included part of a dermal melanocytic tumor formed by moderately pleomorphic, plump and spindle shaped cells arranged in loose nests, fascicles and singly. It extended into the deep dermis including around skin appendageal structures. Some cells included intracytoplasmic melanin pigment. A few scattered melanophages and lymphocytes were also present. There were occasional non-atypical dermal mitoses within lesional cells (up to 1 per mm2). The lesion involved the margins. The epidermis showed surface parakeratosis, hyperkeratosis and acanthosis suggestive of irritation or trauma. A small component of dermal nevus cells of common acquired type was also present. No in situ melanoma was found.
Immunohistochemical findings
Immunohistochemical stains (using alkaline phosphatase as a red chromogen) showed that the lesional cells were strongly positive for S100 (nuclear and cytoplasmic staining) and showed moderate cytoplasmic staining for HMB45. The positive staining for both immunomarkers was present within superficial and deep cells with no differential in the intensity of the staining. Less than 2% of lesional cells stained positively for the proliferation marker Ki67. CD68 highlighted the admixed melanophages.
Epilogue
About one month after the original biopsy, the tumor was completely excised and sent to a private pathology laboratory for examination. The reporting pathologist commented that the features sounded similar to the previous biopsy (from reading the report), however, he was concerned by the presence of increased mitotic activity. He therefore sent the case to us for a further opinion. The tumor in the excisional biopsy indeed displayed similar characteristics to those seen in the original punch biopsy, however, an increase in mitotic activity was apparent. This measured up to 4/mm2 and included an occasional atypical mitosis. No in situ melanoma was present. We, too, were concerned by mitotic activity. However, given
the association of the tumor with a healing scar, uncertainty of the possible effect that wound healing may have had on the lesions proliferative activity, absence of other atypical features (such as an in situ component, marked nuclear pleomorphism or expansile dermal growth) and young age of the patient, we did not believe that there was enough evidence for an unequivocal diagnosis of malignancy. Therefore we regarded it as a combined melanocytic lesion that consisted predominantly of an atypical deep penetrating nevus of uncertain malignant potential. It was also suggested that consideration should be given to performing a sentinel lymph node biopsy. A sentinel lymph node, which was removed six weeks later, contained numerous expansile intraparenchymal (rather than intracapsular) nodules of pigmented spindle and plump cells with a similar appearance to that of the cutaneous tumor. No mitoses were identified. A further two of 17 lymph nodes were found to contain tumor in a subsequent completion lymph node dissection specimen. The patient remains alive and well with no evidence of recurrent or metastatic disease 26 months following the sentinel lymphadenectomy.
Final diagnosis
1. Combined melanocytic lesion with a predominant component of atypical deep penetrating nevus associated with nodal metastases. 2. ??deep penetrating nevus-like melanoma.
Discussion
This case raises several important issues: 1. What is a deep penetrating nevus and is it distinct from other melanocytic tumors? 2. Are there atypical features in deep penetrating nevi that suggest malignancy? 3. Pathologists should be very wary when reporting incomplete biopsies (such as punch or shave biopsies) of melanocytic lesions 4. Should pathologists make management recommendations in their reports? 5. What is the role of sentinel lymph node biopsy in the assessment of atypical melanocytic tumors? 6. Does the presence of tumor from a skin primary with pathologic features of uncertain malignant potential in a sentinel node have the same prognostic significance of those from a clear cut melanoma?
Deep penetrating nevus

The term deep penetrating nevus was introduced into the literature by Seab and colleagues when, in 1989, they reported the clinical and pathologic features of 70 pigmented cutaneous melanocytic lesions from the Armed Forces Institute of Pathology.1 They noted that the
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lesions shared some features with blue nevi and Spitz nevi yet were remarkably uniform histologically and have features that clearly distinguish them, in most cases, from other types of nevi. Seab et al. described predominantly dermal lesions with a wedge-shaped architecture with a broad base abutting the epidermis composed of loosely arranged nests or fascicles of pleomorphic pigmented cells that extended into the deep dermis or subcutis.1 The constituent cells varied in size and shape, nuclear pleomorphism at times was prominent, and hyperchromatic nuclei with smudged chromatin and intranuclear pseudoinclusions were commonly present. Mitotic activity, however, was inconspicuous. Subsequent reports have noted the presence of occasional mitoses within lesional cells, however, these were not frequent (less than 1 per mm2) or atypical.2-4 Frequent extension around adnexal structures, scattered melano-phages and junctional nests in at least 85% of cases were noted by Seab and colleagues.1 They also stated that some lesions described as combined nevus are probably examples of deep penetrating nevus.1 In 1991, Pulitzer and colleagues reported a series of 95 melanocytic nevi that showed a mixture of nevus cell types.5 The authors noted that the commonest variant of combined nevus in their series included cells that resembled those of deep penetrating nevus and therefore suggested that a deep penetrating nevus is a monomorphic variant of the common combined nevus.5 They preferred using this terminology rather than the new term deep penetrating nevus as it predated the description of deep penetrating nevus. Also in 1991, Barnhill and coworkers reported 26 somewhat similar tumors under the term plexiform spindle cell nevus to highlight their frequent plexiform architecture and the observation that not all tumors extended deeply into the reticular dermis or subcutis.6,7 Cooper reported a series of 41 deep penetrating nevi in 1992 and again noted the frequent association of deep penetrating nevus with a conventional nevus (i.e. a combined nevus).2 Other series of deep penetrating nevi include 14 cases reported by Mehregan and Mehregan in 19933 and Robson and colleagues recent series of 31 cases reported in 2003.4 In 2004, Scolyer et al.8 reported the clinical and pathologic features of 182 combined nevi, the largest series report in the literature to date. A deep penetrating nevus was a component of 62% of the cases in this study. Others lesions which may represent combined nevi that include a component of deep penetrating nevus cells have been reported under a variety of alternative names including clonal nevus,9 inverted type A nevus,10 atypical dermal nodule in benign melanocytic nevus11 and melanocytic nevus with focal atypical epithelioid cell component.12 By immunohistochemistry, most of the cells in deep penetrating nevi are positive for S100 and HMB45. The concept of what exactly is a deep penetrating nevus and how to distinguish it from other types of nevi is not uniformly agreed upon in the literature. The main issues are, firstly, whether deep penetrat-
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ing nevi have sufficiently different morphologic features to distinguish them from other types of nevi such as blue nevi and Spitz nevi and, secondly, whether deep penetrating nevus is the same entity as combined nevus?
Is deep penetrating nevus a distinct entity?

Deep penetrating nevi share histological features with blue nevi and Spitz nevi. Features in common with blue nevi include deep extension, associated stromal sclerosis, plump cells showing overlapping features with epithelioid blue nevi, pigmentation and HMB45 positivity.13 Like Spitz nevus, the cells of deep penetrating nevus may have an enlarged epithelioid or spindle shape, enlarged nuclei and nuclear pseudoinclusions.13 However, Spitz nevus cells are negative for HMB45. The overlapping morphologies are probably the phenotypic expression of a common neurocristic phenotype5 and therefore it is not surprising that these melanocytic tumors may display overlapping features. However, we believe that the morphologic features of deep penetrating nevi, as described above, are sufficiently distinctive to allow their recognition in most cases. The most characteristic feature of deep penetrating nevus at low power is its inverted wedge shaped architecture from which it derives its name, however, it also has characteristic cytomorphology. This may result in the recognition of superficial variants that have been described under the oxymoron, superficial variant of deep penetrating nevus. Groben and colleagues highlighted the similarity and overlapping features of some examples of deep penetrating nevus and epithelioid blue nevus.14 In some cases, the morphologic features may be such that it is difficult to classify it as a deep penetrating nevus or another nevus variant. Despite such difficulties, it is perhaps not clinically important whether a lesion is classified as a deep penetrating nevus or another type of nevus, as long as it is recognized as a nevus and not misdiagnosed as melanoma. Crowson, Magro and Mihm state in their text book that there are two variants of deep penetrating nevus, one with an epithelioid cell morphology (that may also have been termed clonal nevus,9 inverted type A nevus,10 atypical dermal nodule in benign melanocytic nevus11 and melanocytic nevus with focal atypical epithelioid cell component10) and the other with spindle cell morphology (that has been termed inverted or plexiform spindle cell nevus).9
Are deep penetrating nevus and combined nevus the same entity?
Some authors have used the terms deep penetrating nevus and combined nevus interchangeably, most acknowledging that a second distinct cell population is present in most cases of deep penetrating nevus.1,2,4 Some authors state that they reserve the diagnosis of combined nevus simply for tumors that have significant proportions of two or more kinds of nevi without stating what percentage they
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require to make this diagnosis.4 In our view, the term combined nevus should be applied to lesions with two or more distinct types of nevus cells in a given lesion irrespective of the percentage of each component.8 While deep penetrating nevi represent the second commonest constituent component nevus of combined nevi,8 most but not all examples of deep penetrating nevus are associated with a second discrete type of nevus. Hence it appears logical to apply the term deep penetrating nevus to monophasic tumors and combined nevus to those composed of two populations of nevus cells. In the latter instance the constituent component nevi present that make up the combined nevus should be described.
1. Pigmented epithelioid melanocytoma
The presence of melanocytic tumors in humans that appear similar to those occurring in old grey horses were first recognized over 75 years ago. Such tumors have been termed animal-type melanomas.15 Zembowicz and colleagues recently documented their experience of heavily pigmented melanocytic lesions including so-called animal-type melanomas and epithelioid blue nevi.16 The authors reported overlapping morphological features between animal-type melanoma and epithelioid blue nevus and found that the two tumors were histologically indistinguishable. Regional lymph node sampling in 24 patients with these lesions (including sentinel lymph node (SLN) biopsies performed in 23 patients) revealed metastatic tumor in 11 patients (46%). It was concluded that it was not possible to predict the tumors biologic behavior from its morphologic features. The term pigmented epithelioid melanocytoma (PEM) was therefore proposed as a provisional diagnostic entity to encompass both animal-type melanoma and epithelioid blue nevus. On the basis of their results, Zembowicz et al. suggested that PEM is a unique lowgrade variant of melanoma with frequent lymph node metastases but an indolent clinical course. These tumors are characterized by the presence of a tumorous proliferation of melanocytes with striking pigment synthesis. They consist of tumorous dermal nodules of heavily pigmented epithelioid cells with heavy intracytoplasmic melanin. Marked cytological atypia or mitotic activity is usually absent. There is often associated pseudoepitheliomatous hyperlasia of the overlying epidermis and scattered very heavily pigmented melanophages are usually present adjacent to the lesional cells. The cells at the periphery of the lesion may be more dendritic in shape and be associated with sclerosis of dermal collagen suggesting a relationship to blue nevus. The description of larger numbers of cases with longer follow up is required to further characterise this entity. Although perhaps some may argue that this case could be an example of pigmented epithelioid
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melanocytoma, we distinguish these lesions from deep penetrating nevus on the basis of their more heavy intracytoplasmic pigmentation, less cellular heterogeneity, and expansile growth pattern. In our view, it is likely that pigmented epithelioid melanocytoma, deep penetrating nevus and blue nevus are closely related entities and hence the difficulty in distinguishing and categorizing some cases.17
2. Melanoma
In contrast to deep penetrating nevus, melanoma usually invades the dermis in an irregular fashion and is associated with an in situ melanoma component involving the epidermis, both of which were absent in this case. While the morphologic features of this case are more suggestive of a deep penetrating nevus than a melanoma, the frequent mitotic activity is an atypical feature and in our view makes it impossible to exclude malignancy in the presented case. Such is the phenotypic heterogeneity in melanoma morphology, the presence of the subsequently discovered lymph node metastases suggest that this case may represent a deep penetrating nevus-like variant of melanoma.
3. Cellular blue nevus

Unlike deep penetrating nevus, cellular blue nevus is characterized by nodules of uniform bland, monomorphous fusiform melanocytes with little cytoplasmic pigment. Scattered melanophages are usually present around the periphery of the nodules. They may be dumbbell shaped. Often a component of dendritic melanocytes and associated stromal collagen sclerosis is present.
Features of malignancy in deep penetrating nevi

Features that indicate malignancy in deep penetrating nevi are unclear. It appears that cytological atypia and low mitotic activity do not portend a sinister outcome from the series reported to date.1-5,18, 19 While the case presented in this report displayed many features of a deep penetrating nevus, the cutaneous primary was unusual because it showed more frequent mitotic activity (up to 4/mm2) than is usually present in a deep penetrating nevus. For this reason the case was interpreted as being atypical and of uncertain malignant potential. No case of a metastasizing deep penetrating nevus has been thoroughly documented although Pulitzer and colleagues allude to a case in the discussion section of their report on combined nevi (although the case was not included in their series).5 Despite the lack of histologic criteria for malignancy, for the reasons outlined below, complete excision should be performed on all melanocytic nevi in which any atypical features are present. Deep penetrating nevus is a relatively recently described entity and therefore long term follow up is still not available in most cases in whom this diagnosis has been made, and for this reason it may also be appropriate to completely excise them.
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Pathologists should be wary when reporting incomplete biopsies (such as punch or shave biopsies) of melanocytic lesions
This case well illustrates the potential diagnostic pitfalls that can occur when assessing incomplete biopsies of melanocytic lesions. Pathologic diagnosis of nevi and melanomas requires careful pathologic assessment, knowledge of diagnostic criteria and awareness of potential diagnostic pitfalls, as well as correlation with clinical data.20 The pathologic diagnosis of melanocytic lesions rests on assessment of a range of architectural and cytological features of the lesion, including those at its deep edge and peripheral margin, together with features of the host response, and should be correlated with clinical data, including the age of the patient and the site of the lesion.21 None of these features alone is diagnostic of any particular lesion. For example, both deep penetrating nevi and melanomas may include large epithelioid melanocytic cells and include dermal mitotic activity. The difficulty in diagnosis is compounded when assessing incomplete/subtotal biopsy specimens, such as shave or punch biopsies, as it is not possible to assess some pathologic features such as those at the deep or peripheral margins.22 Some of these features are critical in establishing a diagnosis. Sometimes it is not possible to establish a definite pathologic diagnosis from examining such specimens. A further possible complication resulting from incomplete biopsies is that following incomplete removal, a nevus may regenerate and display pathologic features that are more commonly associated with melanoma.23,24 In the case here reported, the possibility that the dermal mitotic activity present in the complete excision specimen may have been induced by stimulating growth factors produced as part of the repair process initiated by initial punch biopsy must be considered. Regenerating nevi have sometimes been termed pseudomelanomas,23 and the pathologist unaware of this possibility, or oblivious to the clinical scenario or the subtle pathologic clues that should alert him or her to the diagnosis, may incorrectly diagnose such lesions as melanoma. Furthermore, incomplete biopsy specimens may provide unrepresentative sampling of a heterogeneous lesion. For these reasons we agree with Troxels advice that pathologists should be very wary and circumspect when assessing punch or shave biopsies of melanocytic lesions.25 In addition, the presence of a scar in a biopsy specimen should prompt an even more cautious approach, with review of the prior biopsy whenever possible.
Management guidelines for melanocytic tumors of uncertain malignant potential

In some atypical melanocytic lesions that do not display clear cut features of malignancy it is difficult or impossible to exclude a diagnosis of melanoma. Atypical melanocytic lesions that form tumorous nodules in the dermis such as atypical Spitz nevi, atypical cellular blue nevi, atypical deep penetrating nevi, possible naevoid melanomas and so-called pigmented epithelioid melanocytomas are potentially
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capable of metastasising. The lack of diagnostic agreement in the diagnosis of atypical Spitzoid melanocytic tumors, even between pigmented skin pathology experts, and the inability to predict malignancy from pathologic features in some fatal cases have been well documented in a number of recent studies.26,27 The same may be true for deep penetrating nevi with atypical features. Therefore, in difficult cases, the pathologist should state that the biologic potential of the lesion is uncertain. In reporting such cases we recommend that the pathologist record the features for and against a diagnosis of nevus and melanoma and give a favoured or most likely diagnosis.28 Further opinions should also be sought. Such instances should be managed on a case-by-case basis. Complete excision of the lesion is probably mandatory. It is important that the treating clinician and patient are aware of the diagnostic difficulty and therefore informed decisions about management can be made. The safest course of action is undoubtedly to perform local treatment as for a melanoma of equivalent depth. However, this may not always be the most appropriate option. A wide local excision may cause significant cosmetic disfigurement and the patient concerned by this may elect not have the procedure performed. In some centres sentinel node biopsies are also being performed on some patients with atypical melanocytic lesions.29,30 However, this procedure may not be appropriate in selected patients for a number of reasons, including serious medical comorbidities, an inability to perform accurate lymphatic mapping because the initial excision defect has been repaired with a rotation flap or a skin graft, or simply because a lymphoscintigram reveals drainage to multiple node fields, making sentinel node biopsy inappropriate for that patient from a morbidity-risk and cost-benefit point of view.31
What is the role of sentinel lymph node biopsy in the assessment of atypical melanocytic tumors and what is the significance of the presence of nodal metastases?
In melanoma patients, numerous large studies have demonstrated the tumor harbouring status of the sentinel lymph node biopsy is the most important prognostic factor for them. However, there is, to date, no clinical trial evidence that sentinel node biopsy improves survival outcome,32 and although the procedure is generally regarded as minimally invasive, morbidity rates following sentinel node biopsy are probably higher than originally expected. Recently it has been suggested that sentinel node biopsy may be useful in predicting the biological potential of atypical melanocytic tumors such as atypical Spitzoid tumors and so-called animal-type melanomas/epithelioid blue nevi/pigmented epithelioid melanocytomas by indicating whether lymph node involvement is present.16,29,30 If the sentinel node biopsy is used to identify malignant behavior of atypical melanocytic tumors, it must be accepted that true sentinel node intraparenchymal involvement by tumor (i.e. NOT merely nevus cells involving the
Case 16
capsule or intranodal fibrous trabeculae) indicates malignant behavior. Although it has been stated that metastasis unequivocally marks a tumor as malignant33 this is may not necessarily always be the case. Examples of so-called benign metastasizing lesions exist in other fields of pathology. In gynecological pathology it is well recognized that endometriosis or endosalpingiosis may involve lymph nodes and this does not indicate malignancy.34 So-called benign metastasizing leiomyomas and giant cell tumors of bone are other examples of tumors in which the occurrence of metastases do not necessarily indicate malignancy.35-37 It is more controversial in melanocytic pathology whether benign metastases can occur. It is well documented that nevus cells may occur in the fibrous connective tissue of lymph nodes. Benign metastasizing Spitz nevi and benign metastasizing blue nevi where lesional cells have been present in the peripheral sinuses of regional lymph nodes sometimes followed by prolonged survival have been documented in a number of studies.38,39 However, others have questioned the validity of this concept.29 Some authors have cautioned that when a sentinel lymph node from a patient with an atypical melanocytic tumor of uncertain malignant potential is found to harbour metastases the pathologist should not be tempted to revise the diagnosis to melanoma.40 They suggest that when a melanocytic tumor of uncertain malignant potential is found to be associated with regional lymph node metastases, that the metastases should be reported as metastatic melanocytic tumor of uncertain malignant potential. However the case is reported, the prognosis is clearly more guarded than in the absence of such metastases. Although further studies with long follow up will be required to clarify the significance of sentinel node involvement by atypical melanocytic tumors, from a management perspective patients with a positive sentinel node should probably be managed as for a melanoma.
Conclusions
Although it remains unclear whether this case represents an example of an atypical deep penetrating nevus with lymph node involvement or an unusual deep penetrating nevus-like variant of melanoma, given the atypical features in the original biopsy and presence of nodal involvement the patient has been managed as for a melanoma. The documentation of further cases of atypical deep penetrating nevi with longer follow up is required to determine whether there are morphologic features that indicate malignancy in deep penetrating nevi. The use of molecular analysis of atypical cases to determine whether they share chromosomal aberrations that are more commonly seen in nevi or melanomas may also be useful. Despite the difficulties in diagnosis, this unusual case raises many important issues in contemporary melanocytic pathology that should be considered by all those involved in the diagnosis and treatment of patients with these lesions.
Figure 23
Figure 24
Figure 25
Figure 26
Figure 27
Figure 28
CD68 immunohistochemical stain highlights the admixed heavily pigmented macrophages. Excision specimen showing residual tumor adjacent to a scar.
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Figure 29
Figure 30
Figure 31
Figure 32
Figure 33
Figures 28-33:
The tumor cells are large and predominantly epithelioid in shape. Some cells have a more spindled shape. Occasional nuclear pseudoinclusions are present. Admixed heavily pigmented melanophages are seen amongst the tumor cells. Two mitotic figures are present in Figure 31.
Figure 34
Figure 35
Figure 36
Figure 37
Figures 34-37:
Tumor cells within the sentinel lymph node. Note the large epithelioid cells with scattered admixed heavily pigmented melanophages.
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Figure 38
Figure 39
The tumor cells are positive for HMB45. Note the melanophages are negative. The tumor cells are mostly negative for the proliferation marker Ki67.
References
1. 2. 3. 4. Seab JA, Jr., Graham JH, Helwig EB. Deep penetrating nevus. Am J Surg Pathol 1989; 13:39-44. Cooper PH. Deep penetrating (plexiform spindle cell) nevus. A frequent participant in combined nevus. J Cutan Pathol 1992; 19:172-80. Mehregan DA, Mehregan AH. Deep penetrating nevus. Arch Dermatol 1993; 129:328-31. Robson A, Morley-Quante M, Hempel H, McKee PH, Calonje E. Deep penetrating naevus: clinicopathological study of 31 cases with further delineation of histological features allowing distinction from other pigmented benign melanocytic lesions and melanoma. Histopathology 2003; 43:529-37. Pulitzer DR, Martin PC, Cohen AP Reed RJ. Histologic classification of the combined , nevus. Analysis of the variable expression of melanocytic nevi. Am J Surg Pathol 1991; 15:1111-22. Barnhill RL, Mihm MC, Jr., Magro CM. Plexiform spindle cell naevus: a distinctive variant of plexiform melanocytic naevus. Histopathology 1991; 18:243-7. Barnhill RL, Barnhill MA, Berwick M, Mihm MC, Jr. The histologic spectrum of pigmented spindle cell nevus: a review of 120 cases with emphasis on atypical variants. Hum Pathol 1991; 22:52-8. Scolyer RA, Zhuang L, Palmer AA, Thompson JF, McCarthy SW. Combined naevus: a benign lesion frequently misdiagnosed both clinically and pathologically as melanoma. Pathology 2004; 36:419-27. Crowson AN, Magro CM, Mihm MC Jr. The Melanocytic Proliferations: A Comprehensive Textbook of Pigmented Lesions. New York: Wiley-Liss, 2001. Mihm MC, Jr, Googe PB. Problematic Pigmented Lesions. Philadelphia: Lea and Feiger, 1990. Collina G, Deen S, Cliff S, Jackson P Cook MG. Atypical dermal nodules in benign , melanocytic naevi. Histopathology 1997; 31:97-101. Ball NJ, Golitz LE. Melanocytic nevi with focal atypical epithelioid cell components: a review of seventy-three cases. J Am Acad Dermatol 1994; 30:724-9. McCarthy SW, Scolyer RA. Melanocytic lesions of the face: diagnostic pitfalls. Ann Acad Med Singapore 2004; 33:3-14. Groben PA, Harvell JD, White WL. Epithelioid blue nevus: neoplasm Sui generis or variation on a theme? Am J Dermatopathol 2000; 22:473-88.
5.
6. 7.
8.
9. 10. 11. 12. 13. 14.
15. Crowson AN, Magro CM, Mihm MC, Jr. Malignant melanoma with prominent pigment synthesis: animal type melanoma a clinical and histological study of six cases with a consideration of other melanocytic neoplasms with prominent pigment synthesis. Hum Pathol 1999; 30:543-50. 16. Zembowicz A, Carney JA, Mihm MC. Pigmented epithelioid melanocytoma: a lowgrade melanocytic tumor with metastatic potential indistinguishable from animal-type melanoma and epithelioid blue nevus. Am J Surg Pathol 2004; 28:31-40. 17. Scolyer RA, Thompson JF, Warnke K, McCarthy SW. Pigmented epithelioid melanocytoma. Am J Surg Pathol 2004; 28:1114-5; author reply 1115-6. 18. Edwards SL, Blessing K. Problematic pigmented lesions: approach to diagnosis. J Clin Pathol 2000; 53:409-18. 19. Hassan AS, Schulte KW, Ruzicka T, Megahed M. Linear arrangement of multiple deep penetrating nevi: report of first case and review of literature. Arch Dermatol 2003; 139:1608-10. 20. Scolyer RA, McCarthy SW, Elder DE. Frontiers in melanocytic pathology. Pathology 2004; 36:385-6. 21. Crotty KA, Scolyer RA, Li L, Palmer AA, Wang L, McCarthy SW. Spitz naevus versus Spitzoid melanoma: when and how can they be distinguished? Pathology 2002; 34:612. 22. Scolyer RA, Thompson JF, McCarthy SW, Strutton GM, Elder DE. Letters to the editor. Australas J Dermatol 2006; 47:71-3; author reply 74-5. 23. Kornberg R, Ackerman AB. Pseudomelanoma: recurrent melanocytic nevus following partial surgical removal. Arch Dermatol 1975; 111:1588-90. 24. Suster S. Pseudomelanoma. A pathologists perspective. Int J Dermatol 1986; 25:5067. 25. Troxel DB. Pitfalls in the diagnosis of malignant melanoma: findings of a risk management panel study. Am J Surg Pathol 2003; 27:1278-83. 26. Cerroni L, Kerl H. Tutorial on melanocytic lesions. Am J Dermatopathol 2001; 23:23741. 27. Barnhill RL, Argenyi ZB, From L, Glass LF, Maize JC, Mihm MC, Jr., et al. Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. Hum Pathol 1999; 30:513-20. 28. Scolyer RA, Thompson JF, Stretch JR, Sharma R, McCarthy SW. Pathology of melanocytic lesions: new, controversial, and clinically important issues. J Surg Oncol 2004; 86:200-11. 29. Lohmann CM, Coit DG, Brady MS, Berwick M, Busam KJ. Sentinel lymph node biopsy in patients with diagnostically controversial spitzoid melanocytic tumors. Am J Surg Pathol 2002; 26:47-55. 30. Su LD, Fullen DR, Sondak VK, Johnson TM, Lowe L. Sentinel lymph node biopsy for patients with problematic spitzoid melanocytic lesions: a report on 18 patients. Cancer 2003; 97:499-507. 31. Thompson JF, Scolyer RA. Cooperation between surgical oncologists and pathologists: a key element of multidisciplinary care for patients with cancer. Pathology 2004; 36:496-503. 32. Thompson JF, Stretch JR, Uren RF, Ka VS, Scolyer RA. Sentinel node biopsy for melanoma: Where have we been and where are we going? Ann Surg Oncol 2004; 11:147S-51S. 33. Cotran RS, Kumar V, Tucker T. Pathologic basis of disease. Philadelphia: WB Saunders, 1999. 34. Scolyer RA, Carter J, Russell P Aggressive endometriosis: report of a case. Int J Gynecol . Cancer 2000; 10:257-262. 35. Winkler TR, Burr LH, Robinson CL. Benign metastasizing leiomyoma. Ann Thorac Surg 1987; 43:100-1.
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36. Jautzke G, Muller-Ruchholtz E, Thalmann U. Immunohistological detection of estrogen and progesterone receptors in multiple and well differentiated leiomyomatous lung tumors in women with uterine leiomyomas (so-called benign metastasizing leiomyomas). A report on 5 cases. Pathol Res Pract 1996; 192:215-23. 37. Connell D, Munk PL, Lee MJ, OConnell JX, Janzen D, Vu M, et al. Giant cell tumor of bone with selective metastases to mediastinal lymph nodes. Skeletal Radiol 1998; 27:341-5. 38. Smith KJ, Barrett TL, Skelton HG, 3rd, Lupton GP Graham JH. Spindle cell and epithe, lioid cell nevi with atypia and metastasis (malignant Spitz nevus). Am J Surg Pathol 1989; 13:931-9. 39. Rodriguez HA, Ackerman LV. Cellular blue nevus. Clinicopathologic study of forty-five cases. Cancer 1968; 21:393-405. 40. Elder DE, Xu X. The approach to the patient with a difficult melanocytic lesion. Pathology 2004; 36:428-34.
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Notes
CASE 17
Case History
92-year-old female presented to the pigmented lesion clinic with approximately ten scattered 1-5mm darkly pigmented macules on the left lower leg. The patient had a history of 0.85 mm invasive melanoma on the calf in 2003. A local recurrence developed in June 2004 and the patient underwent limb perfusion therapy September 2004. A biopsy was performed and questioned as melanoma vs lentigo vs scar.
Figure 1
Figure 2
Figure 3
Figure 4
Figures 1 & 2:
Broad plaque of dense pigmentation in the upper dermis in association with upper dermal fibrosis. Note the absence of a junctional melanocytic component. (40x, 100x) Cellular detail is obscured by the dense course pigmentation consistent with melanin. (200x) Additional high-power fields demonstrating the presence of occasional cells with bland vesicular nuclei and inconspicuous nucleoli. No nevomelanocytes are seen. (400x)
Figure 5
Figure 6
Figure 7
Figure 8
Diagnosis
Tumoral melanosis.
Commentary
This case illustrates an example of tumoral melanosis (TM). TM is a histological pattern consisting of a plaque-like or nodular accumulation of pigment-laden macrophages in the dermis that clinically presents as a pigmented lesion. TM is a regressive phenomenon secondary to a variety of conditions associated with dermal presence of melanin-containing cells. Most cases are due to regression of a primary cutaneous melanoma or an epidermotropic metastatic melanoma. Different designations have been given in the past to this condition. These include: nodular melanosis, melanophagic dermatitis or melanophagocytosis. The vast majority of cases present clinically as pigmented papules or nodules. Biopsies are most often performed to exclude malignant melanoma. In some cases the patient will have a known melanoma
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and TM presents as a satellite nodule or a distant soft tissue or lymph node metastasis. The histological features of TM are very characteristic. It is characterized by the presence of a broad plaque, nodule or mass of heavily pigmented epithelioid cells localized at different levels of the papillary or reticular dermis (Figs. 1-3). At higher power, it is sometimes difficult to visualize the nuclear features of the pigmented cells without melanin bleaching (Figs. 4-8). When visible, the cells have bland vesicular nuclei with small eosinophilic nucleoli, consistent with the macrophage lineage (Figs. 9-11). Immunohistochemical stains are important to confirm the nature of pigmented cells. By definition, TM does not contain melanocytes. Thus in TM, the pigmented cells are negative for S-100 and, usually, HBM-45. They are positive for macrophage markers such as CD68. Due to the heavy pigmentation, bleached sections sometimes are needed to allow interpretation of peroxidase reaction-based immunohistochemical stains. Alternatively, employing red alkaline phosphatase-detection assays can facilitate the interpretation of immunohistochemical stains. A fully regressed malignant melanoma is the main diagnostic consideration in terms of clinical-pathological significance of the diagnosis of TM. In fact, the majority of published cases and anecdotal textbook comments about TM indicate a strong association with regressed melanoma. Other features supportive of a regressed primary melanoma include vascularized fibroplasia of the papillary dermis and atrophic changes of the overlying epidermis. Regression of a benign dermal melanocytic nevus associated with brisk inflammation and melanophages (halo response) can also result in TM. Often the number and extent of pigmented melanophages is far greater in a regressed melanoma as compared to a regressed nevus. Before rendering the diagnosis of TM, underlying melanoma has to be excluded by extensive sectioning and immunoperoxidase stains, if necessary, as described above. TM should also be distinguished from pigmented epithelioid melanocytoma, a unique low-grade variant of melanoma indistinguishable from epithelioid blue nevus but with frequent lymph node metastases and an indolent clinical course. These typically present in young adults as heavily pigmented dermal melanocytic tumors with infiltrative borders. The low power appearance on H&E stained sections can resemble closely TM. However, bleached sections and immunohistochemical stains confirm the presence of atypical epithelioid cells. It is also important to consider in the differential diagnosis of TM heavily pigmented examples of blue nevi, deep penetrating nevi, and dermal spindle and epithelioid cell nevi. Again, the distinction between these lesions and TM is based on the identification and proper classification of the melanocytic component of the lesions. Rarely, exuberant cases of post-inflammatory hyperpigmentation will enter into the differential diagnosis of TM. The likely primary
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causes include repeated fixed drug reactions, lichenoid drug reactions and lichenoid keratoses. Identification of histological clues suggestive of the primary inflammatory dermatoses and clinical features are helpful in arriving at the correct diagnosis. Importantly, as recently demonstrated by Flax et al., TM can be associated with epithelial neoplasms such as pigmented basal cell carcinoma. It is important to analyze step sections to identify the primary tumor in these cases. Large numbers of melanophages have also been described in pigmented spindle cell nevus of Reed, partially obscuring the junctional melanocytic component. We have also recently seen TM in association with a giant congenital nevus. It is also essential to distinguish other forms of cutaneous nodular pigment deposition, such as those associated with tattoo, especially when associated with foreign body reaction, pigmentary reactions to drugs such as minocycline or plaquenil, systemic or localized ochronosis. The differential diagnosis in these cases is based on the identification of the nature of the pigment. Cases of true TM are often managed as regressed melanomas. Careful follow-up including oncological evaluation should be considered until the primary cause of TM can be identified or excluded. In patients with a known primary melanoma, the appearance of new nodules of TM is often interpreted as regressed metastases, with appropriate consequence for staging and treatment of the disease.
Figure 9
Figure 10
Figures 9-11:
Melanin bleached sections demonstrating the presence of macrophages and absence of nevomelanocytes. (100x, 200x, 400x)
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Case 17
Figure 11
References
1. 2. 3. 4. 5. Pierard GE. Melanophagic dermatitis and panniculitis. A condition revealing an occult metastatic malignant melanoma. Am J Dermatopathol 1988; 10(2):133-6. Barr RJ, White FM, Liao SY. Tumoral melanophagocytosis: A rare and confusing pattern of regressed melanoma (Abstract P). J Cutan Pathol 1990; 17:278. Barr RJ. The many faces of completely regressed malignant melanoma. Pathology (Phila). 1994; 2(2):359-70. Kossard S. A blue-black macule of recent onset (tumoral melanosis). Australas J Dermatol 1996; 37(4):215-7. Zembowicz A, Carney JA, Mihm MC. Pigmented epithelioid melanocytoma: a lowgrade melanocytic tumor with metastatic potential indistinguishable from animal-type melanoma and epithelioid blue nevus. Am J Surg Pathol 2004 Jan; 28(1):31-40. Flax SH, Skelton HG, Smith KJ, Lupton GP Nodular melanosis due to epithelial neo. plasms: a finding not restricted to regressed melanomas. Am J Dermatopathol 1998; 20(2):118-22. Celleno L, Massi G. A variant of junctional naevus of epithelioid and spindle cell type rich in melanophages. Acta Derm Venereol 2002; 82:456-59.
6.
7.
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Notes
CASE 18
Case History
44-year-old male had left axillary lymph node mapping and sentinel node sampling subsequent to a diagnosis of a nodular melanoma, level IV (1.27 mm) that drained to this nodal chain.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 1: Figure 2: Figure 3: Figure 4:
Low magnification of the biopsied lymph node reveals apparent focal expansion and replacement of the capsule. Intermediate magnification confirms that cells are infiltrating the fibrous tissue that forms the now expanded lymph node capsule. At still higher magnification, the cells infiltrating the capsular collagenous matrix appear bland and nevic in cytologic character. Close inspection at maximal magnification reveals nuclear pleomorphism and contour angulation in many of the infiltrating cells, as well as occasional mitoses (center of field). Comparison of this cytology with the patients primary melanoma confirmed the correct diagnosis.
Diagnosis
Micrometastatic melanoma, with prominent involvement of lymph node capsule mimicking nevus cell rest.
Commentary
In recent years, the pathologist has played an increasingly important role in the care and therapy of melanoma patients by virtue of evaluating sentinel lymph nodes.1 By definition, the sentinel node is the first to receive products and cells carried from the drainage path of the primary tumor. In general, if the sentinel node is negative for melanoma, other nodes in the lymphatic chain are also likely to be negative.2 At most centers, sections are stained with hematoxylin and eosin and by immunohistochemistry with antibodies directed to tumor-associated markers (S100, as well as HMB-45 and/or MelanA/MART-1). At some institutions, multiple levels are evaluated. In addition, there is active inquiry into whether molecular diagnostic approaches utilizing PCR technology can enhance sensitivity of detection while maintaining sufficient specificity to minimize false positive results.1 One of the most common problems in the evaluation of sentinel lymph nodes for metastatic melanoma is represented by nevus cell rests. Current dogma indicates that such nodal rests derive from cells deposited embryologically during neural crest migration. However, in some cases, such rests may relate to nevi, including congenital nevi, involving skin drained by the involved nodes.3 Interestingly, nodal nevi from lymph nodes draining cutaneous nevi appear to be more frequent in patients with melanoma, particularly when congenital features are present in the cutaneous nevi. Moreover, such nodal nevi tend to occur preferentially in sentinel nodes (rather than randomly throughout the lymph node chain), raising the possibility of their mechanical transport from a primary cutaneous nevus. In addition, not all nodal nevic rests are confined to the capsule, and intraparenchymal and intralymphatic localization has been described.4 Nevus cell rests in lymph nodes may also dissect down the fibrous trabelculae that penetrate the nodal parenchyma or bulge into capsular vessels, producing intraparenchymal or intravascular mimicry. Accordingly, the banal cytologic characteristics of nodal nevus cell rests are critical to their differentiation from micrometastatic melanoma. These rests usually lack cytologic atypia and mitoses, and are usually HMB45 and Ki-67 negative5, although they may be positive for p16, a tumor suppressor gene that is less likely to be expressed in melanoma cells.6 Moreover, we have personally seen examples where clear-cut nodal nevus cells express HMB-45. The case presently under discussion further explores the problems inherent in accurate pathological assessment of sentinel lymph nodes for micrometastatic melanoma. Figures 1-3 demonstrate unequivocal
Case 18
involvement of the lymph node capsule by aggregated melanocytic cells. In particular, these cells clearly infiltrate among the collagen bundles that form the capsular matrix. Moreover, and particularly emphasized in Figure 3, these cells are generally bland cytologically. S100 and Mart-1 stains confirmed melanocytic lineage, but did not assist in a diagnostic assignment of benign or malignant. Review of the patients primary melanoma, however, was most revealing in that a significant portion of the vertical growth component had a similarly bland cytologic appearance (yet was clearly malignant based on architecture and mitotic activity). This prompted even closer scrutiny of the capsular deposit (Fig. 4). Note that while the infiltrating cells are considerably more bland than many metastatic melanoma deposits, there is diffuse and uniform atypia, particularly with respect to irregularities in nuclear contour. Note also the mitotic figure in the center of this high power field. In aggregate, the diagnosis is micrometastatic melanoma with an unusual intracapsular location, not a benign nevus cell rest. Some (of many) other challenges that may be encountered in pathological examination of sentinel nodes are depicted in Figures 5-16. The case presented in Figures 5-8 involved a large maximal uptake sentinel node (Fig. 5) that was entirely negative form metastasis, and a smaller, lower uptake node sentinel node (Fig. 6, same magnification as Fig. 5) that was negative except for a relatively inconspicuous plug of tumor within a small vessel situated within a fibrous trabecula that had penetrated into the nodal parenchyma (Figs. 7 & 8). Figures 9 & 10 illustrate the problem of a small cell metastasis to a sentinel lymph node, where the malignant cells may initially blend into the lymphoid stroma. While this could represent metastatic small cell melanoma, this sentinel node is from a patient with primary neuroendocrine carcinoma of the skin (note confirmatory cytokeratin stain; Fig. 10). Occasionally metastatic melanoma will show a diffuse, single cell pattern within the lymph node parenchyma (Fig. 11), mimicking the starry sky architecture that may accompany nodal activation (Fig. 12). The relative cell size and atypical cytology of the former should provide the critical clues to this differential. However, intraparenchymal melanoma may at times be so subtle as to require correlative immunohistochemistry to bolster diagnostic certainty (Figs. 13 & 14). Finally, it is always important to diligently comb through the crosssectional profiles of sentinel nodes, as occasional micrometastases may be manifested as one or several malignant cells amongst literally millions of cells forming the node itself (Figs. 15 & 16). The subtlety and diagnostic pitfalls inherent in accurate sentinel node evaluation are daunting, and the optimal technique for sentinel lymph node assessment in patients with melanoma has not been defined. In one recent study employing immunohistochemistry for three markers (S100, HMB 45 and Melan-A), micrometastases were found in 28% of cases and benign nevus inclusions were found in a similar number.7 Melan-A was the most sensitive marker, and HMB45
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labeled 82% of the metastases and 16% of the benign nevi. Micrometastases were detected on the first level in about half of the patients, and the detection rate increasing with the number of sections. Based on these findings, it was concluded that extensive serial sectioning with immunohistochemical analysis substantially increased the histopathologic detection of micrometastases and nevus rests to a level approaching the level reported for molecular techniques. In a similar recent study, it was concluded that obtaining multiple levels of sentinel nodes, coupled with the use of immunohistochemistry, detected additional metastases up to the last levels obtained for evaluation.8,9 It is important to emphasize that regardless of the diligence and sensitivity of detection approaches employed in the evaluation of sentinel lymph nodes for micrometastatic melanoma, it remains to be convincingly demonstrated that this practice enhances overall survival of melanoma patients (reviewed further in reference 9). However, it is a potentially important component of clinical staging. Indeed, some therapeutic and follow-up protocols may be linked to the pathological analyses of sentinel nodes. Whether these strategies will yield overall benefit with respect to patient morbidity and mortality hopefully will be determined by clinical protocols now in progress.
Figure 5
Figure 6
Figure 5:
Figure 6:
Relatively large high-uptake sentinel node from melanoma patient. Numerous levels and immunohistochemical stains failed to reveal micrometastases in this node. Considerably smaller, low-uptake sentinel node also removed from patient described in Figure 5 (identical magnification).
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Figure 7
Figure 8
Figure 9
Figure 10
Figure 10:
This smaller node (profile depicted in Fig. 6) harbored an intravascular micrometastasis confined to a lumen within a solitary fibrous trabecula. MART-1 stain of the micrometastasis seen at slightly lower magnification in Figure 7. Small cell metastasis to sentinel node. The thin rim of small malignant cells directly beneath the capsule resembles enlarged lymphocytes. The differential includes small cell melanoma as well as small cell carcinoma. Immunohistochemistry of the region depicted in Figure 9 confirms the micrometastasis (here a cytokeratin stain, indicating involvement by a known primary neuroendocrine carcinoma of the skin [Merkel cell carcinoma]).
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Figure 11
Figure 12
Figure 13
Figure 14
Figure 13:
Figure 14:
Diffuse single cell parenchymal pattern of metastatic melanoma to a sentinel node. The pattern depicted in Figure 11 must not be confused with a starry sky pattern of histiocytic and endothelial proliferation, seen here (note that this figure is 2x the magnification of Figure 11, and thus the cells in question in Figure 11 were considerably larger than histiocytes). Subtle intraparenchymal pattern of metastatic melanoma to sentinel lymph node. The conventionally-stained levels only disclosed occasional enlarged and somewhat atypical histiocytoid cells beneath the lymph node capsule. MART-1 stain of slightly deeper region to that depicted in Figure 13 confirmed numerous metastatic melanoma cells within the subcapsular lymph node parenchyma.
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Case 18
Figure 15
Figure 16
High magnification of subcapsular parenchyma similar to that depicted in Figure 13 showing isolated malignant melanocyte. Sentinel lymph node assigned positive as a result of detection of only several malignant cells in a solitary subcapsular sinus. Even though the deeper levels obtained for immunohistochemistry failed to reveal positive cells, this histology is sufficient for a diagnosis of early node involvement.
References
1. Cochran AJ, Huang RR, Guo J, and Wen DR. Current practice and future directions in pathology and laboratory evaluation of the sentinel node. Ann Surg Oncol 2001; 8:13S-17S. Morton DL, Wen D-R, Wong JH, Economou JS, Cagle LA, Storm FK, Foshag LJ, and Cochran AJ. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992; 127:392-399. Holt JB, Sangueza OP Levine EA, Shen P Bergman S, Geisinger KR, and Creager AJ: , , Nodal melanocytic nevi in sentinel lymph nodes. Correlation with melanoma-associated cutaneous nevi. Am J Clin Pathol 2004; 121:58-63. Subramony C, lewin JR. Nevus cells within lymph nodes. Possible metastasis from a benign intradermal nevus. Am J Clin Pathol 1985; 84:220-223. Yan S and Brennick JB: False-positive rate of the immunoperoxidase stains for MART1/MelanA in lymph nodes. Am J Surg Pathol 2004; 28:596-600. Lohmann CM, Iversen K, Jungbluth AA, Berwick M, and Busam KJ: Expression of melanocyte differentiation antigens and ki-67 in nodal nevi and comparison of ki-67 expression with metastatic melanoma. Am J Surg Pathol 2002; 26:1351-1357. Abrahamsen HN, Hamilton-Dutoit SJ, Larsen J, and Steiniche T: Sentinel lymph nodes in malignant melanoma: extended histopathologic evaluation improves diagnostic precision. Cancer 2004; 100:1683-1691. Gietema HA, Vuylsteke RJ, de Jonge IA, van Leeuwen PA, Molenkamp BG, van dS, Jr., Meijer S, and Van Diest PJ. Sentinel lymph node investigation in melanoma: detailed analysis of the yield from step sectioning and immunohistochemistry. J Clin Pathol 2004; 57:618-620. Elder DE and Murphy GF. Atlas of Tumor Pathology: Melanocytic Tumors of the Skin, AFIP Fascicle Series, Armed Forces Institute of Pathology and Universities Associated for Research in Pathology, Washington, D.C., (series 4; in press).
2.
3.
4. 5. 6.
7.
8.
9.
George F. Murphy
Notes
CASE 19
Case History
23-year-old female presented to her dermatologist for evaluation of a small, pigmented lesion located on her right inner arm. A biopsy was performed to rule out suspected lentigo.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 1:
Figure 2:
Figure 3: Figure 4:
Low power scanning magnification demonstrates a relatively, well-preserved dermal-epidermal junction architecture and is notable for a lack of significant solar elastosis. Mid-power magnification reveals a melanocytic proliferation consisting predominantly of small to medium sized melanocytes located above the basal cell layer (floating) in the epidermis. Mid-power magnification reveals a lentiginous and nested intraepidermal melanocytic proliferation consisting of small, mildly atypical melanocytes. This focus demonstrates numerous melanocytes floating within the epidermis as single cells in conjunction with a lentiginous growth pattern.
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Figure 5
Figure 6
Figure 7
Figure 8
Figure 5:
Figure 6:
In rare foci, the mildly atypical melanocytes form small intraepidermal nests composed of 3-5 cells. Note the relative architectural preservation of the dermal-epidermal junction. In some foci, there is a higher concentration of junctional melanocytes. Note the regular spacing of the rete ridges and the lack of papillary dermal fibroplasia.
Figure 9
Figures 7 & 8:
Figure 9:
Additional foci demonstrating a predominantly lentiginous growth pattern with focal nesting of mild to moderately atypical epithelioid melanocytes and singlecell pagetoid spread into the mid to upper levels of the epidermis. On high power magnification, the melanocytes are epithelioid and mildly enlarged with slightly darker staining nuclei.
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Case 19
Diagnosis
Lentiginous melanoma in situ.
Commentary
This case illustrates an example of lentiginous melanoma, a recently described clinicopathological entity (King et al., Davis & Zembowicz) which can be difficult to distinguish from lentigo and lentiginous nevus. Lentiginous melanoma is characterized by an intraepidermal proliferation of mild to moderately atypical melanocytes in a lentiginous and focally nested architectural pattern with single-cell pagetoid spread. Notably, these lesions are not associated with severe solar elastosis, papillary dermal fibroplasia, or architectural disruption of the dermal-papillary junction. Lentiginous melanoma presents in a younger population than lentigo maligna and typically occurs on nonsun-exposed areas such as the trunk and proximal extremities. It may take decades for lentiginous melanoma to progress into invasive melanoma (Davis & Zembowicz)
Histological findings
Lentiginous melanoma shows both lentiginous and nested intraepidermal melanocytic proliferations with pagetoid spread of mildly to moderately atypical melanocytes in the absence of significant solar elastosis, epidermal atrophy or architectural alterations at the dermoepidermal junction (Figs. 1-4). The distribution of melanocytes may vary from just slightly more frequent than that of normal dermal melanocytes to focally crowded, single cell proliferations with small nests of 3-5 cells (Figs. 5 & 6). The neoplastic nature of the melanocytes is evident by the prominent degree of pagetoid spread as single cells that seem to float above the basal cell layer and throughout the entire thickness of the epidermis (Figs. 7 & 8). In most cases, these cells are mildly enlarged, with slightly hyperchromatic nuclear staining and may vary from epithelioid to spindled cell morphology (Fig. 9). The degree of cytological atypia varies from case to case, but is never severe and does not approach that which is generally seen in lesions such as lentigo maligna or superficial spreading melanoma in situ. We have developed the following histological criteria for lentiginous melanoma: 1. Single-cell lentiginous growth pattern with focal crowding and nest formation 2. Normal architecture of the dermoepidermal junction and preservation of rete ridges 3. At most, a moderate degree of cytological atypia with nuclei similar in size to those of the surrounding keratinocytes 4. Single-cell pagetoid spread with melanoma cells floating above the basal layer of the epidermis 5. Lack of significant solar elastosis
There is some degree of overlap in the histological features between early lentiginous melanoma and atypical lentiginous nevi. Lentiginous melanoma does not show an altered dermal-epidermal junctional architecture and is associated with limited cytological atypia and junctional nests. One of the key histological clues to making the diagnosis is the presence of intraepidermal single cell pagetoid spread of mild to moderately atypical melanocytes throughout the full thickness of the epidermis (Figs. 7 & 9). Secondly there is often focal crowding of melanocytes (Fig. 8). Failure to recognize lentiginous melanoma may result in unnecessary delay of treatment. Therefore, one should maintain a high index of suspicion in order to diagnose this entity that may eventually progress to invasive melanoma. Lentiginous melanoma may be an analog of lentigo maligna due to the similarity in clinical behavior. Both lesions may persist as an in situ lesion for prolonged periods of time, often approaching decades, before developing into invasive melanoma. We recently described a case of lentiginous melanoma with a documented 16-year clinical history of repeated recurrences before culminating in superficially invasive melanoma (Davis & Zembowicz). Figures 10-13 show the histological evolution of lentiginous melanoma into invasive malignant melanoma in this case. Lentiginous melanoma shares some overlapping histological features with lentigo maligna including a predominantly lentiginous and pagetoid single cell growth pattern with focal nesting. Lentigo maligna tends to show more prominent cytological atypia and is sometimes associated with severely atypical spindled or epithelioid melanocytes that are usually confined to the basal layer of the epidermis. Additionally, lentiginous melanoma does not show the severe solar elastosis that is uniformly present in lentigo maligna. Similar lesions designated de novo intraepidermal epithelioid cell dysplasia have been described in a textbook by Crowson et al. These lesions are characterized by single cell melanocytes in a pagetoid distribution with abortive nest formation and non-severe melanocytic atypia. They postulate this group of lesions may be a precursor of melanoma in situ. Additionally Weedon and Kossard have described similar lesions such as lentiginous dysplastic nevus of the elderly, atypical junctional nevus, evolving melanoma in situ, and premalignant melanosis that may be analogous to lentiginous melanoma.
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Case 19
Figure 10
Figure 11
Figure 12
Figure 13
Figures 10-12:
Figure 13:
Four serial biopsies from the same patient over a period of 16 years without intervening treatment demonstrate the histological evolution of lentiginous melanoma from an early, less cellular stage with mildly atypical melanocytes distributed only slightly more densely compared to normal with rare nests (Fig. 10, biopsy in 1992), to mildly to moderately atypical melanocytes with foci of pagetoid spread (Fig. 11, biopsy in 1995), to more moderately atypical melanocytes with lentiginous and pagetoid growth patterns and small nests of loosely cohesive spindled cell melanocytes (Fig. 12, biopsy in 1999). The lesion illustrated in Figures 10-12 evolved into superficially invasive spindle cell melanoma (0.8 mm, Clarks level II). This biopsy was performed in 2004.
References
1. 2. 3. Crowson AN, Magro CM, Mihm MC. The melanocytic proliferation: a comprehensive textbook of pigmented lesions, 1st ed. New York: Wiley-Liss, 2001. Davis TL, Zembowicz A. Histological evolution of lentiginous melanoma: a report of five new cases. J Cutan Pathol 2006. In press. Farrahi F, Egbert EM, Swetter SM. Histological similarities between lentigo maligna and dysplastic nevus: importance of clinicopathological distinction. J Cutan Pathol 2005; 32:405.
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4. 5. 6. 7.
8.
Flotte TJ, Mihm MC Jr. Lentigo maligna and malignant melanoma in situ, lentigo maligna type. Hum Pathol 1999; 30:533. King R, Page RN, Googe PB, Mihm MC Jr. Lentiginous melanoma:a histologic pattern of melanoma to be distinguished from lentiginous nevus. Mod Pathol 2005; 18:1397. Kossard S. Atypical lentiginous junctional naevi of the elderly and melanoma. Australas J Dermatol 2002; 43:93. Tannous ZS, Lerner LH, Duncan LM, Mihm MC, Flotte TJ. Progression to invasive melanoma from malignant melanoma in situ, lentigo maligna type. Hum Pathol 2000; 31:705. Weedon D. Skin pathology, 2nd ed. New York: Churchill Livingstone, 2002.
Tracy L. Davis and Artur Zembowicz
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CASE 20
Case History
75-year-old female presented with a 6 mm irregular pigmented macule in her right forearm. A shave biopsy of the lesion was performed. The gross description of the specimen was a skin shave with a central 0.8 x 0.6 cm brown-black macule.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 1: Figure 2:
Figure 3:
Figure 4:
Scanning magnification demonstrating a broad pigmented lesion limited to the epidermis and marked solar elastosis. Intermediate magnification showing diminished rete ridges, melanocytes in the basal layer that are confluent with nest formation, and superficial perivascular lymphocytic infiltrate with melanophages. Higher magnification more clearly demonstrates the confluence of the melanocytes, nest formation and solar elastosis. Note the involvement of the hair follicles. Highest magnification illustrating the cytologic atypia of the melanocytes, nest formation, and pagetoid spread. Note the variability of the nuclear features, the enlargement of the melanocytes as compared to the mid-level keratinocytes, and the hyperchromasia of the nuclear chromatin.
Diagnosis
Malignant melanoma in situ, lentigo maligna type.
Commentary
Lentigo maligna is a pigmented lesion that occurs on sun-exposed skin; particularly the head and neck area.1 Less common sites include the trunk, arms and legs. Lentigo maligna occurs almost exclusively in Caucasians, rarely affecting Asians. The incidence of lentigo maligna increases with age starting at 40 years and peaks in the seventh and eighth decades.2 The lesions of lentigo maligna are tan to brown to black macules with irregular borders.1 They may have white areas that correlate with regression.2 Lentigo maligna lesions may sometimes be amelanotic, in which case, they clinically may resemble eczema, superficial basal cell carcinoma, or Bowens disease.4 Lentigo maligna is considered a potential precursor of melanoma4,6 and its behavior may be varied. Clinical manifestations of malignant transformation may be the development of a nodule, papule, or variegation in color within the lesion.4 The malignant transformation of lentigo maligna represents 4-15% of all malignant melanomas and 1026% of head and neck melanomas.2 The most accepted risk factor to develop lentigo maligna is ultraviolet radiation exposure. Other factors include: light skin color and history of severe burns.2 Melanocyte neoplasia has been linked to gene rearrangement in region 10q24-26 of chromosome 10.2 The main clinical differential diagnoses include seborrheic keratosis, solar lentigo and, more commonly spreading pigmented actinic keratosis.2 The immunohistochemistry of lentigo maligna resembles that of other malignant melanomas. It shows various antimelanoma antibodies including S-100 protein, NK1C3, HMB-45 and FKH1; none of which are 100% sensitive or 100% specific for the diagnosis of melanoma. HMB-45 has been shown to be a useful marker; however, this antibody is not specific for melanoma. It has been used in the surgical removal of lentigo maligna to ensure clear margins.2
Lentigo maligna and malignant melanoma in situ, lentigo maligna type

Some authors consider lentigo maligna as a precursor to lentigo maligna melanoma1,3,4,5 whereas others consider it to be malignant melanoma in situ.2 The term lentigo maligna has been traditionally used to represent lesions ranging from atypical melanocytic hyperplasia to melanoma in situ. Flotte and Mihm1 proposed that the lesions termed as lentigo maligna can be subdivided according to their histologic presentations into two categories:
Case 20
1. Lentigo maligna: characterized by atypical melanocytic hyperplasia (Figs. 5-8) 2. Malignant melanoma in situ, lentigo maligna type: with the following characteristics: a) Atypical melanocytic hyperplasia at the dermoepidermal junction (Figs. 9-11) b) Pagetoid spread of atypical melanocytes (Figs. 9 & 10) c) Confluence of melanocytes replacing the basilar region (Fig. 11) d) Nesting of atypical melanocytes1,5 (Fig. 12) Histologically, both lesions show solar elastosis, periadnexal extension of atypical melanocytes (follicular outer root sheath and eccrine duct)2, epidermal atrophy, effacement of the rete ridges1,2 and a dermal infiltrate composed of lymphocytes, and melanophages, and multinucleated melanocytes.2 Lentigo maligna represents those lesions that have melanocytic hyperplasia situated predominantly as single cells at the dermoepidermal junction. These cells have small to moderate quantity of cytoplasm and the nuclei are not larger in size than the surrounding keratinocyte nuclei. There are characteristic variations in nuclear configuration ranging from round to angulated and even rhomboidal shapes. Multinucleated cells may be present. The pagetoid spread is limited, with only few cells located above the basal layer.1 Malignant melanoma in situ, lentigo malignant type, in contrast, show single cells or nests of cells at varying levels of the epidermis (pagetoid spread). The cells show more cytological atypia than in the lentigo maligna lesions. The nuclei are larger and more hyperchromatic. There is confluence of melanocytes replacing the basilar region (at the dermoepidermal junction) and, in some cases, there may be replacement of the basal layer by two layers of melanocytes. The cells, in general, tend to be more uniform than the ones seen in lentigo maligna. The nuclei are frequently similar in size to the surrounding keratinocytes.1
Progression to invasive melanoma from malignant melanoma in situ, lentigo maligna type
Tannous et al.5 suggested a sequential progression from lentigo maligna to melanoma in situ, lentigo maligna type, and then to invasive lentigo maligna melanoma. This is based on the purported belief that progressive genetic and morphologic alterations lead to the development of malignant melanoma. In their cases of invasive malignant melanoma, they found malignant melanoma in situ, lentigo maligna type in the epidermis overlying the invasive tumor. None of the cases had lentigo maligna (atypical melanocytic hyperplasia) overlying the invasive tumor. The authors conclude that this concept needs to be further studied given its therapeutic implications.5 The evolution of lentigo maligna is variable, and ranges from rare
spontaneous regression, to indefinite persistence of lentigo maligna4 Lentigo maligna has an extended intraepidermal phase before it evolves into lentigo maligna melanoma.4 The radial growth phase, or lentigo maligna phase, may last for 5-20 years before the development of lentigo maligna melanoma.2,4 Other studies suggest a 10-50 year period.2 It has been estimated that a patient with lentigo maligna diagnosed at the age of 45 years has a 3.3% risk of developing lentigo malignant melanoma by age 75 years, and a lifetime risk of 4.7%. Diagnosis at 65 years of age gives the patient a 1.2% risk of lentigo maligna melanoma by age 75 and a 2.2% lifetime risk.6 Once a lentigo maligna progresses to lentigo maligna melanoma its prognosis is similar to other types of melanoma and depends on the tumor thickness.4
Treatment
Lentigo maligna has been treated using a variety of modalities including conventional surgery, Mohs micrographic surgery or destructive therapies like cryotherapy, superficial radiotherapy, azelaic acid, electrodessication and curettage, and topical 5-fluorouracil.2,4 The disadvantages of destructive therapies include: Lack of histologic evaluation to rule out lentigo maligna melanoma.2,4 It spares deep adnexal melanocytes, which may cause later recurrence. It fails to destroy atypical melanocytes extending beyond clinical margins.4 All therapies may have recurrences. This is due in part to melanocytes extending several centimeters beyond the clinical margins, and there is a belief that the lesions may be multicentric within a skin region.4 Tannous et al.3 propose, in their study, the use of confocal microscope to eliminate the inherent problem of sampling error. They suggest that this approach may be able to evaluate an entire lesion before biopsy, help establish appropriate clinical margins, and evaluate lesion progression in vivo.3
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Figure 5
Figure 6
Figure 7
Figure 8
Figure 5:
Figure 6:
Figure 7:
Figure 8:
Intermediate magnification of pigmented lesion that we term lentigo maligna. Note the thickened epidermis, loss of rete ridges, and the presence of solar elastosis. There is an increased number of nevomelanocytes at the dermoepidermal junction with occasional cells above the basal layer. Most of the melanocytes show at least moderate atypia. Immunohistochemistry was performed to more clearly identify the number of melanocytes present. Intermediate magnification of pigmented lesion that we term lentigo maligna stained for MART-1. We use a panel of markers to stain melanocytic proliferations but we find that MART-1 is frequently the best stain to delineate melanocytes in the epidermis in lentigo maligna and lentigo maligna melanoma. This is an adjacent section in Figure 5. Note that there are more melanocytes than one might casually observe on H&E stained sections. This approach is particularly helpful in examining margins in some difficult cases. Intermediate magnification of pigmented lesion that we term lentigo maligna. The atypical melanocytic hyperplasia is more apparent in this lesion as compared to the previous lesion, as is the presence of melanocytes above the basal layer. Note the atypical cytologic appearance of the melanocytes. Intermediate magnification of pigmented lesion that we term lentigo maligna stained for MART-1. This is an adjacent section to Figure 7. Note the increased number of melanocytes, yet they are still not confluent nor is there nest formation. There is pagetoid spread but it is generally limited to the lower half of the epidermis. The extension down the adnexal structures is well demonstrated.
Figure 9
Figure 10
Figure 11
Figure 12
Figure 9:
Figure 10:
Figure 11:
Figure 12:
Intermediate magnification of pigmented lesion that we term malignant melanoma in situ, lentigo maligna type. Note the atypical melanocytic involving all layers of the epidermis and the hair follicle. Note the atypical cytologic appearance of the melanocytes. Intermediate magnification of pigmented lesion that we term malignant melanoma in situ, lentigo maligna type stained for MART-1. This is the same lesion as Figure 9. Note the distribution of the melanocytes at all levels of the epidermis (pagetoid spread). Intermediate magnification of pigmented lesion that we term malignant melanoma in situ, lentigo maligna type. Note the atypical melanocytic hyperplasia on the left side of the lesion and confluence of the atypical melanocytes on the right side. Intermediate magnification of pigmented lesion that we term malignant melanoma in situ, lentigo maligna type. Note the atypical melanocytic hyperplasia at all levels of the epidermis (pagetoid spread), involvement of the hair follicle, and the presence of nests of melanocytes in the basal layer.
150
Case 20
References
1. 2. 3. Flotte TJ, Mihm MC. Lentigo maligna and malignant melanoma in situ, lentigo maligna type. Hum Pathol 1999; 30:533-536. Cohen LM. Lentigo maligna and lentigo maligna melanoma. J Am Acad Dermatol 1995; 33:923-36. Tannous ZS, Mihm MC, Flotte TJ, Gonzalez S. In vivo examination of lentigo maligna and malignant melanoma in situ, lentigo maligna type by near-infrared reflectance confocal microscopy: Comparison of in vivo confocal images with histologic sections. J Am Acad Dermatol 2002; 46:260-3. Bevona C, Fewkes J, Liu V, Sober AJ. Prolonged evolution of a lentigo maligna. J Am Acad Dermatol 2004; 51:830-5. Tannous ZS, Lerner LH, Duncan LM, Mihm MC, Flotte TJ. Progression to invasive melanoma from malignant melanoma in situ, lentigo maligna type. Hum Pathol 2000; 31:705-708. Weinstock MA, Sober AJ. The risk of progression of lentigo maligna to lentigo maligna melanoma. Br J Dermatol 1987; 116:303-306.
4. 5.
6.
Gabriela Rolz-Cruz and Thomas J. Flotte
151
Notes
CASE 21
Case History
he patient is a 72-year-old man who presented with a pigmented lesion on the scalp.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 1:
Figure 2:
Figure 3: Figure 4:
At low-power the benign component of the tumor bulges in to subcutaneous fat with a smooth pushing margin. This is a characteristic low-power feature seen in many cellular blue nevi. This photo shows a benign cellular blue nevus component. A mixture of heavily pigmented melanophages, dendritic melanocytes and amelanotic melanocytes is seen. Higher power shows dendritic melanocytes within a background of bland amelanotic cellular blue nevus cells forming fascicles. Detail of cellular blue nevus cells shows uniformly distributed chromatin. Prominent nucleoli are not seen.
153
Figure 5
Figure 6
Figure 7
Figure 8
Figure 5:
The presence of an expansile nodule or nodules within the background of a cellular blue nevus should alert the pathologist to the possibility of melanoma arising in association with a blue nevus. The sheet-like growth pattern is an important clue to a diagnosis of malignant blue nevus. The malignant component is composed of severely atypical cells with prominent nucleoli and irregularly distributed chromatin. Numerous mitoses were seen in the malignant component. Several mitoses are seen in this 40x field. Confluent areas of necrosis are present.
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Case 21
Figure 9
Figure 8:
High power shows interface between viable and necrotic tumor.
Diagnosis
Malignant blue nevus.
Commentary
The term malignant blue nevus has been applied in different ways by various authors. Traditionally, the term is applied to melanomas arising in association with a cellular blue nevus. Less commonly, melanomas may arise in association with common blue nevus and the term malignant blue nevus has been applied to these cases as well. The term has also been applied less restrictively to melanomas that mimic cellular blue nevi yet lack a benign component. Purists might object to such use of the term for these cases but in our experience lesions that are called malignant blue nevus often arise de novo without any associated benign component. When we undertook a multiinstitutional study of malignant blue nevi, it came as a surprise to us, after examining all the cases contributed by the participants, how many cases (that we had filed in our consult archives under the designations malignant cellular blue nevus and malignant blue nevus) lacked a benign component. Our preconception was that most, if not all, of the cases would be associated with a benign cellular blue nevus. Taken together, all of these variants represent extremely rare forms of melanoma and given their rarity it is not surprising that there is uncertainty regarding diagnostic criteria. Only a few dozen cases of malignant blue nevi have been described in the pathology literature. Melanomas arising in association with a pre-existent cellular blue nevus typically show stable size or very slow growth before coming to clinical attention, often due to an increase in size. Malignant blue nevi have a predilection for the scalp. We reported a malignant blue nevus that arose in a congenital lesion in a 69-year-old woman.
Malignant blue nevi in children are very rare, with only a few documented cases. The bulk of the literature indicates malignant blue nevus is an aggressive form of melanoma, no doubt due to its discovery at a late stage. A recent review of the literature showed that 73% patients with follow-up died as a result of metastatic tumor. In our series, all patients for whom follow-up information was available either developed local recurrence or metastasis, or died of disease. In another series, 10 of 12 cases developed metastasis and eight patients died of their disease. Malignant blue nevi show a propensity for metastasis to the lung, liver, and lymph nodes. Two histologic patterns of malignant blue nevus are recognized. Tumors that contain a benign component (such as the unknown submitted for discussion) are usually easily recognized at low-power by the presence of an expansile asymmetric nodule or nodules representing the malignant component. Such nodules show a sheet-like growth pattern with loss of the typical biphasic (dendritic pigmented cells and amelanotic fascicles of melanocytes) or alveolar architecture that is seen in the cellular blue nevus component. Necrosis is often conspicuous. Melanomas that mimic cellular blue nevus but lack a lacking benign blue nevus component are more diagnostically challenging since a striking juxtaposition between benign and malignant components is lacking. Nevertheless, close examination should show at least some of the following features: infiltrative borders; necrosis; frequent mitoses; nuclear pleomorphism and hyperchromasia; and epithelioid cell morphology. We found epithelioid cell morphology particularly helpful in establishing a correct diagnosis. Some authors citing anecdotal evidence from examination of individual cases or small numbers of cases have suggested that widespread necrosis is the most important criteria for distinguishing benign from malignant cellular blue nevus. In our experience and that of others, necrosis is not a very sensitive feature for the diagnosis of malignant blue nevus. In our study, geographic necrosis was present in only two of 10 of cases and focal necrosis was present in one other case. Connelly and Smith found tumor necrosis was present in only three of 12 patients and necrosis was seen in half of the cases reported by Mehregan et al. Another pitfall is mistaking liquefactive degeneration seen in some cellular blue nevi for true tumor necrosis. The presence of significant numbers of mitoses increases the odds that a given lesion represents a malignant melanoma; however, there is insufficient data regarding the significance of rare or occasional mitoses. In our study of malignant blue nevi, half of our cases had two or fewer mitoses per 10 high-powered fields. In the series of 12 cases reported by Connelly and Smith, the mitotic rate was low for all malignant blue nevi, excluding one exceptional case with greater than two mitoses per 10 high-powered fields. To complicate matters, benign cellular blue nevi can have significant mitotic activity. Clearly,
156
Case 21
using mitotic rate as a sole or even major histologic criterion of malignancy is not advisable. Certainly, any cellular blue nevus with mitotic activity should be carefully examined for other features of malignancy. The term atypical cellular blue nevus has been applied to tumors that lack overt histologic features of malignancy but show some atypical findings such as focal areas of cytologic atypia, increased mitoses, or unusual architecture. Follow-up information on significant numbers of tumors classified as atypical cellular blue nevi is not available. Since atypical cellular blue nevus has not been clearly defined and the clinical significance of this lesion is uncertain, we prefer to classify such tumors as having uncertain malignant potential. In evaluation of difficult cases, histologic scrutiny of the entire lesion is strongly encouraged and may be helpful in allowing for a definitive diagnosis. Cases that are difficult to precisely classify as either benign or malignant should generate a report that reflects this uncertainty and the lesion should completely excised with careful patient follow-up. In conclusion, malignant cellular blue nevus is a highly malignant form of melanoma. The term malignant blue nevus has been applied to melanomas arising in association with blue nevi and, less restrictively, to melanomas that mimic blue nevi but lack a benign component. The former shows a nodular or sheet-like growth of malignant epithelioid or spindled cells in association with common or cellular blue nevus. The latter mimics benign cellular blue nevus at lowpower but closer inspection reveals features of malignancy throughout the tumor. These include a combination of at least some of the following features: infiltrative borders, distinctive expansile nodules, pleomorphism, prominent nucleoli, mitoses, and necrosis. All potential cellular blue nevi should be carefully inspected for evidence of malignant change. In particular, careful evaluation of blue nevi of the scalp in older individuals is advised.
References
1. Granter SR, McKee PH, Calonje E, Mihm MC Jr., Busam K. Melanoma associated with blue nevus: A clinicopathologic study of 10 cases on the spectrum of so-called malignant blue nevus. Am J Surg Pathol 2001; 25:316-323. Aloi F, Pich A, Pippione M. Malignant cellular blue nevus: A clinicopathologic study of 6 cases. Dermatology 1996; 192:36-40. Avidor I, Kessler E. Atypical cellular blue nevus-a benign variant of cellular blue nevus. Presentation of 3 cases. Dermatologica 1977; 154:39-44. Boi S, Barbareschi M, Vigl E, Cistofolini M. Malignant cellular blue nevi. Report of 4 new cases and review of the literature. Histol and Histopathol 1991; 6:427-434. Connelly J, Smith JL. Malignant blue nevus. Cancer 1991; 67:2653-2657. Duteille F, Duport G, Larregue M, et al. Malignant cellular blue nevus: Three new cases and a review of the literature. Ann Plast Surg 1998; 41:674-678. Elder DE, Murphy GF. In, Atlas of Tumor Pathology. 1991; 177-178. Editor Rosai, J.
2. 3. 4. 5. 6. 7.
157
Mehregan DA, Gibson LE, Mehregan AH. Malignant cellular blue nevus: a report of eight cases. J Dermatolo Sci 1992; 4:185-192. 9. Temple-Camp CR, Saxe N. King H. Benign and malignant cellular blue nevus. A clinicopathologic study of 30 cases. Am J Dermatopathol 1988; 10:289-296. 10. Tran TA, Carlson JA, Basaca PC, Mihm MC. Cellular blue nevus with atypia (atypical cellular blue nevus): A clinicopathologic study of nine cases. J Cutan Pathol 1998; 25:252-258.
8.
Scott Granter
158
CASE 22
Case History
22-year-old female who presented with a pigmented lesion on her vulva.
Figure 1a
Figure 1b
Figure 2a
Figure 2b
Figures 1a & 1b: Figures 2a & 2b:
Scanning and low power views of a clearly nevoid melanocytic lesion extending into the reticular dermis. Note that both radial margins are involved. The lesion shows maturation with depth. The nest size has diminished within the reticular dermis and the tumor cell population is dispersed between the collagen bundles.
159
Figure 3a
Figure 3b
Figure 4a
Figure 4b
Figure 4c
Figure 5a
Figures 3a & 3b: Figures 4a-4c: Figures 5a & 5b:
The cell and nuclear size diminish with depth. Nucleoli however are still visible in the deeper reaches. Multiple superficial mitoses are present. Mitoses are present in the depth of the lesion including abnormal forms (b).
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Case 22
Figure 5b
Diagnosis
Nevoid melanoma.
Commentary
This case was seen as a consultation at the request of the patient. The patient, a young woman, presented with a vulval nevus which was shave-biopsied. Its size, color, shape and duration are unknown. She was not pregnant. No additional clinical information was available other than it recurred some time later and was re-biopsied. Both the primary and recurrent lesions were diagnosed as banal nevi by the primary pathologist. The patient subsequently developed regional lymphadenopathy and requested that a second opinion be sought. No further data is available and the cause of the lymphadenopathy is unknown although biopsy was recommended. This is a particularly difficult case for a number of reasons. The patient was a young female and therefore there was no clinical reason to be suspicious of the lesion indeed it was shave-biopsied and submitted with the diagnosis of a dermal nevus. The lesion consists of a predominantly dermal melanocytic proliferation. At scanning and low power examination the nevoid population appears to mature with depth and there is an infiltrating growth pattern at the lower border, features guaranteed to lull the pathologist into a false sense of security (Figs. 1 & 2). High power views of the morphology of the superficial and deep components seem to confirm a diagnosis of a banal nevus (Fig. 3). There is minimal junctional activity and little pleomorphism. Pagetoid spread is not a feature. The nuclei are regular with dispersed chromatin and thin sharply defined membranes containing uniform small nucleoli. However a possible clue to the diagnosis of melanoma may be seen in Fig. 3a where the nests of melanocytes appear somewhat expansile, compressing each other, although the feature is subtle. Much more important is the presence of the mitotic activity found with ease in both the superficial
161
and deep components of the nevus and the finding of occasional abnormal forms (Figs. 4 & 5). The mitotic activity is also readily apparent in the recurrent specimen (Figs. 6 & 7). Re-excisions were not performed following either of the biopsies although margins were involved in both. Following review of the sections, a diagnosis of nevoid melanoma was made on the basis of the brisk mitotic activity including deep location and abnormal variants. Nevoid melanoma is one of the most challenging variants of melanoma. Although only limited literature is available, the entity can most easily be defined as a melanoma that looks like and is misdiagnosed as a banal nevus.1-6 Thus it shows little or no junctional activity, is usually devoid of pagetoid spread, is composed of a monomorphic population of small tumor cells and has a nevoid architectural pattern.2 As a result, many cases, most probably the majority, are recognized only in retrospect when the patient develops tumor recurrence or a metastasis. The incidence is uncertain as most examples are seen in consultation practice. It has been suggested that it accounts for no more than 0.5% of all melanomas routinely accessioned.5 Clinically, nevoid melanoma shows no particular distinguishing features and is commonly thought to represent a benign nevus by the clinician. Other clinical diagnoses may include a cyst, dermatofibroma, changing nevus and atypical nevus. Interestingly, melanoma is never considered. Patients generally present with a tan or flesh colored nodule measuring 1.0 cm or more in diameter.7 The sex incidence is equal and the patients age ranges from 4.5-95 years with a mean age at presentation of 45 years. While the tumor may present at a wide variety of sites, the back is most often affected in males and the leg in females. Although initially this lesion was thought to have a better prognosis than "classical" melanoma, there is no evidence to support this view.5 On the contrary, nevoid melanoma has recurrence and metastasis rates and overall mortality comparable with any other melanoma variant. Thus with sufficient follow-up, the overall local recurrence rate is as high as 75%, the metastasis rate ranges from 37.5-45% and mortality can amount to 37.5-.%.2,5 Histologically verrucous and nodular variants may be encountered (Table 1).
Table 1: Histological features of nevoid melanoma

Verrucous or nodular Nodular variants well circumscribed Usually slightly asymmetrical Often minimal epidermal component Diffuse or nested population Type A nevoid cell population
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Case 22
Impaired maturation Mild cytological atypia Nucleolar prominence Multiple mitoses Atypical mitoses
Verrucous nevoid melanoma is characterized by a warty growth pattern with associated hyperkeratosis, parakeratosis and papillomatosis (Fig. 8). The lesion often appears relatively well circumscribed and may be only mildly asymmetrical. A junctional component is often present although it may be only focal and limited. Junctional nests or a lentiginous component can be evident and there may be slight pagetoid spread. Features of obvious in situ melanoma are very exceptional. The dermal component is most often diffuse with expansion of the papillary dermis. Less often a nested growth pattern is observed. In such instances, the nests often appear expansile and crowded with compression of the papillary dermal connective tissue elements. There may be apparent maturation with depth although sometimes high power examination shows this to be artifactual (Fig. 9). The tumor cells are small, nevoid with abundant eosinophilic or pale staining cytoplasm and round to oval vesicular nuclei. Pleomorphism is by definition mild. Nucleoli are eosinophilic, often slightly enlarged and this feature is typically evident in the deeper reaches of the lesion. Characteristic is the presence of mitoses in the dermal component. These are invariably multiple, sometimes atypical and commonly seen in the deeper reaches of the tumor (Figs. 10 & 11). Nodular variants are often devoid of any junctional activity and as such can be mistaken for metastatic deposits although they lack the distinctly spherical appearance with expansile borders characteristic of the latter. A careful search of multiple levels may sometimes reveal at least small foci of a junctional activity or a lentiginous melanocytic component. The epidermis is often hyperkeratotic, atrophic and stretched over the surface of the melanocytic infiltrate. Rete ridges may be lost. The lesion can appear well circumscribed and fairly symmetrical. It is characterized by a diffuse or nested population of tumor cells similar to that described above. Maturation with depth is generally not a feature and multiple mitoses are invariably evident. Although the deep border may show an infiltrative single cell growth pattern, sometimes an expansile border is a feature (Fig. 12). The differential diagnosis of nevoid melanoma includes banal nevus and metastatic melanoma. In the context of the differential diagnosis of banal nevus, probably the most difficult histological conundrum is the presence of mitoses in the dermal component of what appears to be a typical benign compound or dermal nevus. An occasional dermal mitotic figure however is not uncommon in a banal nevus particularly if the infiltrate is scrutinized carefully and multiple levels examined.
163
Its presence however should alert the pathologist to the possibility of nevoid melanoma and additional and/or atypical mitoses and other worrisome features such as impaired maturation, mild pleomorphism and nucleolar prominence should be sought. Similarly the epidermis should be carefully scrutinized for evidence of an in situ lesion. In cases where doubt exists, immunohistochemistry for MIB-1, cyclin D1 and p53 protein expression may be valuable. In nevi, MIB-1 and cyclin-D1 positivity may be seen in very occasional superficial nuclei whereas in nevoid melanoma expression is often brisk and extends throughout the entire thickness of the tumor. Melanoma may be positive for p53, nevi are negative. Metastatic melanoma may show considerable histological overlap with nodular nevoid melanoma variants. If the metastatic deposit showed nevoid features, then it would be impossible to make the distinction in the absence of clinical information. In general however, metastatic melanoma often shows a nodular or spherical outline with obvious compression of the adjacent dermal connective tissue and lymphovascular invasion is sometimes evident. Although the distinction is to some extent semantic, it is best to regard small cell melanoma as a separate variant although some authors use the term synonymously with nevoid melanoma. By definition, nevoid melanoma mimics type A nevus cells. By way of contrast, in small cell melanoma, the tumor cells are basophilic, small and often hyperchromatic similar to type B nevus cells. As such, the condition can easily be mistaken for other small blue cell tumors including lymphoma, peripheral primitive neuroectodermal tumor and primary cutaneous neuroendocrine carcinoma. Over the past several decades, numerous histological variants of melanoma have been described (Table 2). It is important to recognize that with the possible exception of desmoplastic melanoma, these variants show identical biological behavior. Their relevance primarily relates to difficulties in recognition and the ease of misdiagnosis. Thus Spitzoid melanoma may be confused with a Spitz nevus and rhabdoid melanoma with a carcinoma. This case demonstrates how easily it is to mistake nevoid melanoma for a banal nevus particularly if the lesion is examined at scanning magnification with no attention paid to cytological detail or mitotic activity.
Table 2: Histological variants of melanoma

Lentigo maligna Superficial spreading Acral lentiginous Nodular Desmoplastic Neurotropic Acantholytic Myxoid Rhabdoid Signet ring cell Metaplastic Spitzoid
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Case 22
Nevoid Small cell Balloon cell Clear cell Dermal
Animal type Malignant blue nevus Angiotropic Pseudovascular Epidermotropic metastatic
Figure 6a
Figure 6b
Figure 7a
Figure 7b
Figures 6a & 6b: Figures 7a & 7b:
Scanning and medium power view of recurrent lesion. Multiple mitoses are present.
165
Figure 8a
Figure 8b
Figure 9a
Figure 9b
Figures 8a & 8b:
Figures 9a & 9b:
Verrucous nevoid melanoma showing hyperkeratosis and papillomatosis. The papillary dermis is expanded by a diffuse cellular infiltrate. Note the loss of rete ridges and epidermal attenuation. Apparent maturation with depth is present. Compare the morphology of the superficial tumor cells with that evident in the deeper component.
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Case 22
Figure 10a
Figure 10b
Figure 11a
Figure 11b
Figures 10a & 10b: Figures 11a-11e:
Multiple dermal mitotic figures are present. Scanning view of an apparently banal dermal nevus (a). Multiple dermal mitoses are present predominantly but not exclusively restricted to the area bounded by the dots (b-d). MIB-1 immunohistochemistry shows brisk expression (e). Case courtesy of S R Granter, MD, Department of Surgical Pathology, Brigham and Womens Hospital, Boston, MA.
167
Figure 11c
Figure 11d
Figure 11e
Figure 12a
Figures 12a-12f:
Nodular nevoid melanoma showing epidermal attenuation and loss of the rete ridges. Note the circumscription, relative symmetry and pushing lower border (a). A focal junctional component is present (b). The infiltrate is composed of uniform small nevoid cells. There is no evidence of maturation with depth (c & d). Scattered pleomorphic nuclei are evident and multiple mitotic figures are present (e & f).
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Case 22
Figure 12b
Figure 12c
Figure 12d
Figure 12e
169
Figure 12f
References (limited)
1. Levene A. On the histological diagnosis and prognosis of malignant melanoma. J Clin Pathol 1980; 33:101-124. 2. Schmoeckel C, Castro CE, Braun-Falco O. Nevoid malignant melanoma. Arch Dermatol Res 1985; 277:362-369. 3. Blessing K, Evans AT, al-Nafussi A. Verrucous nevoid and keratotic malignant melanoma: a clinico-pathological study of 20 cases. Histopathology 1993; 23:453-458. 4. Wong TY, Duncan LM, Mihm MC Jr. Melanoma mimicking dermal and Spitzs nevus (nevoid melanoma). Semin Surg Oncol 1993; 9:188-193. 5. Zembowicz A, McCusker M, Chiarelli C, et al. Morphological analysis of nevoid melanoma. A study of 20 cases with review of the literature. Am J Dermatopathol 2001; 23:167-175. 6. Cassarino DS, Fullen DR, Sondak VK, Duray PH. Metastatic nevoid melanoma in a 41/2-year-old child. J Cutan Pathol 2003; 30:647-651. 7. Magro CM, Crowson AN, Mihm MC Jr. Unusual variants of malignant melanoma. Mod Pathol 2006; 19:S41-70.
Phillip H McKee
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CASE 23
Case History
54-year-old male presented with a poorly circumscribed 0.5 cm indurated lesion in the left lower arm.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 1:
Low power view showing a dermal process where multiple nidi of inflammation can be seen amidst a haphazardly arranged spindle cell proliferation in a desmoplastic background. A closer look shows that in this case the epidermis is uninvolved. Note the nidi of inflammation composed mainly of chronic inflammatory cells. In this profile one can appreciate the crowded spindle cell proliferation in an sclerotic stroma. The tumor extends to the deep margin, involving subcutaneous fat, surrounding deep vessels and neural structures.
171
Figure 5
Figure 6a
Figure 6b
Figure 7
Figure 5: Figures 6a & 6b: Figure 7:
In the midst of the malignant spindle cell proliferation a nodular focus with a myxoid background can be observed. 200x and 400x views of neural elements encased by tumoral cells. The malignant cells can be appreciated in detail with their hyperchromatic nuclei and relative pleomorphism.
Diagnosis
Desmoplastic melanoma.
Commentary
Desmoplastic melanoma can present clinically as a firm amelanotic lesion resembling a scar, fibroma or basal cell carcinoma, or as a firm blue-black papule or nodule in a background of atypical pigmentation. On rare occasions the lesion may present with a boggy consistency as a result of increased stromal mucin deposition. They tend to occur in older patients in areas of the skin showing evidence of chronic sun damage, usually the head and neck, and the
Case 23
upper back. They can also occur in acral and mucosal sites, i.e. vulva, oral mucosa, etc.
Histology
Under the microscope the lesion presents as a poorly circumscribed proliferation of hyperchromatic spindle cells, isolated or in fascicles, in the midst of a densely fibrotic stroma. There are also scattered nidi of chronic inflammation highlighting the fibrous areas. The infiltrate is mainly lymphoid with admixed plasma cells. The background stroma is composed predominantly of dense collagen with scattered reactive fibroblasts, melanophages, dendritic cells, and variable amounts of mucin.1,2 The hyperchromatic spindle cells are melanocytes with a fibroblastic phenotype,they show some of the immunohistochemical features of melanocytes being consistently positive for S100 and negative or focally positive for HMB45, tyrosinase, Melan-A and microphtalmia transcription factor. There is also ultrastructural evidence of melanocytic origin proven by the presence of pre-melanosomes by electron microscopy.3 When there is pigmentation clinically this corresponds histologically to overlying atypical lentiginous melanocytic hyperplasia, lentigo maligna, acral lentiginous melanoma or a mucosal lentiginous melanoma. Perineural and intraneural involvement is commonly observed, sometimes at significant distances from the main tumor mass. Because of this feature and the poor circumscription of the tumor, desmoplastic melanoma is particularly prone to local recurrence. Klaus Busam et al.,2,4,5 in recent reviews highlight the importance of morphologic variations encountered in desmoplastic melanomas. They propose a classification according to the percentage of desmoplastic and cellular components. Pure desmoplastic melanomas are defined as lesions in which 90% or more of the tumor is represented by the typical desmoplastic paucicellular component. Combined desmoplastic melanomas are tumors in which there is desmoplasia in less than 90% of the lesion with the remaining area being composed of a more cellular component without fibrosis. These cellular areas can vary widely representing sometimes 50% or more of the tumor. According to their data pure desmoplastic melanomas are associated with less regional lymph node involvement and longer disease-free survival. The distinction of desmoplastic melanoma as a different biologic subtype of melanoma is supported by the clinical appearance, biologic behavior, microscopic features and immunohistochemical profile. Furthermore recent studies by gene expression profiling6 showed that desmoplastic melanomas differ from conventional melanomas at a genetic level. Desmoplastic melanomas show an upregulation of neurotropic factors and genes involved in the production of extracellular
matrix, as well as lower levels of expression of genes related to melanin pigment synthesis.
Lesions to be considered in the differential diagnosis include melanocytic lesions such as desmoplastic Spitz nevus, sclerosing blue nevus, sclerosing type A nevus, etc. Non-melanocytic lesions that can mimic desmoplastic melanoma include leiomyosarcoma, neurothekeoma, and spindle cell squamous cell carcinoma. The absence of HMB45 expression is useful in differentiating desmoplastic melanoma from other spindle cell melanocytic lesions. The presence or absence of smooth muscle markers, keratin, S100, etc, will mutually exclude or confirm melanocytic versus non-melanocytic lesions. Therapy: Due to its poor circumscription and frequent perineural involvement desmoplastic melanomas are highly recurrent, therefore for adequate therapy a wide local excision is recommended. To avoid recurrences the pathologist must make certain that the margins are free of desmoplastic stroma, vascular invasion and perineural involvement.
Figure 8a
Figure 8b
Figures 8a-8c: A different case shows epidermal involvement by lentigo maligna melanoma (a). The S100 stain shows positivity of the intraepidermal as well as the dermal spindle cell component (b). HMB45 only highlights the lentiginous intraepidermal component. The dermal spindle cells in the desmoplastic stroma are negative (c).
Figure 8c
Case 23
References
1. 2. 3. 4. Crowson N, Magro CM, Mihm M C Jr. Desmoplastic Melanoma in Crowson, Magro and Mihm, The melanocytic proliferations. Wiley Liss New York 2001. Busam KJ. Cutaneous Desmoplastic Melanoma. Adv Anat Pathol 2005; 12:92-102. From L., Hanna W, Kahn HJ, et al. Origin of the desmoplasia in desmoplastic malignant melanoma. Hum Pathol 1983; 14:1072-1080. Busam KJ, Mujumdar U, Hummer AJ, et al. Cutaneous desmoplastic melanoma. Reappraisal of morphologic heterogeneity and prognostic factors. Am J Surg Pathol 2004; 28:1518-1525. Hawkins WG, Busam KJ, Ben-Porat L, et al. Desmoplastic melanoma: a pathologically and clinically distinct form of cutaneous melanoma. Ann Surg Oncol 2005 Mar; 12(3):207-13. Busam KJ, Zhao H, Coit DG, et al. Distinction of desmoplastic melanoma from nondesmoplastic melanoma by gene expression profiling. J Invest Dermatol 2005; 124:412-419.
5.
6.
Adriano Piris and Martin C. Mihm Jr.
175
Notes
CASE 24
Case History
77-year-old male attorney presented with a rapidly growing 1.5 cm red nodule on the right parietal scalp with central ulceration and bleeding. A shave biopsy was performed which showed a poorly differentiated S-100 negative, CD-68 positive malignant epithelioid neoplasm consistent with an atypical fibroxanthoma. He was scheduled for Mohs micrographic excision.
Figure 1
Figure 2
Figure 3
Figure 4
Figures 1 & 2: Figure 3: Figure 4:
Shave biopsy. H&E stain. Poorly differentiated epithelioid neoplasm with atypical mitoses. Shave biopsy. S100. Focal dermal dendritic cell staining for S100. Shave biopsy. CD68. CD68 positive multinucleated giant cells.
177
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 5: Figures 6 & 7: Figures 8 & 9:
Mohs excision. H&E stain. Low power field showing atypical melanocytic proliferation (right) and poorly differentiated epithelioid nodule (left) in continuity. Mohs excision. H&E stain. Low and high power views of highly atypical proliferation of melanocytes present at the margin of the lesion. Mohs excision. H&E stain. Multinucleated osteoclast-like giant cells and mitoses are present within the poorly differentiated epithelioid component.
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Case 24
Figure 11
Figure 12
Figure 13
Figure 14
Figure 15
Figures 10-12: Figures 13-15:
Mohs excision. H&E stain; S100; MART-1 (anti-MelanA). The atypical melanocytic population stains strongly positive for S100 and MART-1. Mohs excision. CD68; S100; MART-1. The osteoclast-like giant cells within the epithelioid cell component are strongly positive for CD68, and negative for S100 and MART-1.
179
Diagnosis
Pleomorphic melanoma with osteoclast-like giant cells.
Commentary
Pleomorphic melanoma with osteoclast-like giant cells is a rare morphologic variant of malignant melanoma comprised of an epithelioid component with multinucleated osteoclast-like giant cells.1 Numerous mitoses, including atypical forms, are present within the poorly differentiated epithelioid component. This case is an example of a diagnostic dilemma encountered infrequently but in which accurate diagnosis may have profound prognostic significance.2 The main differential is with cutaneous fibrohistiocytic lesions including atypical fibroxanthoma, dermatofibroma with giant cells, pleomorphic fibroma, sarcomatoid squamous cell carcinoma, and cutaneous leiomyosarcoma. Unique to this lesion, the central giant cell component is closely apposed to the conventional melanocytic proliferation at the margins. Both areas are distinct but show cellular overlap. This gradual histomorphologic transition from the typical melanoma to the epithelioid component as seen here makes a collision tumor unlikely.3 Histologic examination of the conventional melanoma component of this lesion revealed a nodular atypical melanocytic cell proliferation, greater than 2.5 mm in thickness, extending to anatomic Clarks level IV, and present at the deep surgical resection margin. No radial growth phase component was noted. No melanin pigment or HMB-45 expression was noted but there was strong positive staining of the tumor cells in this region for S-100 and MART-1. The poorly differentiated epithelioid component of this lesion shows a lysozyme negative, factor XIIIa negative, S-100 negative, MART-1 negative, HMB-45 negative, cytokeratin 903 negative immunophenotype. However, the osteoclast-like giant cells within the epithelioid cell component showed strong positive immunoreactivity for CD68. Osteoclast-like giant cells have infrequently been described in cutaneous melanoma and have been termed monster cells and macrophage polykaryon for their marked pleomorphism, large hyperchromatic nuclei and macrophage staining characteristics.1,4,5 The presence of giant cells is considered by some to represent an unusual host inflammatory response - dedifferentiated neoplastic cell derived chemoattractants that stimulate monocyte fusion and formation of multinucleate osteoclast-like giant cells.3,6 Others have shown that these giant cells are transformed elements of the neoplastic process through K-ras mutation analyses in tumors of the pancreas and liver.6,7 This is an ongoing area of debate. Long-term studies demonstrating the prognostic significance of this morphologic subtype of melanoma have not been reported. However, it has been suggested that the presence of osteoclast-like giant cells confers a poorer prognosis on the basis of their positive
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association with nodular melanomas of greater thickness.4 Further light microscopic, immunohistochemical, ultrastructural and molecular analyses may provide clues to elucidate their importance.
Follow-up
A wider re-excision was scheduled using 2 cm surgical margins with skin grafting and clinical observation of lymph nodes.
The unusual finding of giant cells in these lesions presents a diagnostic challenge and may often lead to a misdiagnosis as a fibrous tumor, as in one previously reported case of metastatic amelanotic melanoma mimicking a giant cell tumor of bone.8 The distinction of melanoma from fibrohistiocytic proliferations is further complicated by the compound immunoreactivity of melanoma cells and macrophages for histiocytic markers, including CD-68 (KP1).9 A vigilant analysis of the immunohistochemical staining profile is essential for making the right diagnosis.
Atypical fibroxanthoma (AFX)

Synonyms: cutaneous malignant fibrous histiocytoma, pleomorphic dermal sarcoma. This entity is the main lesion in the differential diagnosis of pleomorphic melanoma with osteoclast-like giant cells. Atypical fibroxanthoma is often seen as a nodule on sun-damaged skin of the head and neck in elderly patients. This lesion is characterized by a polymorphic population of spindled cells, pleomorphic histiocytic cells with foamy cytoplasm and multinucleated osteoclast-like giant cells.10 Typically, there is stronger, more diffuse reactivity of the multinucleate osteoclast-like giant cells for CD-68 in comparison to other cell types within this lesion. Atypical mitoses are frequently encountered. The lesion may extend to the subcutaneous fat and has an approximately 5% recurrence rate, although metastases are rare.11 The overlying epidermis may be attenuated or ulcerated and often forms a collarette around the dome-shaped lesion.11 Differentiation from pleomorphic melanoma with osteoclast-like giant cells may be difficult, particularly in pigmented and focally necrotic lesions. Immunohistochemical stains are often needed to establish a diagnosis (Table 1).
Sarcomatoid squamous cell carcinoma (SSCC)

Synonym: carcinosarcoma of the skin. This lesion shows areas consistent with typical squamous cell carcinoma including continuity with the overlying epidermis, keratin pearl formation and intercellular junctions, as well as a prominent pleomorphic or spindled sarcomatoid component. The sarcomatous differentiation is thought to represent a metaplastic process and is characterized by vimentin positive, CD-68 negative giant polygonal
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cells with vesicular nuclei, prominent nucleoli and numerous mitoses including atypical forms.10
Cutaneous leiomyosarcoma (CL)

The primary cutaneous form of leiomyosarcoma is derived from the smooth muscle of arrector pili and typically occurs on the extremities. Differentiation from other lesions can be made by an absence of epidermal continuity, and keratin negative, vimentin, desmin and smooth muscle actin positive staining of tumor cells. This poorlydefined lesion is composed of a fascicular arrangement of pleomorphic cells with abundant eosinophilic cytoplasm and cigar shaped nuclei.10 Mitotic figures and giant cells may be seen.10 Prognosis is related to aggressive local recurrence and depth of invasion into the subcutis.
Dermatofibroma with monster cells (DFMC)

Synonym: atypical pseudosarcomatous cutaneous fibrous histiocytoma. Dermatofibroma with monster cells is an uncommon variant of dermatofibroma characterized by benign vimentin positive spindled cells, xanthoma cells, and histiocytes with atypical multinucleate forms and large bizarre nuclei.5,12 The lesion typically shows a Grenz zone beneath a hypertrophic epidermis and CD-34 positive chickenwire vasculature within the dermis. Positive staining for CD-68 is seen to a greater degree within the multinucleate histiocytic component, whereas the mononuclear component, comprised of dermal dendritic cells, is highlighted by factor XIIIa.13 Mitoses and necrosis are not typical.14 Dermatofibroma with monster cells often presents on the extremities of young to middle aged individuals as a small redbrown nodule.14
Pleomorphic fibroma (PF)

Synonym: collagenoma. Pleomorphic fibroma is a benign exophytic lesion with attenuated overlying epidermis often found in the perianal region. This well-circumscribed polypoid lesion is composed of plump mononucleate and multinucleate dermal stromal cells with irregular pleomorphic nuclei and scattered normal mitoses.14 The tumor cells express CD-34, unlike DFMC.14 The stromal collagen to cell ratio is increased in older lesions.
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Table 1: Summary of immunohistochemical findings

Keratin PMGC AFX SSCC CL DFMC PF + CD68 Vimentin + +* + + +* + + + + + + S100 + HMB45 MART1 + -** + -** SMA + +/+ + Lyso + + NK FXIIIa Desmin CD34 + NK + + -*** +
Abbreviations
PMGC, pleomorphic melanoma with osteoclast-like giant cells; AFX, atypical fibroxanthoma; SSCC, sarcomatoid squamous cell carcinoma; CL, cutaneous leiomyosarcoma; DFMC, dermatofibroma with monster cells; PF, pleomorphic fibroma; SMA, smooth muscle actin; Lyso, lysozyme; FXIIIa, factor XIIIa; +, positive staining observed; -, negative staining observed; NK, not known. * CD68 (KP1) reactivity is greater in multinucleate giant cells than in the fibrous component of these lesions. ** One reported case in the literature shows aberrant focal positive staining of multinucleate cells for HMB-45 and MART-1.15 *** Positive CD34 staining is seen in vascular endothelial cells.5
Figure 16
Figure 17
Figures 16-18:
Atypical fibroxanthoma. H&E stain, two fields. Low and high power views showing polymorphic spindle cells, histiocytes with marked nuclear pleomorphism and abundant eosinophilic cytoplasm, and multinucleate osteoclast-like giant cells.
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Figure 18
Figure 19
Figure 20
Figure 21
Sarcomatoid SCC. H&E stain. Epidermally derived malignant squamous cell lesion with areas of sarcomatoid differentiation. Sarcomatoid SCC. H&E stain. Squamous cell component showing prominent intercellular junctions. Sarcomatoid SCC. H&E stain. Predominantly sarcomatous spindle cell component with scattered large hyperchromatic cells. Sarcomatoid SCC. H&E stain. Giant polygonal cells with vesicular nuclei.
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Figure 22
Figure 23
Figure 24
Figure 25
Figure 23: Figure 24: Figures 25 & 26:
Sarcomatoid SCC. Cytokeratin. The typical squamous cell component stains strongly positive with cytokeratin. Sarcomatoid SCC. Vimentin. The sarcomatoid component is highlighted with strong positive staining for vimentin. Leiomyosarcoma. H&E stain. Fascicular arrangement of cells with elongated eosinophilic cytoplasm and cigar-shaped nuclei. Occasional large hyperchromatic atypical nuclei and proximity of the lesion to a hair follicle are observed.
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Figure 26
Figure 27
Figure 28
Figure 29
Figure 30
Figure 31
Figures 27-29:
Figures 30 & 31:
Dermatofibroma with monster cells. H&E stain, two fields. Polymorphic spindle cells and multinucleate histiocytes with large pleomorphic vesicular nuclei. A thin Grenz zone and delicate dermal vasculature may be appreciated. Pleomorphic fibroma. H&E stain. Thick eosinophilic collagen bands intersected by irregular mononucleate and multinucleate stromal cells.
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References
1. 2. 3. 4. 5. Denton KJ, Stretch J, Athanasou N. Osteoclast-like giant cells in malignant melanoma. Histopathol 1992; 20:179-181. Zelger BG, Steiner H, Wambacher B, et al. Malignant melanoma simulating various types of soft tissue tumors. Dermatol Surg 1997; 23:1047-1054. Al-Brahim N, Salama S. Malignant melanoma with osteoclast-like giant cells: An unusual host response. Am J Dermatopathol 2005; 27(2):126-129. Boyd AS, Huiyun W, Shyr Y. Monster cells in malignant melanoma. Am J Dermatopathol 2005; 27(3):208-210. Setoyama M, Fukumaru S, Kanzaki T. Case of dermatofibroma with monster cells: a review and an immunohistochemical study. Am J Dermatopathol 1997; 19(3):312315. Leung KM, Wong S, Chow TC, et al. A malignant gastrointestinal stromal tumor with osteoclast-like giant cells. Arch Pathol Lab Med 2002; 126(8):972-4. Westra WH, Sturm P Drillenburg P et al. K-ras oncogene mutations in osteoclast-like , , giant cell tumors of the pancreas and liver: genetic evidence to support origin from the duct epithelium. Am J Surg Pathol 1998; 22(10):1247-54. Daroca PJ, Reed RJ, Martin PC. Metastatic amelanotic melanoma simulating giant cell tumor of bone. Hum Pathol 1990; 21(9):978-981. Groisman GM, Amar M, Schfer I. The histiocytic marker PG-M1 is helpful in differentiating histiocytes and histiocytic tumors from melanomas. App Immunohistochem Mol Morph 2002; 10(3):205-209. Silvis NG, Swanson PE, Manivel JC, et al. Spindle-cell and pleomorphic neoplasms of the skin. Am J Dermatopathol 1988; 10(1):9-19. Diaz-Cascajo C, Weyers W, Borghi S. Pigmented atypical fibroxanthoma. Am J Dermatopathol 2003; 25(1):1-5. Tamada S, Ackerman B. Dermatofibroma with monster cells. Am J Dermatopathol 1987; 9(5):380-387. Wilk M, Zelger BG, Nilles M, et al. The value of immunohistochemistry in atypical cutaneous fibrous histiocytoma. Am J Dermatopathol 2004; 26(5):367-371. Rudolph P Schubert C, Zelger BG, et al. Differential expression of CD34 and Ki-M1p , in pleomorphic fibroma and dermatofibroma with monster cells. Am J Dermatopathol 1999; 21(5):414. Smith-Zagone MJ, Prieto VG, Hayes RA, et al. HMB-45 (gp103) and MART-1 expression within giant cells in an atypical fibroxanthoma: a case report. J Cutan Pathol 2004; 31:284-286.
6. 7.
8. 9.
10. 11. 12. 13. 14.
15.
Rosalynn M. Nazarian and Lyn M. Duncan
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Notes
CASE 25
Case History
89-year-old male with a diffuse macular pigmentation on the bulbar conjunctiva of the left eye extending to the caruncle.
Figure 1
Figure 2
Figure 3
Figure 4
Figures 1-4:
The sections show intraepithelial conjunctival melanocytic proliferation showing high cellularity, and predominantly single cell lentiginous growth pattern. There is significant cell crowding. Importantly, the cells show epithelioid cytological features with round vesicular pleomorphic nuclei, prominent nucleoli and abundant cytoplasm.
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Diagnosis
Conjunctival melanoma in situ (Conjunctival primary acquired melanosis with atypia, high-risk).
Commentary
The illustrated case shows histologically malignant intraepithelial conjunctival melanocytic proliferation. The malignant nature of the lesion is revealed by the high cellularity, pagetoid spread and most importantly epithelioid cytological atypia of the melanocytes. There is little doubt that similar proliferation elsewhere in the body would be classified as melanoma in situ. While this is a very appropriate designation in this case, ophthalmic pathologist and ophthalmologists usually refer to all atypical intraepithelial conjunctival melanocytic proliferations as primary acquired melanosis (PAM) with atypia. Interestingly, the current WHO classification of conjunctival melanocytic lesions does not recognize a category of melanoma in situ at all.1 Conjunctival melanocytic proliferations are divided into benign nevi, malignant melanoma and broad category of primary acquired melanosis, which is further subdivided into PAM with atypia and PAM without atypia. The term melanoma is applied only if the atypical melanocytic proliferation is associated with invasion. WHO classification of conjunctival melanocytic proliferations has been criticized for its idiosyncratic approach. However, in real life, regardless whether one agrees with WHO classification and ophthalmologists or not, understanding of the concept of primary acquired melanosis and terminology used by ophthalmologists is essential for proper communication regarding conjunctival melanocytic lesions. The term primary acquired melanosis (PAM) is used both as a clinical and histopathological category. Clinically, PAM is a localized or diffuse macular pigmentation of the conjunctiva, which is not secondary to a known cause such as Addison disease or inflammation. PAM is acquired, as it usually develops de novo in the middle aged or older individuals, in contrast to racial melanosis, which is often congenital. PAM is usually unilateral and asymmetrical. It presents as slowly growing flat areas of pigmentation with predilection to perilimbar conjuctiva. Histologically, lesions corresponding to clinical description of PAM can be divided into two groups based on the presence or absence of melanocytic proliferation (?) and degree of cytological atypia. PAM without atypia represents lesions showing only epithelial pigmentation or only mildly increased number of normal-appearing conjunctival melanocytes. Dermatopathologists not familiar with conjunctiva will find analogy between PAM without atypia and lentigo. In the WHO terminology, PAM with atypia is a broad category, which includes all intraepithelial melanocytic proliferations resulting in increased cell density and/or showing any degree of cytological or
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architectural atypia. PAM without atypia is benign. PAM with atypia correlates with development of conjunctival melanoma in a significant subset of patients.2-4 We have recently studied 29 cases of PAM with atypia and melanoma arising in PAM with atypia with the goal of determining histological features in PAM with atypia, which correlate with progression to invasive melanoma. We were able to divide our cases into low- and high-risk groups based on cytological features.5 Low-risk lesions show conjunctival proliferation of small to medium-size melanocytes with darkly staining hyperchromatic nuclei and minimal amount of cytoplasm. High-risk lesions are composed of melanocytes showing different degree of epithelioid cell morphology with hyperchromatic or vesicular nuclei and discernible or abundant cytoplasm. Architectural features appear to be less discriminating, as it is more difficult to assess growth pattern, especially pagetoid spread, in the conjunctiva. Both groups of lesions were associated with similar risk of local recurrence. However, low-risk lesions showed invasion in only 2/13 cases. In contrast, in all but one (15/16 cases) high-risk lesions at least focal single invasion could be identified. Metastases occurred only in PAM with atypia showing high-risk features. The illustrated case shows features of a high-risk lesion. The proliferating melanocytes show vesicular nuclear morphology and cytoplasm can be appreciated in most of the cells (Figs. 1-4). For comparison, Figures 5-7 illustrate a biopsy of PAM with atypia showing lowgrade features. Distinction between the high and low-risk variants of PAM has management consequences. The desired treatment of all forms of PAM with atypia is complete surgical excision. If this is not possible, the patients with high-risk lesions should be followed up closely with frequent biopsies of suspicious lesions to allow earliest possible detection of invasive melanoma. We also believe that the terminology of conjunctival melanocytic proliferations should be modified. We are strong proponents of adopting the term melanoma in situ at least for PAM showing high-risk features in order to alert physicians about likelihood of developing invasive melanoma.
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Figure 5
Figure 6
Figure 7
Figures 5-7:
A different case, an example of a low-risk PAM with atypia. Melanocytes show single cell lentiginous growth pattern and are confined to the lower portion of conjunctival epithelium. In evaluation of conjunctival melanocytic proliferations assessment of cytological features is absolutely essential. In contrast to the discussed case, the cells in this lesion have hyperchromatic nuclei with no discernible cytoplasm or nucleoli. Low level pagetoid spread and cell crowding are present.
References
1. Zimmerman LE, Sobin LH. Histologic typing of tumors of the eye and its adnexa. In: International Histologic Classification of Tumors. Geneva: World Health Organization, 1980:23-4. 2. Folberg R, McLean IW, Zimmerman LE. Conjunctival melanosis and melanoma. Ophthalmology 1984; 91:673-8. 3. Folberg R, McLean IW, Zimmerman LE. Malignant melanoma of the conjunctiva. Hum Pathol 1985; 16:136-43. 4. Jakobiec FA, Folberg R, Iwamoto T. Clinicopathologic characteristics of premalignant and malignant melanocytic lesions of the conjunctiva. Ophthalmology 1989; 96:14766. 5. Sugiura M, Colby KA, Mihm MC, Zembowicz A. High and low risk features in conjunctival primary acquired melanosis with atypia: Clinicopathological analysis of 29 cases. Am J Surg Pathol 2006. In press.

CASE 26
Case History
64-year-old woman presented to a local ophthalmologist with history of pigmented lesion on the perilimbal conjunctiva. The lesion was suspicious clinically for melanoma as it appeared to involve cornea. A biopsy was performed.
Figure 1
Figure 2
Figure 3
Figure 4
Figures 1-4:
Biopsy of the perilimbal conjunctiva and peripheral cornea showing poorly circumscribed intraepithelial melanocytic proliferation. The lesion involves the surface corneal epithelium and invades the anterior corneal stroma causing its pigmentation.
193
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figures 5-10:
Invasion of the corneal stroma by the tumor. There is connection between the intraepithelial and stromal tumor through compromised Bowman's layer. Invasion of the cornea, destruction of Bowman's membrane and invasion of corneal stroma are very specific histological features of conjunctival melanoma. Conjunctival nevi do not do that. Please note severe cytological atypia (Fig. 9).
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Figure 11
Figure 12
Figures 11-12:
Invasion of the cornea by the tumor.
Diagnosis
Conjunctival malignant melanoma.
Commentary
Diagnosis of melanoma can be made in this biopsy even at low magnification by observing invasion of the corneal tissue by the tumor. Nevi can sometimes extend into peripheral corneal epithelium, but they never infiltrate the corneal stroma or penetrate through the Bowmans layer. Additional diagnostic features include confluent destructive growth pattern, large nest formation and marked cytological atypia. Conjunctival malignant melanoma is a rare malignancy. It accounts for 3% of the ocular cancer in the United States and represents only 1.6% of non-cutaneous malignant melanoma. The incidence is about 0.24-0.8 per million per year in white populations and is rising due to the same epidemiological factors affecting melanoma in the skin. White race is particularly vulnerable. The average age at diagnosis of the patient is 50-60 years old. Only few cases have been reported in children and adolescents. It has equally common in both sexes. The etiology of conjunctival melanoma is uncertain. Long-term exposures to ultraviolet light and a natural precarcinogen from the Meibomian gland have been implicated in the formation of the tumor. Conjunctival melanoma can occur in three different settings. Large population-based studies indicate that about 53-75% of conjunctival malignant melanomas arises in the context of primary acquired melanosis with atypia. Four (4) to 18% of cases are associated with a preexisting nevus.1-5 The remaining 18-30% of conjunctival malignant melanomas arise de novo. The presence or absence of a precursor does not seem to affect the clinical course or prognosis.
Clinically, the lesions present as discrete single or multiple pigmented macules or nodules on the conjunctiva. The suspicious features include the lack of mobility in relation to the sclera, extension onto cornea and evidence of canalicular obstruction. Color ranges from light to dark brown; rare cases are amelanotic. The most common location is the perilimbal bulbar conjunctiva. Pigmented lesions involving the caruncle, or forniceal or palpebral conjunctiva are much less common, but when occur, malignant melanoma is the most likely diagnosis. Malignant melanoma in these regions also shows poorer outcome than one in the bulbar conjunctiva. Conjunctival malignant melanoma is an aggressive tumor with potential for local spread and distant metastases. Initially, the tumor spreads within the epithelium before invading the subepithelial region. The Bowman's layer of cornea and sclera function as barriers to local spread. The invasion of tumor to episclera, sclera, and cornea are significantly risk factors for distant metastases and are associated with shortened survival. Malignant melanoma tends to metastasize through the lymphatic system. The first metastatic sites are the regional preauricular, submandibular or parotid lymph nodes. Later on the lungs, brain, and liver and other visceral sites can be involved. The melanoma related survival is approximately 70-90% at 5 years, 7077% at 10 years, and 67-75% at 15 years.3-11 The histological features of conjunctival melanoma are similar to those of the cutaneous counterpart. However, diagnosis is often challenging for pathologists not experienced with interpretation of melanocytic lesions in the anatomical context of the conjunctiva. One has to pay more attention to cytological features then to architecture. Various cell types were described in conjunctival melanoma including small polyhedral cells, spindle cells, epithelioid cells and balloon cells. Tumor composed mainly of the small polyhedral cells can be confused with conjunctival nevi. The following histological features are suspicious for melanoma: 1. intraepithelial component showings pagetoid growth (this features has to be interpreted with caution, as assessment of pagetoid spread is difficult in thin conjunctiva), 2. radial extension of the intraepithelial component beyond the lateral edge of subepithelial component, 3. patchy or band-like inflammation at the base of the lesion, 4. mitotic activity, 5. lack of maturation toward the base of the lesion, 6. cytological atypia, especially when associated with epithelioid or spindle cell morphology, 7. invasion of the cornea. Immunohistochemical studies such as HMB-45, S100, and MART-1 stains are helpful to confirm melanocytic differentiation but cannot help to differentiate between a melanoma and a nevus. Therefore, the diagnosis depends mainly on the clinical and histopathological features.
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Conjunctival melanoma is usually treated by complete surgical removal with at least 3-5 mm free margin. The incomplete excision is associated with high risk for local recurrence, metastasis, and death. Adjuvant therapy including cryotherapy, laser ablation, local radiation, topical chemotherapy or combined methods reduce risk of local recurrence and increase survival. Adjuvant therapy is especially important in large or multifocal lesions. Enucleation is not indicated in any case because it spares large area of the conjunctiva, which may be the source of residual tumor cells. Intraocular invasion is extremely rare and requires more aggressive surgery than enucleation alone. Exenteration is preferable for palliation in the large melanoma extending to the eyelid or orbit even though it will not change the patients survival or metastatic rate.2,8,14 The local recurrence is common. About 35-60% of patients experience single or multiple recurrences of the tumor. The average time interval from the primary treatment to the first recurrence is 3 years (range from 0.4-23 years). The survival rate is poor when the patient has lymph node metastases. The prognostic indicators in conjunctival melanoma are not well established. Thickness of 0.8 mm and in other studies of 1.5-2 mm has been associated with unfavorable prognosis. Unfavorable histological features include full thickness epithelial replacement by the tumor cells, epithelioid cytology and paucity of small polyhedral cells in subepithelial component, severe nuclear atypia, mitoses more than 5 per 10 high power fields, and absent inflammatory response to the tumor.2,12,13 The mortality rate from conjunctival melanoma is increased in tumors arising in the caruncle, fornix and palpebral conjunctiva and if the excision is incomplete.2-6,8,10,11,15,16
References
1. 2. 3. Jay B. Naevi and Melanomata of the Conjunctiva. Br J Ophthalmol 1965 April; 49:169-204. Folberg R, McLean IW, Zimmerman LE. Malignant melanoma of the conjunctiva. Hum Pathol 1985 February; 16(2):136-43. Paridaens AD, Minassian DC, McCartney AC, Hungerford JL. Prognostic factors in primary malignant melanoma of the conjunctiva: a clinicopathological study of 256 cases. Br J Ophthalmol 1994 April; 78(4):252-9. Missotten GS, Keijser S, De Keizer RJ, Wolff-Rouendaal D. Conjunctival melanoma in the Netherlands: a nationwide study. Invest Ophthalmol Vis Sci 2005 January; 46(1):75-82. Shields CL, Shields JA, Gunduz K, Cater J, Mercado GV, Gross N, Lally B. Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis, and death in 150 consecutive patients. Arch Ophthalmol 2000 November; 118(11):1497-507. Anastassiou G, Heiligenhaus A, Bechrakis N, Bader E, Bornfeld N, Steuhl KP . Prognostic value of clinical and histopathological parameters in conjunctival melanomas: a retrospective study. Br J Ophthalmol 2002 February; 86(2):163-7. Esmaeli B, Wang X, Youssef A, Gershenwald JE. Patterns of regional and distant metastasis in patients with conjunctival melanoma: experience at a cancer center over four decades. Ophthalmology 2001 November; 108(11):2101-5.
4.
5.
6.
7.
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8.
9.
10. 11. 12. 13.
14.
15.
16.
Lommatzsch PK, Lommatzsch RE, Kirsch I, Fuhrmann P Therapeutic outcome of . patients suffering from malignant melanomas of the conjunctiva. Br J Ophthalmol 1990 October; 74(10):615-9. Norregaard JC, Gerner N, Jensen OA, Prause JU. Malignant melanoma of the conjunctiva: occurrence and survival following surgery and radiotherapy in a Danish population. Graefes Arch Clin Exp Ophthalmol 1996 September; 234(9):569-72. Seregard S, Kock E. Conjunctival malignant melanoma in Sweden 1969-91. Acta Ophthalmol (Copenh) 1992 June; 70(3):289-96. Werschnik C, Lommatzsch PK. Long-term follow-up of patients with conjunctival melanoma. Am J Clin Oncol 2002 June; 25(3):248-55. Fuchs U, Kivela T, Liesto K, Tarkkanen A. Prognosis of conjunctival melanomas in relation to histopathological features. Br J Cancer 1989 February; 59(2):261-7. Jakobiec FA, Folberg R, Iwamoto T. Clinicopathologic characteristics of premalignant and malignant melanocytic lesions of the conjunctiva. Ophthalmology 1989 February; 96(2):147-66. Paridaens AD, McCartney AC, Minassian DC, Hungerford JL. Orbital exenteration in 95 cases of primary conjunctival malignant melanoma. Br J Ophthalmol 1994 July; 78(7):520-8. Bobic-Radovanovic A, Latkovic Z, Marinkovic J, Radovanovic Z. Predictors of survival in malignant melanoma of the conjunctiva: a clinico-pathological and follow-up study. Eur J Ophthalmol 1998 January; 8(1):4-7. Tuomaala S, Eskelin S, Tarkkanen A, Kivela T. Population-based assessment of clinical characteristics predicting outcome of conjunctival melanoma in whites. Invest Ophthalmol Vis Sci 2002 November; 43(11):3399-408.
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CASE 27
Case History
26-year-old man presented with a lightly pigmented brown nodule measuring 2x1cm on his left shoulder. The lesion had been present for more than five years and had undergone recent enlargement. A punch biopsy of the lesion was performed.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 1: Figure 2: Figures 3 & 4:
Punch biopsy of skin showing a cellular lesion extending from the base of the epidermis. Deep aspect of punch biopsy of skin showing the lesion extending into the subcutaneous adipose tissue. The lesion is composed of spindle cells and virtually abuts the undersurface of the epidermis, which is mildly thinned and shows attenuation of the rete ridges with mild increase in basal pigmentation.
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Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figures 9 & 10:

200
Deep aspect of tumor showing extensive infiltration into subcutaneous adipose tissue with fat entrapped within the tumor. Small numbers of bipolar and multipolar dendritic cells containing abundant brown pigment are scattered within the more dominant non-pigmented spindle cell component; somewhat atrophic adnexal structures are entrapped within the tumor. The spindle cells exhibit a prominent tight storiform pattern.
Case 27
Figure 11
Figure 12
Figure 13
Figure 14
Figure 15
Figure 16
Figures 11 & 12: Figures 13-16:
Bipolar and multipolar pigmented dendritic cells. The degree of pigmentation makes evaluation of cytologic detail in these cells difficult. The spindle cells are arranged in short fascicles and storiform arrays.
201
Figure 17
Figure 18
Figure 19
Figure 20
Figure 21
Figure 22
Occasional mitotic figures are present. At the deep edge, the tumor invades subcutaneous fat, entrapping individual adipocytes and groups of adipocytes within tumor in a honeycomb pattern. The interface of tumor with the adjacent dermis is poorly defined, but lacks entrapment of dermal collagen characteristically seen at the edge of fibrous histiocytoma/dermatofibroma.
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Figure 23
Figure 24
Figures 20 & 21: Figure 22: Figure 23: Figure 24:
The pigment within the dendritic cells is melanin and stains positively for Schmorl stain (Fig. 20) and negatively for Perls stain (Fig. 21). CD34 is diffusely positive in the spindle cell component. Factor XIIIa is negative. The dendritic cells show positive staining with S-100 (red chromogen).
Diagnosis
Pigmented Dermatofibrosarcoma Protuberans (Bednar Tumor).
Commentary
Case findings
Histopathologic findings
Microscopic features. The sections showed a punch biopsy of skin including the superficial subcutis. Occupying the entire dermis and focally abutting the under-surface of the epidermis was a spindle cell lesion exhibiting a prominent storiform architecture. The lesion was composed of mildly atypical, slender spindle cells with indistinct cytoplasmic borders. Occasional mitotic figures were seen in the spindle cell component. In addition, a small number of heavily pigmented bipolar and multipolar cells were identified within the lesion. These cells contained abundant cytoplasmic brown pigment, which obscured their nuclear features. The pigment was melanin, and stained positively with Schmorl stain and negatively with Perls stain. The lesion infiltrated into the superficial subcutaneous fat, entrapping adipocytes in a honeycomb pattern. Immunohistochemistry. The spindle cells were positive for vimentin and CD34, and were negative for factor XIIIa and S-100. The pigmented cells were positive for S-100 and negative for CD34 and factor XIIIa.
203
Diagnosis
Pigmented dermatofibrosarcoma protuberans (Bednar tumor).
Follow-up
A subsequent wide excision was performed, and showed a pigmented dermatofibrosarcoma protuberans (Bednar tumor) exhibiting similar histologic and immunohistochemical features. The tumor in the excision specimen was close to, but clear of the deep margin. The patient was seen at irregular intervals for a period of one year, with no evidence of local recurrence, after which time he was lost to follow-up.
Discussion
Dermatofibrosarcoma protuberans (DFSP) was first described in the 1920s and its histological features were characterized in detail in the 1950s and 1960s. DFSP accounts for less than 1% of all malignancies and its incidence has been estimated at less than 1 case per million persons per year.1 In 1957, Bednar2 described nine tumors characterized by indolent growth and a prominent storiform pattern; four of these cases contained melanin pigment. Bednar considered these lesions variants of neurofibroma (due to the occurrence of similar areas within neural nevi) and termed them storiform neurofibroma. The clinical, macroscopic and histologic features (of the non-pigmented areas) of these tumors are virtually identical to conventional DFSP 3 Consequently, these tumors are regarded as pigmented vari. ants of DFSP and are termed pigmented DFSP (PDFSP) or Bednar tumor.1 PDFSP is rare, accounting for less than 5% of all DFSP cases.2-35 Cases containing components of conventional DFSP PDFSP and , giant cell fibroblastoma (another variant of DFSP), occurring synchronously in primary tumors or metachronously in recurrent tumors have also been reported.7,20,27,30
Clinical features
PDFSP occurs in patients over a broad age range (six months to 67 years), but typically occurs in young to middle-aged adults. Males and females are affected equally. The tumor most commonly occurs on the trunk, particularly the shoulder; less common sites include the head and neck region and the upper and lower extremities.3,5,6,25 PDFSP usually presents as a slow-growing protuberant nodule (or less often a plaque) present over a period of months or years, sometimes with recent accelerated growth. A history of trauma to the region is elicited in some patients,3,5,6 and association with a history of prior vaccination at the site of tumor has been reported.31
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Macroscopic features
The tumors appear as one or more, relatively demarcated nodules located in the dermis and/or subcutis, ranging from 1.6-13cm in size.3,5,6 The nodules are grey-white in color, but some cases show flecks of pigmentation5,6 and up to 25% of cases are slate-grey or black. Surface skin ulceration is uncommon.3 Hemorrhage is rare and necrosis is not seen.5,6,12
Microscopic features
PDFSPs often abut the overlying epidermis, in contrast to conventional DFSP which is usually separated from the epidermis by a grenz , zone.3,5 The overlying epidermis is usually atrophic. The central cellular areas of tumor are composed of spindle cells arranged in short fascicles forming a distinctive storiform or cartwheel pattern typical of DFSP The storiform pattern is less apparent at the periphery of the . lesion. The spindle cells are slender, elongated and tapering, resembling fibroblasts; they exhibit mild cytologic atypia and occasional mitotic figures (usually less than 5 per 10 high power fields).3,5,6,9,12,21,34 In addition, a second population of pigmented, bipolar or multipolar dendritic cells (generally accounting for less than 1% of tumor cells) is present. These cells are predominantly found in the central and deep portions of the tumor, but may be scattered randomly throughout. Often the dendritic cells are very heavily pigmented, and the brown-black pigment stains positively with Schmorl, Warthin Starry and Fontana-Masson stains and negatively with Perls stain.3,5,6,12 Hair follicles and other appendageal structures are entrapped within the tumor, rather than being destroyed by it.5 At low magnification, the tumors appear relatively well demarcated, but closer examination reveals ill-defined margins, where slender bundles of spindle cells infiltrate adjacent dermal collagen and subcutaneous adipose tissue, isolating groups of adipocytes in a honeycomb pattern.3,5 Secondary elements such as inflammatory cells, giant cells and foamy histiocytes are not seen.3,5 Silver stains highlight a reticulin meshwork enveloping individual tumor cells.12 Rare cases of PDFSP undergo fibrosarcomatous change, in which a portion of the tumor is composed of spindle cells with plump hyperchromatic nuclei arranged in a fascicular or herringbone pattern, exhibiting frequent mitoses (often >10 per 10 high power fields), and foci of hemorrhage and/or necrosis. These areas lack storiform architecture and melanin pigment.6,21,28,32
Immunohistochemistry
Like DFSP the spindle cells in PDFSP exhibit positive staining for , CD34, vimentin, BCL-2 and ApoD.4-6,10,34,36 They are negative for S-100, CD163, lysozyme and alpha-1-antitrypsin.3,5,6,37 Fibrosarcomatous areas, when present, are often negative for CD34.26,28 Although most PDFSPs are negative for EMA,3,5,6 occasional cases may contain small numbers of EMA+ cells, typically in the spindle cell areas.38 The den-
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dritic cells are positive for vimentin and S-100, variably positive for HMB-45 and negative for EMA.4-6,9,10,29
Ultrastructure
PDFSP contains fibroblast-like cells, which accounting for the majority of cells. These cells are symmetrical and spindled with oval nuclei, moderate amounts of rough endoplasmic reticulum and small intercellular attachment sites; basal lamina is absent.3,5,6,10,12,35 Also present are pigmented cells with dendritic cell processes, containing premelanosomes and mature melanosomes. They are invested by discontinuous basal lamina and contain pinocytotic vesicles.3,5,6,10,12,35 A third population of cells, thought to resemble perineural fibroblastic cells, has been identified in some studies of PDFSP3 and conventional DFSP 39,40 but not in others.5,6 These cells possess slender interdigitat, ing cell processes, are partially or completely surrounded by basal lamina, and contain pinocytotic vesicles, thin cytoplasmic filaments and small intercellular attachment sites.
Genetics
More than 20 DFSP karyotypes have now been reported. Most represent supernumerary ring chromosomes, containing low level amplification of chromosomes 17 and 22 sequences. In some cases, balanced or unbalanced translocations involving chromosomes 17 and 22 were involved. Both supernumerary rings and t(17;22)(q22;q13) seen in DFSP represent the same molecular rearrangements that fuse the COL1A1 and PDGFB genes.41,42 Similar genetic aberrations have been identified in PDFSP 43,44 .
The nature and line of differentiation of PDFSP

Studies investigating the histogenesis or line of differentiation of PDFSP have yielded conflicting results and the issue is not clearly resolved to date. Fibroblastic45 and histiocytic46 differentiation has been proposed for DFSP and implied for PDFSP given the close similarities between , , the tumors. However, alpha-1-antitrypsin and lysozyme (markers of histiocytic differentiation) are negative in PDFSP 3 . Bednar originally considered it a variant of neurofibroma.2 However, PDFSP does not occur in the diversity of sites where neurofibromas occur, it does not occur more frequently in association with neurofibromatosis, it is S100-negative and has not been documented arising from nerves.3 Nevertheless, Dupree et al.3 favored a neuroectodermal origin for PDFSP based on the presence of melanin- and melanosome-containing cells, and the presence of basal lamina around some tumor cells (indicating Schwann cell or perineurial cell differentiation). They proposed that PDFSP originates from a single neuroectodermal cell line demonstrating the capacity of neural crest-derived tumors (such as pigmented neurofibroma and melanotic Schwannoma) to display both Schwannian and melanocytic differentiation.
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The neuroectodermal hypothesis has been questioned by others who have not been able to identify perineural fibroblastic differentiation, or cells transitional between fibroblastic-like cells and melanosomecontaining cells (suggesting that the two components are independent) in PDFSP 5,6 Others have suggested a neuromesenchyme theory, . where a partly committed stem cell (neuromesenchymal cell) can develop one or more lines of differentiation, such as mesenchymal (CD34+ fibroblast-like cells), melanocytic (S100+ dendritic cells), myofibroblastic, histiocytic and/or nerve sheath (EMA+ cells).19,38,47 A dual cell origin, namely that PDFSP arises from 2 different cell lines, CD34+ spindle cells of mesenchymal origin and pigmented cells of neuroectodermal origin) has also been proposed.4,29,35 An alternative hypothesis is that PDFSP is a fibroblastic tumor, in which pigmented melanocytes are present due to melanocytic colonization, namely the colonization of conventional DFSP by non-neoplastic melanocytes from the overlying epidermis. The occurrence of this phenomenon in other tumors (such as basal cell carcinoma, squamous cell carcinoma, pilomatrixoma), and the common finding of PDFSP abutting the overlying epidermis (in contrast to its uncommon occurrence in conventional DFSP) appears supportive of this theory.5-7,18,19 Although the pigmented cells are often in the central or deeper portions of the tumor, this may be due to colonization by melanocytes from entrapped follicles.5 Alternatively, the colonization may result from the (possibly coincidental) origin of a PDFSP in association with a melanocytic nevus.17,47
1. Desmoplastic Melanoma3,21,34,48 Desmoplastic melanoma occurs in older individuals, and is more frequent in the head and neck region. It shows considerable morphologic overlap with PDFSP such as uniform, spindle cells with, in collagenous stroma, storiform growth pattern, scattered mitotic figures, entrapped cutaneous appendages, and only focal pigmentation. However, desmoplastic melanoma, unlike PDFSP also , shows neurotropism, focal junctional melanocytic activity, diffuse S100-positivity and aggregates of lymphocytes, and lacks a storiform growth pattern. In contrast, PDFSP shows diffuse CD34 positivity and S-100 positivity only in the dendritic cell component. 2. Deep Fibrous histiocytoma/Dermatofibroma containing pigmented cells (hemosiderotic variant)3,5,36,37,49 Deep fibrous histiocytoma may resemble PDFSP including the , presence of mitotic figures and infiltration of subcutaneous fat, but the former more often arises on the extremities, is smaller (<2cm), associated with overlying epidermal hyperplasia, and usually contain inflammatory cells and foamy histiocytes. The invading margin of deep fibrous histiocytoma, even when extending into subcutaneous fat, has a smooth, rounded outline, in
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contrast to the honeycomb pattern of infiltration of PDFSP Deep . fibrous histiocytoma is positive for factor XIIIa and CD163, and negative for CD34 and ApoD, in contrast to PDFSP . 3. Pigmented Neurofibroma3,15,34,50,51 Pigmented neurofibromas show a diffuse or plexiform growth pattern, and are composed of a heterogenous population of plump, fusiform, elongate spindle and oval Schwann cells amid a myxocollagenous stroma. They contain pigmented cells which are S100positive. They may exhibit a tight storiform pattern focally. In contrast to PDFSP they occur in children or young adults, are associ, ated with neurofibromatosis, lack a strong truncal predilection, lack a diffuse tight storiform architecture and are diffusely S100positive (in both pigmented and non-pigmented cells) and CD34negative. 4. Psammomatous melanotic schwannoma34 These are rare tumors which usually arise in spinal nerves and gastrointestinal tract and only rarely occur in subcutaneous tissues. They share most of the histologic features of conventional schwannoma. In contrast to PDFSP they are associated with , Carney complex and are circumscribed, predominantly composed of epithelioid cells, heavily pigmented and contain psammoma bodies. In addition, they show diffuse positive staining for vimentin, S-100 and HMB-45. 5. Soft tissue Perineurioma38,52 Soft tissue perineurioma is a very rare tumor, usually seen in adults with a female predominance. It is composed of bland spindled, wavy cells with thin cytoplasmic processes amid a collagenous matrix. Partial whorls and storiform patterns are common. Both PDFSP and perineurioma can be CD34+ and EMA+, and both can show storiform architecture. In contrast to PDFSP per, ineurioma is a well circumscribed nodule lacking honeycomb infiltration of subcutaneous tissue, and is diffusely EMA-positive.
Management and prognosis

Like DFSP PDFSP exhibits slow, indolent growth, and is considered , a tumor of intermediate malignancy.3,6 Treatment of PDFSP like that , for DFSP involves surgical excision with clear margins. Wide excision , margins (preferably 3 cm) are recommended in order to reduce the , risk of local recurrence.14,53 Similar to the behavior of DFSP PDFSP exhibits local recurrence, and metastasis is very rare.3,6,8,21,24 The reported local recurrence rates of PDFSP (11-17%) appear lower than that for conventional DFSP (20-50%), though this might be related to differences in the numbers of reported cases and duration of followup.3,6,21 Some reports indicate that the presence of fibrosarcomatous areas in PDFSP (as in conventional DFSP) is associated with a more
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rapid course, and higher rates of local recurrence and metastasis.6,14,21,28,32,54 Interestingly, some authors have found that fibrosarcomatous transformation of conventional DFSP was not associated with a poorer outcome when treated with wide local excision; they conclude that the poor clinical course reported in other studies likely reflects inadequate local control.55,56
References
1. 2. 3. Laskin WB. Dermatofibrosarcoma protuberans. CA Cancer J Clin 1992; 42(2):116-25. Bednar B. Storiform neurofibromas of the skin, pigmented and nonpigmented. Cancer 1957; 10(2):368-76. Dupree WB, Langloss JM, Weiss SW. Pigmented dermatofibrosarcoma protuberans (Bednar tumor). A pathologic, ultrastructural, and immunohistochemical study. Am J Surg Pathol 1985; 9(9):630-9. Kobayashi T, Hasegawa Y, Konohana A, Nakamura N. A case of Bednar tumor. Immunohistochemical positivity for CD34. Dermatology 1997; 195(1):57-9. Fletcher CD, Theaker JM, Flanagan A, Krausz T. Pigmented dermatofibrosarcoma protuberans (Bednar tumour): melanocytic colonization or neuroectodermal differentiation? A clinicopathological and immunohistochemical study. Histopathology 1988; 13(6):631-43. Ding JA, Hashimoto H, Sugimoto T, Tsuneyoshi M, Enjoji M. Bednar tumor (pigmented dermatofibrosarcoma protuberans). An analysis of six cases. Acta Pathol Jpn 1990; 40(10):744-54. De Chadarevian JP Coppola D, Billmire DF. Bednar tumor pattern in recurring giant , cell fibroblastoma. Am J Clin Pathol 1993; 100(2):164-6. Onoda N, Tsutsumi Y, Kakudo K, et al. Pigmented dermatofibrosarcoma protuberans (Bednar tumor). An autopsy case with systemic metastasis. Acta Pathol Jpn 1990; 40(12):935-40. Lopez JI, Elizalde JM, Fernandez Larrinoa A. Pigmented dermatofibrosarcoma protuberans (Bednar tumour). Dermatology 1992; 184(4):281-2. Kagoura M, Toyoda M, Nagahori H, Makino T, Morohashi M. An ultrastructural and immunohistochemical study of pigmented dermatofibrosarcoma protuberans (Bednar tumor). Eur J Dermatol 1999; 9(5):366-9. Kulkarni VB, Vyas AS, Bhatambrekar SV, Pandit GA, Bhople KS. Pigmented dermatofibrosarcoma protuberans (Bednar tumour). Indian J Pathol Microbiol 1996; 39(1):379. Nakamura T, Ogata H, Katsuyama T. Pigmented dermatofibrosarcoma protuberans. Report of two cases as a variant of dermatofibrosarcoma protuberans with partial neural differentiation. Am J Dermatopathol 1987; 9(1):18-25. Miyamoto Y, Morimatsu M, Nakashima T. Pigmented storiform neurofibroma. Acta Pathol Jpn 1984; 34(4):821-6. Porter C, Vincetic A, Saleh ME, Goldstein H. Pigmented dermatofibrosarcoma protuberans of the foot with fibrosarcomatous changes: a review and case presentation. J Foot Ankle Surg 2002; 41(3):186-91. Vandeweyer E, Deraemaecker R, Somerhausen ND, Geledan L, Gebhart M. Bednar tumor of the foot: a case report. Foot Ankle Int 2001; 22(4):339-41. Santa Cruz DJ, Yates AJ. Pigmented storiform neurofibroma. J Cutan Pathol 1977; 4(1):9-13. Bednar B. Storiform neurofibroma in the core of naevocellular naevi. J Pathol 1970; 101(2):199-201.
4. 5.
6.
7. 8.
9. 10.
11.
12.
13. 14.
15. 16. 17.
209
18. Lambert MW, Lambert WC, Schwartz RA, et al. Colonization of nonmelanocytic cutaneous lesions by dendritic melanocytic cells: a simulant of acral-lentiginous (palmarplantar-subungual-mucosal) melanoma. J Surg Oncol 1985; 28(1):12-8. 19. Kuruvila S, Ramadan FA. Bednar tumor. Saudi Med J 2004; 25(12):2016-7. 20. Zamecnik M, Michal M, Chlumska A. Composite dermatofibrosarcoma protuberansgiant cell fibroblastoma recurring as Bednar tumor-giant cell fibroblastoma with mucoid lakes and with amputation neuroma. Cesk Patol 2002; 38(4):173-7. 21. Kini H, Raghuveer CV, Pai MR, S K. Fibrosarcomatous Bednar tumor with distant metastases--a case report. Indian J Pathol Microbiol 2004; 47(1):26-9. 22. Gorczyca W, Woyke S, Ucinski M. Storiform neurofibroma (Bednar tumor). A case report. Patol Pol 1991; 42(4):126-7. 23. Yagi Y, Ueda K, Maruyama S, Noborio R. Bednar tumor: a report of two cases. J Dermatol 2004; 31(6):484-7. 24. Mochizuki Y, Narisawa Y, Kohda H. A case of Bednar tumor recurring after 23 years. J Dermatol 1996; 23(9):614-8. 25. Akasaka T, Ohyama N, Kon S. A case of pigmented dermatofibrosarcoma protuberans (Bednar tumor). J Dermatol 1997; 24(6):390-4. 26. Tan AW, Tan SH. Dermatofibrosarcoma protuberans: A clinicopathological analysis of 10 cases in Asians. Australas J Dermatol 2004; 45(1):29-33. 27. Zamecnik M, Michal M. Giant-cell fibroblastoma with pigmented dermatofibrosarcoma protuberans component. Am J Surg Pathol 1994; 18(7):736-40. 28. Mentzel T, Beham A, Katenkamp D, Dei Tos AP Fletcher CD. Fibrosarcomatous (high, grade) dermatofibrosarcoma protuberans: clinicopathologic and immunohistochemical study of a series of 41 cases with emphasis on prognostic significance. [see comment]. Am J Surg Pathol 1998; 22(5):576-87. 29. Kaburagi Y, Hatta N, Kawara S, Takehara K. Pigmented dermatofibrosarcoma protuberans (Bednar tumor) occurring in a Japanese infant. Dermatology 1998; 197(1):4851. 30. Rytina ER, Ball RY. Transformation of recurrent dermatofibrosarcoma protuberans to its pigmented variant (Bednar tumour). Histopathology 1998; 32(4):384-5. 31. Elgart GW, Hanly A, Busso M, Spencer JM. Bednar tumor (pigmented dermatofibrosarcoma protuberans) occurring in a site of prior immunization: immunochemical findings and therapy. J Am Acad Dermatol 1999; 40(2 Pt 2):315-7. 32. Suehara Y, Yazawa Y, Hitachi K. Metastatic Bednar tumor (pigmented dermatofibrosarcoma protuberans) with fibrosarcomatous change: a case report. J Orthop Sci 2004; 9(6):662-5. 33. Zardawi IM, Kattampallil J, Rode J. An unusual pigmented skin tumour. Bednar Tumour, dorsum of left foot (pigmented dermatofibrosarcoma protuberans). Pathology 2004; 36(4):358-61. 34. Reis-Filho JS, Milanezi F, Ferro J, Schmitt FC. Pediatric pigmented dermatofibrosarcoma protuberans (Bednar tumor): case report and review of the literature with emphasis on the differential diagnosis. Pathol Res Pract 2002; 198(9):621-6. 35. Seo IS, Goheen M, Min KW. Bednar tumor: report of a case with immunohistochemical and ultrastructural study. Ultrastruct Pathol 2003; 27(3):205-10. 36. West RB, Harvell J, Linn SC, et al. Apo D in soft tissue tumors: a novel marker for dermatofibrosarcoma protuberans.[erratum appears in Am J Surg Pathol. 2004 Oct;28(10):1400 Note: Chih Long, Lui [corrected to Chih Long, Liu]. Am J Surg Pathol 2004; 28(8):1063-9. 37. Sachdev R, Sundram U. Expression of CD163 in dermatofibroma, cellular fibrous histiocytoma, and dermatofibrosarcoma protuberans: comparison with CD68, CD34, and Factor XIIIa. J Cutan Pathol 2006; 33(5):353-60. 38. Zamecnik M, Michal M. EMA+ cells in dermatofibrosarcoma protuberans. A study of 11 tumors suggesting perineurial cell differentiation. Cesk Patol 2002; 38(2):55-62. 39. Alguacil-Garcia A, Unni KK, Goellner JR. Histogenesis of dermatofibrosarcoma protuberans. An ultrastructural study. Am J Clin Pathol 1978; 69(4):427-34.
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40. Hashimoto K, Brownstein MH, Jakobiec FA. Dermatofibrosarcoma protuberans. A tumor with perineural and endoneural cell features. Arch Dermatol 1974; 110(6):87485. 41. Wang J, Hisaoka M, Shimajiri S, Morimitsu Y, Hashimoto H. Detection of COL1A1PDGFB fusion transcripts in dermatofibrosarcoma protuberans by reverse transcription-polymerase chain reaction using archival formalin-fixed, paraffin-embedded tissues. Diagn Mol Pathol 1999; 8(3):113-9. 42. Sirvent N, Maire G, Pedeutour F. Genetics of dermatofibrosarcoma protuberans family of tumors: from ring chromosomes to tyrosine kinase inhibitor treatment. Genes Chromosomes Cancer 2003; 37(1):1-19. 43. Maire G, Martin L, Michalak-Provost S, et al. Fusion of COL1A1 exon 29 with PDGFB exon 2 in a der(22)t(17;22) in a pediatric giant cell fibroblastoma with a pigmented Bednar tumor component. Evidence for age-related chromosomal pattern in dermatofibrosarcoma protuberans and related tumors. Cancer Genet Cytogenet 2002; 134(2):156-61. 44. Nishio J, Iwasaki H, Ishiguro M, et al. Supernumerary ring chromosome in a Bednar tumor (pigmented dermatofibrosarcoma protuberans) is composed of interspersed sequences from chromosomes 17 and 22: a fluorescence in situ hybridization and comparative genomic hybridization analysis. Genes Chromosomes Cancer 2001; 30(3):305-9. 45. Escalona-Zapata J, Alvarez Fernandez E, Llorca Escuin F. The fibroblastic nature of dermatofibrosarcoma protuberans. A tissue culture and ultrastructural study. Virchows Arch A Pathol Anat Histol 1981; 391(2):165-75. 46. Ozzello L, Hamels J. The histiocytic nature of dermatofibrosarcoma protuberans. Tissue culture and electron microscopic study. Am J Clin Pathol 1976; 65(2):136-48. 47. Goncharuk V, Mulvaney M, Carlson JA. Bednar tumor associated with dermal melanocytosis: melanocytic colonization or neuroectodermal multidirectional differentiation? J Cutan Pathol 2003; 30(2):147-51. 48. McCarthy S, Scolyer R, Palmer A. Desmoplastic melanoma: a diagnostic trap for the unwary. Pathology 2004; 36(5):445-51. 49. Kamino H, Jacobson M. Dermatofibroma extending into the subcutaneous tissue. Differential diagnosis from dermatofibrosarcoma protuberans. Am J Surg Pathol 1990; 14(12):1156-64. 50. Fetsch JF, Michal M, Miettinen M. Pigmented (melanotic) neurofibroma: a clinicopathologic and immunohistochemical analysis of 19 lesions from 17 patients. Am J Surg Pathol 2000; 24(3):331-43. 51. Inaba M, Yamamoto T, Minami R, Ohbayashi C, Hanioka K. Pigmented neurofibroma: report of two cases and literature review. Pathol Int 2001; 51(7):565-9. 52. Kleihues P Cavenee WK, International Agency for Research on Cancer. Pathology and , genetics of tumours of the nervous system. Lyon: IARC Press; 2000. 53. Marcus JR, Few JW, Senger C, Reynolds M. Dermatofibrosarcoma protuberans and the Bednar tumor: treatment in the pediatric population. J Pediatr Surg 1998; 33(12):1811-4. 54. Abbott JJ, Oliveira AM, Nascimento AG. The prognostic significance of fibrosarcomatous transformation in dermatofibrosarcoma protuberans. Am J Surg Pathol 2006; 30(4):436-43. 55. Goldblum JR, Reith JD, Weiss SW. Sarcomas arising in dermatofibrosarcoma protuberans: a reappraisal of biologic behavior in eighteen cases treated by wide local excision with extended clinical follow up. Am J Surg Pathol 2000; 24(8):1125-30. 56. Zelger B, Zelger B. Sarcomas arising in dermatofibrosarcoma protuberans: collision or illusion? [comment] Am J Surg Pathol 2001; 25(8):1106-8.
Rajmohan Murali and Richard A. Scolyer
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Case History
39-year-old male presented with a 6 mm tender nodule on his right forearm. The clinical diagnosis was dermatofibroma. A punch biopsy was performed, followed by a conservative re-excision. There is no sign of recurrence after three years.
Figure 1
Figure 2
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Figure 4
The tumor is located in the reticular dermis and shows a vaguely lobulated growth pattern. The tumor has a micronodular, infiltrative appearance. The tumor lacks a junctional component, and the overlying epidermis is unremarkable. Nodules and bundles of tumor cells infiltrate dermal collagen.
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Figure 5: Figure 6: Figure 7: Figure 8: Figure 9: Figure 10:
Irregular fascicles of tumor cells separated by hyalinized dermal collagen. The tumor has a variably nested and solid architecture with scattered pleomorphic cells. Nests of epithelioid to spindled cells with pale cytoplasm. The tumor is poorly marginated: neoplastic cells infiltrate into the adjacent dermis. Nests of tumor cells showing palely eosinophilic cytoplasm. In areas, the dermal collagen within the tumor is markedly hyalinized.
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Figure 11
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Figure 15
Figure Figure Figure Figure Figure
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Epithelioid to spindled cells with somewhat syncytial pale cytoplasm. Scattered pleomorphic cells including binucleated forms. Rare atypical mitotic figures are present. The tumor cells show diffuse immunoreactivity for NKI-C3. NSE is positive in tumor cells.
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Diagnosis
Cellular neurothekeoma.
Commentary
Background
Cellular neurothekeomas are uncommon distinctive benign cutaneous tumors of uncertain histogenesis. They continue to pose diagnostic problems to pathologists and are not infrequently mistaken for malignant tumors. The term neurothekeoma (Gr. theke, sheath) was first coined by Gallager and Helwig in 19804 in a study of benign tumors of the dermis that the authors believed were neural in origin. This unfortunate designation has resulted in considerable confusion surrounding the histogenesis of these lesions. In fact, many of the lesions illustrated by Gallager and Helwig appear identical to the nerve sheath myxomas previously described by Harkin and Reed.5 Furthermore, the desmoplastic variant of nerve sheath myxoma later illustrated by Pulitzer and Reed in 19857 closely resembles some of the lesions that Gallager and Helwig described. The neurothekeomas that have little or no myxoid stroma became generally known as cellular neurothekeomas following publications by Rosati et al. in 19868 and Barnhill and Mihm in 1990.1 Several additional studies over the ensuing decade further confused the issue by publishing series of neurothekeomas that included putative examples of cellular, mixed-type and myxoid variants (many of the latter representing nerve sheath myxomas). However, although immunophenotypic and ultrastructural studies have confirmed that dermal nerve sheath myxomas are Schwannian in nature, there is no good evidence that cellular neurothekeomas are nerve sheath tumors at all. Based upon the results of two recent large series,3,6 it appears that nerve sheath myxomas are unrelated to cellular and so-called mixed-type neurothekeomas, which instead simply represent cellular neurothekeomas with focally myxoid stroma. At present, the line of differentiation exhibited by the cells of cellular neurothekeoma remains unknown.
Clinical features
Cellular neurothekeomas typically affect patients in the first three decades of life (mean age, 25 years), with a 2:1 female predominance. Only 15% of patients with cellular neurothekeomas are greater than 40 years of age. Most cellular neurothekeomas arise on the upper extremities and head and neck, the face being the single most common anatomic site. Patients typically present with a painless nodule; the clinical diagnosis is often a cyst or a dermatofibroma. Cellular neurothekeomas only occasionally recur locally in a non-destructive fashion, generally following incomplete excision. No cellular neurothekeomas have metastasized.
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Pathologic features
Most cellular neurothekeomas are between 0.5 and 2 cm in greatest dimension (mean size, 1 cm); larger tumors are uncommon. Cellular neurothekeomas may be limited to the dermis or may also involve the subcutis. Histologically, cellular neurothekeomas show a lobulated or micronodular architecture and are poorly marginated with infiltrative borders into the surrounding dermal collagen. A subset of cellular neurothekeomas show infiltration into fat, and occasional lesions on the face entrap underlying skeletal muscle. Cellular neurothekeomas are composed of nests or bundles of variably epithelioid to spindled cells containing abundant palely eosinophilic cytoplasm, frequently separated by dense hyalinized collagen. Occasional tumors show areas of sheet-like growth. Approximately 30% of cellular neurothekeomas contain focally myxoid stroma, which rarely predominates. The fact that some cellular neurothekeomas have myxoid stroma was the basis for confusion with dermal nerve sheath myxoma (formerly also known as myxoid neurothekeoma, as described above). Cytologically, the cells within cellular neurothekeomas typically contain round to ovoid nuclei with fine chromatin and often show mild nuclear atypia in the form of nuclear variability and small nucleoli. The cells contain abundant pale cytoplasm and have ill-defined cell borders, sometimes with a syncytial appearance. The mitotic rate is generally low, ranging from 1-4 per 10 HPF Some cellular neu. rothekeomas contain pleomorphic cells with large nuclei and prominent nucleoli and a high mitotic rate (occasionally including atypical mitotic figures). These examples have been known as atypical cellular neurothekeomas.2 However, the presence of atypical histologic features has no clinical significance and does not affect the rate of local recurrence. There are no specific immunohistochemical stains to confirm the diagnosis of cellular neurothekeoma. However, NKI-C3 and NSE are virtually always diffusely positive. Although these markers lack specificity, they can be useful to support the diagnosis in the appropriate context. Nearly 60% of cellular neurothekeomas show at least focal positivity for SMA, whereas desmin is negative. Most importantly, S-100 protein, HMB-45, and melan-A are always negative in cellular neurothekeomas.
The main differential diagnosis for cellular neurothekeoma is melanocytic tumors (in particular, Spitz nevus), dermal nerve sheath myxoma, pilar leiomyoma, and plexiform fibrohistiocytic tumor. Spitz nevi occur at a similar age and at similar anatomic sites as cellular neurothekeoma. They also share a nested architecture and variably epithelioid to spindled cytomorphology. However, cellular neurothekeomas lack the junctional component and downward maturation characteristic of Spitz nevi. In addition, the presence of focal
melanin pigment can be another diagnostic clue for a Spitz nevus. Immunostains can easily distinguish between these possibilities, since cellular neurothekeomas lack melanocytic markers (e.g., S-100 and HMB-45). As mentioned above, cellular neurothekeomas may contain variably prominent myxoid stroma and may thus resemble dermal nerve sheath myxoma. However, nerve sheath myxoma lacks the infiltrative architecture of cellular neurothekeoma. Instead, the lobules of dermal nerve sheath myxoma are very sharply demarcated. Since it is composed of Schwann cells, dermal nerve sheath myxoma is positive for S-100 protein and GFAP whereas these markers are negative in , cellular neurothekeoma. Pilar smooth muscle tumors are composed of bundles of spindle cells that ramify between dermal collagen bundles. Although they share the infiltrative growth and spindle cell morphology of some cellular neurothekeomas, pilar leiomyomas typically contain cells with more brightly eosinophilic cytoplasm and more elongated nuclei. Since leiomyomas are nearly always diffusely positive for desmin, whereas cellular neurothekeomas are negative, this marker is helpful to differentiate between these tumors. Plexiform fibrohistiocytic tumors arise on the upper extremities of children and young adults, very similar to cellular neurothekeomas. Plexiform fibrohistiocytic tumors are typically superficial, involving the subcutis and dermis. Since cellular neurothekeomas may infiltrate into the subcutaneous fat, this differential diagnosis can be problematic. Plexiform fibrohistiocytic tumors are multinodular and biphasic. They are composed of small nodules of bland mononuclear histiocytoid cells and scattered osteoclasts, interconnected by fascicles of fibroblast-like spindle cells. Cellular neurothekeoma lacks this biphasic architecture and generally contains cells with more epithelioid cytomorphology. Immunohistochemistry is not helpful in this differential diagnosis.
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Figure 16
Figure 17
Figure 18
Figure 19
A cellular neurothekeoma containing bundles of epithelioid to spindled cells infiltrating between hyalinized dermal collagen. The cells in cellular neurothekeoma contain abundant palely eosinophilic cytoplasm and typically show mild nuclear atypia in the form of nuclear variability and small nucleoli. A cellular neurothekeoma composed of nests of epithelioid cells with abundant pale cytoplasm. Nodules of tumor cells in a cellular neurothekeoma showing a somewhat plexiform growth pattern.
219
Figure 20
Figure 21
Figure 20:
Nests of cytologically uniform tumor cells infiltrate the reticular dermis in a cellular neurothekeoma. Some cellular neurothekeomas contain myxoid stroma. Cellular neurothekeomas are positive for NKI-C3.
Figure 22
References
1. Barnhill RL, Mihm MC, Jr. Cellular neurothekeoma. A distinctive variant of neurothekeoma mimicking nevomelanocytic tumors. Am J Surg Pathol 1990; 14:113-120. 2. Busam KJ, Mentzel T, Colpaert C, et al. Atypical or worrisome features in cellular neurothekeoma: a study of 10 cases. Am J Surg Pathol 1998; 22:1067-1072. 3. Fetsch JF, Laskin WB, Miettinen M. Nerve sheath myxoma: a clinicopathologic and immunohistochemical analysis of 57 morphologically distinctive, S-100 protein- and GFAP-positive, myxoid peripheral nerve sheath tumors with a predilection for the extremities and a high local recurrence rate. Am J Surg Pathol 2005; 29:1615-1624. 4. Gallager RL, Helwig EB. Neurothekeoma a benign cutaneous tumor of neural origin. Am J Clin Pathol 1980; 74:759-764. 5. Harkin JC, Reed RJ. Atlas of Tumor Pathology: Tumors of the Peripheral Nervous System, second series, fascicle 3. Washington, D.C.: Armed Forces Institute of Pathology, 1969. 6. Hornick JL, Fletcher CDM. Cellular neurothekeoma: detailed characterization in a series of 133 cases. Am J Surg Pathol 2006, in press. 7. Pulitzer DR, Reed RJ. Nerve-sheath myxoma (perineurial myxoma). Am J Dermatopathol 1985; 7:409-421. 8. Rosati LA, Fratamico FC, Eusebi V. Cellular neurothekeoma. Appl Pathol 1986; 4:186191.
Jason L. Hornick
220
CASE 29
Case History
his 34-year-old gentleman presented with a two-year history of a pigmented papule with a surrounding halo on the anterior aspect of the left thigh.
Figure 1
Figure 2
Figure 3
Figure 4
This dermal based neoplasm shows cellular and myxoid areas with an admixture of adipose tissue. Note the hyperplasia of the overlying epidermis. Solid sheets of epithelioid to spindle cells with indistinct cell borders and ovoid nuclei form the majority of this tumor. A mitotic figure is present in the center of the field. A myxoid matrix containing bland appearing spindle cells is an additional finding.
221
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10

222
Tumor cells display a more epithelioid cytomorphology in areas of stromal hyalinization. Fascicular growth is a further pattern. Higher magnification of the fascicular areas highlights the spindle cell differentiation reminiscent of smooth muscle. Adipocytic metaplasia is demonstrated in this field.
Case 29
Figure 11
Figures 9-11:
Tumor cells stain positively for S-100, SMA and EMA.
Diagnosis
Cutaneous myoepithelioma.
Commentary
Introduction
Myoepitheliomas are rare but distinctive tumors that are well-recognized in salivary glands but have only recently been described in the skin. They are closely related to mixed tumors but lack the ductal differentiation. Mixed tumors of skin (chondroid syringomas) are not uncommon benign cutaneous neoplasms with a predilection for the head and neck. They present as circumscribed tumors involving the deep dermis and subcutaneous tissue. Analogous to their counterparts in salivary gland tissue (pleomorphic adenoma), cutaneous mixed tumors are characterized by an admixture of ducts and a proliferation of myoepithelial cells within a myxoid stroma. The morphologic spectrum of the myoepithelial cell component is wide and includes plasmacytoid as well as epithelioid, spindle or clear cell features. Architecturally, myoepithelial cells most often form solid sheets, but a trabecular, reticular and nested architecture may also be seen. The immunohistochemical myoepithelial phenotype is characterized by expression of epithelial antigens in addition to S-100, GFAP and , markers of myoid differentiation. Purely myoepithelial tumors (cutaneous myoepithelioma) show a similar range of features. They are rare and less than 30 cases have been reported in the literature so far.
223
Clinical findings
This rare cutaneous tumor shows a wide age distribution, but most commonly affects adolescents and young adults with a male predominance. The typical clinical presentation is of a flesh colored papule or nodule measuring around 1 cm. There is a strong predilection for the extremities but other anatomic sites including the head and neck area and trunk may also be involved.
Histological findings
Cutaneous myoepitheliomas show close morphologic resemblance to their salivary gland counterparts and display a wide morphologic spectrum. They are centered within the dermis as a well-circumscribed, uni- or multilobulated but unencapsulated neoplasm (Fig. 1). Involvement of subcutaneous tissue may be a feature. The overlying epidermis is often hyperplastic, occasionally with formation of a collarette. The most characteristic pattern is the presence of solid sheets of uniform epithelioid to spindle cells with ovoid nuclei and small, inconspicuous nucleoli (Fig. 2). Cytologically, they show somewhat histiocytoid features with abundant palely eosinophilic cytoplasm (Fig. 2). The cell borders are indistinct giving rise to a syncytial appearance. Mitoses can be identified and average about 1-2/10 HPF (Fig. 3). Nuclear pleomorphism is not a feature. A myxoid matrix may be identified containing slender spindle cells (Fig. 4). Cells with more epithelioid morphology are often seen within a background of stromal fibrosis or hyalinization (Fig. 5). Other features include fascicular growth reminiscent of smooth muscle tumors (Figs. 6 & 7), a reticular architecture within an abundant myxoid stroma, prominent plasmacytoid cytomorphology as well as adipocytic metaplasia (Fig. 8). By definition, ductal differentiation is absent. Immunohistochemically, cutaneous myoepitheliomas show expression of epithelial markers (cytokeratins or EMA) in conjunction with reactivity for S-100 and/or GFAP (Figs. 9 & 10). Of note, the distinctive syncytial variant of cutaneous myoepithelioma is positive for EMA, but generally negative for cytokeratins. In addition, myogenic markers such as SMA and calponin are typically expressed (Fig. 11). Detection of p63 and desmin is observed in few cases.
Prognosis
Myoepitheliomas have a tendency for local recurrence in about one third of cases. Lymph node metastasis is exceedingly rare and no death from disease has been documented so far. It is difficult at this point to identify histologic predictors of more aggressive behavior but increased mitotic count appears to correlate at least to some extent with local recurrence and metastatic potential. Histologic criteria for classification as myoepithelial carcinoma have been adopted from soft tissue tumors and include marked cytological atypia, high mitotic rate and tumor necrosis. Experience with these cases is, however, extremely limited at the moment.
Case 29
The differential diagnosis of myoepithelioma is wide and depends largely on the histological pattern. Myoepithelioma shares many of the architectural, cytological and immunohistochemical features with melanocytic lesions such as Spitz naevus and melanoma, which are the main entities to be considered in the differential diagnosis. Distinguishing features include the lack of a junctional component, nested architecture or melanin pigment in myoepitheliomas. In addition, myoepitheliomas lack cytological and architectural maturation with depth as observed in Spitz nevi and do not display the degree of pleomorphism typically seen in melanoma. Nevertheless, this can be a challenging differential diagnosis on morphologic grounds. Immunohistochemistry is helpful when the differential diagnosis of myoepithelioma is entertained. Cellular neurothekeoma is a distinctive benign cutaneous neoplasm presenting in the head and neck and upper extremities of adolescents and young adults. It shares at least some cytological features with myoepithelioma, but tends to show a more infiltrative growth in bundles and small nests within the dermis with a higher degree of pleomorphism. Immunohistochemically, cellular neurothekeoma expresses NKI-C3, NSE and SMA but lacks staining for S-100 or epithelial markers. Epithelioid fibrous histiocytoma is a rare benign tumor that typically presents as an erythematous polypoid nodule on the lower extremities of young adults. Histologically, it is well-circumscribed and characterized by a polypoid or nodular architecture with prominent collarette formation. It is composed of large polygonal epithelioid cells with abundant eosinophilic cytoplasm and vesicular nuclei with small nucleoli. Multinucleate forms are frequently observed and mitotic figures are scarce. Frequently, there is a background of a spindle cell population reminiscent of classic fibrous histiocytoma/dermatofibroma and there is increased vascularity. Tumor cells may express smooth muscle actin but, in contrast to myoepithelioma, they are negative for S-100 or epithelial markers. Epithelioid sarcoma presents on the distal extremities of young adults. It is typically a tumor of soft tissue but it can involve the skin and can then be confused with cutaneous myoepithelioma. The clinical behavior is characterized by a high rate of local recurrence as well as metastasis to lymph nodes. Other sites of distant metastasis include lung, skin and soft tissue. Even though five-year survival appears relatively good, long-term survival is estimated to be less than 50%. Epithelioid sarcoma typically involves dermis and subcutaneous tissue and shows a multilobulated architecture. It is composed of individual nodules frequently showing central necrosis reminiscent of necrobiotic lesions. Frequently, bright red collagen is present within the tumor, which is composed of epithelioid to spindle cells with indistinct cell borders and eosinophilic cytoplasm. By immunohistochemistry, reactivity
with EMA, cytokeratin and CD34 is observed. Only rare examples show expression of S-100 or CD31.
References
1. 2. Hornick JL, Fletcher CD. Cutaneous myoepithelioma: a clinicopathologic and immunohistochemical study of 14 cases. Hum Pathol 2004; 35(1):14-24. Mentzel T, Requena L, Kaddu S, Soares de Aleida LM, Sangueza OP Kutzner H. , Cutaneous myoepithelial neoplasms: clinicopathologic and immunohistochemical study of 20 cases suggesting a continuous spectrum ranging from benign mixed tumor of the skin to cutaneous myoepithelioma and myoepithelial carcinoma. J Cutan Pathol 2003; 30(5):294-302. Kutzner H, Mentzel T, Kaddu S, Soares LM, Sangueza OP Requena L. Cutaneous , myoepithelioma: an under-recognized cutaneous neoplasm composed of myoepithelial cells. Am J Surg Pathol 2001; 25(3):348-55. Michal M, Miettinen M. Myoepitheliomas of the skin and soft tissues. Report of 12 cases. Virchows Arch 1999; 434(5):393-400. Fernandez-Figueras MT, Puig L, Trias I, Lorenzo JC, Navas-Palacios JJ. Benign myoepithelioma of the skin. Am J Dermatopathol 1998; 20(2):208-12. Kilpatrick SE, Hitchcock MG, Kraus MD, Calonje E, Fletcher CD. Mixed tumors and myoepitheliomas of soft tissue: a clinicopathologic study of 19 cases with a unifying concept. Am J Surg Pathol 1997; 21(1):13-22. Hornick JL, Fletcher CD. Myoepithelial tumors of soft tissue: a clinicopathologic and immunohistochemical study of 101 cases with evaluation of prognostic parameters. Am J Surg Pathol 2003; 27(9):1183-96.
3.
4. 5. 6.
7.
Thomas Brenn
226
CASE 30
Case History
n 83-year-old woman, status post cerebral bleed, presents with a 6 x 4.5 mm blue macule on her right elbow. Please rule out an atypical versus a blue nevus.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 1:
Figure 2:
Figure 3: Figure 4:
Scanning magnification showing minimal changes. The changes at this magnification can be subtle and raise the differential of normal skin. However, even at this magnification, the involvement of the elastic fibers can be noted in the lower left. High magnification illustrating the fine pigment deposition in the basement membrane of the eccrine sweat ducts. The pigments appear as small black particles. High magnification showing pigment deposition on elastic fibers in the dermis. The pigments appear as small black particles. High magnification showing perivascular pigment deposition. The pigments appear as small black particles.
227
Diagnosis
Argyria (Silver deposition).
Commentary
Argyria is an iatrogenic disorder provoked by prolonged mucocutaneous contact with silver or by ingestion of silver-containing compounds.1 Cutaneous manifestations present as bluish-gray or ash gray pigmentation affecting the skin, nail bed, and oral mucous membranes, that is intensified in areas exposed to sunlight. The photoactivated reduction of the absorbed silver salts to metallic silver and increased epidermal melanin synthesis are considered to cause these pigmentary changes that usually remain invariable with time.2 Argyria may occur localized or generalized. Localized argyria resulting from direct external contact with silver has been described after the use of acupuncture needles,3 catheters,4 dental amalgan,5 and after wearing of silver earrings in pierced ears among other conditions.6 Generalized argyria is acknowledged to develop from inhalation, ingestion, or injection of silver compounds into the body, and also from application to mucosal surfaces. The dominant histological features in argyria are numerous fine dark brown to black granular particles in the papillary dermis (Fig. 1) particularly concentrated in the basement membrane zones of eccrine sweat glands (Fig. 2), in elastic fibers (Fig. 3), and to a lesser amount in capillary walls (Fig. 4), perifollicular sheaths, and in the arrector pili muscles. The minute granules present brown-black in hematoxylin and eosin stained sections and measure less than 1.0 m in diameter. There are no silver particles found in the epidermis but hypermelanosis is evident in the basal layer, especially in sunexposed areas. Ultrastructurally, the granules may appear as membrane-bound within macrophage lysosomes or present loosely in the dermis.7 Silver deposits are more simply identified on dark-field examination suggesting a stars in heaven structure. Gold granules that may also be visualized on dark filed exam are larger in size and, in contrast to silver, do not manifest as deposition on membranes but present in vascular endothelia and dermal phagocytes. Usually, there is no increased epidermal melanin pigmentation as seen in argyria. Gold deposition (chrysiasis) resulting from prolonged gold injections, e.g. for the treatment alternative of rheumatoid arthritis and pemphigus, manifests clinically as lasting blue-gray discoloration of the skin, most prominent in sun-exposed areas. Further differential diagnosis of argyria includes various pigmented deposits such as ochronosis, hemochromatosis, Monsels reaction, and tattoo. For several of these agents diffuse, generalized blue to gray-brown pigmentation is common. Drug-induced skin pigmentation may be induced by a wide variety of drugs, including non-steroidal anti-inflammatory drugs (NSAIDs), phenytoin, antimalarials, amiodarone, antipsychotic
228
Case 30
drugs, cytotoxic drugs, tetracyclines (Figs. 5 & 6), and heavy metals. Tattoo pigments present as small black granules usually in macrophages but unlike to argyria they do not show accentuation along basement membranes (Figs. 7 & 8). They can be easily detected in macrophages (revealing a granular or crystalline pattern) and in fibroblasts surrounding vessels in the dermis. Late-stage conditions show histological features of dermal contact dermatitis, lichenoid dermatitis, epidermal spongiosis, foreign-body and sarcoidal granulomatous reactions. Tattoo may arise accidentally caused by unintentional introduction of exogenous pigmented substances such as asphalt, graphite, or carbon into the skin but more frequently result from deliberate cosmetic injections of dye substances. Tattoo typically contains a variety of different pigments of diverse colors that allows the distinction between other pigmented deposits including argyria. Dermal deposits of golden brown, irregularly shaped material appear in hemochromatosis, a multisystemic disorder of iron metabolism in which cutaneous pigmentation manifests in a large number of patients varying from bronze to blue-gray discoloration. The granules are commonly found in and around the basement membrane of eccrine units, around blood vessels or in association with sebaceous glands and their stroma. Increased melanin pigmentation in the basal layer, probably resulting from the hemosiderin deposits in the dermis, and coexisting thinning of the epidermis lead to the typical bronze coloration of the skin. Hemosiderin deposits in the skin have also been reported after the use of ferric subsulfate (Monsels solution) as a hemostatic agent. In this condition, referred to as Monsels reaction, aqueous ferric subsulfate induces ferrugination of collagen fibers with several siderophages and multinucleate giant cells in the interstitial tissue of the dermis (Figs. 9-11). Furthermore, hemosiderin causes hyperpigmentation when extravasated blood cells lyse and release iron stores. In this condition, so called hemosiderosis, dermal deposits of a yellow brown chunky material, mostly in perivascular spaces can be detected. However, the golden semblance of hemosiderin and a positive Perls stain permit separation from argyria and other pigments, Similar to argyria, in ochronosis pigment granules present in the basement membrane of eccrine glands (Figs. 12 & 13), in the endothelial cells of blood vessels, and within dermal macrophages.8 The most diagnostic feature of deposition are clearly defined crescentic or irregularly shaped ochre-colored dermal collagen fibers apparent in the superficial dermis that become swollen and fragmented. In advanced more severe stages degeneration of the ochronic fibers, the occurrence of inflammatory mediators including multinucleate giant cells, plasma cells, and histiocytes, and a transepidermal elimination of pigment has been observed.9,10 The typically homogentisic acid crystals within the particles stain black with cresyl violet or methylene blue. The term ochronosis, first described by Virchow in 1966 as the occurrence of clinically blue-black pigmentation in the skin associated with the
229
microscopic findings of an ochre-colored pigment, refers not only to homogentisic acid accumulation in collagen-containing tissues in alkaptonuria but is also used for the deposition of similar hydroquinone derivates in certain exogenously induced conditions following the use of products containing hydroquinone, phenol, resorcinol, mercury or picric acid.11 The above described assorted heavy metals cause various deposits and pigmentary changes that can be distinguished in the different histopathologic features presenting with. However, clinical history should establish the diagnosis in the majority of the cases.
Figure 5
Figure 6
Figure 7
Figure 8
Figure 5:
Figure 6:
Minocycline (a second generation tetracycline) pigment deposition. Scanning magnification showing vascular proliferation with surrounding inflammation. The pigment can be noted even at scanning magnification. Minocycline pigment deposition. Note the dark brown pigment granules in perivascular macrophages.
230
Case 30
Figure 9
Figure 10
Figure 11
Figure 12
Figure 7:
Figure 8:
Figure 9:
Figure 10:
Tattoo. Scanning magnification showing tattoo pigment deposition. Note pigment in fibroblasts in the superficial dermis and in perivascular macrophages throughout the dermis. Tattoo. High magnification illustrating the tattoo pigment in the perivascular macrophages. Graphite and other carbon based tattoos such as seen in this figure show small black particles similar to silver deposits, however, they are located intracellularly. Monsels reaction. Scanning magnification reveals a dermal scar, consistent with a prior surgical procedure. In addition, the presence of a brown pigment can be noted in the scar. Monsels reaction. High magnification illustrating the brown pigment in macrophages. Note that the particle sizes are variable, not the uniform small sizes seen in argyria. Monsel's reaction. High magnification of the Perls stain showing the Prussian blue reaction of the pigments in the Monsels reaction. Ochronosis. Scanning magnification showing the deposition of golden brown pigment in the basement membrane zone of eccrine glands and in dermis.
231
Figure 13
Figure 13:
Ochronosis. High magnification illustrating the deposition in the basement membrane zone of eccrine glands. Note the homogenous, brown pigment.
References
1. Granstein Rd, Sober AJ. Drug- and heavy metal-induced hyperpigmentation. J Am Acad Dermatol 1981; 5:1-18. 2. Shelley WB, Shelley ED, Burmeister V. Argyria: the intradermal photograph, a manifestation of passive photosensitivity. J Am Acad Dermatol 1987; 16:211-217, 3. Suzuki H, Baba S, Uchigasaki S, Murase M. Localized argyria with chrysiasis caused by implanted acupuncture needles. J Am Acad Dermatol 1993; 29:833-837. 4. Saint S, Veenstra DL, Sullivan SD, Chenoweth C, Fendrick AM. The potential clinical and economic benefits of silver alloy urinary catheters in preventing urinary tract infection. Arch Intern Med 2000; 160:2670-5. 5. Catsakis LH, Sulica VI. Allergy to silver amalgams. Oral Surg 1978; 46:371-5. 6. Morton CA, Fallowfield M, Kemmet D. Localized argyria caused by silver earrings. Br J Dermatol 1996; 135(3):484-5. 7. Bleehen SS, Gould DJ, Harrington CI, Durrant TE, Slater DN, Underwood JC. Occupational argyria; light and electron microscopic studies and X-ray microanalysis. Br J Dermatol 1981; 104:19-26. 8. Lichtenstein L, Kaplan L, Hereditary ochronosis. Pathologic changes observed in two necropsied cases. Am J Pathol 1954; 30:99-125. 9. Jacyk WK. Annular granulomatous lesions in exogenous ochronosis are manifestations of sarcoidosis. Am J Dermapathol 1995; 17:18-22 10. Levin CY, Maibach H. Exogenous ochronosis. An update on clinical features, causative agents and treatment options. Am J Clin Dermatol 2001; 2(4):213-7. 11. Hardwick N, Gelder LW, Merwe CA, Merwe MP Exogenous ochronosis: an epidermi. ological study. Br J Dermatol 1989; 120:229-38.
Ruth Holzmann and Thomas J. Flotte
232
CASE 31
Case History
46-year-old woman presented with mottled blue-gray macules on her cheeks which worsened following prolonged use of a bleaching cream.
Figure 1
Figure 2
Figures 1 & 2:
The tissue sections demonstrate the characteristic finding of degenerated banana-shaped dermal collagen fibers which become swollen, rigid and fragmented, with deposition of yellow-brown (ochre-colored) pigment.
Diagnosis
Exogenous ochronosis.
Commentary
Exogenous ochronosis results from topical application of phenolic intermediates such as hydroquinone, carbolic acid (phenol), picric acid and resorcinol. Hydroquinone specifically inhibits the enzyme homogentisic acid oxidase locally, resulting in accumulation of this substance on the collagen fibers and elastic fibers in the dermis. Histologically, the pigment in the dermis has a yellow-brown or ochre color with H&E stain. Clinically, the blue-gray color is produced by scattering of light from the deep-seated ochre-colored pigment (Tyndall effect). The diagnostic finding is the degenerated banana-shaped dermal collagen fibers which become swollen, rigid and fragmented, with deposition of pigment, and stain black with crystal violet or methylene blue. Exogenous ochronosis and alkaptonuria have identical changes on skin biopsy. Alkaptonuria is inherited as an autosomal recessive trait, and is caused by a deficiency in the renal and hepatic homogentisic
acid oxidase, the enzyme necessary for the catabolism of homogentisic acid to acetoacetic and fumaric acids. This disorder is characterized by the excretion of homogentisic acid in the urine to produce a black-staining urine, the deposition of a brown-black pigment in the connective tissue, and ochronotic arthropathy. The pigment in the connective tissue becomes apparent in the third decade of life. The earliest sign is the pigmentation of the sclera (Oslers sign) and the cartilage of the ears. Later on, the cartilage of the nose and tendons, especially those on the hands are involved. Mottled blue-gray macules develop on the skin, with a predilection for the fingers, ears, nose, genital regions, axillae, buccal and vaginal mucosa, and palmoplantar surfaces. The larynx, blood vessels, heart valves, kidneys, esophagus, tonsils and dura mater may also be affected. The cerumen is often black. The sweat glands are rich in ochronotic pigment granules, and intradermal injection of epinephrine into the skin of the axilla gives rise to black sweat droplets. Ochronotic arthropathy affects the spinal joints first, followed by knees, shoulders and hips.
References
1. 2. 3. Bongiomo MR, et al. Exogenous ochronosis and striae atrophicae following the use of bleaching creams. Int J Dermatol 2005; 44:112. Gutzmer R, et al. Alkaptonuric ochronosis. J Am Acad Dermatol 1997; 37:305. Lubics A, et al. Extensive bluish gray skin pigmentation and severe arthropathy. Arch Dermatol 2000; 36:548.
Alison Z. Young
234
CASE 32
Case History
35-year-old African man from Congo presented with a brownblack spot on his palm.
Figure 1
Figure 2
Figure 3
Figure 4
Figures 1-4:
Microscopic examination reveals abundant branching brown hyphal elements in the upper stratum corneum on routine H&E stained sections. There is no significant inflammation. In contrast to most dermatophyte infection, special stains are not necessary as the hyphae are pigmented. Histological findings in the context of clinical history of a pigmented macule are diagnostic.
235
Diagnosis
Tinea nigra.
Commentary
Tinea nigra is a superficial cutaneous mycosis caused by Hortaea or Exophiala werneckii (formerly Phaeoannellomyces werneckii), which is a black yeast-like hyphomycete found in hot, humid tropical regions. In the US, the infection is seen along the gulf coast. Clinically, tinea nigra presents as one or several brown or black spots on the palms or soles, occasionally mistaken as nevi or melanoma. Dermoscopy has been used to differentiate the lesions from melanocytic proliferations. The pigment is confined to the stratum corneum and scrapes off easily. The fungus can be easily demonstrated by means of a KOH preparation and microscopic examination or culture. In KOH preparations, the hyphae appear brown or golden in color. Young colonies are glossy, black and yeast-like, but older colonies are filamentous and gray. The pigment produced by the fungal hyphae is melanin. Culture will identify the organism. Histologically, abundant branching brown hyphal elements are present in the upper stratum corneum on H&E examination. There may be associated parakeratosis and a sparse superficial dermal perivascular inflammatory cell infiltrate.
References
1. 2. 3. Abliz P et al. Specific oligonucleotide primers for identification of Hortaea werneckii, , a causative agent of tinea nigra. Diagn Microbiol Infect Dis 2003; 46:89. Pegas JR, et al. Tinea nigra: report of two cases in infants. Pediatr Dermatol 2003; 20:315. Smith SB, et al. Dermoscopy in the diagnosis of tinea nigra plantaris. Cutis 2001; 68:377.
Alison Z. Young
236
CASE 33
Case History
n 83-year-old Caucasian man presented with asymptomatic blueblack patches on his bilateral shins and dorsal feet that had developed over a few months (Figs. 1 & 2). His medical history was notable for bullous pemphigoid, for which he had been taking minocycline and low-dose prednisone for several months to years. A punch biopsy was performed on a representative pigmented patch on the right pretibial area, revealing prominent pigment deposition noted perivascularly and interstitially in the superficial dermis (Figs. 3-5). Pigment granules show positive staining with Fontana-Masson and Perls Prussian blue stains (Figs. 6-8).
Figure 1
Figure 2
Figure 1: Figure 2:
Posterior view of the same patient with grey-black patches extending to calves. Eighty-three-year-old man with irregular grey-black patches over his pretibial areas and dorsal feet.
237
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Scanning magnification of the biopsy specimen show pigment-laden macrophages in upper dermis, most prominent around vessels (100x). Higher magnification of the biopsy specimen demonstrates brown coarse pigment granules within macrophages (200x). High magnification highlights brown, coarse pigment granules within macrophages (400x). Positive staining with Fontana-Masson stain (200x). Bleached sections of the biopsy specimen are negative for Fontana-Masson staining, but pigment granules can be seen within macrophages (100x). Positive staining with Perls Prussian blue stain (200x).
238
Case 33
Diagnosis
Minocycline-induced cutaneous pigmentation.
Commentary
Minocycline and its use in treatment of acne
As a semi-synthetic, second-generation tetracycline that has been in use since 1967, minocycline is a macrolide antibiotic, inhibiting protein synthesis by binding to the 30S ribosomal sub-unit. With relatively broad-spectrum antimicrobial activity, minocycline is bacteriostatic and exhibits activity against many Gram-positive and Gram-negative bacteria, allowing it to treat infections such as atypical pneumonias, sexually transmitted diseases, rickettsial infections, periodontal disease, and methicillin-resistant Staphylococcus aureus colonization.1,2 Minocyclines Gram-positive spectrum includes Propionibacterium acnes, which is implicated in inflammatory acne.3 Furthermore, minocycline also possesses other non-antibiotic properties including anti-inflammatory effects that likely are important in its efficacy in treatment of acne vulgaris, as well as in its use in other conditions such as bullous dermatoses and autoimmune disorders.4 Minocycline offers several advantages over the other tetracyclines in that it is a well-absorbed, broad spectrum, highly lipophilic antibiotic that shows little bacterial resistance, and little risk of phototoxicity. The high lipid solubility allows wide distribution, with high penetration into brain, thyroid, fat, nasal sinuses, bile, liver, breast milk, and saliva.7,8,9 Unfortunately, however, minocycline also can induce cutaneous hyperpigmentation. Interestingly, this pigmentation is not limited to skin2,10,11 alone, but has also been reported to involve nails, lips, oral mucosa, gingivae, post acne osteoma cutis, bones, teeth,12 costal cartilage, heart valves, thyroid,13 prostate, lymph nodes, substantia nigra, atherosclerotic plaques, conjunctival cysts, sclerae,11 breast milk, tongue, skeletal muscle, and even basal cell carcinoma.8,9 The incidence of minocycline-induced pigmentation is reportedly between 2.4% and 14%8, with the incidence of hyperpigmentation in patients treated with minocycline for pemphigus and pemphigoid reportedly higher than that reported in patients treated for acne and rheumatoid arthritis.2
Types of minocycline-induced pigmentation

Clinically and pathologically, three different types of minocyclineinduced cutaneous hyperpigmentation have been described (Table 1). Patients can present with more than one type simultaneously.14 The pigmentation tends to gradually fade and resolve over the course of months after minocycline has been discontinued. 1. Type I cutaneous pigmentation clinically appears as blue-black macules localized to sites of inflammation or scarring.5,6,10,15 Classically occurring within acne scars on the face, other sites
have also been reported including the chest of a patient with leprosy and the lower extremities of a patient who was status post sclerotherapy.5,16 Histologically, golden-brown to black-brown coarse granules are seen predominantly within macrophages, which are scattered throughout the papillary and reticular dermis in a mostly perivascular and peri-eccrine gland distribution. Histochemical analysis shows these granules to stain positively with Perls Prussian blue and negatively with Fontana-Masson, suggesting a component of hemosiderin, iron, or ferritin, but not melanin.15 Electron microscopy demonstrates two types of electron dense, non-membrane bound particles, consistent with hemosiderin or ferritin, within dermal macrophages.15 2. Type II cutaneous pigmentation is not associated with prior inflammation or scarring, but instead appears as generalized (either well-circumscribed or diffuse) blue-black, brown, or slate gray pigmentation on previously healthy normal skin, with a propensity to involve the extremities (Figs. 1 & 2).5,15 Routine hematoxylyn and eosin sections show similar morphologic features to type I, demonstrating dermal and subcutaneous gold-brown pigment-laden spindled macrophages (Figs. 9-12). However, unlike type I, these granules stain positively for both Perls Prussian blue (Fig. 13) and Fontana-Masson (Fig. 14). Treatment with hydrogen peroxide bleaching does not reduce the latter pigment, thus suggesting some substance other than melanin is the reactant.14,15 The main pigment present is iron, but two other pigments have been found, one of which has staining properties of melanin and the other of which is a minocycline degradation product. Iron is chelated by minocycline and forms an insoluble complex, possibly accounting for two of the pigments. This complex might induce melanogenesis.14,17 Ultrastructural studies reveal similar findings to those of type I with no melanosomes identified.14,18 X-ray energy spectroscopy shows these deposits to contain iron, as well as smaller amounts of sulfur, calcium, and chlorine.14,18 3. Like type II, type III cutaneous pigmentation involves clinically healthy normal skin. Classically described as a generalized, diffuse, and symmetrical muddy brown pigmentation, it shows an affinity for sun exposed areas.15,19 Microscopically, sections show basal keratinocyte hypermelanosis with associated pigmentary incontinence. These pigmentladen macrophages differ from both type I and type II by staining only with Fontana-Masson, and not with Prussian blue, thereby confirming the presence of melanin.19 More recently, a fourth type has been proposed.8 Similar in clinical presentation to type I, two patients were reported with blue-gray pigmentation confined to acne scars localized to the back. Light
240
Case 33
microscopy showed the classic dermal brown-black pigment deposition in both an intracellular (macrophages and dendritic cells) and extracellular location. The histochemical staining pattern was unique from the other types in that it showed no staining with Perls Prussian blue (iron), positive staining with Fontana-Masson (which was resistant to hydrogen peroxide bleaching suggesting a melanin-like substance), and positive staining for Von Kossa (calcium). Ultrastructurally, free and membrane-bound small and large electron dense granules were identified in both macrophages and fibroblast like cells. Additionally, electron translucent fissures were also appreciated within the granules suggestive of a calcium component. Energy-dispersive X-ray analysis detected calcium, sodium, phosphorus, and sulfur, but no iron.8 Additional reports have not yet been published, however, so it remains unclear if this truly represents a new type of minocycline pigmentation. Other reports of minocycline-induced pigmentation have noted a variation occurring on the lips, which histologically showed pigmentary incontinence, and may, in fact, represent a fixed drug eruption.20 Recently minocycline-induced pigmentation isolated to the subcutaneous tissue was reported.9 The mechanism by which minocycline causes pigment deposits within skin and other organs is not completely understood, though several theories have been proposed. Since minocycline is capable of chelating with bivalent ions such as iron and calcium, development of a reactive quinone iminium ion metabolite, iron chelation, or stimulation of melanin production, have all been explored as pathogenetic factors.8 Whatever the mechanism, it would seem that duration of therapy and total cumulative dose do not seem to influence type I pigmentation. Type II and III do appear to occur more frequently in those treated for longer period and/or with higher doses. The intensity of pigmentation, however, seems unrelated to both. And while types I and II seem to be reversible with withdrawal of the medication and with time, type III may persist indefinitely.5,8
241
Table 1: Types of cutaneous minocycline pigmentation

Clinical findings Type I Blue-black pigmentation at sites of prior injury. Most commonly occurs on the face. Histopathological findings Special stains
Epidermis normal. Large Fontana-Masson Perls macrophages containing Prussian blue + brown-black pigment are seen throughout the dermis and can extend into subcutaneous fat. Epidermis normal. Fontana-Masson Perls Spindle histiocytes with Prussian blue + coarse, gold-brown pigment granules scattered through the dermis and into the subcutaneous tissue. Increased pigmentation Fontana-Masson Perls in the basal layer of the Prussian blue + epidermis. Brown pigment in dermal macrophages.
Type II
Blue-gray pigmentation that occurs in previously normal skin. Most commonly occurs on legs and forearms.
Type III
Muddy-brown hyperpigmentation most prominent on sunexposed skin.
Histopathologic differential diagnosis of minocycline-induced hyperpigmentation

The main histopathological differential diagnosis for minocyclineinduced hyperpigmentation includes other types of drug-induced cutaneous hyperpigmentation (Fig. 15), or post-inflammatory pigmentation (Figs. 16 & 17) though for early or localized lesions, melanocytic lesions, particularly those that have undergone regression, and even tattoos (Figs. 18 & 19) may merit differential consideration. Table 2 lists the clinical and histological appearance and staining properties of the drugs that most commonly cause cutaneous hyperpigmentation.
Table 2: Drug-induced cutaneous pigmentation

Drug Amiodarone
21
Clinical appearance Slate-gray to bluishviolaceous pigmentation. Most prominent on sunexposed skin.
Histopathological findings Yellow-brown granules within macrophages and free in the superficial dermis. Pigment collection is most prominent perivascularly.
Staining material and special stains Amiodaronestains with periodic acidSchiff, tends to stain with FontanaMasson, but not Perls iron.
Clofazimine
21
Brown pigmentation, most prominent at sites of/over leprosy lesions.
Foamy macrophages Lipofuscinstains with in reticular dermis lipofuscin and containing brownish periodic acid-Schiff. granular pigment.
242
Case 33
Drug Antimalarials
22,23
Clinical appearance Blue-gray to dark purple pigmentation, most common on anterior shins, but can involve nails and head.
Histopathological findings
Staining material and special stains
Pigment both within Melanin and macrophages and hemosiderin. extracellularly throughout the dermis but most prominent in deeper dermis. Melanin is seen in deeper dermis and hemosiderin around capillaries. Pigment within macrophages throughout dermis but particularly around superficial vessels. Drug, melanin and melanin/drug complex. Stains with Fontana-Masson and DOPA.
Phenothiazines
22,23
Violet or purple-gray pigmentation of sun-exposed skin, often sparing facial wrinkles. Slate-gray pigmentation most prominent on sunexposed skin with sparing of skin folds.
Silver (Argyria)
23
Silver particles with Silver. a dark, brown/black granular appearance scattered in the dermis, but concentrated in membrane propria of eccrine sweat glands. Small, black, ovalshaped granules of varying size within macrophages and around blood vessels. Gold.
Gold (Chrysiasis)
23
Blue-gray pigmentation, most prominent around eyes with relative sparing of skin folds. Slate-gray pigmentation at sites of topical application, accentuated in skin folds.
Mercury
23
Coarse brown-black Mercury. granules in the upper dermis in macrophages, around capillaries and free.Sometimes increased basal layer epidermal hyperpigmentation.
243
Figure 9
Figure 10
Figure 11
Figure 12
Figure 13
Figure 14
Minocycline Pigmentation type II: Scanning magnification shows perivascular pigment-laden macrophages (100x). Minocycline Pigmentation type II: Higher magnification shows perivascular pigment-laden macrophages (200x). Minocycline Pigmentation type II: High magnification reveals granular brown perivascular pigment deposits (400x). Minocycline Pigmentation type II: Close-up view of the coarse granularity of pigment (600x). Minocycline Pigmentation type II: Positive staining for Perl's Prussian blue (iron) (100x). Minocycline Pigmentation type II: Positive staining for Fontana-Masson (melanin-like pigment) (400x).
244
Case 33
Figure 15
Figure 16
Figure 17
Figure 18
Figure 19
Figure 15: Figure 16: Figure 17: Figure 18: Figure 19:
Argyria. High power view shows melanin granules within eccrine coils and within basement membrane of eccrine coils (600x). Post-inflammatory pigmentation. Melanin is seen within macrophages in upper dermis (200x). Post-inflammatory pigmentation. Higher power view shows melanin within macrophages in upper dermis (400x). Tattoo pigment. Red pigment is seen with prominent surrounding granulomatous inflammation (100x). Tattoo pigment. Higher power view (200x).
245
References
1. 2. Tilley BC, Alarcon GS, Heyse SP et al. Minocycline in rheumatoid arthritis: A 48-week, double-blind, placebo controlled trial. Ann Intern Med 1995; 122(2):81-89. Ozog DM, Gogstetter DS, Scott G, Gaspari A. Minocycline-induced hyperpigmentation in patients with pemphigus and pemphigoid. Arch Dermatol 2000; 136:11331138. Sadick NS. Systemic Antibacterial Agents. In: Wolverton SE. Comprehensive dermatologic drug therapy. W.B. Saunders Company: 2001; 28-54. Spadin AN, Fleischmajer R. Tetracyclines: Nonantibiotic properties and their clinical implications. J Am Acad Dermatol 2006; 54:258-65. Eisen D, Hakim M. Minocycline-induced pigmentation: Incidence, prevention and management. Drug Safety 1998. Jun; 18(6):431-440. Treister NS, Magalnick D, Woo SB. Oral mucosal pigmentation secondary to minocycline therapy: Report of two cases and review of the literature. Oral Surgery Oral Medicine Oral Pathology 2004 Jun; 97(6):718-725. Siller GM, Tod MA, Savage NW. Minocycline-induced oral pigmentation. J Am Acad Dermatol 1994; 30:350-354. Mouton RW, Jordaan HF, Schneider JW. A new type of minocycline-induced cutaneous hyperpigmentation. Clinical and Experimental Dermatology 2004; 29:8-14. Rahman Z, Lazova R, Antaya R. Minocycline hyperpigmentation isolated to the subcutaneous fat. J Cutan Pathol 2005; 32:516-519. Fenske NA, Millns JL, Greer KE. Minocycline-induced pigmentation at sites of cutaneous inflammation. JAMA 1980; 244:1103-1106. Pepine M, Flowers FP Ramos-Caro FA. Extensive cutaneous hyperpigmentation , caused by minocycline. J Am Acad Dermatol 1993; 28:292-295. Poliak SC, Digiavanna JJ, Gross EG et al. Minocycline-associated tooth discoloration in young adults. JAMA 1985; 254:2930-2932. Attwood HD, Dennett X. A black thyroid and minocycline treatment. BMJ 1976; 2:1109-1110. Argenyi ZB, Finelli L, Bergfeld WF, Tuthill RJ, McMahon JT, Ratz JL, Petroff N. Minocycline-related cutaneous hyperpigmentation as demonstrated by light microscopy, electron microscopy and X-ray energy spectroscopy. J Cutan Pathol 1987; 14:176-180. Basler RS. Minocycline-Related Hyperpigmentation. Arch Dermatol 1985; 121:606608. Leffell DJ. Minocycline hydrochloride hyperpigmentation complicating treatment of venous ectasia of the extremities. J Am Acad Dermatol 1991; 24:851-853. Ridgway HA, Sonnex TS, Kennedy CT, Millard PR, Henderson WJ, Gold SC. Hyperpigmentation associated with oral minocycline. Br J Dermatol 1982; 107:95102. Gordon G, Sparano BM, Iatropoulos MJ. Hyperpigmentation of the Skin Associated with Minocycline Therapy. Arch Dermatol 1985; 121:618-623. Simons JJ, Morales A. Minocycline and generalized cutaneous pigmentation. J Am Acad Dermatol 1980; 3:244-247. Chu P Van SL, Yen TSB, Berger TG. Minocycline hyperpigmentation localized to the , lips: An unusual fixed drug reaction. J Am Acad Dermatol 1994; 30:802-803. Fitzpatrick JE. New histopathologic findings in drug eruptions. Dermatologic Clinics 1992; 10:19-36. Dereure O, Drug-induced skin pigmentation. Am J Clin Dermatol 2001; 2 (4):253262. Granstein RD, Sober AJ. Drug- and heavy metal-induced hyperpigmentation. J Am Acad Dermatol 1981; 5:1-18.
3. 4. 5. 6.
7. 8. 9. 10. 11. 12. 13. 14.
15. 16. 17.
18. 19. 20. 21. 22. 23.
Arni K. Kristjansson, Kirsten Bellucci, Mark Harbeck, and Vincent Liu

CASE 34
Case History
he patient is a 45-year-old male with a darkly pigmented macule on his palm of less then one-month duration.
Figure 1
Figure 2
Figures 1 & 2:
The sections show biopsy of an acral skin with corneal hemorrhage. There is no evidence of melanocytic proliferation.
Diagnosis
Manus (talon) noir.
Commentary
Talon Noir (which in French means black foot), originally called Calcaneal petechiae, was first described in 1961 as a highly characteristic traumatic petechial eruption of the heels peculiar to basketball players.1 Since this initial description, talon noir has enjoyed many names including the aforementioned calcaneal petechiae, black heel,3 post-traumatic punctate hemorrhage of the skin,2 plantar pseudochromhidrosis,2 keratosis hemorrhagica,3 and basketball heels.6 Talon noir is an asymptomatic, trauma-related petechial lesion found primarily on acral sites that histologically is characterized by blood within the stratum corneum.4 The lesions may consist of multiple punctate petechiae or a coalescence of petechiae forming what may appear to be a darkly pigmented macule. They are often bilateral,1 and although characteristically found on the heel, may be found on any acral surface.2 The lesions are traumatic in origin, and likely are due to tangential force applied to the skin as may be encountered during a game of basketball, with the hard running, quick stops, and pivoting. These lesions have reportedly
been identified following other types of sports including football and tennis,4 and following pedestrian mishaps like striking ones finger with a hammer.2 The histologic features of talon noir are characteristically limited to the stratum corneum where homogeneous rounded masses of redbrown material is sequestered.3,4 The material does not stain positively with iron stains such as Prussian blue. However, the material, which consists of lysed red blood cells, does stain positively with Benzidine, a stain specific for hemoglobin.3 Occasionally, extravasated red blood cells can be found in the dermal papillae, where the transepidermal elimination of the blood begins. The histologic differential diagnosis is limited. The key to making the correct diagnosis is recognition of the material within the stratum corneum and correlating this finding with the clinical diagnosis of a pigmented lesion. These harmless lesions disappear spontaneously. No treatment is required.
References
1. 2. 3. Crissey JT, Peachey JC: Calcaneal petechiae. Arch Derm 1961; 83:501. Levit F, Blankenship ML: Posttraumatic punctate hemorrhage of the skin: a better name than black heel. Arch Derm 1972; 105:759. Hafner J, Haenseler E, et al.: Benzidine stain for the histochemical detection of hemoglobin in splinter hemorrhage (subungual hematoma) and black heel. Am J Dermatopathol 1995; 17:362-7. Elder D, Elensitas R, Jaworsky C, et al., in: Levers Histopathology of the Skin, 8th Edition. Philadelphia, Lippincott-Raven, 1997, p315. Crowson AN, Magro CM, Mihm MC, in: The Melanocytic Proliferations: A Comprehensive Textbook of Pigmented Lesions. New York, Wiley-Liss, 2001, p307. Fromer JL (eds): Talon noir. Arch Derm 1971; 104:452.
4. 5. 6.
Aaron Caplan and Artur Zembowicz
248
CASE 35
Case History
he patient is a 47-year-old female from Honduras with a history of iron-deficiency anemia who presents with a persistent brown patch of discoloration along the right deltoid for approximately ten months. A 1.5 mm punch biopsy was performed to confirm the clinical suspicion.
Figure 1
Figure 2
Figure 3
Figure 4
Figures 1-6:
The iron pigment involves the full thickness of the dermis and even subcutaneous tissue. The particles coat collagen fibers and are also deposited within dermal macrophages. (H&E 20x, 100x, 200x, 200x, 400x, 400x)
249
Figure 5
Figure 6
Diagnosis
Iron hyperpigmentation.
Commentary
This case illustrates hyperpigmentation due to iron injection. The patient previously received iron injections for iron deficiency anemia as a consequence of chronic menometrorrhagia. Although typically given intramuscularly to the buttocks, this patient received her injections in the deltoid region. As occurred with this patient, one clinically observes permanent brownish-black pigmentation at the sites of injection. This is due to small particles of iron leaking out of the syringe and into the needle path despite the injection being intramuscular. Another frequent clinical scenario in which iron hyperpigmentation can be seen is iron tattooing as a consequence of using ferric subsulfate (Monsels solution) as a hemostatic agent. Histologically, the iron pigment coats collagen fibers and is deposited within dermal macrophages (Figs. 1-6). Although not required for diagnostic purposes, a Perls stain (Prussian blue) will highlight the ferric iron by producing ferric ferrocyanide, an insoluble blue compound (Figs. 7-9). Hemosiderin may also cause hyperpigmentation when extravasated red cells lyse and release iron stores. This could occur in chronic capillaritis (pigmented purpuric dermatosis) or as a complication of sclerotherapy of superficial veins. The pigment in these cases would mainly be localized in a perivascular distribution and within macrophages (hemosiderin-laden macrophages). Other potential causes of iron-induced hyperpigmentation include primary hemochromatosis, porphyria cutanea tarda (related to iron overload), chronic blood transfusions, and chronic liver disease. Other differential diagnostic considerations include argyria, and minocycline and other drug-induced hyperpigmentation.
Case 35
Figure 7
Figure 8
Figure 9
References
1. 2. 3. Bolognia JL, editor. Dermatology. Vol 1, 1st ed. C.V. Mosby, 2003. Bock O, Mrowietz U, Glser R. Schwrtzliche Hautpigmentierungen bei drei Patienten. Hautarzt 2002; 53:416-20. Olmstead PM, Lund HZ, Leonard DD. Monsels solution: a histologic nuisance. J Am Acad Dermatol 1980; 3:492-8.
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DERMATOPATHOLOGY

Common Problems in Diagnosis of Pigmented Lesions

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Large spindle and/or epithelioid cell nevus (Spitz nevus)

Pigmented spindle cell nevus of Reed

Recurrent melanocytic nevus (at site of prior biopsy)

Irritated melanocytic nevus

Inverted type A nevus

Conjunctival compound nevus

Atypical genital nevus

Amelanotic cellular blue nevus

Junctional dysplastic melanocytic nevus with moderate cytologic atypia

Melanocytic tumor of uncertain malignant potential (MELTUMP)

Superficial atypical melanocytic proliferation of uncertain significance (SAMPUS)

Pigmented epithelioid melanocytoma

Severely atypical proliferative nodule (borderline lesion) arising in a congenital nevus

Case 19 Case 20 Case 21 Case 22 Case 23 Case 24 Case 25

139 145 153 157 171 177 189

Malignant melanoma in situ, lentigo maligna type

Malignant blue nevus

Pleomorphic melanoma with osteoclast-like giant cells

Conjunctival malignant melanoma

Pigmented dermatofibrosarcoma protuberans (Bednar tumor)

Argyria (silver deposition)

Minocycline-induced cutaneous pigmentation

Manus (talon) noir

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Dr. Thomas J. Flotte

Dr. Martin C. Mihm

Dr. George F. Murphy

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