Tumorigenic Melanocytic Proliferations [1 ed.] 9781933864648, 1933864648

Table of contents :
Contents
Series Foreword
Preface
Acknowledgments
1. Acquired Melanocytic Nevi
1.1 Atypical Nevus vs. Nevoid Melanoma
1.2 Dysplastic Nevus with Mitoses vs. Nevoid Melanoma
1.3 Nevus with Ancient Change vs. Tumorigenic Melanoma, and Squamous Cell Carcinoma In Situ vs. In Situ Melanoma
1.4 Atypical Halo Nevus vs. Nevoid Melanoma
1.5 Halo Nevus with Atypia vs. Nevoid Melanoma
1.6 Special Site Genital Skin Nevus vs. Melanoma in Pregnancy
1.7 Congenital Nevus with Mild Dysplasia and Pseudolymphatics vs. Melanoma with Lymphatic Invasion
1.8 Regressed Halo Nevus vs. Regressed Melanoma
2. Congenital Nevi and Tumefactions in Them
2.1 Congenital Pattern Nevus with Mitoses vs. Nevoid Melanoma
2.2 Congenital Nevus with Mitoses vs. Nevoid MM
2.3 Cellular Nodule vs. Melanoma
2.4 Cellular and Proliferative Nodule vs. MM
2.5 MELTUMP vs. Cellular Nodule vs. MM in CN in Neonate
2.6 Congenital Melanocytic Nevus with Heterotopic Cartilage and Bone, Benign vs. Malignant
3. Spindle and/or Epithelioid Cell Nevi/Tumors
3.1 Angiomatoid Spitz Nevus/Tumor vs. Desmoplastic Melanoma
3.2 Spitz tumor vs Spitzoid Melanoma
3.3 Atypical Spitz Tumor vs. Spitzoid Melanoma
3.4 Pagetoid Spitz nevus vs. Spitzoid Melanoma
3.5 Atypical Spitz Tumor vs. Spitzoid Melanoma
3.6 Atypical Spitz Tumor vs. Spitzoid Melanoma
3.7 Spitzoid Melanoma vs. Atypical Spitz Tumor
3.8 Atypical Spitz vs. Spitzoid Melanoma
3.9 Atypical Pigmented Spindle Cell Nevus vs. SSM
3.10 Spitz Tumor vs. Deep Penetrating Nevus
3.11 Spitzoid Melanoma vs. Atypical Spitz
3.12 Spitzoid Melanoma vs. Atypical Spitz
3.13 Atypical Spitz vs. MM
3.14 Atypical Spitz vs. Spitzoid Melanoma
4. Deep Penetrating Nevi
4.1 Deep Penetrating Nevus vs. Nodular Melanoma
4.2 Deep Penetrating Nevus vs. Epithelioid Blue Nevus
4.3 Atypical Deep Penetrating Nevus vs. Nodular Melanoma
4.4 Deep Penetrating Nevus vs. Nodular Melanoma
4.5 Deep Penetrating Nevus vs. Nodular Melanoma
4.6 Atypical Deep Penetrating Nevus vs. Nodular Melanoma
4.7 Deep Penetrating Nevus vs. Cellular Blue Nevus
4.8 Deep Penetrating Nevus vs. Nodular Melanoma
4.9 Deep Penetrating Nevus vs. Nodular Melanoma
5. Blue Nevi (BN) and variants: Cellular Blue Nevus (CBN), Atypical CBN (ACBN), and Malignant Blue Nevus (MBN)
5.1 Atypical Cellular Blue Nevus vs. Malignant Blue Nevus
5.2 Cellular Blue Nevus vs. Malignant Blue Nevus
5.3 Atypical Cellular Blue Nevus vs. Malignant Blue Nevus
5.4 Atypical Cellular Blue Nevus vs. Malignant Blue Nevus
5.5 Malignant Blue Nevus vs. Malignant Melanoma
5.6 Malignant Blue Nevus vs. Pigmented Epithelioid Melanocytoma vs. Pigment Synthesizing Malignant Melanoma
5.7 Malignant Blue Nevus vs. Atypical Cellular Blue Nevus
5.8 Malignant Blue Nevus vs. Metastatic or Primary Melanoma
5.9 MELTUMP, Cellular vs. Malignant Blue Nevus
5.10 Atypical Cellular Blue Nevus vs. Malignant Blue Nevus
6. Combined Nevi
6.1 Combined Cellular Blue and Congenital Pattern Nevus vs. Pigmented Epithelioid Melanocytoma
6.2 Combined Deep Penetrating and Congenital Pattern Nevus vs. Melanoma
6.3 Combined Deep Penetrating and Congenital Nevus
7. Pigmented Epithelioid Melanocytoma
7.1 Pigmented Epithelioid Melanocytoma vs. Nodular Melanoma
7.2 Pigmented Epithelioid Melanocytoma vs. Vulvar Melanoma
7.3 Pigmented Epithelioid Melanocytoma vs. Nodular Melanoma
7.4 Pigmented Epithelioid Melanocytoma vs. Nodular Melanoma
7.5 Recurrent Pigmented Epithelioid Melanocytoma vs. Melanoma
8. Tumorigenic Melanomas of WHO Classification Categories
8.1 Nodular Melanoma with Microscopic Satellites
8.2 Balloon Cell Melanoma vs. Nevus
8.3 Melanoma with Accretive Vertical Growth Phase vs. Radial Growth Phase Only
8.4 Melanoma with Accretive VGP vs. Severely Dysplastic Nevus
8.5 Malignant Melanoma, Lentigo Maligna type, with Nevoid VGP
8.6 Nodular Melanoma vs. Malignant Blue Nevus with Lymph Node Involvement vs. Nevus
8.7 Regressed Tumorigenic Melanoma vs. Inflammatory Dermatosis with Pigmentary Incontinence
9. Nevoid Melanoma
9.1 Nevoid Melanoma vs. Nevus
9.2 Nevoid Melanoma vs. Nevus
9.3 Nevoid Melanoma vs. Nevus
9.4 Nevoid Melanoma vs Nevoid Epidermotropic Metastatic Melanoma
9.5 Nevoid Vertical Growth Phase vs. Recurrent Nevus
10. Desmoplastic and Neurotropic Melanoma
10.1 Desmoplastic Melanoma vs. Malignant Peripheral Nerve Sheath Tumor
10.2 Desmoplastic Vertical Growth Phase vs. Regression in Lentigo Maligna Melanoma
10.3 Desmoplastic Melanoma vs. Desmoplastic Nevus F34 10258
10.4 Lentigo Maligna Melanoma with Early Vertical Growth Phase, Desmoplastic vs. Spindle Cell, vs. Severe Dermal and Epidermal Dysplasia vs. Special Site Nevus of the Ear
10.5 Desmoplastic Melanoma vs. Malignant Peripheral Nerve Sheath Tumor (MPNST)
10.6 Desmoplastic Melanoma vs. Scar in Re-Excision
11. Metastatic Melanoma: Epidermotropic, Regressed, Nevoid
11.1 Epidermotropic Metastatic Melanoma vs. Nodular Melanoma
11.2 Epidermotropic Metastatic Melanoma vs. Nodular Melanoma
11.3 Tumoral Melanosis: Regressed Satellite vs. Regressed Primary Melanoma
11.4 Metastatic Melanoma with Regression and Tumoral Melanosis
11.5 Tumorigenic Melanoma with Prominent Capsular and Sinusoidal Nevus Cells vs. Micrometastases in Sentinel Node
12. Nonmelanocytic Melanoma Simulants
12.1 Monsel’s Reaction vs. Residual Melanoma
12.2 Pigmented Carcinoma vs. Nodular Melanoma
12.3 Tumoral Melanosis Rule Out Regressed Melanoma vs. Other Regressed Pigmented Lesion
12.4 Tumoral Melanosis Regressed Melanoma vs. Other Pigmented Tumor
Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
R
S
T
U
V
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Citation preview

C o n s u l t a n t Pa t h o l o g y

tum o r i g e n i c m ela n o c y t i c pro lif e r at i o n s

Consultant Pathology Series David E. Elder, MB, ChB Series Editor

Tumorigenic Melanocytic Proliferations David E. Elder Brain Tumors Richard Prayson, Bette K. Kleinschmidt-DeMasters, and Mark L. Cohen Forthcoming Volumes in the Series Thyroid Papillary Lesions Virginia A. LiVolsi and Jennifer L. Hunt Urinary Bladder Diagnosis Robert O. Petersen Head and Neck Pathology Leon Barnes, Raja Seethala, and Simion Chiosea Liver Pathology Linda Ferrell and Sanjay Kakar

C o n s u l t a n t Pa t h o l o g y volume 1

tum o r i g e n i c m ela n o c y t i c pro lif e r at i o n s

David E. Elder, MB, ChB, FRCPA Professor of Pathology and Laboratory Medicine Hospital of the University of Pennsylvania Philadelphia, Pennsylvania

New York

Acquisitions Editor: Richard Winters Cover Design: Joe Tenerelli Compositor: Publication Services, Inc. Printer: Sheridan Press Visit our website at www.demosmedpub.com © 2010 Demos Medical Publishing, LLC. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher. Medicine is an ever-changing science. Research and clinical experience are continually expanding our knowledge, in particular our understanding of proper treatment and drug therapy. The authors, editors, and publisher have made every effort to ensure that all information in this book is in accordance with the state of knowledge at the time of production of the book. Nevertheless, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, express or implied, with respect to the contents of the publication. Every reader should examine carefully the package inserts accompanying each drug and should carefully check whether the dosage schedules mentioned therein or the contraindications stated by the manufacturer differ from the statements made in this book. Such examination is particularly important with drugs that are either rarely used or have been newly released on the market. Library of Congress Cataloging-in-Publication Data Elder, David E. Tumorigenic melanocytic proliferations / David E. Elder. p. ; cm. — (Consultant pathology) Includes bibliographical references and index. ISBN 978-1-933864-64-8 (hardcover) 1. Melanoma—Case studies. 2. Mole (Dermatology) — Case studies. I. Title. II. Series: Consultant pathology. [DNLM: 1. Melanoma — diagnosis — Case Reports. 2. Diagnosis, Differential — Case Reports. 3. Melanoma — pathology — Case Reports. 4. Nevus, Pigmented — diagnosis — Case Reports. 5. Nevus, Pigmented — pathology — Case Reports. WR 500 E37t 2010] RC280.M37E43 2010 616.99’477 — dc22 2009040380

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Made in the United States of America 9 10 11 12 13

5 4 3 2 1

Contents

Series Foreword Preface Acknowledgments

ix xi xv

1. Acquired Melanocytic Nevi

1

1.1 Atypical Nevus vs. Nevoid Melanoma 1.2 Dysplastic Nevus with Mitoses vs. Nevoid Melanoma 1.3 Nevus with Ancient Change vs. Tumorigenic Melanoma, and Squamous Cell Carcinoma In Situ vs. In Situ Melanoma 1.4 Atypical Halo Nevus vs. Nevoid Melanoma 1.5 Halo Nevus with Atypia vs. Nevoid Melanoma 1.6 Special Site Genital Skin Nevus vs. Melanoma in Pregnancy 1.7 Congenital Nevus with Mild Dysplasia and Pseudolymphatics vs. Melanoma with Lymphatic Invasion 1.8 Regressed Halo Nevus vs. Regressed Melanoma

2. Congenital Nevi and Tumefactions in Them 2.1 2.2 2.3 2.4 2.5 2.6

Congenital Pattern Nevus with Mitoses vs. Nevoid Melanoma Congenital Nevus with Mitoses vs. Nevoid MM Cellular Nodule vs. Melanoma Cellular and Proliferative Nodule vs. MM MELTUMP vs. Cellular Nodule vs. MM in CN in Neonate Congenital Melanocytic Nevus with Heterotopic Cartilage and Bone, Benign vs. Malignant

3. Spindle and/or Epithelioid Cell Nevi/Tumors 3.1 3.2 3.3 3.4 3.5

Angiomatoid Spitz Nevus/Tumor vs. Desmoplastic Melanoma Spitz tumor vs Spitzoid Melanoma Atypical Spitz Tumor vs. Spitzoid Melanoma Pagetoid Spitz nevus vs. Spitzoid Melanoma Atypical Spitz Tumor vs. Spitzoid Melanoma

v

5 8 13 16 20 23 27 30

33 36 39 43 46 49 54

57 63 67 71 75 78

vi CONTE NTS

3.6 3.7 3.8 3.9 3.10 3.11 3.12 3.13 3.14

Atypical Spitz Tumor vs. Spitzoid Melanoma Spitzoid Melanoma vs. Atypical Spitz Tumor Atypical Spitz vs. Spitzoid Melanoma Atypical Pigmented Spindle Cell Nevus vs. SSM Spitz Tumor vs. Deep Penetrating Nevus Spitzoid Melanoma vs. Atypical Spitz Spitzoid Melanoma vs. Atypical Spitz Atypical Spitz vs. MM Atypical Spitz vs. Spitzoid Melanoma

4. Deep Penetrating Nevi 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9

Deep Penetrating Nevus vs. Nodular Melanoma Deep Penetrating Nevus vs. Epithelioid Blue Nevus Atypical Deep Penetrating Nevus vs. Nodular Melanoma Deep Penetrating Nevus vs. Nodular Melanoma Deep Penetrating Nevus vs. Nodular Melanoma Atypical Deep Penetrating Nevus vs. Nodular Melanoma Deep Penetrating Nevus vs. Cellular Blue Nevus Deep Penetrating Nevus vs. Nodular Melanoma Deep Penetrating Nevus vs. Nodular Melanoma

5. Blue Nevi (BN) and variants: Cellular Blue Nevus (CBN), Atypical CBN (ACBN), and Malignant Blue Nevus (MBN) 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 5.10

Atypical Cellular Blue Nevus vs. Malignant Blue Nevus Cellular Blue Nevus vs. Malignant Blue Nevus Atypical Cellular Blue Nevus vs. Malignant Blue Nevus Atypical Cellular Blue Nevus vs. Malignant Blue Nevus Malignant Blue Nevus vs. Malignant Melanoma Malignant Blue Nevus vs. Pigmented Epithelioid Melanocytoma vs. Pigment Synthesizing Malignant Melanoma Malignant Blue Nevus vs. Atypical Cellular Blue Nevus Malignant Blue Nevus vs. Metastatic or Primary Melanoma MELTUMP, Cellular vs. Malignant Blue Nevus Atypical Cellular Blue Nevus vs. Malignant Blue Nevus

6. Combined Nevi 6.1 Combined Cellular Blue and Congenital Pattern Nevus vs. Pigmented Epithelioid Melanocytoma 6.2 Combined Deep Penetrating and Congenital Pattern Nevus vs. Melanoma 6.3 Combined Deep Penetrating and Congenital Nevus

82 86 89 93 97 100 103 107 110 115 117 120 122 126 129 131 135 138 141

145 148 151 156 160 163 166 169 172 175 179 185 187 190 193

vii CONTE NTS

7. Pigmented Epithelioid Melanocytoma 7.1 7.2 7.3 7.4 7.5

Pigmented Epithelioid Melanocytoma vs. Nodular Melanoma Pigmented Epithelioid Melanocytoma vs. Vulvar Melanoma Pigmented Epithelioid Melanocytoma vs. Nodular Melanoma Pigmented Epithelioid Melanocytoma vs. Nodular Melanoma Recurrent Pigmented Epithelioid Melanocytoma vs. Melanoma

8. Tumorigenic Melanomas of WHO Classification Categories 8.1 Nodular Melanoma with Microscopic Satellites 8.2 Balloon Cell Melanoma vs. Nevus 8.3 Melanoma with Accretive Vertical Growth Phase vs. Radial Growth Phase Only 8.4 Melanoma with Accretive VGP vs. Severely Dysplastic Nevus 8.5 Malignant Melanoma, Lentigo Maligna type, with Nevoid VGP 8.6 Nodular Melanoma vs. Malignant Blue Nevus with Lymph Node Involvement vs. Nevus 8.7 Regressed Tumorigenic Melanoma vs. Inflammatory Dermatosis with Pigmentary Incontinence

9. Nevoid Melanoma 9.1 9.2 9.3 9.4 9.5

Nevoid Melanoma vs. Nevus Nevoid Melanoma vs. Nevus Nevoid Melanoma vs. Nevus Nevoid Melanoma vs Nevoid Epidermotropic Metastatic Melanoma Nevoid Vertical Growth Phase vs. Recurrent Nevus

10. Desmoplastic and Neurotropic Melanoma 10.1 10.2 10.3 10.4

Desmoplastic Melanoma vs. Malignant Peripheral Nerve Sheath Tumor Desmoplastic Vertical Growth Phase vs. Regression in Lentigo Maligna Melanoma Desmoplastic Melanoma vs. Desmoplastic Nevus F34 10258 Lentigo Maligna Melanoma with Early Vertical Growth Phase, Desmoplastic vs. Spindle Cell, vs. Severe Dermal and Epidermal Dysplasia vs. Special Site Nevus of the Ear 10.5 Desmoplastic Melanoma vs. Malignant Peripheral Nerve Sheath Tumor (MPNST) 10.6 Desmoplastic Melanoma vs. Scar in Re-Excision

11. Metastatic Melanoma: Epidermotropic, Regressed, Nevoid 11.1 Epidermotropic Metastatic Melanoma vs. Nodular Melanoma 11.2 Epidermotropic Metastatic Melanoma vs. Nodular Melanoma

197 200 205 210 214 219

223 227 232 235 241 244 249 256

261 263 266 270 273 276

281 284 288 294

298 301 305

311 314 316

viii CONTE NTS

11.3 Tumoral Melanosis: Regressed Satellite vs. Regressed Primary Melanoma 11.4 Metastatic Melanoma with Regression and Tumoral Melanosis 11.5 Tumorigenic Melanoma with Prominent Capsular and Sinusoidal Nevus Cells vs. Micrometastases in Sentinel Node

12. Nonmelanocytic Melanoma Simulants 12.1 Monsel’s Reaction vs. Residual Melanoma 12.2 Pigmented Carcinoma vs. Nodular Melanoma 12.3 Tumoral Melanosis Rule Out Regressed Melanoma vs. Other Regressed Pigmented Lesion 12.4 Tumoral Melanosis Regressed Melanoma vs. Other Pigmented Tumor Index

319 322 325

329 331 334 338 341 345

Series Foreword

D

iagnostic surgical pathology remains the gold standard for diagnosis of most tumors and many inflammatory conditions in most, if not all, organ systems. The power of the morphologic method is such that, in many instances, a glance at a thin section of tissue stained with two vegetable dyes is sufficient to determine with absolute certainty whether a patient should undergo a major procedure or not, or whether a patient is likely to live a healthy life or die of an inoperable tumor. In such cases, the diagnostic process is one of “gestalt,” a form of almost instantaneous pattern recognition that is similar to the recognition of faces, different brands of automobiles, or breeds of dogs. In other “difficult” cases, the diagnosis is not so obvious. In many of these cases, a diagnosis may be possible, but may be outside of the experience of the routine practitioner. In such a circumstance, it may be possible for a practitioner with more experience— a consultant—to make a diagnosis rather readily. In other cases, the problem may really not be suited to the histologic method. In these cases as well, a consultant may be invaluable in determining that it is simply not possible to make a reliable diagnosis with the materials available. In yet other cases, the diagnosis may be ambiguous, and again a consultant’s opinion can be important in establishing a differential diagnosis that may guide clinical investigation. There are many fine consultants available to the practicing surgical pathology community. Many of them have authored textbooks, and many of them give presentations at national meetings. However, these materials can offer only a superficial insight

into the vast amount of knowledge that is embedded in these individuals’ cerebral cortices—and in their filing cabinets. This series represents an effort to enable the dissemination of this hitherto-inaccessible knowledge to the wider community. Our authors are individuals who have accumulated large collections of difficult cases and are willing to share their material and their knowledge. The cases are based on actual consultations, and the indications for the consultation, when available, are presented, because these are the records of the manner in which these cases presented themselves as being problematic. We have asked the consultants, when possible, to present their consultation letters in much the same form (albeit edited to some degree) as that in which they were first presented, because these represent the true records of the clinical encounter. In addition, we asked the authors to amplify upon these descriptions, with brief reference to the literature, and to richly illustrate the case reports with high-quality digital images. The images from the book, as well as additional images to amplify the presentation of the case, are available on a website for downloading, study, and use in education. These images, in some cases, have been derived from virtual slides, which also may be made available in the future from a digital repository for their additional educational value. David E. Elder, MB, ChB, FRCPA Professor of Pathology and Laboratory Medicine Hospital of the University of Pennsylvania Philadelphia, Pennsylvania ix

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P r e fac e

T

in benign nevi, in which the lesional cells become smaller, and then spindled, as they appear to descend from the epidermis deeper into the dermis. The spindled phenotype appears to adopt features of schwannian differentiation, including wavy fiber bundles and spindle cells with serpentine nuclei, as seen in neurofibromas, or even attempts at recapitulating benign structures such as Wagner-Meissner sensory end organs (5). This tendency to adopt both epithelioid and spindled morphology is another defining “clue” to the melanocytic nature of a neoplasm, even in metastatic lesions. The phenomenon is most marked in desmoplastic and/or neurotropic melanomas, which can mimic a neurofibroma so well as to occasionally be mistaken for one. Yet another property, common to both benign and malignant lesions, distinguishes melanocytic tumors from most epithelial tumors. This is the tendency of both benign and malignant melanocytes to extend from the epidermal compartment into the stromal compartment. In a benign nevus, this phenomenon is often termed “migration” and is the process whereby nevi that are initially “junctional” and confined to the epidermis become “compound” or epidermal and dermal in character, typically in an “accretive” manner (6). In some nevi, such as Spitz nevi and perhaps also congenital nevi, the lesional cells appear to have invaded actively from their original location in the epidermis deep into the reticular dermis (7). This, the process of “invasion,” unlike in carcinomas, cannot be regarded as unequivocal evidence of malignancy in a melanocytic tumor, greatly

he common (and most of the uncommon) cutaneous neoplasms derived from skin melanocytes can be divided into two major categories (1). In the first category, there is proliferation of neoplastic melanocytes in the epidermis, and similar cells may enter the papillary dermis, without having the capacity to proliferate there. In either case, a mass lesion is not formed in the dermis, and these lesions are termed “nontumorigenic.” In the second category, a mass is formed in the dermis, and the lesions are termed “tumorigenic.” The latter category is the subject of this monograph. Tumors formed by melanocytes have a number of features in common that help distinguish them from other tumors, such as basal cell carcinomas or sweat gland tumors. They are, of course, comprised of neoplastic melanocytes, which (whether benign or malignant) differ from normal melanocytes in three ways: they tend to retain pigment in their cytoplasm, especially when located in the epidermis and superficial dermis; they tend to lose their dendritic morphology and become either rounded (or “epithelioid”), or spindled; and they tend to lose their contact inhibition and form nests, often comprising epithelioid cells, or fascicles (often of spindle cells) (2). This tendency toward nest formation is one of the key features in identifying a lesion as melanocytic, especially when pigment is minimal or absent. Another very frequent property of melanocytic tumors, as in many other neoplasms, is a process usually termed “maturation” (3), which may, in actuality, be one of senescence (4). This is most marked xi

xii P RE FACE

complicating their interpretation. In this respect, some melanomas, especially spindle cell melanomas of the desmoplastic and/or neurotropic type, may be as much akin to sarcomas as to carcinomas. The key role of histopathology in the analysis of a melanocytic tumor is the recognition, or exclusion, of a malignant melanoma. Attributes useful in this endeavor, as in other tumors, include both architectural and cytologic features. When a junctional component is present, strong clues to the diagnosis are provided by architectural features such as high cellularity and confluence of cells, and pagetoid or continuous basal proliferation, and reactions of the epidermis, in addition to cytologic features such as severe uniform atypia and mitotic activity. When the junctional component is absent or minimal, the diagnosis depends on recognition of clues to malignancy in the dermal component, such as loss of symmetry, high cellularity with sheets of cells, relative loss of maturation, and invasion of the reticular dermis in tongues or fascicles of cells rather than as single cells. This latter pattern differs from that in nevi, in which cells that invade the reticular dermis tend to remain single rather than undergo continued proliferation as in melanomas. The result of this proliferation in melanomas is the formation of nests or fascicles of malignant cells among the collagen fibers at the base of the tumor, rather than single cells as in nevi (8). In addition to these architectural features, cytologic atypia is usually present, usually “uniform” (i.e., present in the majority of cells) and moderate or severe in degree (9). There may also be ulceration (10), necrosis (11), and lymphatic or vascular invasion (12); these are signs of advanced melanomas that usually do not present problems in diagnosis. Although analysis of features such as these leads to a correct diagnosis in the vast majority of cases, there are cases that present problems, because of criteria that are conflicting or insufficient, for a confident determi-

nation to be made. These cases are rare (a few per year) in a diversified pathology practice, infrequent (several per month) in a busy dermatopathology practice, and common (several cases per week) in a busy national or international consultation practice. Consultants may therefore build up extensive experience that, in most referred cases, enables them to make a rapid and correct diagnosis. There is still a residual group of cases, however, in which the difficulties of diagnosis are so considerable that only a descriptive diagnosis can be given (1). These cases, in general, are the subject matter of this book. It is possible that, in the relatively near future, molecular tests currently in development will become available to assist with this interpretation, likely only as an adjunct to traditional diagnosis, and likely only in this small group of “histologically ambiguous” cases (13). However, it is also likely that a—hopefully much smaller—residual group of lesions with unpredictable behavior will continue to exist. David E. Elder

References 1 Elder DE, Xu X. The approach to the patient with a difficult melanocytic lesion. Pathology 2004 Oct;36(5):428–34. 2 Whimster IW. Recurrent pigment cell naevi and their significance in the problem of endogenous carcinogenesis. Ann Ital Dermatol Clin Sper 1965;19:168–91. 3 Urso C, Borgognoni L, Saieva C, Tinacci G, Zini E. Efficacy of histologic criteria in the diagnosis of melanoma. J Cutan Pathol. In press 2007. 4 Gray-Schopfer VC, Cheong SC, Chong H, Chow J, Moss T, Abdel-Malek ZA, Marais R, Wynford-Thomas D, Bennett DC. Cellular senescence in naevi and immortalisation in melanoma: a role for p16? Br J Cancer 2006 Aug 21;95(4):496–505. 5 Reed RJ. Neuromesenchyme. The concept of a neurocristic effector cell for dermal mesenchyme. Am J Dermatopathol 1983;5:385–95. 6 Tuthill RJ, Reed RJ. Failure of senescence in the dysplasiamelanoma sequence: demonstration using a tissue microarray and a revised paradigm for melanoma. Semin Oncol 2007 Dec;34(6):467–75. 7 Ferrier CM, van Geloof WL, Straatman H, van de Molengraft FJ, van Muijen GN, Ruiter DJ. Spitz naevi may express

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components of the plasminogen activation system. J Pathol 2002 Sep;198(1):92–9. 8 Smolle J. Biological significance of tumor thickness. Theoretical considerations based on computer simulation. Am J Dermatopathol 1995 Jun;17(3):281–6. 9 Li LX, Crotty KA, Scolyer RA, Thompson JF, Kril JJ, Palmer AA, McCarthy SW. Use of multiple cytometric markers improves discrimination between benign and malignant melanocytic lesions: a study of DNA microdensitometry, karyometry, argyrophilic staining of nucleolar organizer regions and MIB1-Ki67 immunoreactivity. Melanoma Res 2003 Dec;13(6):581–6. 10 Spatz A, Cook MG, Elder DE, Piepkorn M, Ruiter DJ, Barnhill RL. Interobserver reproducibility of ulceration assessment in primary cutaneous melanomas. Eur J Cancer 2003 Sep;39(13):1861–5.

11 Urso C, Rongioletti F, Innocenzi D, Batolo D, Chimenti S, Fanti PL, Filotico R, Gianotti R, Lentini M, Tomasini C, Pippione M. Histological features used in the diagnosis of melanoma are frequently found in benign melanocytic naevi. J Clin Pathol 2005 Apr;58(4):409–12. 12 Xu X, Gimotty PA, Guerry D, Karakousis G, Van BP, Liang H, Montone K, Pasha T, Ming ME, Acs G, Feldman M, Barth S, Hammond R, Elenitsas R, Zhang PJ, Elder DE. Lymphatic invasion revealed by multispectral imaging is common in primary melanomas and associates with prognosis. Hum Pathol 2008 Jun;39(6):901–9. 13 Bauer J, Bastian BC. Distinguishing melanocytic nevi from melanoma by DNA copy number changes: comparative genomic hybridization as a research and diagnostic tool. Dermatol Ther 2006 Jan;19(1):40–9.

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e gratefully acknowledge the contributions of the pathologists who have sent cases for consultation, the clinicians who have performed biopsies, and especially the patients who have entrusted us with their care.

Although the cases presented in this volume are based on real consultations, potential identifying details, such as the age and, in some cases, the gender of the patients and the sites of the lesions, have been changed in order to preserve anonymity.

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1 Acquired Melanocytic Nevi

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elanocytic nevi are benign tumors of melanocytes, which are dendritic pigment-synthesizing cells that normally reside in the basal layer of the epidermis, with their dendrites ramifying among keratinocytes. Melanocytes normally produce pigment and promptly transfer it to their associated keratinocytes, together constituting what has been termed “the epidermal melanin unit.” Recently, it has been demonstrated that most acquired nevi have activating mutations of the oncogene BRAF (1). After a phase of initial growth, the lesions become stable through a mechanism of “oncogene-induced senescence” that is mediated, at least in part, by the suppressor gene CDKN2A and its protein product p16 (2;3). In contrast, truly congenital nevi (i.e., those that are actually present at birth) tend to have mutations of NRAS (4), indicative of a fundamental difference in their pathogenesis. Melanocytic nevi, it has been said, are defined primarily by “the presence of nevus cells.” Nevus cells, in turn, differ from melanocytes by, in general, being less dendritic in their cytoplasmic configuration, by forming nests rather than residing as single cells in the epidermis, and by tending to retain pigment in their cytoplasm, rather than transferring it to adjacent keratinocytes (5). Nevi initially form as a junctional proliferation of single and nested “nevoid” melanocytes, characterized by the previously mentioned attributes. Although many nevi may remain junctional in their lifetime, there seems to be an inherent property of nevus cells to migrate from the epidermis into the dermis to form a “compound nevus.” Whether this is

a property of “invasion” or simply a separation of nests of melanocytes from the epidermis to then build up through a process of accretion like a brick wall—with nests piling upon nests to form a papular compound nevus—is perhaps a matter of semantics. Dysplastic nevi are characterized by atypia of the junctional component (6;7). However, these benign lesions may also exhibit atypia of dermal melanocytes, probably as a result of this property of migration of the atypical cells from the epidermis into the dermis. This “dermal dysplasia” should not automatically be diagnosed as melanoma. Most papular compound nevi are confined to the papillary dermis, but a few exhibit evidence of infiltration into the reticular dermis. This is a particularly common property of Spitz nevi, but also of a group of lesions termed “congenital pattern nevi.” These lesions exhibit some features that may also be seen in truly congenital nevi; however, these features may be related more to lesional size than to mode of onset (8), and, as mentioned previously, recent molecular studies have demonstrated that the majority of them share the same molecular markers as other acquired nevi (9). Although most acquired nevi are quite stereotypic in their morphologic features, there is a considerable range of variation. The prototypic acquired junctional nevus is a relatively small (usually less than 4 mm), ovoid or circular, well-circumscribed, uniformly colored lesion clinically. Histologically, it is comprised of single and nested melanocytes arranged near the tips and sides of elongated rete ridges, without continuous proliferation between the rete and 1

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without confluence of nests. The latter two properties, if present in a junctional proliferation, are concerning for the possibility of evolving or established in situ melanoma. Junctional nevi may evolve initially as “simple lentigines,” which are lesions that lack nests but have single cells arranged about the tips and sides of elongated rete ridges, without continuous proliferation between rete. Continuous proliferation of single cells between rete ridges usually leads to effacement of the rete, with irregular thickening or thinning of the epidermis, and is a property that suggests an evolving or established lentiginous form of in situ melanoma, to be discussed later. Although many lentigines persist indefinitely as such, others may develop nests and then, by definition, are termed junctional nevi. The nests generally tend to remain discrete, at the tips or sides of elongated rete ridges. In dysplastic nevi, there may be bridging between adjacent rete. Confluence of nests, or considerable variation in the size and shape of nests, or irregularities of the distribution, are features that could be suggestive of evolving or established in situ melanoma. As noted previously, there seems to be a tendency for nevus cells to migrate from the epidermis into the dermis to form a compound nevus. An important property of nevus cells in the dermis is their tendency for “maturation,” which is seen morphologically as a diminution in size of the cells from larger, more epithelioid or “Type A” cells superficially—to smaller, lymphocyte-like or “Type B” cells deeper in the lesion. As this process continues, spindle cell differentiation (“Type C”) is manifested, considered to represent a process of schwannian differentiation or neurotization (10). Whether these processes represent maturation, or differentiation, has been questioned (11–13), and many of the attributes manifested by maturing nevi can be explained as a process of “oncogene-induced senescence” (14;15). Whatever the mechanism, this process of “matura-

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tion” is diagnostically very important in distinguishing nevi from melanomas. Other distinguishing features of malignant dermal melanocytic proliferations include cytologic atypia, especially when this is “severe” rather than mild or moderate, and “uniform” rather than being confined to randomly scattered lesional cells. Proliferative activity, as recognized by the presence of mitotic figures or substantial Ki-67 reactivity, is another concerning feature in a dermal melanocytic proliferation, especially when associated with severe atypia and failure of maturation (16–19). Finally, because dermal cells are often derived from a junctional component, assessment of this junctional component can be of considerable diagnostic value. If the junctional pattern of proliferation is diagnostic of in situ melanoma and is cytologically continuous with a questionable atypical dermal component, the latter is more likely to be melanoma, whereas, conversely, if a junctional pattern is that of a dysplastic nevus, the dermal component is likely to be benign. Varieties of acquired nevi, including those with unusual features such as balloon cell change (20), ancient change (21), pseudolymphatic spaces (22), halo nevi (23), special site nevi (24), dysplastic nevi, and so on, may present diagnostic difficulties; these have been described elsewhere (25–27). In this volume, we are concentrating on dermal tumorigenic proliferations. The nuances of the junctional proliferations are discussed in so far as they relate to the assessment of the dermal tumors. Special variants of acquired nevi discussed here include halo nevi, so-called “special site” nevi, and nevi with “ancient change.” The latter are benign nevi with scattered enlarged nevi, resembling a phenomenon thought to be related to senescence and originally described in schwannomas (28). Halo nevi are defined clinically as nevi that develop a depigmented circumferential area of depigmentation. Histologically, they are characterized by a dense infiltrative lymphocytic reaction,

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resembling brisk “tumor-infiltrating lymphocytes” or TILs, as seen in some primary and metastatic melanomas. There are some nevi that exhibit this TIL reaction but lack a halo (29), and, conversely, there are some clinical halo nevi that do not exhibit a particularly dense TIL reaction (30). Some halo nevi exhibit moderate to severe cytologic atypia that is generally considered “reactive” (31); however, the lack of an in situ melanoma component, the usually low cellularity of the dermal component, the presence of mitoses, and an absence or paucity of mitoses are usually reassuring factors. In addition, these lesions are most common in children and teenagers (32). Over the last several years, it has become recognized that some sites of the body may be “special” in terms of the morphology of some of the nevi that are excised from them. The first and best recognized of these “special sites” to be recognized was genital skin, especially from the vulva of premenopausal women (33), and occasionally also on the male genitalia and on nearby sites such as the perineum. Other sites that have been associated with similar changes include the breast (in males as well as females), skin flexures such as the knee and elbow joints, the axilla and the groin, and also the skin of the ear, and the scalp in children. Special site nevi are usually considered to be benign clinically, and histologically they tend to be relatively small, well circumscribed, and symmetrical. The atypia is usually recognized superficially in the form of large cells with large nuclei, mostly in nests, and often with dyshesion (“dyshesive and nested pattern”) (34–39). Importantly, there is maturation of the lesional cells in the dermis, dermal mitoses are lacking, and the junctional component, although atypical, usually does not meet criteria for melanoma in situ and does not extend beyond the dermal component. Of note, the existence of special site nevi does not preclude the existence of more significant lesions, such as authentic dysplastic nevi and melanomas,

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on these sites (40), and also it should be recognized that most nevi on these special sites have no specific features relating to their location and are not at all unusual, either histologically or clinically (33).

References 1 Yazdi AS, Palmedo G, Flaig MJ, Kutzner H, Sander CA. Different frequencies of a BRAF point mutation in melanocytic skin lesions. Pigment Cell Res 2003 Oct;16(5):580. 2 Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, Majoor DM, Shay JW, Mooi WJ, Peeper DS. BRAFE600-associated senescencelike cell cycle arrest of human naevi. Nature 2005 Aug 4;436(7051):720–4. 3 Bennett DC. Human melanocyte senescence and melanoma susceptibility genes. Oncogene 2003 May 19;22(20):3063–9. 4 Bauer J, Curtin JA, Pinkel D, Bastian BC. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol 2007;127, 179–182. Epub 2006 Aug 3. 5 Whimster IW. Recurrent pigment cell naevi and their significance in the problem of endogenous carcinogenesis. Ann Ital Dermatol Clin Sper 1965;19:168–91. 6 Elder DE, Goldman LI, Goldman SC, Greene MH, Clark WH Jr. Dysplastic nevus syndrome: a phenotypic association of sporadic cutaneous melanoma. Cancer 1980 Oct 15;46(8):1787–94. 7 Elder DE. The dysplastic nevus. Pathology 1985;17:291–7. 8 Everett MA. Histopathology of congenital pigmented nevi. Am J Dermatopathol 1989;11:11–2. 9 Ichii-Nakato N, Takata M, Takayanagi S, Takashima S, Lin J, Murata H, Fujimoto A, Hatta N, Saida T. High frequency of BRAFV600E mutation in acquired nevi and small congenital nevi, but low frequency of mutation in medium-sized congenital nevi. J Invest Dermatol 2006 Sep;126(9):2111–8. 10 Gray MH, Smoller BR, McNutt NS, Hsu A. Neurofibromas and neurotized melanocytic nevi are immunohistochemically distinct neoplasms. Am J Dermatopathol 1990 Jun;12(3):234–41. 11 Xu X, Elder DE. A practical approach to selected problematic melanocytic lesions. Am J Clin Pathol 2004 Jun;121 Suppl: S3–32. 12 Soyer HP. Ki 67 immunostaining in melanocytic skin tumors. Correlation with histologic parameters. J Cutan Pathol 1991 Aug;18(4):264–72. 13 Goovaerts G, Buyssens N. Nevus cell maturation or atrophy. Am J Dermatopathol 1988;10:20–7. 14 Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, Majoor DM, Shay JW, Mooi WJ, Peeper DS. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 2005 Aug 4;436(7051):720–4.

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15 Bennett DC. Human melanocyte senescence and melanoma susceptibility genes. Oncogene 2003 May 19;22(20):3063–9. 16 Soyer HP, Smolle J, Smolle Juettner FM, Kerl H. Proliferation antigens in cutaneous melanocytic tumors—an immunohistochemical study comparing the transferrin receptor and the Ki 67 antigen. Dermatologica 1989;179:3–9. 17 Cassarino DS, Cabral ES, Kartha RV, Swetter SM. Primary dermal melanoma: distinct immunohistochemical findings and clinical outcome compared with nodular and metastatic melanoma. Arch Dermatol 2008 Jan;144(1):49–56. 18 Nasr MR, El-Zammar O. Comparison of pHH3, Ki-67, and survivin immunoreactivity in benign and malignant melanocytic lesions. Am J Dermatopathol 2008 Apr;30(2):117–22. 19 Chorny JA, Barr RJ, Kyshtoobayeva A, Jakowatz J, Reed RJ. Ki-67 and p53 expression in minimal deviation melanomas as compared with other nevomelanocytic lesions. Mod Pathol 2003 Jun;16(6):525–9. 20 Schrader WA, Helwig EB. Balloon cell nevi. Cancer 1967 Sep;20(9):1502–14. 21 Kerl H, Soyer HP, Cerroni L, Wolf IH, Ackerman AB. Ancient melanocytic nevus. Semin Diagn Pathol 1998 Aug;15(3):210–5. 22 Sagebiel RW. Histologic artifacts of benign pigmented nevi. Arch Dermatol 1972;106:691–3. 23 Mooney MA, Barr RJ, Buxton MG. Halo nevus or halo phenomenon? A study of 142 cases. J Cutan Pathol 1995 Aug;22(4):342–8. 24 Elder DE. Precursors to melanoma and their mimics: nevi of special sites. Mod Pathol 2006 Feb;19 Suppl 2:S4–20. 25 Elder DE, Elenitsas R, Murphy GF, Xu X. Benign pigmented lesions and malignant melanoma. In: Elder DE, Elenitsas R, Johnson BL, Murphy GF, editors. Lever’s Histopathology of the Skin. 9 ed. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 715–805. 26 Elder DE, Xu X. The approach to the patient with a difficult melanocytic lesion. Pathology 2004 Oct;36(5):428–34. 27 Xu X, Elder DE. A practical approach to selected problematic melanocytic lesions. Am J Clin Pathol 2004 Jun;121 Suppl: S3–32. 28 Kerl H, Soyer HP, Cerroni L, Wolf IH, Ackerman AB. Ancient melanocytic nevus. Semin Diagn Pathol 1998 Aug;15(3):210–5.

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29 Mooney MA, Barr RJ, Buxton MG. Halo nevus or halo phenomenon? A study of 142 cases. J Cutan Pathol 1995 Aug;22(4):342–8. 30 Gauthier Y, Surleve-Bazeille JE, Texier L. Halo nevi without dermal infiltrate. Arch Dermatol 1978 Nov;114(11):1718. 31 Mooney MA, Barr RJ, Buxton MG. Halo nevus or halo phenomenon? A study of 142 cases. J Cutan Pathol 1995 Aug;22(4):342–8. 32 Rivers JK, MacLennan R, Kelly JW, Lewis AE, Tate BJ, Harrison S, McCarthy WH. The eastern Australian childhood nevus study: prevalence of atypical nevi, congenital nevus-like nevi, and other pigmented lesions. J Am Acad Dermatol 1995 Jun;32(6):957–63. 33 Christensen WN, Friedman KF, Woodruff JD, Hood AF. Histologic characteristics of vulval nevocellular nevi. J Cutan Pathol 1987;14:87–91. 34 Fabrizi G, Pagliarello C, Parente P, Massi G. Atypical nevi of the scalp in adolescents. J Cutan Pathol 2007 May;34(5):365–9. 35 Gleason BC, Hirsch MS, Nucci MR, Schmidt BA, Zembowicz A, Mihm MC Jr., McKee PH, Brenn T. Atypical Genital Nevi: A Clinicopathologic Analysis of 56 Cases. Am J Surg Pathol 2008 Jan;32(1):51–7. 36 Lazova R, Lester B, Glusac EJ, Handerson T, McNiff J. The characteristic histopathologic features of nevi on and around the ear. J Cutan Pathol 2005 Jan;32(1):40–4. 37 Rongioletti F, Ball RA, Marcus R, Barnhill RL. Histopathological features of flexural melanocytic nevi: a study of 40 cases. J Cutan Pathol 2000 May;27(5):215–7. 38 Rongioletti F, Urso C, Batolo D, Chimenti S, Fanti PA, Filotico R, Gianotti R, Innocenzi D, Lentini M, Tomasini C, Pippione M, Rebora A. Melanocytic nevi of the breast: a histologic case-control study. J Cutan Pathol 2004 Feb;31(2):137–40. 39 Saad AG, Patel S, Mutasim DF. Melanocytic nevi of the auricular region: histologic characteristics and diagnostic difficulties. Am J Dermatopathol 2005 Apr;27(2):111–5. 40 Elder DE. Precursors to melanoma and their mimics: nevi of special sites. Mod Pathol 2006 Feb;19 Suppl 2:S4–20.

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1.1 Atypical Nevus vs. Nevoid Melanoma

relatively small and uniform, although focally confluent. There is only slight if any evidence of maturation from superficial to deep. At least one equivocal mitotic figure has been observed. I will order immunostains to better characterize this atypical lesion. For the present, I regard the differential diagnosis as lying between a nevus with severe dermal and epidermal dysplasia or a nevoid melanoma.

C L I N I C A L I N F O R M AT I O N

F43, lesion of left chin. REASON FOR REFERRAL

Not known if this lesion was previously traumatized or excised—we favor an atypical nevus with papillary dermal scarring or regression. DESCRIPTION

COMMENT

The sections show a shave biopsy of skin containing a moderately to highly cellular junctional component comprised of single cells along the dermal-epidermal junction with a few nests hanging down from the interface but without bridging nests. There is some tendency for cells to rise above the junction. In the dermis, there is a proliferation of nevoid to epithelioid melanocytes, arranged in nests that tend to be

FIG URE 1.1.1.

(A few days later): We have completed immunostains. A Melan-A study does not demonstrate excessive confluence of the junctional component. An HMB-45 study is “top heavy;” however, there is some staining that extends to the bottom of the lesion in the dermal component. A Ki-67 study demonstrates a few positive cells in the dermis, less than 1% of the total population.

Scanning magnification of a fairly small, moderately cellular dome-shaped melanocytic lesion. 5

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The lesion is comprised of nests of nevoid to epithelioid cells in the dermis. In the overlying epidermis, there are single and nested melanocytes, arranged with nests predominating, predominantly near the dermalepidermal junction. There is only slight if any evidence of maturation of the dermal cells from superficial to deep. FIG URE 1.1.2.

The dermal cells demonstrate moderate nuclear atypia in the form of enlargement, hyperchromatism, and slight irregularity. Mitotic figures are not observed. FIGURE 1.1.4.

The junctional component tends to be confluent in focal areas. FIG URE 1.1.3.

A Ki-67 study demonstrates only rare positive cells in the dermis. FIGURE 1.1.5.

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1.1 DIAGNOSIS

Skin, left jaw line: Compound nevus with severe dermal and epidermal atypia; see previous discussion and comment. A Melan-A study demonstrates a focal area of confluence of the junctional component; however, this is not extensive. FIG URE 1.1.6.

An HMB-45 study is generally “top heavy;” however, there is staining of cells at the bottom of the lesion, presumably indicating “immaturity.” FIG URE 1.1.7.

COMMENT

Taken together, these findings provide insufficient evidence to characterize this lesion as a nevoid melanoma; however, I regard it as markedly atypical and recommend a re-excision procedure, to be sure that it has been removed with a margin of normal skin. Although the junctional component is not that of a classical dysplastic nevus, I also recommend consideration of follow-up for the patient, especially if there are other clinically atypical nevi and/or a personal or family history of melanoma.


OVERALL COMMENT


This lesion presents with concerning dermal atypia, but this is not associated with either an overlying diagnostic in situ component, or with highly cellular “sheets” of cells in the dermis or with dermal mitoses, and there is evidence of incomplete maturation. Nevoid melanomas, to be discussed in a later section, typically demonstrate all of these features. If a lesion

such as this extends to specimen margins, it is judicious to ensure that it is completely removed, with a margin of normal skin around the scar or the biopsy and any residual lesion, and the occurrence of such a lesion should also prompt clinical assessment of other melanoma risk markers as previously discussed.

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1.2 Dysplastic Nevus with Mitoses vs. Nevoid Melanoma

near the dermal-epidermal junction, with nests bridging between adjacent elongated rete ridges in a pattern of melanocytic dysplasia. Cytologically, there is moderate to severe atypia of lesional cells, randomly scattered in some areas and more uniform in other areas. In the center of the lesion, lesional cells descend into the papillary dermis, showing evidence of maturation from superficial to deep, and some evidence of dispersion as single cells into the reticular dermis collagen at the base. All of these features are consistent with a compound nevus with severe dermal and epidermal melanocytic dysplasia. An additional finding, however, is the presence of mitotic activity, mostly near

C L I N I C A L I N F O R M AT I O N

F33yrs, left abdomen. REASON FOR REFERRAL

This is a skin lesion from the abdominal wall from a 33-year-old woman, which appears to represent a compound nevus, possibly of the Spitz type. DESCRIPTION

These sections show a moderately to highly cellular melanocytic lesion measuring 3–4 mm in diameter on the slide. It is comprised at its periphery of predominantly nested melanocytes, arranged predominantly

FIG URE 1.2.1.

A fairly broad, reasonably well-circumscribed, and fairly symmetrical lesion. 8

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1.2 the junction, mostly in keratinocytes, although at least a few lesional cells in mitosis are also observed. It is difficult to demonstrate mitotic activity that is clearly in the dermis, and there are no mitoses in the lower

two-thirds of the lesion. Although the differential diagnosis could include an evolving more significant lesion, I consider these findings to be consistent with a severely dysplastic nevus that I further characterize as follows:

The lesion has a dermal component in the center and a junctional component at each periphery, forming “shoulders.” FIG URE 1.2.2.

The lesion is well circumscribed, with the last cells on each side being in nests rather than attenuated single cells. The nests are located mainly near the tips and sides of elongate rete ridges, and there are nests bridging between adjacent rete. There is a patchy lymphocytic infiltrate with melanophages in the dermis. There is mild to moderate cytologic atypia, predominantly in randomly scattered lesional cells (“moderate random cytologic atypia”). There is no continuous proliferation between the rete and no pagetoid spread of lesional cells into the epidermis. FIGURE 1.2.3.

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In the center of the lesion, there is a dermal component, with evidence of maturation of the lesional cells from superficial (the “youngest” cells) to deep (the more “mature” or “senescent” lesional cells). FIG URE 1.2.4.

FIG URE 1 . 2 . 5 .

Continued.

The cells in the superficial dermis resemble those in the overlying epidermis, also demonstrating generally moderate atypia (“dermal dysplasia”). FIGURE 1.2.5.

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A mitotic figure is present in the center of the field. This mitosis is clearly in a keratinocyte. Mitotic figures, even in “paracrine” cells like keratinocytes, endothelial cells, fibroblasts, and so on, are uncommon in dysplastic nevi. FIGURE 1.2.7.

The cells at the base demonstrate lesser atypia and are cytologically continuous with the more superficial cells, demonstrating “maturation.” FIG URE 1.2.6.

Another mitotic figure is clearly present in a junctional lesional cell. Based on the absence of other compelling features of malignancy, such as failure of maturation, high-grade uniform atypia, extensive and high-level pagetoid proliferation or extensive continuous basal proliferation, this lesion was not interpreted as melanoma, despite the mitotic activity. FIGURE 1.2.8.

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1.2 DIAGNOSIS

Skin, left abdomen: Compound nevus with severe dermal and epidermal melanocytic dysplasia, extending close or to a specimen margin; see previous discussion and comment.

COMMENT

melanoma. I do not believe the bulk of the dermal component is melanoma. However, because of this differential diagnosis and the close or positive margin, I recommend an additional procedure to be sure this lesion has been completely removed, with a margin of normal skin around the scar of this procedure and any residual lesion. Especially if this patient has other clinically atypical nevi and/or a family or personal history of melanoma, periodic surveillance of her skin may also be appropriate.

Because of the junctional mitotic activity, the differential diagnosis could include an evolving superficial


OVERALL COMMENT


As in Case 1.1, this lesion exhibits maturation and lacks sheetlike growth, dermal mitoses, and an in situ melanoma component. As a “rule of thumb,” I tend to regard even junctional mitoses as strong evidence for melanoma and may use this finding as a “tiebreaker” in a difficult case; however, in this case, adequate

supporting evidence for melanoma was lacking. The differential diagnosis could also include a Spitz tumor; however, the characteristic “large spindle and/or epithelioid cell” type is not well represented, there is variation of cell size across the lesion, and there are no Kamino bodies.

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1.3 Nevus with Ancient Change vs. Tumorigenic Melanoma, and Squamous Cell Carcinoma In Situ vs. In Situ Melanoma atypia of cells connected by desmosomes, with focal acantholysis, and abnormal mitoses. In the dermis, there is severe actinic elastosis, and toward the center of the specimen there is a lesion characterized by nests and sheets of nevoid melanocytes extending from near the epidermis well into the reticular dermis and around skin appendages. Within the lesion there is fatty metaplasia. A striking feature is atypia of randomly scattered lesional cell nuclei in the form of enlargement, irregularity, hyperchromatism, and vacuolated nuclear material. Although there is some confluence of nests, the proliferation is not diffuse or “sheetlike.”

C L I N I C A L I N F O R M AT I O N

F81, Nose. REASON FOR REFERRAL

There is a melanocytic proliferation that has marked cytologic atypia. It extends quite deeply but is associated with a hair follicle. The marked cytologic atypia is striking; however, the cells still appear to be nested. DESCRIPTION

These sections show a generous biopsy of skin that contains extensive involvement of the epidermis by in situ neoplasia, characterized by full-thickness

Scanning magnification shows changes in the epidermis, characterized by hyperkeratosis and irregular thickening and hypercellularity, and a nodule in the dermis. FIG URE 1.3.1.

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1.3

The nodule in the dermis is comprised of epithelioid cells that are partly nested and partly more diffusely placed, with an admixture of mature adipocytes. The appearances are those of a congenital pattern nevus, with so-called “ancient change,” which is thought to be a senescent phenomenon first described in schwannomas. FIG URE 1.3.2.

There is quite marked enlargement, irregularity, and hyperchromatism of scattered lesional cell nuclei. FIGURE 1.3.3.

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Lesion in the epidermis is squamous cell carcinoma in situ, characterized by full-thickness squamous dysplasia. Note the collections of dermal nevus cells in the papillary and reticular dermis. FIGURE 1.3.5.

COMMENT

The admixture of mature adipocytes is consistent with so-called “fatty change,” thought to be a degenerative/senescent change in dermal nevi. FIG URE 1.3.4 .

DIAGNOSIS

Skin, nose: Squamous cell carcinoma in situ, extending to specimen margins, and an inci-

In the absence of higher cellularity, more uniform atypia, mitotic activity, necrosis, or ulceration, I do not believe these changes are indicative of malignancy and consider them to represent so-called “ancient change” in a nevus, serendipitously associated with carcinoma in situ. Ancient change is a process that is thought to be degenerative and was first described in schwannomas but is more commonly seen in nevi. I see no evidence of malignancy in the dermal component of this biopsy.

dental congenital pattern dermal nevus with ancient change; see previous discussion and comments.


OVERALL COMMENT


It is not unusual to see squamous dysplasia in association with a melanocytic lesion. The most common

scenario is the finding of actinic keratosis in a biopsy or re-excision for lentigo maligna melanoma.

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1.4 Atypical Halo Nevus vs. Nevoid Melanoma

infiltrating among a rather sparsely scattered population of lesional melanocytes. These latter tend to be relatively large, nevoid to epithelioid in configuration, with relatively large somewhat irregular nuclei and prominent nucleoli. A rare mitotic figure is identified in a superficial dermal lesional cell. In the epidermis, there are nests and a few single cells, without evidence of a melanoma in situ architecture. In sum, this lesion presents conflicting criteria; however, despite the cytologic atypia and dermal mitotic figure, in view of the low cellularity and also taking into account the youthful age of the patient, I consider that it most likely represents an atypical halo nevus.

C L I N I C A L I N F O R M AT I O N

M12. Rule out Spitz nevus vs. other. 7 × 6 mm. REASON FOR REFERRAL

We are considering a halo nevus with atypia secondary to irritation or trauma, especially because the patient is young. However, the epidermal and dermal cytological atypia is worrisome for a more significant lesion. DESCRIPTION

These sections show a dome-shaped tumor in skin, several millimeters in breadth and depth, comprised predominantly of lymphocytes and histiocytes,

FIG URE 1.4.1.

Sections of a dome-shaped, very highly cellular lesion of skin. 16

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1.4 Atypia considered to be “reactive” is regularly seen in halo nevi, although not usually to this extent and not usually associated with mitotic activity. Because

FIG URE 1.4.2.

of these conflicting criteria, I therefore interpret this lesion descriptively as follows:

At first glance, a lymphocytic infiltrate may

be simulated.

Closer scrutiny reveals large epithelioid cells, often with prominent nucleoli, placed on the infiltrating lymphocytes. These have morphology consistent with melanocytes, which should be confirmed with a more specific stain (see Figures 5–7). FIGURE 1.4.3.

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1.4

Mart 1 staining demonstrates that the density of lesional cells is quite low by comparison with the massive lymphocytic infiltrate. FIGURE 1.4.5.

Two mitotic figures recognized in the lesion. One of the mitotic figures is probably in a lesional cell, located within the epidermal component. Another is located in a lesional cell, just beneath the epidermis. FIG URE 1.4.4.

There is little or no evidence of continuous basal or high-level pagetoid proliferation. FIG URE 1.4.6.

FIGURE 1.4.7.

ficial to deep.

There is evidence of maturation from super-

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1.4 COMMENT DIAGNOSIS

Skin, malar region: Melanocytic tumor of uncertain malignant potential, favor an atypical halo nevus, transected at the specimen base; see previous discussion and comment.

Because of the atypical features and positive margin, I recommend an additional procedure, to be sure this lesion has been completely removed. I expect the likelihood of metastatic potential for a lesion of this type to be exceedingly low, and I would not therefore expect sentinel lymph node sampling to be beneficial.


OVERALL COMMENT


Although, as a “rule of thumb,” the presence of mitotic activity in association with dermal cytologic atypia is always concerning, the mitotic rate in this case is low,

the density of the lesional cells in the dermis is low, and the lesion is occurring in a young individual—all of which are reasons to favor a benign lesion.

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1.5 Halo Nevus with Atypia vs. Nevoid Melanoma

overlying and adjacent epidermis, there is vacuolar change with lymphocytes tagging along the interface, for several rete ridges beyond the dermal component, constituting a halo. Peripheral to this area, there is a narrow zone of uninvolved epidermis. Careful scrutiny of several sections reveals several mitotic figures in the dermal component. Some of these are clearly stromal cells, whereas at least a few are clearly lesional cell mitoses. Despite this activity, I do not believe this lesion should be called a melanoma because of the lack of a more characteristic in situ component, the presence of maturation, the symmetry, the characteristic halo nevus pattern of the infiltrate, and the youthful age of the patient. Nevertheless, I regard this lesion as atypical and characterize it as follows:

C L I N I C A L I N F O R M AT I O N

M17, lesion of right chest. REASON FOR REFERRAL

We favor a halo nevus with atypia. DESCRIPTION

The sections show a shave biopsy of a papular lesion characterized, at first glance, by a dense lymphocytic infiltrate. Within this infiltrate, one can rather readily appreciate nests of nevoid melanocytes, present superficially and in the papillary dermis, and also scattered throughout the lymphocytic infiltrate, and infiltrating among collagen fibers at the base, showing evidence of maturation from superficial to deep. In the

Scanning power shows a somewhat asymmetric, variably cellular, plaquelike tumor/mass. Green circles indicate the location of two mitoses, seen in Figure 5. FIG URE 1.5.1.

20

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At first glance, the mass is comprised largely of lymphocytes and histiocytes. FIGURE 1.5.2.

There is evidence of maturation of the nevoid cells from a larger type superficially to a smaller cell type near the base of the biopsy. At the base of the lesion, there is an admixture of smaller nevoid cells, providing evidence of maturation compared to the more superficial cells, and histiocytes. FIGURE 1.5.4.

Larger epithelioid cells arranged in nests can be seen on closer inspection in some areas of the lesion. These are consistent with Type A nevus cells. FIGURE 1.5.3.

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Two mitoses are seen in one high-power field. In general, however, the mitotic rate was low, and mitoses were confined to the upper third. Green circles in Figure 1 indicate the location of the mitoses. FIGURE 1.5.5.

Mart 1 staining demonstrates a relatively low density of lesional cells within the infiltrate and evidence of maturation to a smaller cell type dispersed among lymphocytes at the base. The appearances are consistent with a regressing melanocytic tumor comprised of nevus cells (“halo nevus”). FIGURE 1.5.6.

DIAGNOSIS

Skin, right chest: Compound nevus with a dense lymphocytic infiltrate of the type seen in halo nevi, with atypia and mitotic activity, probably reactive; see previous discussion and comment.

COMMENT

As noted previously, I believe that this lesion is a halo nevus and that the atypia and mitotic activity

are most likely reactive. However, these findings are unusual even in halo nevi, and I recommend complete excision of this lesion, with a margin of normal skin around the scar of this procedure and any residual lesion, in order to rule out a more significant lesion and to preclude any possibility of persistence, recurrence, and possible progression of this atypical lesion. A Mart 1 study reassuringly demonstrates a relatively low density of the cell population in the dermis and in the epidermis.


OVERALL COMMENT


The absence of an in situ component, the presence of maturation, the low mitotic rate, the low cellularity

seen in the Mart stain, and the youthful age of the patient are all reassuring factors in this lesion.

C A S E 6 : S P E C I A L S I T E G E N I TA L S K I N N E V U S V S . M E L A N O M A I N P R E G N A N C Y

1.6 Special Site Genital Skin Nevus vs. Melanoma in Pregnancy

C L I N I C A L I N F O R M AT I O N

DESCRIPTION

“Vulvar mole” in a 26-year-old pregnant woman.

This complex lesion presents considerable difficulties of interpretation. At scanning magnification, the appearances are those of a compound nevus with congenital pattern features, with orderly maturation of

R E A S O N F O R C O N S U LTAT I O N

Excision biopsy, rule out malignancy.

Scanning magnification of a lesion characterized by sheets of cells extending from near the epidermis into the deep reticular dermis. FIG URE 1.6.1.

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1.6 cells from superficial to deep and dispersion of single cells at the base in the reticular dermis, extending to a depth of approximately 3 mm, and with lesional cells extending downward around skin appendages. Closer inspection, however, reveals that there are large cells in relatively large nests at the dermal-epidermal interface, demonstrating significant cytologic atypia in the form of nuclear enlargement, some irregularity, some degree of hyperchromatism, and prominent nucleoli. In addition to the cytologic atypia, multiple mitotic figures are observed within the dermal component of the lesion, including within the more atypical as well as the less atypical more mature cells. Although this combination is concerning, the overall cellularity of the lesion is relatively low, unlike

the confluent, sheetlike growth that characterizes most nevoid melanomas. In addition, the junctional component expresses several features of so-called “special site” nevi of genital skin, including cells of large size, with maturation from superficial to deep. In addition, there is no in situ component characteristic of a melanoma in the epidermis either above or to the side of the dermal component. Finally, it is noted that the patient is pregnant, and mitotic figures have been described in the dermal component of nevi in this situation. The mitotic rate in this case is relatively low, of the order of 1–2 per square millimeter. In addition, there is no ulcer. Because of these conflicting criteria, a descriptive diagnosis has been rendered.

There is a junctional component overlying a cellular dermal component. FIGURE 1.6.3.

FIGURE 1.6.2.

proliferation.

There is no adjacent junctional or in situ

25 C A S E 6 : S P E C I A L S I T E G E N I TA L S K I N N E V U S V S . M E L A N O M A I N P R E G N A N C Y

1.6

There are large nests of large epithelioid cells in the epidermis and clusters of similar epithelioid cells in the subjacent dermis, showing evidence of maturation to the smaller more nevoid cell type toward the base of the lesion. These features are fairly characteristic of those seen in special site nevi of genital skin. FIG URE 1.6.4.

Maturation to smaller cells at the base, and of dispersion of single cells among reticular dermis collagen fibers near the base. These features are consistent with a congenital pattern (and perhaps truly congenital) nevus. FIGURE 1.6.6.

DIAGNOSIS

Skin, “vulvar mole inside right thigh,” biopsy: Melanocytic tumor of uncertain malignant potential, favor an atypical genital pattern nevus; however, an unusual form of nevoid melanoma cannot be ruled out entirely.

COMMENT

Clusters of large cells in the dermis near the surface of the lesion. FIGURE 1.6.5.

I favor that this lesion is most likely an atypical genital pattern nevus with mitotic activity attributable to pregnancy. However, the possibility of an unusual form of melanoma, perhaps with competence for not only local persistence and recurrence but also perhaps for metastasis, cannot be ruled out entirely. I recommend an additional excision procedure, to be sure this lesion has been completely removed, with a margin of normal tissue around the scar of this procedure and any residual lesion, and also, in problematical lesions of this type, a sentinel lymph node procedure may be considered, for staging and possible therapeutic value.

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1.6
OVERALL COMMENT


A sentinel lymph node dissection was done in this case and was negative. The atypia of the epidermal and superficial dermal component in this lesion are within the range of what is seen in genital pattern nevi. There is no in situ component that extends beyond the dermal component. There is maturation of the dermal component, and dermal mitoses are rare. Mitotic figures present in this case were not present in the section available for scanning. The

presence of dermal mitoses in the case, however, is the major reason for considering this lesion as of uncertain potential. As is not uncommonly the case in my experience of special site nevi of the vulva, this lesion exhibits a “congenital pattern” of its dermal component; however, recent molecular evidence suggests that most of these small congenital pattern lesions share the BRAF-mutant genotype of most acquired nevi.

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1.7 Congenital Nevus with Mild Dysplasia and Pseudolymphatics vs. Melanoma with Lymphatic Invasion reticular dermis. There is a slight adjacent intraepidermal component, with mildly dysplastic features. The dermal component matures along nevic lines and disperses into the reticular dermis as single cells at the base. There are spaces between the cells that simulate lymphatics but are not lined by endothelium and represent “pseudolymphatic” spaces. In summary, I interpret this lesion as follows:

C L I N I C A L I N F O R M AT I O N

The patient is a 17-year-old, fair-skinned male with multiple nevi. Three were biopsied. REASON FOR REFERRAL

We felt that all three are dysplastic nevi. DESCRIPTION

Sections show a papular lesion comprised of orderly nevus cells extending from near the epidermis into the

A papular, fairly well-circumscribed lesion. Although the lesion is not perfectly symmetrical in terms of its profile, the pathological changes are similar from side to side at any given level across the lesion. FIG URE 1.7.1.

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The lesional cells in the dermis are arranged predominantly in nests, separated by relatively abundant stromal collagen. There is no tendency to confluence of nests or to sheetlike confluent proliferation and the dermis. The lesional cells become smaller with descent into the dermis (“maturation”). FIGURE 1.7.2.

Spaces are present among the lesional cells in the dermis (see also Figure 2). These have been likened to lymphatic spaces; however, they are not lined by endothelial cells and are “pseudolymphatics.” FIGURE 1.7.4.

Lesional cells disperse as single cells among reticular dermis collagen fiber bundles at the base. Most melanomas differ in this latter property, because, if a single cell of a melanoma tends to invade the dermis, it tends to divide and form a cluster or tongue of cells rather than a single cell column. FIGURE 1.7.3.

Lesional cells extend down into the reticular dermis and around skin appendages, features associated with congenital nevi. However, these changes are not invariably found in truly congenital nevi, and changes similar to these may be found in nevi that are documented to be acquired. Therefore, we refer to these changes as “congenital pattern features.” FIGURE 1.7.5.

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1.7 DIAGNOSIS

Skin, left lower back: Compound nevus with congenital pattern features with pseudolymphatic spaces, and mild dysplasia, completely excised.

Adjacent to the dermal component, there is a junctional component forming a “shoulder” to the lesion. It is only mildly cellular, and there is only minimal nuclear irregularity. The changes can be characterized as mild dysplasia. This patient had other more severely dysplastic nevi elsewhere. Changes similar to those seen in the shoulder are also present in the center of the lesion (e.g., Figure 2). These changes could be classified as “mildly dysplastic features,” but they are not independently diagnostic of a dysplastic nevus, which is typically found in a junctional component adjacent to any dermal component, if the latter is present in the lesion. FIGURE 1.7.6.


OVERALL COMMENT


Pseudolymphatic spaces are relatively common in mature dermal nevi and may represent a degenerative/ senescent phenomenon. They have no significance. Although involvement of the reticular dermis is a “congenital pattern” feature, most of these lesions are acquired after birth, probably usually in early child-

hood. In my experience, mild dysplasia may be an isolated finding, likely to be of little significance, or, as in this case, may be associated with dysplastic nevi elsewhere and therefore likely with an increased lifetime risk for melanoma.

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1.8 Regressed Halo Nevus vs. Regressed Melanoma

history of “halo nevus.” On closer scrutiny, there are a few large cells scattered among the lymphocytes. Your immunostains are very helpful, particularly the Melan-A stain, which shows the presence of melanocytes in the basal layer of the epidermis outside the area of fibroplasia and inflammation, with absence of them within it. In addition, within the area of fibrosis, there are a few clusters of positive cells consistent with remnants of a dermal nevus. I see no high-grade atypia, mitotic activity, or proliferative or tumorigenic proliferation, to suggest the possibility of melanoma. I therefore agree with your diagnosis as follows:

C L I N I C A L I N F O R M AT I O N

F22. “Chest halo nevus.” Patient has history of dysplastic nevus. REASON FOR REFERRAL

We favor a halo nevus but are concerned about the possibility of a regressed melanoma. DESCRIPTION

The sections show an excision of a lesion characterized at first glance by fibroplasia and a lymphocytic infiltrate in the papillary dermis. Of note, the patient was apparently accessioned with a clinical

FIG URE 1.8.1.

Skin magnification shows a subtle area of fibroplasia in the papillary dermis, with a central area of increased

cellularity. 30

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The increased cellularity is comprised mostly of lymphocytes and histiocytes. FIGURE 1.8.2.

Peripheral to the area of hypercellularity, there is slight widening of the papillary dermis with fibroplasia and a few scattered lymphocytes along the dermal-epidermal junction. Melanocytes are absent from the epidermis above the fibroplasia (left half) and present on the right. FIGURE 1.8.4.

In this region, there is fibroplasia and no melanocytes in the epidermis. FIGURE 1.8.5.

FIGURE 1.8.3.

lymphocytes.

A few larger cells are scattered among the

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1.8

Beyond the region of fibroplasia, melanocytes are present in the epidermis. FIGURE 1.8.6.

In the central area of the lesion, there are a few Melan-A positive nevus cells scattered among the lymphocytic infiltrate. They lack cytologic atypia or mitotic activity, and the cellularity is low. FIGURE 1.8.7.

DIAGNOSIS

Skin, chest: Dermal fibrosis and inflammation with residual nevoid-epithelioid melanocytes, consistent with a subtotally regressed halo nevus; see previous discussion and comment.

COMMENT In the region of the lymphocytic infiltrate, there is a transition from an epidermis within the halo that does not contain melanocytes (on the left) to the normal epidermis beyond the halo in which Melan-A positive melanocytes are readily identified. The lymphocytic infiltrate seems to represent a region of active (presumably immunologic) destruction of melanocytes. FIG URE 1.8.8.

As you note, the differential diagnosis could potentially include a regressing melanoma; however, the lesion appears to be relatively symmetrical, and there is no expansile tumorigenic proliferation, mitotic activity, or severe atypia of the residual lesional cells. The architecture suggests that this lesion may have been a dysplastic nevus (“halo dysplastic nevus”). The process appears to be completely excised.


OVERALL COMMENT


This lesion was regarded as benign because of its symmetry, the lack of cytologic atypia in the residual cells,

and the overall architecture, which is consistent with a halo nevus.

2 Congenital Nevi and Tumefactions in Them

C

oncogene mutations (2). Thus, they appear to represent a subset of acquired nevi. In an influential early study, the histology of “congenital” melanocytic nevi was described (3). Features commonly found in these lesions and initially thought to be diagnostic of a congenital nevus included involvement of the reticular dermis, involvement of skin appendages, and large size. However, this study was apparently based on the large, “clinically congenital” lesions, and true congenital onset was not documented. Furthermore, studies of neonates subsequently demonstrated that lesions that were demonstrably present at birth commonly lack these features, many of them being small, some junctional, and most of those that involve the reticular dermis being superficial, without skin appendage involvement (4). The clinical significance of congenital nevi has been the subject of debate. The least ambiguous setting is that of giant congenital nevi because of their dramatic clinical presentation. As previously mentioned, these are cosmetic tragedies and are generally not amenable to surgical excision. Efforts at dermabrasion for cosmesis have produced mixed results, and this procedure is not widely performed. Like other nevi, congenital melanocytic nevi can be potential precursors of melanoma (5). Estimates of the incidence of melanoma in giant congenital nevi tend to be biased by clinic-based or registry based series (6). Population-based or adjusted cohort studies demonstrate a statistically significantly increased incidence, perhaps in the 5–10% range over a lifetime (7–10). The incidence of melanoma in intermediate

ongenital melanocytic nevi and the tumefactions that may occur in them may, on occasion, present considerable difficulties of interpretation. These will be discussed in adults, in children, and in neonates. Congenital melanocytic nevi may be simply defined as melanocytic nevi that are present at birth. However, there are morphologically indistinguishable lesions that clearly arise after birth, usually in early childhood, known as “tardive” congenital pattern nevi. Clinically, these lesions (congenital and tardive) have been divided into three major groups, namely “small,” which are nevertheless usually larger than most common acquired nevi, “intermediate,” and large or “giant.” The latter constitute a dramatic, cosmetically tragic, and, fortunately, rare phenomenon in which a child is born with a pigmented and often hairy lesion covering large areas of the body, also known for this reason as “garment nevus.” At the other end of the spectrum, small congenital nevi are defined as less than 1.5 cm in their greatest dimension; intermediate congenital nevi are generally defined as lesions that are larger than 1.5 cm yet amenable to resection with primary closure, ranging up to about 20 cm or so (1). Recent studies have demonstrated important genetic distinctions between acquired and congenital nevi. Most acquired nevi contain mutations of the BRAF oncogene. These mutations are rare in true congenital nevi, which tend to have a mutated NRAS oncogene. Tardive congenital pattern nevi (most of which are also relatively small) appear to resemble acquired nevi in tending to have BRAF 33

34 CO N G EN I TA L

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and small congenital nevi is even less well understood. In the case of small congenital nevi, the association is generally recognized histologically by the presence of an associated nevus with “congenital pattern features,” namely those previously listed. However, despite the existence of some degree of correlation between these features and a congenital history (11), it is clear that not all such nevi are truly congenital. Nevi of this type are seen in association with melanomas in about 10% of cases, which is greater than what would be expected by chance (12). There is evidence that nevi with these pattern features may be at somewhat greater risk of progression to melanoma (9) and may be markers of individuals at increased risk for melanoma (9). However, simple calculations also suggest that the rate of transformation of any given such nevus is quite low, so that these lesions are not suitable targets for public health preventive interventions. When a melanoma develops in a congenital nevus or a congenital pattern nevus, it tends to follow a pathway of evolution similar to that of ordinary melanoma of the superficial spreading type. Thus, there is an in situ or microinvasive radial growth phase component that develops in relation to the junctional component of the nevus, which may be followed over time by the development of a tumorigenic vertical growth phase. Often, the superficial portion of the nevus is obliterated, and the dermal nevus cells represent the only remnants of the precursor. Melanomas in congenital nevi tend to develop at a relatively early age, often (but by no means always) in childhood. However, in our limited experience and in a small literature (13), alarmingly cellular tumefactions that have been present at birth or in the neonatal period have sometimes been followed by a benign course, despite evidence in some of these cases of high-grade atypia, destructive invasion of surrounding structures, mitotic activity, necrosis, and ulceration. On

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the other hand, cases of fatal infantile and congenital melanomas have been described (14;15). Therefore, interpretation of these lesions should be circumspect, and management should be based on clinicopathologic correlation. In former times, the concept of melanoma occasionally arising in the dermal component of a congenital nevus was accepted. However, follow-up studies of large series of these cases were not available. More recently, it has been recognized that cellular and/or proliferative nodules may develop in the dermal component of congenital nevi, representing tumefactions that may have some capacity for local persistence and recurrence if not completely excised, but which appear rarely if ever to have capacity for metastasis. These lesions have been studied at the cytogenetic level and found to have minimal or no chromosomal aberrations. In a follow-up study of more than 30 cases by Xu et al., there were no instances of metastasis (16). Anecdotally, however, we have seen a few examples of incompletely excised cellular nodules that have recurred locally, sometimes creating problems of interpretation. In addition to malignant melanomas and cellular nodules, other tumefactions have been described, albeit very rarely, in congenital melanocytic nevi (13;17). These have included heterotopic tumors, both benign and malignant, including cartilage, striated muscle, bone, and epithelial structures. Interpretation of their biological significance is problematic, because of limited experience.

References 1 Tannous ZS, Mihm MC Jr., Sober AJ, Duncan LM. Congenital melanocytic nevi: clinical and histopathologic features, risk of melanoma, and clinical management. J Am Acad Dermatol 2005 Feb;52(2):197–203. 2 Bauer J, Curtin JA, Pinkel D, Bastian BC. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol 2007;127:179–182 Epub 2006 Aug 3.

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3 Mark GJ, Mihm MC Jr, Liteplo MG, Reed RJ, Clark WH Jr. Congenital melanocytic nevi of the small and garment type. Clinical, histologic, and ultrastructural studies. Hum Pathol 1973;4:395–418. 4 Walton RG, Jacobs AH, Cox AJ. Pigmented lesions in newborn infants. Br J Dermatol 1976;95:389–96. 5 Zaal LH, Mooi WJ, Sillevis Smitt JH, van der Horst CM. Classification of congenital melanocytic naevi and malignant transformation: a review of the literature. Br J Plast Surg 2004 Dec;57(8):707–19. 6 Kopf AW, Bart RS, Hennessey P. Congenital nevocytic nevi and malignant melanomas. J Am Acad Dermatol 1979;1:123–30. 7 Lorentzen M, Pers M, Bretteville-Jensen G. The incidence of malignant transformation in giant pigmented nevi. Scand J Plast Reconstr Surg 1977;71:163–7. 8 Swerdlow AJ, English JS, Qiao Z. The risk of melanoma in patients with congenital nevi: a cohort study. J Am Acad Dermatol 1995 Apr;32(4):595–9. 9 Kopf AW, Levine LJ, Rigel DS, Friedman RJ, Levenstein M. Congenital-nevus-like nevi, nevi spili, and cafe-au-lait spots in patients with malignant melanoma. J Dermatol Surg Oncol 1985 Mar;11(3):275–80. 10 Hale EK, Stein J, Ben-Porat L, Panageas KS, Eichenbaum MS, Marghoob AA, Osman I, Kopf AW, Polsky D. Association

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13

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of melanoma and neurocutaneous melanocytosis with large congenital melanocytic naevi—results from the NYU-LCMN registry. Br J Dermatol 2005 Mar;152(3):512–7. Walsh MY, MacKie RM. Histological features of value in differentiating small congenital melanocytic naevi from acquired naevi. Histopathology 1988;12:145–54. Rhodes AR, Sober AJ, Day CL, Melski JW, Harrist TJ, Mihm MC Jr, Fitzpatrick TB. The malignant potential of small congenital nevocellular nevi. An estimate of association based on a histologic study of 234 primary cutaneous melanomas. J Am Acad Dermatol 1982;6:230–41. 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 Mar;5(2):109–35. Sweet LK, Connerty HV. Congenital melanoma. Am J Dis Childh 1951;62:1029–40. Richardson SK, Tannous ZS, Mihm MC Jr. Congenital and infantile melanoma: review of the literature and report of an uncommon variant, pigment-synthesizing melanoma. J Am Acad Dermatol 2002 Jul;47(1):77–90. Xu X, Bellucci KS, Elenitsas R, Elder DE. Cellular nodules in congenital pattern nevi. J Cutan Pathol 2004 Feb;31(2):153–9. Reed RJ. Giant congenital nevi: a conceptualization of patterns. J Invest Dermatol 1993 Mar;100(3):300S–12S.

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2.1 Congenital Pattern Nevus with Mitoses vs. Nevoid Melanoma

and extending well into the reticular dermis and around skin appendages. The lesional cells are nevoid to epithelioid in configuration, with relatively abundant cytoplasm and fairly large nuclei, with small nucleoli. They show evidence of maturation from superficial to deep. The junctional component is quite sparse, without any evidence of an in situ component of a melanoma. As you note, occasional lesional cell mitoses are present. However, there is no striking suggestion of expansile growth of the dermal component, and, as already noted, atypia is slight, and there is evidence of maturation. I therefore conclude that these changes are benign—although, interestingly, one might speculate that these slight proliferative changes might correlate with the symptoms experienced by the patient. In summary, I interpret this material as follows:

C L I N I C A L I N F O R M AT I O N

This 27-year-old man had this nevus on the scalp all his life. In comparison to a photograph from about a year prior to excision, the lesion appeared to have enlarged laterally and also darkened. R E A S O N F O R C O N S U LTAT I O N

Histologically it looks like a congenital pattern nevus with some features of a “nevus spilus.” However, scattered mitoses are present, none in the base of the lesion. DESCRIPTION

The sections show an excision of a broad and deep melanocytic lesion characterized by orderly nevus cells present in nests at the dermal epidermal junction,

FIG URE 2.1.1.

A broad and deep plaquelike lesion extending deep into the reticular dermis and subcutis. 36

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At the periphery the lesion is quite well

FIGURE 2.1.3.

A rare mitosis was present in the dermal component. However, in view of the lack of any in situ component and of cytologic atypia and given the maturation and dispersion of single cells at the base, the mitoses were not considered sufficient for a diagnosis of malignancy.

FIGURE 2.1.5.

FIG URE 2.1.2.

circumscribed.

The nested character of the cells superficially indicates the melanocytic nature of the lesion. At the base, the proliferation is more sheetlike; however, there is evidence of maturation and dispersion of single cells at the base.

FIG URE 2.1.4.

Lesional cells are present around—but, in this case, not within—the epithelium of skin adnexa.

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2.1 DIAGNOSIS

Skin, scalp: Congenital melanocytic nevus, with scattered mitotic activity; see previous discussion and comment.

COMMENT

As you know, occasional mitoses may be seen in nevi, and, if there are no other indications of malignancy, this is not necessarily indicative of a melanoma. This present lesion is completely excised, and I see no indication for any additional therapy.

FIGURE 2.1.6.

Reassuringly, the Ki-67 proliferation rate is

low.


OVERALL COMMENT


“Nevi with mitoses” are not necessarily melanomas. The major differential diagnosis is with “nevoid melanoma,” which is characterized by greater cellularity (with sheets of cells), lesser maturation, some degree of cytologic atypia, and perhaps more frequent mitoses. There is, of course, overlap between these lesions, and, in some cases, a descriptive diagnosis of

“melanocytic tumor of uncertain malignant potential” may be the best that can be arrived at. In such cases, a differential diagnosis should be given, and it is often possible to favor one or the other diagnosis. In my opinion, however, the existence of significant diagnostic uncertainty should not be concealed from the patients and their physicians.

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2.2 Congenital Nevus with Mitoses vs. Nevoid MM

the reticular dermis, showing evidence of maturation from superficial to deep and dispersion of single cells into reticular dermis collagen at the base. The lesion has a nested and trabecular architecture, without marked hypercellularity. In some areas, there is evidence of neurotization. One area of the lesion is somewhat more cellular than the remainder, although not forming a well-defined nodule. In this area, scattered mitotic figures are observed. In a formal count of 50 high-power fields, with one mitosis in the first field, only a single additional mitosis was identified. Adjacent to this dermal tumor, there

C L I N I C A L I N F O R M AT I O N

F35, lesion of right arm. R E A S O N F O R C O N S U LTAT I O N

Favor compound melanocytic nevus with mildly atypical features, final diagnosis pending consultation. DESCRIPTION

The sections show an excision of a skin lesion that has a scanning magnification architecture of a congenital pattern nevus, characterized by orderly nevus cells extending from near the epidermis well into

39

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2.2

FIG URES 2.2.1 A ND 2 .

Scanning magnification shows a polypoid-dome-shaped tumor of the skin.

is a junctional component comprised of single and nested melanocytes, arranged along the dermalepidermal junction, mainly near the tips and sides of elongated rete ridges, with some nests bridging between adjacent rete, and with slight random

atypia of some lesional cells. These appearances constitute mild melanocytic dysplasia. In summary, I do not believe these appearances are diagnostic of melanoma and interpret this lesion, to some extent, descriptively.

There is a junctional component at the “shoulder” of the lesion on the left-hand side, but not on the right.

FIGURE 2.2.4.

FIG URE 2.2.3.

There is a relatively low cellularity junctional component, comprised of single cells and nests arranged mainly around the tips and sides of elongated rete ridges, with some nest bridging adjacent rete.

There is evidence of maturation of the cells in the dermis from superficial to deep. They are arranged in an ill-defined nested pattern. At the base, lesional cells disperse as single cells among reticular dermis collagen fiber bundles. There is minimal to slight nuclear size and shape variation of lesional cells in the epidermis and in the superficial dermis. These are characteristics of benign nevus cells. FIG URES 2.2.5 A N D 6 .

Mitotic figures were readily detected, including one near the base of the lesion. Figure 9 shows the location of the two mitoses illustrated. FIG URES 2.2.7 – 9 .

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2.2 DIAGNOSIS

Skin, right arm: Compound nevus with congenital pattern features, mild melanocytic dysplasia, and rare lesional cell mitoses; see previous discussion and comment.

COMMENT

be interesting to know if this patient is pregnant. In any event, I do not believe these changes are sufficient for a diagnosis of melanoma in the absence of any other significant criteria. Because of the mitotic activity and the adjacent dysplasia, it might be appropriate to follow this patient, especially if she should have other clinically atypical nevi and/or a family or personal history of melanoma. This present lesion is completely excised, with a clear margin of normal skin and subcutaneous tissue.

“Nevi with mitoses” have been described, sometimes in association with pregnancy, and it would


OVERALL COMMENT


This lesion may overlap between the “nevus with mitoses” and the nevi with cellular nodules to be described

later in this section. Complete excision would have been recommended if margins were positive.

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in a so-called “congenital pattern.” There is evidence of maturation from superficial to deep in some areas of the lesion. In the overlying epidermis, there are a few scattered foci where there are larger epithelioid melanocytes; however, there is no high-level or extensive pagetoid or continuous basal proliferation to support a diagnosis of in situ melanoma. Nevertheless, in the dermal component, there is an ill-defined area of greater cellularity, where the lesional cells, despite having relatively abundant cytoplasm, demonstrate substantial nuclear enlargement, irregularity, and hyperchromatism. In this area also, as you have noted on the slides, there are scattered mitotic figures, with at least one area containing two mitotic figures in one high-power field. However, overall, the mitotic rate is not greater than 2/mm2. The differential diagnosis for this lesion could include a nevoid melanoma, a melanoma arising in the dermal component of a nevus, or the phenomenon of cellular and proliferative nodules

C L I N I C A L I N F O R M AT I O N

F48, lesion of left hip. The submitted clinical history is rule out inflamed nevus versus atypia. The patient has had this lesion for as long as she can remember but noted a change in color over the past month. She describes having irritated it while shaving in the past. She is not known to be pregnant. R E A S O N F O R C O N S U LTAT I O N

I appreciate your assistance with this case, with regard to diagnosis and any management recommendations. DESCRIPTION

These sections show a shave biopsy, containing a moderately to focally more highly cellular proliferation of nevoid melanocytes in the dermis, with a few nests and single cells in the overlying epidermis, without an adjacent junctional component. Lesional cells extend well into the reticular dermis at the base of the lesion

FIG URE 2.3.1.

Multiple levels of a quite bulky, moderately cellular tumor in the skin. 43

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2.3 that may occur in congenital pattern nevi. This particular lesion blends with surrounding more mature nevoid melanocytes, as one expects to see in cellular nodules; however, it does not form a well-defined nodularity. I nevertheless believe it is best placed into this general category and interpret this lesion descriptively as follows:

The superficial configuration is that of a compound nevus with congenital pattern features, with orderly small nevoid cells extending from near the epidermis into the reticular dermis. A smaller superficially located nevoid cell type blends with a larger more epithelioid cell type, which constitutes an ill-defined nodule visible at scanning magnification. FIGURE 2.3.4.

Closer view demonstrating partly nested and partly sheetlike patterns of growth. FIG URE 2.3.2.

There are changes in the epidermis consistent with severe melanocytic dysplasia. FIGURE 2.3.5.

At the periphery of the lesion, the pattern is predominantly nested, and the cells are smaller and more nevoid in configuration and cytology. Toward the center of the lesion, there is an ill-defined nodule comprised of larger cells. FIG URE 2.3.3.

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A few “melanocytic giant cells” are present within the larger more epithelioid component. FIG URE 2.3.6.

A mitotic figure is present in the cellular portion of the lesion, associated with moderate to severe cytologic atypia. A Web figure low-power view shows the location of two mitotic figures in the lesion. FIGURE 2.3.7.

DIAGNOSIS

Skin, right hip: Cellular and proliferative nodule of uncertain malignant potential, occurring in a nevus with congenital pattern features; see previous discussion and comment.

COMMENT

In the absence of a more compelling in situ component or more severe uniform atypia or a higher mitotic rate, I do not believe these changes are diagnostic of nevoid melanoma; however, one cannot rule out this possibility entirely. It is not clear that microstaging attributes developed for ordinary forms of melanoma

should be applied uncritically to these unusual lesions; however, if interpreted as a melanoma, it would be 4.1 mm in Breslow thickness, with a dermal mitotic rate of 2/mm2, absent tumor infiltrating lymphocytes, no ulcer, no satellites, and no evidence of vascular, lymphatic, or neural invasion. I do not favor this possibility; however, I recommend an additional procedure, to be sure this lesion has been removed, with, at a minimum, a margin of normal skin around the scar of this procedure and any residual lesion. One might also consider at least discussing a sentinel lymph node sampling procedure; however, I do not believe that this is necessarily the standard of care in lesions of this type.


OVERALL COMMENT


Because the area of nodularity is not especially well defined, this lesion is not a characteristic example of this condition. In view of the combination of dermal

atypia (albeit mild) and mitotic activity, the possibility of a lesion with some potential for metastasis could not be ruled out.

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2.4 Cellular and Proliferative Nodule vs. MM

C L I N I C A L I N F O R M AT I O N

DESCRIPTION

F12. This lesion had been present on her back for many years and was taken off because it was irritated by her clothing. The patient has no other lesions like this, and there is no family history of melanoma or other skin tumors except for a few relatives with basal cell carcinoma.

These sections show, as you describe in your letter, a cellular nodule in the dermis, comprised of relatively large epithelioid cells, with a relatively high nuclear to cytoplasmic ratio, and with relatively large nuclei. These cells were reportedly strongly S100 positive in stains done in your institution. Although the nuclei are large, they have fairly regular nuclear membranes and relatively open chromatin, and only occasional small nucleoli. Mitotic figures are present, although generally not numerous, except that at least one high-power field contains two mitoses. In short, the appearances are those of a cellular nodule of nevoid to epithelioid melanocytes in the dermis. The changes bear some resemblance to the phenomenon

R E A S O N F O R C O N S U LTAT I O N

We think that this lesion may represent some form of hyperplastic intradermal nevus. Based on the clinical history of the lesion and the appearance, at this time we believe this is mostly likely a benign lesion. The lesional cells were strongly positive for S100 and negative for cytokeratin stains and for EMA.

Scanning magnification shows two profiles of the cellular tumor forming a polypoid lesion, elevating an otherwise unremarkable epidermis. FIG URE 2.4.1.

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2.4 of “cellular and/or proliferative nodules” that may be seen in congenital melanocytic nevi. However, in this case, there is no background nevus. These nodules tend to show evidence of maturing along nevoid lines at their periphery, which is not evident in this particular lesion. In addition, as noted previously, mitotic figures are present, with at least one high-power field that contains two mitotic figures, although abnormal mitotic figures have not been observed and, overall, the mitotic rate is low. In addition, although the lesion is quite cellular, it is not homogeneously cellular, having broad trabeculae of connective tissue

separating smaller and larger nodules of lesional cells. This is a most unusual lesion. Because of the relatively low overall mitotic rate, the lack of more high-grade uniform atypia, the lack of necrosis, and the lack of more extensive confluent growth, as well as the lack of an overlying in situ component and the youthful age of the patient, one is reluctant to make a diagnosis of malignant melanoma. Nevertheless, the features mentioned, especially the combination of dermal atypia and mitotic activity, suggest to me that this is a lesion of somewhat uncertain malignant potential. I therefore interpret it as follows.

The tumor cells are arranged in ill-defined lobules separated by a quite vascular fibrous stroma.

FIGURE 2.4.3.

FIG URE 2.4.2.

At the periphery of the lesion and above it, there is no evidence of any in situ component of a melanoma. The tumor is separated from the overlying epidermis by a free zone of papillary and upper reticular dermis collagen. There is no ulcer.

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The lesional cell nuclei are cytologically bland, with fairly uniform finely divided chromatin. There is little or no evidence of maturation from superficial to deep. The lesional cells are fairly uniform throughout the nodule. There is no necrosis. FIG URE 2.4.4.

DIAGNOSIS

Skin, lower back: Melanocytic tumor of uncertain malignant potential, most consistent with a dermal “cellular and proliferative nodule” of the type usually seen in congenital nevi; see previous discussion and comment.

COMMENT

If this lesion does represent an example of a cellular nodule in which the background nevus is either

Mitotic figures are readily detected; however, the overall mitotic rate is low. FIGURE 2.4.5.

absent or obliterated, we have found the behavior of these to be usually benign, at least from the perspective of metastatic disease. However, at least a couple of examples known to us have recurred locally after incomplete excision. This present lesion extends to specimen margins, and I recommend an additional procedure, to be sure it has been completely removed. One might consider discussing the possibility of sentinel lymph node sampling as a staging procedure for a tumorigenic and mitogenic atypical melanocytic proliferation such as this one. However, I do not believe that this is, by any means, the standard of care for such an unusual lesion as this. In any event, I recommend at a minimum careful follow-up of this patient after complete removal of the lesion locally.


OVERALL COMMENT


The cellular nodule is not as well defined as it is in many examples. The differential diagnosis could include a “nevus with mitoses” and a nevoid melanoma.

Because cytologic atypia and a degree of hypercellularity are both present, it is difficult to rule out the latter entirely.

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2.5 MELTUMP vs. Cellular Nodule vs. MM in CN in Neonate

ruled out entirely because of the combination of necrosis, focally prominent mitotic activity, some pagetoid proliferation in the epidermis, and infiltration of the dermis to the subcutaneous fat. Against the diagnosis of melanoma is the suggestion of maturation from the larger cells to the smaller cells, and quite limited but substantial experience that suggests that atypical proliferations and congenital nevi in very young

C L I N I C A L I N F O R M AT I O N

This is a biopsy of the central nodular portion of what clinically appears as a congenital nevus on the left calf of this 1-month-old baby girl. R E A S O N F O R C O N S U LTAT I O N

We cannot rule out malignancy in this lesion. DESCRIPTION

The sections show a most interesting and unusual biopsy of a lesion from the center of an intermediate congenital nevus on the forearm of a 1-month-old baby. The sections show a highly cellular proliferation of lesional cells that range from large epithelioid cells with abundant finely divided melanin pigment, to smaller nevoid cells that are placed among reticular dermis collagen fiber bundles, and around skin appendages, the latter in the pattern of a congenital nevus. The larger epithelioid cells are more problematic. One could consider the possibility of a cellular and proliferative nodule in a congenital nevus; however, these usually do not involve the epidermis to this extent, nor are they associated with focally prominent mitotic activity, necrosis, or ulceration, as a rule. Another general but very ill-defined category of lesions in congenital nevi is that of atypical proliferations that are present at birth or in neonates and seem to represent a stage of maturation of the nevus. Finally, of course, one must consider the possibility of a malignant melanoma. This is a very rare event in a neonate, but I believe, in this case, that it cannot be

Scanning magnification shows a cellular tumor, extending from the epidermis into the subcutis. The overlying epidermis is covered by a scale crust. The lesion is highly cellular, with large epithelioid cells superficially. Toward the base of the tumor, the cells become somewhat smaller. The tumor extends into the subcutaneous fat at the base. FIGURE 2.5.1.

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2.5 children—and in older individuals as well—may be unpredictable in their behavior, and those markedly atypical lesions may follow a benign course. For these reasons, I interpret this lesion descriptively as follows (Figures 1–4):

Scattered mitotic figures were present in the superficial cells (arrow). The highest focal mitotic rate was 2/mm2. FIGURE 2.5.4.

DIAGNOSIS There is focal necrosis of the superficial cells, with associated hemorrhage. FIG URE 2.5.2.

Skin, left calf: Melanocytic tumor of uncertain malignant potential, favor an atypical proliferation in a neonatal congenital nevus; see previous discussion and comment.

COMMENT

At the periphery of the biopsy, and in association with skin appendages, an admixture of smaller nevoid melanocytes can be seen, representing elements of the background congenital nevus. This measured about 4 cm in diameter and was a uniform brown in color. FIG URE 2.5.3.

Although I would favor the notion that this lesion will have a benign course, I cannot rule out an unusual form of melanoma, and, if interpreted as a melanoma, this lesion could, unfortunately, have competence for metastasis. I recommend, at a minimum, a re-excision procedure that encompasses this atypical proliferation, and I believe that, either immediately or over time, complete excision of this nevus would be wise. The question of sentinel node sampling obviously might arise, because this lesion, if interpreted as melanoma, would extend to Clark level V and a greatest thickness of approximately 2.7 mm, with ulceration. I believe that this is a decision that should be made in consultation with the patient’s family. Problematic lesions

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2.5 in childhood and infancy, even when associated with positive findings in a regional node, can have long and uneventful survivals, although our experience, of course, is quite limited with these unusual lesions. FOLLOW-UP C L I N I C A L I N F O R M AT I O N

This is a re-excision of a lesion in a 7-week-old infant. You consulted on it recently. R E A S O N F O R C O N S U LTAT I O N

by larger more epithelioid cells, with relatively bland nuclei but with occasional mitotic activity. I agree that these cells, which are arranged in a generally nested pattern, have some features of an “inverted Type A nevus” or of a deep penetrating nevus. The original biopsy, however, had more extensive confluent sheetlike proliferation and had areas of necrosis. In any event, the findings in this biopsy do not add more information regarding possible behavior of this atypical proliferation, and I interpret this material descriptively as follows (Figures 5–7):

On superficial review, I favored that this is an atypical proliferative nodule or an inverted Type A nevus within a congenital pattern nevus; however, given the necrosis and quite prominent mitotic activity that you saw on the original biopsy and the scattered mitoses seen in my specimen, I do not feel comfortable that this is not a more aggressive process. DESCRIPTION

The sections show a broad melanocytic lesion, characterized by a relatively prominent junctional component, comprised of nested and some single melanocytes, with nests predominating, predominantly near the dermal-epidermal junction. There is some variation in size and shape of nests, and there are few areas where cells rise into the epidermis, in a pagetoid pattern; however, this is focal and generally does not extend beyond the middle third of the epidermis. The cells in the epidermis are pigmented. Similar cells with little or no pigment are present in the dermis, extending down around and within skin appendages, including within sebaceous units, supposed to be quite specific for congenital onset, which, as I understand it, is also supported by the history. In the center of the specimen, there is a scar consistent with prior biopsy, and there are residual elements of the same lesion, characterized

A re-excision specimen showed a biopsy site reaction, a background congenital nevus, and residual tumor at the base of the biopsy. FIGURE 2.5.5.

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2.5

Nevus cells “within” and “around” skin appendages in a pattern typical of a congenital nevus. FIG URE 2.5.6.

DIAGNOSIS

Skin, left calf: Residual melanocytic tumor of uncertain malignant potential, present in an intermediate-sized congenital melanocytic nevus in relation to a previous biopsy site reaction, favor an atypical cellular and proliferative nodule in a neonatal congenital nevus; see previous discussion and comment.

The residual tumor was less atypical than the tumor in the first biopsy. There is a suggestion of blending with the background nevus cells. FIGURE 2.5.7.

COMMENT

As discussed in my original letter, I tend to favor the notion that this lesion represents an atypical cellular and proliferative nodule occurring in a large or intermediate congenital nevus; however, the cellularity and mitotic activity and the necrosis are at the upper end of the spectrum of these lesions. Nevertheless, tumefactions that may occur in congenital nevi, especially in neonates, have, in our experience, sometimes presented cytologic features even more atypical than in this case, with subsequent long benign follow-up. In addition, the degree of atypia in the residual tumor is less than that in the original biopsy. I therefore encourage an optimistic attitude about this lesion but, of course, recommend continuing careful follow-up for this young patient.

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2.5
OVERALL COMMENT


The degree of atypia in this lesion is considerably greater than that in most cellular nodules, and the epidermal involvement and necrosis are also unusual. For this reason, microstaging attributes have been presented as a “worst-case scenario.” However, malignant melanoma is, of course, extremely rare in a neonate. Clinically, there was clear evidence of a background, clinically benign, congenital pattern nevus. This is a situation in which the clinical behavior is very difficult

or impossible to predict, although, in my opinion, the behavior is most likely to be benign. The residual lesion in this material tends to be arranged in nests placed on reticular dermis collagen fiber bundles. There is a tendency to blending with the background nevus, similar to findings in a cellular nodule; however, the necrosis and mitotic activity seen in the original biopsy would not be compatible with this completely benign diagnosis.

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2.6 Congenital Melanocytic Nevus with Heterotopic Cartilage and Bone, Benign vs. Malignant C L I N I C A L I N F O R M AT I O N

COMMENT

This excision was done primarily for cosmetic/ functional reasons in this infant with a giant congenital nevus involving the genitalia.

The sections show, as you describe, a lesion characterized by nevoid melanocytes present in the reticular dermis and subcutis, and in the epidermis. In addition, there are sheets of cartilage that appear to be intimately admixed with this nevus, and also foci of osseous differentiation. There is even a suggestion of blending

R E A S O N F O R C O N S U LTAT I O N

Do you agree that this lesion is benign?

FIG URE 2.6.1.

Scanning magnification shows masses of pale staining cartilage in the dermis, which is hypercellular. 54

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2.6 between the cartilage and the nevus, which is accentuated in the S100 stain. However, of course, both cartilage and nevus cells are normally positive with this marker. Melan-A stain does not decorate the cartilage cells. Both the nevus (including its junctional component) and the associated cartilage are histologically benign. Although it is very unusual, heterotopic differentiation has been described in congenital melanocytic nevi, especially in giant lesions such as this one. I do not believe this has any particular significance

The mesenchymal cells appear undifferentiated while the cartilage is mature. It is difficult to distinguish dermal nevus cells from undifferentiated mesenchymal cells. FIG URE 2.6.2.

regarding the future behavior of this lesion. In summary, I agree with your interpretation as follows: Sections of the second specimen show changes characteristic of a “giant” congenital nevus, with orderly nevus cells extending throughout the reticular dermis and subcutis to the base of the biopsy. Superficially, the cells tend to be more nested and to be pigmented. There is no substantial junctional component in this region of the lesion. There is no significant cytologic atypia. In summary, I interpret this material as follows:

Melan-A stain demonstrates numerous melanocytes in the overlying epidermis. Although solitary, they do not exhibit significant cytologic atypia. FIGURE 2.6.3.

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Scattered Melan-A positive melanocytes are present in the dermis and also in the subcutaneous fat. FIG URE 2.6.4.

S100 stains the cartilage and also a few nevus cells distributed among the mesenchymal cells in the dermis, as well as the overlying junctional melanocytes. FIGURE 2.6.5.

DIAGNOSIS

COMMENT

Skin, and subcutaneous tissue, vulva: Congenital

As noted previously, I see no evidence of malignancy in this material.

melanocytic nevus with heterotopic cartilage and bone; see previous discussion and comment.


OVERALL COMMENT


The heterotopic cartilage in this lesion is a histological curiosity of no consequence, likely related to the neural crest origin of these lesions. The giant congen-

ital nevus, depending on its location and size, may be a cosmetic tragedy for the patient.

3 Spindle and/or Epithelioid Cell Nevi/Tumors

T

Architecturally, the lesions are also characterized by architectural and cytologic symmetry. The latter term is used to indicate that the lesional cells are monotonously similar from side to side across the lesion. Importantly, as in the case of other benign nevi, there is also evidence of maturation from larger cells at the surface to smaller cells at the base, and dispersion of single cells into the reticular dermis collagen at the base. This latter pattern contrasts with the more varied pattern of melanomas that involve the reticular dermis, in which clusters or tongues of cells may be present at the advancing edge. This appears to be the result of continued proliferation of the cells in the dermis after invasion, initially by single cells, has occurred (5). Ulceration is uncommon, except occasionally in young children, presumably as a result of trauma. It has recently been demonstrated that Spitz tumors tend to lack a property termed “consumption of the epidermis,” defined as “thinning of the epidermis with attenuation of the basal and suprabasal layers and loss of rete ridges in areas of direct contact with neoplastic melanocytes” (6). In contrast, the epidermis in a Spitz tumor is often hyperplastic. Spindle and epithelioid or Spitz nevi were regarded for many years as unequivocally benign. If a lesion that had previously been termed a Spitz nevus was found to have metastasized, it was considered that the original diagnosis was in error. More recently, however, it has been recognized that morphologic distinction between metastasizing and nonmetastasizing Spitzoid lesions may be impossible (7;8), and the term “Spitz nevus/tumor” has been proposed in

hese are among the most problematic melanocytic tumors seen by pathologists. Categories include the following: Spitz nevi/tumors Spitzoid melanomas and melanocytomas of childhood and of adults Spitzoid melanocytic tumors of uncertain malignant potential (MELTUMP) Epithelioid melanocytomas Pigmented spindle cell nevus of Reed (PSCN)

This group of lesions was first described by Sophie Spitz in 1948 (1). She described a group of lesions that she termed “juvenile melanomas,” considering them to be malignancies, but with a better prognosis than usual melanomas of adults. Subsequently it was recognized that the vast majority of appropriately classified lesions are benign, and the term “Spitz nevus” became current, being used synonymously with the more descriptive term “spindle and epithelioid cell nevus”(2), or Ackerman’s somewhat more cumbersome but more precise term, “nevus of large spindle and/or epithelioid cells” (3). This latter term, in particular, provides a capsular definition of the lesion, which is typically comprised of a monomorphic population of cells that, in different profiles, may adopt an epithelioid or a spindled morphology. In addition, they have large nuclei with open chromatin, usually regular nuclear membranes and prominent nucleoli. The characteristic presence of globoid eosinophilic “Kamino bodies” at the dermal-epidermal junction is a helpful and surprisingly robust diagnostic feature (4). 57

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recognition of this uncertainty (7;9). A set of criteria has been proposed for the recognition of “atypical Spitz tumors” (7;9), including diagnosis at age greater than 10 years, diameter of the lesion greater than 10 mm, presence of ulceration, involvement of the subcutaneous fat (level V), and mitotic activity of at least 6/mm2 (10). Comparative genomic hybridization studies have demonstrated that there are quite striking cytogenetic differences between atypical Spitz tumors and authentic malignant melanomas, although it is not clear that this analysis can be used as a definitive diagnostic test, because there is some degree of overlap (11). Many of these tumors, in my opinion, are best regarded as “melanocytic tumors of uncertain malignant potential.” Recently, a group of cases assembled by Lorenzo Cerroni, M.D. was studied by a group of experts and discussed at the annual meeting of the International Society of Dermatopathology in Graz, Austria. This presentation included follow-up of cases presented at a similar workshop eight years earlier (8). These cases were selected as bulky tumors comprised of a uniform population of epithelioid or spindled cells. Not all were especially “Spitzoid;” some had features of “deep penetrating nevi” or “pigmented epithelioid melanocytomas.” Despite the size of the lesions, only a few small ulcers were observed, and there was no in situ melanoma component. The cells had abundant cytoplasm, with large round or ovoid nuclei with regular nuclear membranes, pale chromatin, and a single prominent nucleolus. Mitoses were absent in many lesions, and, when present, the rate was low. About one-third of these lesions had metastases, most often to regional nodes, and about 20% were fatal, often after a protracted at least initially indolent course. There were many instances of relatively long-term survival after regional metastases, suggesting that some of these metastases, like the primary lesions, may be

CE L L

NE VI/TUMO RS

of “uncertain malignant potential.” It was considered that these lesions represented a form of relatively lowgrade malignancy compared to ordinary melanomas of similar depth, and use of the term “melanocytoma” was suggested as an expression of their intermediate characteristics between benign nevi and malignant melanomas. Risk factors for aggressive behavior included the presence of mitoses, mitoses in the lower third of the lesion, greater pigmentation, and older age. Tentatively it has been proposed to classify these lesions into risk groups: Minimal risk with none of these four adverse factors, low risk with one of them, intermediate risk with two or three, and high risk with four of the factors. Lesions in these categories that have been termed “atypical” or of uncertain malignant potential or risk, or diagnostically problematic in some way, may be offered therapy that takes into consideration the differential diagnosis of malignant melanoma. This may include a wider excision procedure and sentinel lymph node sampling. There are at least six small series of cases of such tumors in which sentinel lymph node sampling has been done, and in these series at least 36 patients have had positive sentinel nodes, yet, albeit with limited followup, there have been no reported deaths (12–20). It therefore appears that these “Spitzoid melanomas,” or “melanocytomas,” often in childhood but sometimes in adults, may have better prognosis than would be expected from a usual form of melanoma of the same stage. We have therefore considered that the concept of “metastatic melanocytic tumor of uncertain malignant potential” may be more appropriate than simply revising the diagnosis from “Spitz tumor” to “malignant melanoma.” In any event, management of these lesions requires dealing with uncertainty, discussing this uncertainty frankly with patients, and obtaining their informed participation in a treatment program that is designed to minimize any risk, while

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avoiding unnecessary overtreatment, or labeling the patient with a malignant diagnosis that may be unwarranted. Several variants of Spitz tumors have been described, including desmoplastic and angiomatoid Spitz tumors/nevi, that may simulate desmoplastic melanomas or angiomatous tumors. Angiomatoid Spitz nevi have been recently described as a distinctive variant of desmoplastic Spitz nevus (21;22). Clinically, the 12 reported lesions (6 from our own files) have presented as a benign-appearing solitary papule on the extremities of young adults. Microscopically, the striking feature is the presence of numerous mature blood vessels, with relatively thick vessel walls and plump endothelial cells, so that the initial impression may be that of an angioma. On closer inspection, large spindle and/or epithelioid melanocytes are seen among the vessels, infiltrating a dense fibrous stroma. Recurrence or metastasis following complete excision has not been described.

PIGMENTED SPINDLE CELL NEVUS Pigmented spindle cell nevus is a lesion that was first described by Richard Reed (23;24) and is also known as “Reed nevus” (25). There is overlap with Spitz nevi, and some observers have termed these lesions “pigmented Spitz nevi.” The major area of overlap is that both of these lesions are nevi/tumors of “large spindle and/or epithelioid cells.” However, there are a number of relatively reproducible differences that distinguish these two lesions (26–28). Pigmented spindle cell nevi most typically occur on the lower extremity, often on the thigh, of a young adult, often female, patient (27). In contrast, the most common presentation of a Spitz nevus is as a pink papule, often on the head and neck of a young child. In follow-up studies, the lesions have been completely benign. Complete excision is recommended for treatment (28).

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There are several histological differences between PSCN and Spitz nevi/tumors. First, although hypopigmented variants have been described (25), the heavy pigmentation of most of these lesions differs from that of most Spitz nevi, which contain little or no pigment and present as pink papules in contrast to the dark brown to black plaques that characterize the clinical presentation of pigmented spindle cell nevi. This pigmentation is observed histologically as relatively coarsely divided pigment granules, filling the cytoplasm of the cells and sometimes obscuring the nuclei. Second, the lesional cells are typically narrow, elongated spindle cells, rather than the plump spindle and/or epithelioid cells of characteristic Spitz tumors. Third, the cells are arranged in nests that tend to blend with adjacent keratinocytes, rather than exhibiting clefting artifact, as is typical in Spitz tumors. Kamino bodies may be present in the junctional component of pigmented spindle cell nevi, as in Spitz tumors (29). Pagetoid extension of lesional cells into the epidermis is not uncommonly seen, leading to simulation of a melanoma in situ of the superficial spreading type (30). Fourth, as the lesional cells enter the dermis, they tend to remain confined to the papillary dermis (rather than entering the reticular dermis, as in most Spitz tumors) and to show evidence of maturation along nevoid lines. Mitotic figures are commonly numerous in the junctional component, but they are usually rare or absent in the dermal component. A lesion with the attributes of a pigmented spindle cell nevus in which lesional cells involve the reticular dermis is unusual, and this finding may be regarded as somewhat concerning, in contrast to its almost universal presence in typical Spitz tumors. Because the cells of pigmented spindle cell nevi tend to be confined to the papillary dermis, and not to form an expansile tumor, these lesions are usually thin. Lesions that involve the reticular dermis are regarded as atypical and have been termed “plexiform” pigmented spindle cell nevi (27).

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Because of their heavy pigmentation and a history, often, of recent appearance, pigmented spindle cell nevi are often submitted with the diagnosis “rule out melanoma,” in contrast to Spitz tumors, for which the diagnosis of melanoma tends to be raised histologically but not clinically. The differential diagnosis of pigmented spindle cell nevus, histologically, typically lies with superficial spreading melanomas in radial or early vertical growth phase, whereas the differential diagnosis of a Spitz tumor is usually with nodular melanoma. In addition, there is overlap with dysplastic nevi, so that these lesions may sometimes present as examples of “superficial atypical melanocytic lesions of uncertain significance,” or SAMPUS, where the differential diagnosis may include not only a pigmented spindle cell nevus, but also superficial spreading melanoma in situ, severe melanocytic dysplasia, and, possibly even, a nevus of special sites. In this section, a few cases of putative pigmented spindle cell nevi are presented, in which a more extensive than usual dermal tumorigenic component has raised the possibility of an unusual form of nevoid melanoma, and sometimes creating such a degree of uncertainty that the best diagnosis is that of a melanocytic tumor of uncertain malignant potential (MELTUMP), or, in cases with lesser degrees of atypia, a diagnosis of atypical pigmented spindle cell nevus. When a lesion is interpreted as a “melanocytic tumor of uncertain malignant potential,” we generally recommend management with the differential diagnosis of melanoma versus nevus taken into consideration. This may include “minimal” treatment for melanoma, the definition of which can lead to controversy. To facilitate informed decision making, we also provide routine staging information, including the presence or absence of ulceration, the Clark level, the Breslow thickness, and the presence or absence of satellites. Because these tumors are often thicker

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than 1 mm, a consideration of sentinel lymph node sampling often arises in addition to that of complete local excision. It is not clear that prognostic attributes developed for routine forms of melanoma, developed from studies done almost exclusively in adults, necessarily apply to these unusual tumors. Multiple studies, reviewed previously, have demonstrated that positive sentinel lymph nodes following procedures done for ambiguous tumors, especially in children, are often not followed by continuing progression. Interestingly, however, when a complex prognostic model, such as that published by Clark et al. in 1989 (31), is applied to an atypical Spitz tumor, the predicted probability of 8-year survival is often excellent. This model includes six prognostic attributes, which include tumor infiltrating lymphocytes, mitotic rate, tumor thickness, the gender of the patient (with females enjoying a better prognosis than males), the location of the lesion (with tumors on the limb having a better prognosis than those on the trunk), and the presence of regression, which is an adverse prognostic attribute. Even though atypical Spitz tumors are often quite bulky lesions extending to Clark level IV, the predicted probability of survival is often excellent, because the mitotic rates are relatively low compared to usual forms of melanoma in this thickness range, tumor infiltrating lymphocytes are often present, regression is usually absent, and the lesions are commonly located on the prognostically favorable extremities. In the light of these considerations, some have concluded that sentinel lymph node sampling is not necessarily the standard of care for lesions of this type, and “watchful waiting” may be an acceptable alternative. Most authorities today recommend complete excision for Spitz tumors when possible, even in the absence of atypical features. In the case of atypical Spitz tumors in which the differential diagnosis includes melanoma, this could lead to the consideration of a

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margin of 1 or even 2 cm. However, it is not clear that this represents the standard of care, and, with appropriate informed consent, a lesser margin might be contemplated. Even a benign Spitz tumor may recur locally after incomplete excision, sometimes with increased atypia, which could lead to a mistaken diagnosis of melanoma (32–34). However, follow-up studies have shown that the majority of Spitz tumors do not recur even after incomplete excision, so that, for a classical lesion in a problematic location such as the cheek of a child, observation may be a reasonable alternative to excision (35). In the case of atypical lesions, however, recurrence may at least occasionally represent the expression of a lesion with metastatic potential (36). Marker studies have shown some utility in the differential diagnosis of Spitz tumors and melanomas. Most useful of these is probably the Ki-67 proliferation marker, which has been studied by several authors. Reviewing earlier studies (37–39), Vollmer concluded that a proliferation index of more than 10% favors a melanoma diagnosis and that of less than 2% favors a Spitz nevus. Values between 2% and 10% are ambiguous and can be interpreted in the context of other variables discussed previously, especially the age of the patient (40). Molecular studies now available have begun to shed increasing light on the differences between atypical Spitz tumors and melanomas and may become useful in diagnosis in the near future. Studies by comparative genomic hybridization and other methods have shown that most Spitz tumors (and other nevi) have few or no aberrations, whereas melanomas, with few exceptions, have many (11;41). A subset of atypical Spitz tumors has amplification and activating mutations of HRAS and its locus on chromosome 11p. Thus, these tumors appear to have a different biology than that of most melanomas and nevi, in which BRAF or NRAS or KIT mutations are

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the predominant mutated oncogenes. It is likely, by analogy with common acquired nevi, that other activating mutations will be identified in Spitz nevi, and it is possible that atypical Spitz tumors may represent a separate lineage of melanocytic lesions, perhaps best regarded as of uncertain, although usually low, malignant potential (42).

References 1 Spitz S. Melanomas of childhood. Am J Pathol 1948;24: 591–609. 2 Weedon D, Little JH. Spindle and epithelioid cell nevi in children and adults. A review of 211 cases of the Spitz nevus. Cancer 1977;40:217–25. 3 Paniago-Pereira C, Maize JC, Ackerman AB. Nevus of large spindle and/or epithelioid cells (Spitz’s nevus). Arch Dermatol 1978 Dec;114(12):1811–23. 4 Kamino H, Flotte TJ, Misheloff E, Alba Greco M, Ackerman AB. Eosinophilic globules in Spitz’s nevi. New findings and a diagnostic sign. Am J Dermatopathol 1979;1:319–24. 5 Smolle J, Smolle-Juettner FM, Stettner H, Kerl H. Relationship of tumor cell motility and morphologic patterns. Part 1. Melanocytic skin tumors. Am J Dermatopathol 1992 Jun;14(3):231–7. 6 Hantschke M, Bastian BC, LeBoit PE. Consumption of the epidermis: a diagnostic criterion for the differential diagnosis of melanoma and Spitz nevus. Am J Surg Pathol 2004 Dec;28(12):1621–5. 7 Schmoeckel C. How consistent are dermatopathologists in reading early malignant melanomas and lesions “precursor” to them? An international survey. Am J Dermatopathol 1984;6:13–24. 8 Cerroni L, Kerl H. Tutorial on melanocytic lesions. Am J Dermatopathol 2001 Jun;23(3):237–41. 9 Barnhill RL. The Spitzoid lesion: rethinking Spitz tumors, atypical variants, ‘Spitzoid melanoma’ and risk assessment. Mod Pathol 2006 Feb;19 Suppl 2:S21–S33. 10 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. 11 Bastian BC, Olshen AB, LeBoit PE, Pinkel D. Classifying melanocytic tumors based on DNA copy number changes. Am J Pathol 2003 Nov;163(5):1765–70. 12 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 Jan;26(1):47–55. 13 Su LD, Fullen DR, Sondak VK, Johnson TM, Lowe L. Sentinel lymph node biopsy for patients with problematic

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Spitzoid melanocytic lesions: a report on 18 patients. Cancer 2003 Jan 15;97(2):499–507. Roaten JB, Partrick DA, Bensard D, Pearlman N, Gonzalez R, Fitzpatrick J, McCarter MD. Survival in sentinel lymph node-positive pediatric melanoma. J Pediatr Surg 2005 Jun;40(6):988–92. Roaten JB, Partrick DA, Pearlman N, Gonzalez RJ, Gonzalez R, McCarter MD. Sentinel lymph node biopsy for melanoma and other melanocytic tumors in adolescents. J Pediatr Surg 2005 Jan;40(1):232–5. Gamblin TC, Edington H, Kirkwood JM, Rao UN. Sentinel Lymph node biopsy for atypical melanocytic lesions with Spitzoid features. Ann Surg Oncol 2006;13:1664–70. Epub 2006 Oct 7. Urso C, Borgognoni L, Saieva C, Ferrara G, Tinacci G, Begliomini B, Reali UM. Sentinel lymph node biopsy in patients with “atypical Spitz tumors.” A report on 12 cases. Hum Pathol 2006 Jul;37(7):816–23. McArthur GJ, Banwell ME, Cook MG, Powell BW. The role of sentinel node biopsy in the management of melanocytic lesions of uncertain malignant potential (MUMP). J Plast Reconstr Aesthet Surg 2007;60(8):952–4. Murakami M, Wada T, Kashiwagi T, Ishida-Yamamoto A, Iizuka H. Nodular malignant melanoma with Spitz nevus-like pathological features finally confirmed by the pathological feature of the sentinel lymph node. J Dermatol 2007 Dec;34(12):821–8. Murali R, Sharma RN, Thompson JF, Stretch JR, Lee CS, McCarthy SW, Scolyer RA. Sentinel lymph node biopsy in histologically ambiguous melanocytic tumors with Spitzoid features (so-called atypical Spitzoid tumors). Ann Surg Oncol 2008 Jan;15(1):302–9. Diaz-Cascajo C, Borghi S, Weyers W. Angiomatoid Spitz nevus: a distinct variant of desmoplastic Spitz nevus with prominent vasculature. Am J Dermatopathol 2000 Apr;22(2):135–9. Fabrizi G, Massi G. Angiomatoid Spitz naevus: a close simulator of regressing malignant melanoma. Br J Dermatol 2001 Nov;145(5):845–6. Reed RJ, Ichinose H, Clark WH Jr, Mihm MC Jr. Common and uncommon melanocytic nevi and borderline melanomas. Semin Oncol 1975;2:119–47. Reed RJ. The histological variance of malignant melanoma: the interrelationship of histological subtype, neoplastic progression, and biological behaviour. Pathology 1985;17:301–12. Requena C, Requena L, Sanchez-Yus E, Kutzner H, Llombart B, Sanmartin O, Botella-Estrada R, Nagore E, Serra C, Guillen C. Hypopigmented Reed nevus. J Cutan Pathol 2008 Oct;35 Suppl 1:87–9. Epub 2008 Jun 28. Sagebiel RW, Chinn EK, Egbert BM. Pigmented spindle cell nevus. Clinical and histologic review of 90 cases. Am J Surg Pathol 1984;8:645–53.

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27 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. 28 Sau P, Graham JH, Helwig EB. Pigmented spindle cell nevus: a clinicopathologic analysis of ninety-five cases. J Am Acad Dermatol 1993;28:565–71. 29 Wistuba I, Gonzalez S. Eosinophilic globules in pigmented spindle cell nevus. Am J Dermatopathol 1990 Jun;12(3): 268–71. 30 Haupt HM, Stern JB. Pagetoid melanocytosis: Histologic features in benign and malignant lesions. Am J Surg Pathol 1995;19:792–7. 31 Clark WH Jr, Elder DE, Guerry DIV, Braitman LE, Trock BJ, Schultz D, Synnestvedt M, Halpern AC. Model predicting survival in stage I melanoma based on tumor progression. JNCI 1989;81:1893–904. 32 Omura EF, Kheir SM. Recurrent Spitz’s nevus. Am J Dermatopathol 1984;6 Suppl:207–12. 33 Tanaka K, Mihara M, Shimao S, Taniguchi K. The local recurrence of pigmented Spitz nevus after removal. J Dermatol 1990 Sep;17(9):575–80. 34 Stern JB. Recurrent Spitz’s nevi. A clinicopathologic investigation. Am J Dermatopathol 1985;7 Suppl:49–50. 35 Cesinaro AM, Foroni M, Sighinolfi P, Migaldi M, Trentini GP. Spitz nevus is relatively frequent in adults: a clinicopathologic study of 247 cases related to patient’s age. Am J Dermatopathol 2005 Dec;27(6):469–75. 36 Harvell JD, Bastian BC, LeBoit PE. Persistent (recurrent) Spitz nevi: a histopathologic, immunohistochemical, and molecular pathologic study of 22 cases. Am J Surg Pathol 2002 May;26(5):654–61. 37 Bergman R, Malkin L, Sabo E, Kerner H. MIB-1 monoclonal antibody to determine proliferative activity of Ki-67 antigen as an adjunct to the histopathologic differential diagnosis of Spitz nevi. J Am Acad Dermatol 2001 Mar;44(3):500–4. 38 Li LX, Crotty KA, McCarthy SW, Palmer AA, Kril JJ. A zonal comparison of MIB1-Ki-67 immunoreactivity in benign and malignant melanocytic lesions. Am J Dermatopathol 2000 Dec;22(6):489–95. 39 Rudolph P, Schubert C, Schubert B, Parwaresch R. Proliferation marker Ki-S5 as a diagnostic tool in melanocytic lesions. J Am Acad Dermatol 1997;37:169–78. 40 Vollmer RT. Use of Bayes rule and MIB-1 proliferation index to discriminate Spitz nevus from malignant melanoma. Am J Clin Pathol 2004 Oct;122(4):499–505. 41 Takata M, Saida T. Genetic alterations in melanocytic tumors. J Dermatol Sci 2006 Jul;43(1):1–10. 42 Kaye VN, Dehner LP. Spindle and epithelioid cell nevus (Spitz nevus). Natural history following biopsy. Arch Dermatol 1990 Dec;126(12):1581–3.

C A S E 1 : A N G I O M AT O I D S P I T Z N E V U S / T U M O R V S . D E S M O P L A S T I C M E L A N O M A

3.1 Angiomatoid Spitz Nevus/Tumor vs. Desmoplastic Melanoma

C L I N I C A L I N F O R M AT I O N

DESCRIPTION

A lesion from the right anterior thigh of a 32-year-old female. The clinical description was “elevated, purple domelike lesion.”

The sections show a moderately cellular tumor comprised of plump spindle and/or epithelioid melanocytes that have abundant amphophilic cytoplasm, and relatively large nuclei with fairly regular nuclear membranes, pale chromatin, and fairly prominent nucleoli. Mitotic figures are rare or absent, and there is no high-grade cytologic atypia. The S100 and focally HMB45 positive lesional cells are embedded

R E A S O N F O R C O N S U LTAT I O N

The histology appears to represent an unusual nevus with Spitz-like cytologic features. We look forward to your opinion.

FIG URE 3.1.1.

A dome-shaped tumor, spanning much of the reticular dermis and much of the breadth of the specimen. 63

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3.1 in a desmoplastic stroma, and a striking feature is the presence of numerous relatively thick-walled blood vessels. These have outer walls that stain positive with actin and are lined by plump endothelial cells that are positive with factor VIII and CD 31. Given

the absence of severe cytologic atypia, frequent or abnormal mitoses, or high cellularity and the presence of maturation from superficial to deep, I consider this lesion to be benign and characterize it as follows:

On closer inspection, the architecture of the reticular dermis is altered with thickened collagen bundles and infiltrating cells. Prominent vessels are a striking feature at scanning and intermediate magnification. The vessels have thick walls and plump endothelial cells. In addition, there are plump spindle cells, placed among thickened collagen bundles in the stroma.

FIGURE 3.1.3.

FIGURE 3.1.2.

The spindle cells show only slight evidence of diminution in size from superficial to deep in this example. They have abundant amphophilic cytoplasm and relatively large somewhat hyperchromatic nuclei with nucleoli.

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Only a few of the lesional cells are positive with HMB 45. The positive cells are confined to the superficial portion of the lesion, and in addition there is scant melanin pigment in a few melanophages in this area. FIGURE 3.1.5.

An S100 stain demonstrates numerous positive cells throughout the lesion. The large spindle cells are strongly and brightly S100 positive. They are present in greater numbers than can easily be appreciated on the hematoxylin and eosin sections. FIG URE 3.1.4.

An actin stain demonstrates the prominent vessels scattered throughout the tumor. The actin stain highlights myoepithelial cells at the periphery of the vessels. FIGURE 3.1.6 AND 7.

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3.1 DIAGNOSIS

Skin, right posterior thigh: Spindle and epithelioid cell melanocytic tumor, Spitz type, with desmoplastic and angiomatoid features (angiomatoid Spitz nevus), see previous discussion and comment.

COMMENT A factor 8 stain also highlights the vessels. The plump endothelial cells are positive, surrounded by the unstained myoepithelial cells. FIG URE 3.1.8.

These lesions have been recently described and need to be distinguished from desmoplastic and regressing melanomas and vascular neoplasms. There is no evidence of malignancy in this material.


OVERALL COMMENT


The range of diversity of desmoplastic melanoma is very broad, and this differential diagnosis should be considered in a melanocytic lesion of this type, with its striking vascularity and fibrous stroma. Features arguing against a desmoplastic melanoma include the lack of an in situ component (although this is not universally present in these lesions) and the plump spindle and/or epithelioid cell type of the

lesional cells themselves, contrasting with the more narrow, elongated spindle cells of a desmoplastic melanoma. However, in angiomatoid Spitz tumors, the lesional cells can be relatively inconspicuous. Once the diagnosis is suspected, the finding of positive HMB-45 and Melan-A studies presents a strong argument against the diagnosis of desmoplastic melanoma.

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3.2 Spitz tumor vs. Spitzoid Melanoma

cells have abundant amphophilic cytoplasm, with relatively large nuclei that have uniform nuclear membranes, relatively pale chromatin, and prominent nucleoli. There is some evidence of maturation from superficial to deep, and there is an incomplete tendency to dispersion as single cells at the base of the tumor. Mitotic figures appear to be rare or absent; however, a Ki-67 study demonstrates scattered positive cells, for an overall rate of approximately 5% or less. Interpretation is somewhat complicated by reactive infiltrating lymphocytes. Taken together, I agree that this is a Spitzoid neoplasm, which I consider to be most consistent with an atypical Spitz nevus/tumor. Atypical features include the pagetoid proliferation and the relative failure of maturation.

C L I N I C A L I N F O R M AT I O N

Lesion of the right buttock in a 36-year-old woman. R E A S O N F O R C O N S U LTAT I O N

Our differential diagnosis includes atypical Spitz nevus and Spitzoid melanoma. DESCRIPTION

The sections show a shave biopsy of skin containing a moderately to highly cellular proliferation of nevoid of large spindle and/or epithelioid melanocytes, present in groups but also singly near the dermalepidermal junction, with pagetoid extension of some single cells into the epidermis, although generally not beyond the mid-spinous layer. Cytologically, the

Scanning magnification shows a relatively symmetrical melanocytic tumor, with the dermal component extending well into the reticular dermis and in adjacent junctional component, symmetrically oriented on each side. The epidermal rete ridges are irregularly thickened, approaching a pattern of pseudoepitheliomatous hyperplasia in the center.

FIGURE 3.2.1.

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3.2 An HMB 45 study is “top heavy,” indicating some degree of maturation. Features more characteristic of a Spitz tumor include the cytology, its uniformity from side to side, the presence of at least some degree of maturation, the presence of Kamino bodies, albeit

not well developed at the dermal epidermal junction, and the paucity of mitotic activity. In addition, the proliferation in the dermis is predominantly nested without extensive sheets of cells. I therefore interpret this lesion as follows:

The cells in the dermis show some evidence of maturation from superficial to deep, but this is incomplete. At the base, the lesional cells disperse incompletely into the reticular dermis collagen, retaining a nested architecture and showing only slight evidence of maturation. FIGURE 3.2.3.

The cells in the epidermis and in the dermis are large spindle and/or epithelioid cells. FIG URE 3.2.2.

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An area where the proliferation is predominantly of single cells, with pagetoid cells rising into the epidermis, although generally not beyond the mid-spinous layer. FIGURE 3.2.5.

There is a globoid eosinophilic Kamino body in the epidermis. In this area, the proliferation is predominantly nested. FIG URE 3.2.4.

F I G UR E 3 . 2 . 5 .

Continued.

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3.2 DIAGNOSIS

Skin, left inferior buttock: Spindle and epithelioid cell melanocytic tumor, Spitz type, apparently completely excised; see previous discussion and comment.

COMMENT

HMB 45 staining is “top heavy,” standing only a few cells near the junctional component. FIG URE 3.2.6.

As you know, there is some degree of uncertainty regarding the behavior of atypical Spitz tumors, especially in adult patients; however this, in my opinion, is a benign or very low-risk lesion. Even if interpreted as a Spitzoid melanoma, it would be tumorigenic but nonmitogenic, with a Breslow thickness of 1.1 mm, and non-brisk tumor-infiltrating lymphocytes without regression and without ulceration. In terms of the 1989 “Clark prognostic model,” a melanoma with such attributes would have literally 100% probability of 8-year disease-free survival. I therefore do not believe there is any necessary indication for sentinel lymph node sampling in this case, although some authorities might discuss this as a possibility.


OVERALL COMMENT


Although this lesion shows evidence of pagetoid proliferation in the epidermis and failure of maturation at the base, mitoses are rare or absent. The finding of

“no mitoses at all” is a very highly reassuring finding. The Clark prognostic model, which includes mitotic rate as a strong prognostic variable, illustrates this.

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3.3 Atypical Spitz Tumor vs. Spitzoid Melanoma

cells in the epidermis above. The cellularity of the dermal component is relatively high, with sheets of cells rather than nests in some areas. The mitotic rate is relatively high for Spitz tumor, with mitotic figures readily detected across the lesion and in the lower third, although the mitotic rate is not dramatically higher than 2–3/mm2, which is in the range for Spitz tumors. Ki-67 stains demonstrate reactivity in dermal lesional cells, especially superficially, with focal staining in the 10–20% range, although a much lower rate than this overall. Although lesional cells in the dermis mature from the larger cell type in the epidermis, there is little further maturation, and the cells tend to infiltrate the reticular dermis as clusters rather than single cells. This is a pattern of infiltration more characteristic of melanoma than of a Spitz lesion. Taken together,

C L I N I C A L I N F O R M AT I O N

A nodule on left flank of a 49-year-old man. R E A S O N F O R C O N S U LTAT I O N

The findings are concerning for Spitzoid melanoma. DESCRIPTION

These sections show a cellular melanocytic tumor, comprised of relatively large spindle to epithelioid melanocytes, arranged near the dermal-epidermal junction, predominantly in nests, with prominent clefting artifact. In addition, there is extension of a few lesional cells, arranged as small nests and as single cells, into the epidermis adjacent to the tumor. The tumor itself is comprised of more epithelioid melanocytes, although these are continuous with the spindle

Scanning magnification shows a fairly broad, quite symmetrical, dome-shaped melanocytic tumor. The left and right halves of the lesion appear generally similar in architectural configuration. FIG URE 3.3.1.

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3.3 and also considering the age of the patient, I do not believe that this lesion can be characterized as a benign Spitz tumor. As you know, there is uncertainty in the

behavior of these lesions, especially as atypical features accumulate. This lesion has several such features, and I therefore interpret it descriptively as follows:

The lesion is not particularly well circumscribed, with single cells at the periphery in the epidermis.

FIGURE 3.3.4.

FIGURE 3.3.2.

The phenomenon of “consumption of the epidermis in which the epidermis is thinned and appears to be destroyed and replaced by the tumor cells” is seen in these images.

There is some evidence of maturation to a smaller type, with less pigment at the base of the tumor. The lesional cells do not disperse into the reticular dermis as single cells in the pattern that is most characteristic in Spitz nevi. A rare mitotic figure was present near the base of the tumor (not shown here). FIGURE 3.3.5.

The cellularity of the dermal component is quite high, with sheetlike proliferation of uniform epithelioid to somewhat spindle-shaped cells. FIG URE 3.3.3.

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An occasional dermal mitotic figure was observed for an overall mitotic rate of 2/mm2. FIG URE 3.3.6.

Ki-67 staining demonstrated reactivity of lesional cells in junctional nests and also in superficial dermal nests; however, the overall Ki-67 proliferation rate was not high. FIGURE 3.3.8.

HMB 45 staining is to some extent “top heavy,” as expected in benign lesions. However, there is substantial staining near the base of the tumor. FIGURE 3.3.9.

Occasional mitotic figures were also present in the epidermis. FIG URE 3.3.7.

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3.3 COMMENT

3 . 3 . 1 0 . Bland-looking lesional cells extend unusually far in the epithelium of skin appendages, well into the reticular dermis. FIGURE

DIAGNOSIS

Skin, left flank: Melanocytic tumor of uncertain malignant potential, Spitzoid melanoma cannot be ruled out; see previous discussion and comment.

Although this lesion may well represent an atypical Spitz nevus/tumor, I cannot rule out the possibility of a Spitzoid melanoma, and, if interpreted as a melanoma, this lesion would show Clark level IV invasion, with a Breslow thickness of approximately 1.2 mm. The dermal mitotic rate is low for a melanoma at 2/mm², tumor-infiltrating lymphocytes are non-brisk, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, although there is extension of lesional cells far down skin appendages, and there is no evidence of vascular, lymphatic, or neural invasion in this material. The lesion appears to be completely excised with borders of 1–2 mm. One might consider an additional excision procedure and also discuss the possibility of a sentinel lymph node sampling procedure for a lesion of this type. As you know, some lesions that have been characterized as atypical Spitz tumors or Spitzoid melanomas, often in children but also occasionally in adults, have sometimes been found to have positive lymph nodes, followed by long survivals, although follow-up durations are, as yet, not long.


OVERALL COMMENT


The proliferative activity and the relative failure of maturation in this lesion are concerning for a lesion

with metastatic potential, especially in a middle-aged man with a lesion on the trunk.

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3.4 Pagetoid Spitz Nevus vs. Spitzoid Melanoma

liferation. In the junctional component, there is an area where there are large nests of large spindle and/or epithelioid cells with clefting artifact and with focal Kamino body formation, quite strongly suggestive of a junctional Spitz nevus/tumor. At the further periphery, however, the proliferation is more predominantly as single cells, with extensive pagetoid involvement of the epidermis, a pattern much more reminiscent of melanoma in situ of the superficial spreading type. There is a dermal component in this area, which has some features of a Spitz tumor; however, I am concerned about the presence of severe uniform atypia and failure of maturation and dispersion of the lesional cells at the base of the tumor. On the other hand, this population is continuous with an overlying junctional complement of Spitz type and lacks mitotic activity, the latter in particular a quite reassuring feature. A Ki-67 study does not appear to demonstrate any significant reactivity of dermal lesional cells, and

C L I N I C A L I N F O R M AT I O N

A pink papule on the calf of a 10-year-old. R E A S O N F O R C O N S U LTAT I O N

Concerned about a melanoma or a severely dysplastic nevus. DESCRIPTION

These sections show an excision of a lesion in skin characterized by a moderately to highly cellular proliferation of nevoid to epithelioid melanocytes in the epidermis, with single similar cells protruding into the papillary and upper reticular dermis. At one periphery of the lesion, the proliferation is predominantly in the form of single cells and small nests near the dermal epidermal junction, with a few similar cells in the papillary and upper reticular dermis showing evidence of nevoid maturation. This is continuous with a much more cellular junctional and dermal pro-

Scanning magnification of one of two different profiles of a tumor in the skin. On the left-hand side, there is focal pagetoid proliferation of nevoid to epithelioid melanocytes, with moderate to focally severe random nuclear atypia, consistent with severe melanocytic dysplasia. FIGURE 3.4.1.

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3.4 an HMB 45 study is quite decidedly “top heavy,” a characteristic, as you know, that is more in favor of a benign diagnosis. In summary, this lesion presents considerably conflicting criteria, with some features of a compound nevus, but also a dysplastic nevus, an atypical Spitz tumor, and even melanoma in situ. The

On another profile, on the left, there is a more extensive pagetoid proliferation of single cells, with moderate to severe atypia, suggestive of melanoma in situ. In the center, there are nests of large spindle and/ or epithelioid melanocytes, with clefting artifact with adjacent keratinocytes and with globoid eosinophilic Kamino bodies, a “junctional Spitz” pattern.

latter pattern, of course, could potentially be alternatively regarded as “pagetoid Spitz nevus.” Therefore, particularly taking the age of this young patient into account, I am reluctant to make a formal diagnosis of melanoma and characterize this lesion descriptively as follows:

FIG URE 3.4.2.

FIGURE 3.4.4.

of the lesion.

The lesional cells do not mature well toward the base of the lesion and do not disperse as single cells into the reticular dermis collagen. FIGURE 3.4.5.

FIGURE 3.4.3. The pagetoid proliferation of the left of Figure 2.

The junctional Spitz pattern from the center

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3.4 COMMENT

Melan-A staining demonstrates confluence of melanocytes along the dermal-epidermal junction and pagetoid proliferation into the epidermis. FIG URE 3.4.6.

DIAGNOSIS

Skin, left calf: Melanocytic tumor of uncertain malignant potential, favor an atypical pagetoid Spitz tumor; see previous discussion and comment.

As noted previously, it is difficult to rule out an unusual form of Spitzoid melanoma. As you know, these lesions may have a better prognosis than the microstaging attributes developed for ordinary melanomas might suggest. However, if this lesion were interpreted as a melanoma of the ordinary type, it would show focal Clark level IV invasion at a greatest Breslow thickness of 0.85 mm. The dermal mitotic rate is zero, there are sparse tumor-infiltrating lymphocytes, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic, or neural invasion. There would be evidence, in this scenario, of an associated severely dysplastic nevus. I recommend an additional procedure, to be sure that this lesion has been completely removed, with a margin of normal skin, and consideration of follow-up for the patient, especially if she should have other clinically atypical nevi and/or a family or personal history of melanoma.


OVERALL COMMENT


This lesion presents a not uncommon scenario of a differential diagnosis that includes a melanoma, with, at least, the capacity for local persistence, recurrence, and continued progression, or a dysplastic nevus that could be indicative of an increased

lifetime risk for melanoma. Alternatively, if it is a pagetoid Spitz nevus, as seems most likely, it would have no significance at all. Sensible management, as outlined previously, should take into account all of these possibilities.

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3.5 Atypical Spitz Tumor vs. Spitzoid Melanoma

nent clefting artifact with adjacent keratinocytes and with prominent globoid eosinophilic Kamino bodies. Lesional cells descend through the papillary and reticular dermis to the base of the biopsy. There is some tendency to maturation from superficial to deep, although this is incomplete, and the lesional cells are quite similar from side to side across the lesion. Cytologically, they have abundant amphophilic cytoplasm and large nuclei, with somewhat irregularly clumped chromatin and with prominent nucleoli. Occasional mitotic figures are present,

C L I N I C A L I N F O R M AT I O N

A pink nodule on the cheek of an 8-year-old boy. R E A S O N F O R C O N S U LTAT I O N

Is this a Spitz nevus? DESCRIPTION

These sections show a moderately to highly cellular, quite symmetrical melanocytic tumor, comprised of plump spindle and/or epithelioid cells, present along the dermal-epidermal junction in nests, with promi-

Scanning magnification shows a cellular tumor comprised of cells that extend from the epidermis well into the reticular dermis. The epidermis shows hyperkeratosis and tends to be hyperplastic, with a focal area amounting to pseudoepitheliomatous hyperplasia. There is no evidence of “consumption of the epidermis.” FIG URE 3.5.1.

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3.5 mostly in the upper third. Abnormal forms are not observed. A Ki-67 study shows numerous reactive cells; however, most of these are probably lymphocytes. Most of the lesional cell nuclei appear to be positive for Cyclin D. In summary, I agree with your interpretation as follows:

Although not prominent, there are suggestions of focal globoid eosinophilic Kamino bodies near the dermal-epidermal junction. FIG URE 3.5.2.

F I G UR E 3 . 5 . 3 .

Continued.

In this particular example, there is only slight, if any, evidence of “maturation” or diminution of size of the lesional cells from superficial to deep (compare with Figure 2). In addition, the cells do not disperse as single cells into reticular dermis collagen at the base. FIGURE 3.5.3.

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A Mart 1 stain demonstrates the nested architecture superficially and an incompletely dispersed pattern at the base. In this lesion, there appears to be a suggestion of immunologically mediated regression of the tumor, in the form of a brisk, tumor-infiltrating lymphocyte response. FIGURE 3.5.5.

Although the cells are quite uniform from side to side, there are a few scattered larger cells, with large, hyperchromatic nuclei. An occasional mitotic figure is present, mostly in the upper third of the tumor; abnormal mitoses were not observed. FIG URE 3.5.4.

A Ki-67 stain demonstrates scattered positive lesional cells. Most of the positive cells appear to be lymphocytes or histiocytes. FIGURE 3.5.6.

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3.5 DIAGNOSIS

Skin, cheek: Spindle and epithelioid cell melanocytic tumor, Spitz type, with atypical features; see previous discussion and comment.

COMMENT

Although for the most part, this is a relatively classical lesion, it is quite thick at approximately 2 mm, and there is rather confluent, sheetlike growth in the

dermis. Mitotic rate is low; however, there is evidence of proliferation, as judged by Ki-67 and Cyclin D, although I do not know precisely how to interpret the latter finding. Especially in a child of this age, I would expect this lesion to have a benign course. Changes extend to specimen margins, and, because we have seen examples of Spitz tumors that have recurred after incomplete excision, sometimes with increased atypia, I recommend an additional procedure, to be sure that this lesion has been removed, with a margin of normal tissue around the scar and any residual lesion.


OVERALL COMMENT


This lesion presents most of the definitive features of a Spitz lesion and, in a child of this age, is likely to have a benign course. In a more characteristic Spitz

nevus/tumor, especially in such a young patient, careful follow-up of the lesional site may be reasonable, especially in a cosmetically sensitive location.

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3.6 Atypical Spitz Tumor vs. Spitzoid Melanoma

There are some collections of apoptotic lesional cells near the junction, and there are at least two structures consistent with Kamino bodies at the interface. Significantly, mitotic figures are quite rare, with only two identified in a formal count of 50 consecutive high-power fields. I note that a Ki-67 study was done at an outside laboratory and was reported as “mildly to moderately” positive. Taking into account the considerable size of the lesion, the failure of maturation, and also the failure of dispersion of single cells at the base in the pattern that is characteristic of Spitz tumors, as well as the unusual cytology and the

C L I N I C A L I N F O R M AT I O N

A pink papule on the eyelid of a 9-year-old girl. R E A S O N F O R C O N S U LTAT I O N

This may represent an atypical Spitz nevus; however, we cannot rule out a Spitzoid melanoma. S100 protein and Melan-A immunostains demonstrate junctional and dermal melanocytic proliferation, whereas the HMB 45 immunostain demonstrates only the junctional melanocytic proliferation. DESCRIPTION

The sections show a fairly bulky and quite highly cellular melanocytic tumor, which measures about 8 mm in breadth and 6 mm in depth, extending from the epidermis through the reticular dermis and into the subcutis, including infiltration of skeletal muscle. It is comprised of uniformly large epithelioid to somewhat spindle-shaped cells, which show little or no evidence of maturation from superficial to deep. There is an admixture of giant cells. Cytologically, the cells have abundant amphophilic cytoplasm and large nuclei, with fairly irregular nuclear membranes, and generally pale chromatin, with prominent nucleoli and with some tendency to irregular clumping of basophilic chromatin. These cells could be consistent with those of a Spitz tumor but are not entirely characteristic. In the overlying epidermis, there is a proliferation of single and nested epithelioid to spindle-shaped melanocytes, with some nests showing clefting artifact with adjacent keratinocytes.

A bulky, highly cellular melanocytic tumor, more than a centimeter in breadth and depth, from the eyelid of a 9-year-old girl. The tumor arises near the epidermis and spans the reticular dermis, infiltrating subcutaneous fat and muscle with both pushing and infiltrating margin. The tumor infiltrates reticular dermis and fat, as well as focal skeletal muscle, and involves multiple margins. FIGURE 3.6.1.

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3.6 mitotic activity, albeit slight, I do not believe this lesion can be regarded as a characteristic Spitz tumor. On the other hand, especially taking into consideration the youthful age of the patient, I do not believe

this lesion can be interpreted as a usual form of melanoma. I therefore agree with the opinions of the other observers and characterize this lesion descriptively as follows.

The tumor is, for the most part, separated from the overlying epidermis and extends to the subcutis. There is little or no evidence of maturation. Although there are a few slightly enlarged nevoid melanocytes in the overlying epidermis; there is no well-organized junctional or in situ component. Focal tumor-infiltrating lymphocytes (TIL) are present. FIGURES 3.6.2 AND 3.

FIGURES 3.6.2.

Continued.

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The cells in the dermis tend to lie in confluent sheets, and scattered cells show substantial nuclear enlargement, hyperchromatism, and irregularity, consistent with “random” but severe cytologic atypia. Mitotic figures (not shown) were rare, with two mitoses identified in 50 consecutive high-power fields. FIG URE 3.6.4.

The re-excision specimen contained tumor present at one margin. A subsequent excision also contained tumor at a margin (see Web figures). FIGURE 3.6.6.

DIAGNOSIS

Skin, right upper eyelid: Melanocytic tumor of uncertain malignant potential, most consistent with an atypical Spitz tumor; Spitzoid melanoma cannot be ruled out; see previous discussion and comments.

COMMENT

The tumor approached or was transected at multiple margins. Note the infiltration of skeletal muscle. FIG URE 3.6.5.

As noted previously, I favor the idea that this lesion is an atypical Spitz nevus/tumor. As you know, these lesions, perhaps especially in childhood but also occasionally in adults, can have uncertain and unpredictable behavior, including the possibility of local persistence and recurrence, sometimes with increased atypia, and involvement of regional nodes, often and perhaps usually followed by prolonged survivals, although mature long-term series of well-defined cases are not available. I therefore consider that this

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3.6 lesion should, at a minimum, be completely excised, with a margin of normal tissue. This lesion is probably minimally excised. Given the uncertain nature of the biology in this case and the problematic location, I believe that it would be a reasonable option to follow this patient closely, with careful examination for the possibility of local recurrence. Alternatively, if this can be done without compromising function of the

eyelid, an additional narrow margin might be contemplated, to provide greater assurance of complete removal. As briefly discussed previously, follow-up for this patient should also include attention to the possibility of regional lymph node involvement, which can occur in these problematic lesions, although with uncertain biological significance, as also briefly discussed previously.


OVERALL COMMENT


The head and neck area, especially the face, is a common location for typical and atypical Spitz lesions, especially in children, and, as in this case, can give rise to problems in management. Although we have seen examples of recurrent Spitz lesions with increased atypia leading to difficulties in interpretation, formal studies of Spitz tumors with positive

margins have shown that recurrence is uncommon (42), although it sometimes can occur with problematic histologic features, which can include desmoplasia and atypia to the extent of resembling nodular melanoma (34;36). In part, for this reason, most authorities today recommend complete excision of these lesions when possible

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some basal nests of uniform atypical melanocytes in the epidermis. Taken together, the appearances in this nodule are very concerning for malignant melanoma, despite some Spitzoid features. However, although the cells have abundant amphophilic cytoplasm and prominent nucleoli and are relatively uniform from side to side, spindle cell differentiation is minimal, there is little evidence of maturation or dispersion at the base, and there is no characteristic junctional component, including no Kamino bodies. It is unusual also for Spitz tumor to arise in association with a background pattern of melanocytic dysplasia. For all of these reasons,

C L I N I C A L I N F O R M AT I O N

Submitted as a 4- to 5-mm pink-brown papule on the back of a 49-year-old man. Rule out nevus versus angioma; check margins. R E A S O N F O R C O N S U LTAT I O N

This is a difficult lesion. The cytologic morphology is that of a Spitz nevus. However, the presence of marked pleomorphism and lack of maturation are atypical worrisome features. DESCRIPTION

The sections show a complex melanocytic lesion, characterized at its periphery by a junctional component comprised of relatively small nests, arranged many near the tips and sides of elongated rete ridges. In this area, there is generally moderate cytologic atypia and a patchy lymphocytic infiltrate in the dermis. A few lesional cells descend into the dermis and seem to mature along nevic lines. These appearances are consistent with severe dermal and epidermal melanocytic dysplasia. A more prominent feature in the lesion, however, is the presence of a dome-shaped papular or nodular component, comprised of uniformly atypical epithelioid melanocytes, extending from near the epidermis into the upper reticular dermis. There is little or no evidence of maturation of the cells from superficial to deep. There is a sprinkling of lymphocytes. At least a single mitotic figure is observed. There is no evidence of melanoma in situ above the nodule, although adjacent to it on one side there are

Scanning magnification views of a somewhat asymmetrical, dome-shaped tumor. FIGURE 3.7.1.

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3.7 and also including mitotic activity and occasional proliferating cells in a Ki-67 study, as well as the age of

the patient, I believe this lesion is best interpreted as a melanoma, which I characterize as follows:

Adjacent to the tumor, there is a junctional component comprised of nests, arranged mainly near the tips and sides of elongate rete ridges, with some bridging nests, and with moderate cytologic atypia involving random lesional cell nuclei. FIG URE 3.7.2.

The lesional cells are large epithelioid cells. A rare mitotic figure was observed (not shown). FIGURE 3.7.4.

Adjacent to the tumor and between it and the region of dysplasia, there are smaller cells consistent with a remnant of a dermal nevus with random atypia (“ancient change”). FIG URE 3.7.3.

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There is little or no evidence of maturation from superficial to deep, and the lesional cells at the base do not disperse into reticular dermis collagen fiber bundles. There is relatively uniform moderate to severe atypia of lesional cell nuclei. Note that these differ from the characteristic nuclei of Spitz tumors, which have more open chromatin, regular nuclear membranes, and prominent nucleoli. FIG URE 3.7.5.

DIAGNOSIS

Skin, left back: Malignant melanoma, nodular type, with Spitzoid tumorigenic and mitogenic vertical growth phase, arising in association with a compound dysplastic nevus, Clark level IV, greatest Breslow thickness 1.2 mm; see previous discussion and comment.

Occasional lesional cells in the dermis were positive with the Ki-67 proliferation marker. In this field, most of the positive cells in the epidermis are keratinocytes, and the positive cells near the base of the tumor are lymphocytes. FIGURE 3.7.6.

COMMENT

The dermal mitotic rate is low for a melanoma at 1/mm², tumor-infiltrating lymphocytes are sparse, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic, or neural invasion. Although the prognosis of “Spitzoid melanomas” may perhaps be better than that of ordinary forms of melanoma with equivalent microstage, I believe that this is a lesion that could have capacity for metastasis and therefore recommend appropriate definitive therapy for it.


OVERALL COMMENT


In a patient of this age group, a few “Spitzoid” features do not, in my opinion, justify a benign diagnosis.

Typically, minimal therapy for a melanoma of similar microstage would be the recommendation.

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3.8 Atypical Spitz vs. Spitzoid Melanoma

with little or no evidence of maturation from superficial to deep, although with some tendency to disperse as single cells at the base. Although some of these features create a somewhat Spitzoid impression at scanning magnification, mitotic figures are relatively numerous, there is an overlying scale-crust, and there are small satellite foci in the reticular dermis at the base of the tumor, some of which suggest the possibility of lymphatic invasion. In summary, I essentially agree with the other consultant’s interpretation as follows:

C L I N I C A L I N F O R M AT I O N

Lesion of the left arm in a 39-year-old man. R E A S O N F O R C O N S U LTAT I O N

I favor a melanoma with “Spitzoid” features. DESCRIPTION

These sections show a moderately to highly cellular tumor comprised of large spindled to epithelioid melanocytes, filling and expanding the papillary dermis and infiltrating into the mid-reticular dermis,

FIG URE 3.8.1.

A quite broad and thick, highly cellular, somewhat asymmetrical melanocytic tumor.

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Two mitotic figures present in one highpower field. The overall mitotic weight was 3/mm², borderline high for a Spitz tumor. FIGURE 3.8.4.

The lesional cells show little evidence of maturation from superficial to deep and do not disperse well into the reticular dermis at the base. FIG URES 3.8.2 A N D 3 .

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There is a structure suggestive of lymphatic invasion. A D-240 stain lymphatic channels within and around the tumor. One of these channels appears to be invaginated but not penetrated by a nest of lesional cells. FIG URES 3.8.5 A N D 6 .

DIAGNOSIS

Skin, right arm: Malignant melanoma, nodular type, with tumorigenic and mitogenic vertical growth phase, nonulcerated, Clark level IV, greatest Breslow thickness 2.8 mm; see previous discussion and comment.

COMMENT

As noted previously, this lesion has somewhat Spitzoid features, but I agree with the diagnosis of malignant melanoma for the reasons stated previously. The

dermal mitotic rate is intermediate at 3/mm², tumorinfiltrating lymphocytes are essentially absent, there is no radial growth phase regression, there is a scalecrust but no fully developed ulcer, several microscopic satellites are present at the base of the tumor, and there is no evidence of vascular or perineural invasion. There is a suggestion of lymphatic invasion; however, a D2-40 study was done and shows an interesting phenomenon of a cluster of cells invaginating a dermal lymphatic, compressing its lumen, but not being present in the lumen. Therefore, this study does not support the finding of lymphatic invasion. There is no associated nevus, and actinic elastosis in the adjacent dermis is minimal.

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OVERALL COMMENT


The invagination of a lymphatic channel by tumor is an interesting phenomenon that has no known significance. True lymphatic invasion is difficult to recognize in H&E sections, and the incidence

of this feature is greatly increased when a double staining method for lymphatic endothelium and melanoma cells is used.

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3.9 Atypical Pigmented Spindle Cell Nevus vs. SSM

dermis while, in general, appearing to retain their connection to the epidermis. There is no extensive tumorigenic proliferation of the dermal component. Lesional cell mitoses are readily identified in the epidermal component of the lesion. In addition, there are a few dermal lesional cell mitoses, one of which appears to be abnormal. Within the junctional component, there are occasional apoptotic eosinophilic Kamino bodies. Taking all of these features together, this is a quite difficult lesion to interpret, although the appearances tend to favor an atypical but benign lesion with mixed features of pigmented spindle cell nevus and Spitz nevus. The lesion is somewhat larger than most examples of the former and occurs in a somewhat older patient. The differential diagnosis also includes a malignant melanoma, with rather strong Spitzoid features. Based on the rather large size and cellularity of this lesion, as well as the

C L I N I C A L I N F O R M AT I O N

A tumor of the back in a 42-year-old woman. R E A S O N F O R C O N S U LTAT I O N

Concerned about melanoma. DESCRIPTION

The above-captioned material shows an excision of a lesion characterized by a cellular proliferation of plump elongated spindle cells, arranged predominantly in nests, predominantly near the dermalepidermal junction. The lesion is quite broad, at 7–8 mm in diameter on the slide, and quite highly cellular. There is focal evidence of transepidermal elimination of nests of lesional cells, but there is no extensive pagetoid proliferation or continuous basal proliferation of uniform the atypical lesional cells. The cells in nests protrude into the papillary

A broad, plaquelike lesion expanding the papillary dermis. The lesion is bilaterally symmetrical. The proliferation in the epidermis is predominantly nested, with nests tending to be vertically oriented, with some tendency to clefting artifact in some instances. FIG URE 3.9.1.

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3.9 dermal mitotic activity and cytologic atypia, I cannot entirely rule out the possibility of melanoma

and therefore interpret this material descriptively as follows:

Lesional cells extend from the epidermis into the dermis and show some tendency to nevoid maturation upon descent. The overlying epidermis is hyperkeratotic, and the epidermis is focally thinned, with a suggestion of “consumption of the epidermis.”

FIGURE 3.9.3.

FIG URE 3.9.2.

There is only slight evidence of maturation from superficial to deep, and the lesional cells remain confined to the papillary dermis, rather than infiltrating the reticular dermis, as is characteristic of most pigmented spindle cell nevi of Reed, but not of most Spitz nevi/tumors. Pigmentation is reduced at the base of the lesion, perhaps an expression of “maturation.”

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Globoid eosinophilic Kamino bodies are present near the dermal-epidermal junction, although not especially well represented. Some of the cells in the dermis and in the epidermis are heavily pigmented. FIG URE 3.9.4.

DIAGNOSIS

Skin, back: Melanocytic tumor of uncertain malignant potential, favor an atypical spindle and epithelioid cell nevus; see previous discussion and comment.

COMMENT

As noted previously, I cannot rule out the possibility of an unusual form of melanoma in this case, although I favor the idea of a benign spindle and epithelioid

Mitotic figures are readily detected in the dermis, with some high-power fields containing two mitoses. However, overall, the mitotic rate is low. FIGURE 3.9.5.

cell nevus. If interpreted as melanoma, this lesion would be tumorigenic and mitogenic in the dermis, showing Clark level III invasion and a greatest Breslow thickness of 1.2 mm. The dermal mitotic rate is low at 1/mm², tumor-infiltrating lymphocytes are non-brisk, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic, or neural invasion. Changes extend close or to lateral specimen margins, and I recommend definitive management of this lesion with the previously described differential diagnoses taken into consideration. This might include consideration of sentinel lymph node sampling.

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3.9
OVERALL COMMENT


Although pagetoid scatter may be seen quite commonly in pigmented spindle cell nevi, the added

presence of an atypical dermal component without maturation raises additional concern for melanoma.

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3.10 Spitz Tumor vs. Deep Penetrating Nevus

to the base of the biopsy to a depth of at least 2 mm. The lesional cells have abundant cytoplasm, generally containing relatively copious amounts of melanin pigment in granules of intermediate size, and there is a sprinkling of melanophages. There is also a sprinkling of lymphocytes and histiocytes arranged in clusters. The lesional cells infiltrate among reticular dermis collagen fiber bundles. The overlying epidermis is focally hyperplastic, and a few lesional cells are present in the basal layer, without extensive continuous proliferation or pagetoid proliferation and without a characteristic junctional nevus component. Kamino bodies are not observed. These changes present considerable

C L I N I C A L I N F O R M AT I O N

A pink nodule on the arm of a 6-year-old girl. R E A S O N F O R C O N S U LTAT I O N

We favor an inflamed Spitz nevus. What do you think? DESCRIPTION

These sections show a most unusual melanocytic tumor, characterized by a somewhat mixed population of cells, generally spindle and/or epithelioid in configuration, but with an admixture of smaller round or dendritic cells. The cells form a tumor that extends from near the epidermis into the deep reticular dermis

FIG URE 3.10.1.

Biopsy of a relatively bulky tumor, at least 5 mm in breadth and depth, transected at specimen margins. 97

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3.10 difficulties of interpretation. The differential diagnosis for this lesion could include a deep penetrating nevus, a cellular blue nevus, a proliferation occurring in a congenital nevus, or even a melanoma. However, the latter diagnosis appears unlikely in a child of this age and in the absence of mitotic activity. I therefore interpret this lesion descriptively as follows:

The lesion lacks symmetry from side to side, with variation in cellular density, pigmentation, and cell size. FIGURE 3.10.4.

The lesion extends from the epidermis well into the reticular dermis and is transected at the base. It is comprised of spindle cells, which infiltrate extensively among reticular dermis collagen fiber bundles. There are nodular clusters of lymphocytes. FIG URE 3.10.2.

The lesional cells are relatively large spindle cells, with somewhat hyperchromatic, somewhat irregular nuclei. Mitotic figures, however, are rare or absent. There are clusters of infiltrating lymphocytes focally. FIGURE 3.10.5.

There is epidermal hyperplasia focally above the lesion, and a few cells extend up in a pagetoid pattern, although not extensively across the lesion. FIG URE 3.10.3.

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3.10 DIAGNOSIS

Skin, site not stated: Melanocytic tumor of uncertain potential, favor an atypical Spitz tumor; see previous discussion and comment.

COMMENT

This lesion is not entirely characteristic of any of the previously discussed conditions and might perhaps best be considered as an atypical Spitzoid lesion, although by no means typical for its extensive and relatively uniform pigmentation, present from the surface to the base. Deep penetrating nevus (with atypical features)

is another reasonable consideration. The admixture of lymphocytes would be unusual in this condition. Although I doubt that this lesion is a melanoma, I consider that it could have some potential for at least local persistence and recurrence. Because specimen margins are involved, I recommend an additional procedure, to be sure this lesion has been removed, with a margin of normal skin around the scar of this procedure and any residual lesion, and I recommend careful follow-up of the lesional site. In problematic lesions of this type, sentinel lymph node sampling is sometimes considered as a staging procedure; however, in my opinion, this is by no means the “standard of care.” I am most interested in any follow-up information that may become available in this case.


OVERALL COMMENT


This lesion presents several atypical features, including its very large size; however, the absence of mitoses and the age of the patient are reassuring features.

There are overlap features between deep penetrating nevus and “pigmented Spitz nevus,” a not uncommon circumstance of little or no clinical consequence.

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3.11 Spitzoid Melanoma vs. Atypical Spitz

C L I N I C A L I N F O R M AT I O N

Lesion of the ear in a 16-year-old boy. R E A S O N F O R C O N S U LTAT I O N

Although the lesion shows Spitz features, we favor a diagnosis of malignant melanoma. DESCRIPTION

These sections show portions of a highly cellular tumor comprised of uniformly large spindle and/or epithelioid melanocytes, present in nests near the

dermal-epidermal junction and protruding down through the papillary dermis into the reticular dermis to be transected at the base of the biopsy. The lesional cells have abundant amphophilic cytoplasm and large, only slightly irregular nuclei, with fairly pale chromatin and prominent nucleoli. These cytologic features would be quite consistent with a Spitz nevus/tumor. However, the cells are very closely packed in a dense, sheetlike pattern of growth, and there are frequent mitoses, with numerous high-power fields, containing three and up to five or even more mitotic figures

Scanning magnification of a slide containing multiple sections of a bulky tumor from the skin of the ear, removed by shave biopsy. The tumor is extensively transected at the base of the biopsy. FIG URE 3.11.1.

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3.11 and with a mitotic rate of about 10/mm2. Some of the mitotic figures are probably abnormal. Although one cannot adequately evaluate the base of the lesion, there does not seem to be evidence of maturation within this specimen. I also note that your Ki-67 study showed 5–10% of the cells to be positive. In summary, I agree with your concerns about this lesion and characterize it as follows:

In some areas, there is extensive epidermal spongiosis and subepidermal edema. FIGURE 3.11.4.

The lesion is extensively ulcerated. The lesional cells are closely packed in sheets and are uniformly, albeit moderately, atypical. FIG URE 3.11.2.

Mitotic figures are quite numerous, here seen close to the epidermis. However, mitotic figures were scattered throughout all levels of the lesion. FIGURE 3.11.5.

There is no characteristic in situ pattern of a melanoma, nor is there a characteristic junctional component of a Spitz nevus/tumor. FIGURE 3.11.3 .

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3.11 DIAGNOSIS

Skin, ear: Malignant melanoma, with Spitzoid tumorigenic and mitogenic vertical growth phase, extensively ulcerated (greater than 10 mm in breadth), Clark level not less than IV, Breslow thickness not less than 4 mm, transected at the base of the biopsy; see previous discussion and comment.

COMMENT

As noted previously, the lesion is extensively ulcerated. The dermal mitotic rate is relatively high at approximately 10/mm2, tumor-infiltrating lymphocytes are

sparse to absent in this material, radial growth phase regression cannot be evaluated, microscopic satellites cannot be evaluated, and there is no clear evidence of vascular or lymphatic invasion. The lesion is transected at multiple margins. I recommend definitive management for this lesion at this site, to include a definitive wide local excision. I also recommend consideration of a sentinel lymph node sampling procedure. This lesion fits into the category of “Spitzoid melanomas of childhood,” although similar tumors may also be seen in adults. In several published series, even after a positive sentinel lymph node has been found, these patients can have relatively long survivals. However, extensive long-term follow-up studies are not available, and I am quite concerned about this particular lesion’s capacity for progression.


OVERALL COMMENT


If the concept of “Spitzoid melanoma” has validity, it is possible that the prognosis for this lesion may be

better than its size and high mitotic rate might otherwise indicate.

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3.12 Spitzoid Melanoma vs. Atypical Spitz

C L I N I C A L I N F O R M AT I O N

A biopsy from the left lateral knee of a 16-year-old female, submitted as “dermatofibroma.” R E A S O N F O R C O N S U LTAT I O N

Within our group there was a spread of opinion that ranged from a traumatized compound nevus and an atypical Spitzoid neoplasm, including an evolving Spitzoid melanoma, given the presence of mitoses and high Ki-67 positive rate. We would like your help to classify this neoplasm and any suggestions regarding appropriate treatment and management. DESCRIPTION

These sections show a biopsy of skin containing a moderately to highly cellular lesion characterized in

FIG URE 3.12.1.

the junctional component by single and nested melanocytes, arranged mainly near the tips and sides of elongated rete ridges, with some nests bridging adjacent rete and with moderate to focally severe atypia of scattered lesional cells, consistent with severe junctional melanocytic dysplasia. Somewhat eccentrically placed within the lesion, there is a dermal component that has two parts. Toward the base, there is a more nevoid component extending among reticular dermis collagen fiber bundles. More superficially, there is a larger more epithelioid cell type, within which mitotic figures are readily identified, demonstrating moderate to severe quite uniform cytologic atypia. This combination of cytologic atypia and mitotic activity in the dermal component is very concerning unless one can regard this lesion as a characteristic

Scanning magnification shows two pieces of tissue from a single biopsy. 103

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3.12 Spitz tumor. However, the junctional component is that of melanocytic dysplasia rather than a junctional Spitzoid proliferation. Furthermore, although the deeper component does exhibit some tendency to nevoid maturation, this is incomplete, and the cells do not disperse well into the reticular dermis at the base. At least one mitotic figure is identified in this dermal component, in the lower third. A Ki-67 study supports the evidence of proliferation in the dermis, with reactivity that is, overall, probably less than 5%

but focally approaches 10%. An HMB 45 study stains the deep dermal component as well as the junctional component. An S100A6 is diffusely positive. These findings present considerable difficulties of interpretation, as summarized in your letter. I agree that there are some Spitzoid features of the dermal component; however, the junctional component is not typical. The youthful age of the patient suggests a cautious approach to the diagnosis, and I therefore interpret this lesion descriptively as follows:

One of the two pieces of tissue contains nevoid to epithelioid cells, arranged predominantly in mass, predominantly near the tips and sides of elongate rete ridges, with some bridging nests, and with mild atypia, consistent with junctional melanocytic dysplasia.

FIGURE 3.12.3.

FIG URE 3.12.2.

The other piece of tissue shows a cellular dermal component, comprised of large epithelioid cells contrasting with the smaller cell type toward the base. The superficial cells are large, and there is a relatively sharp demarcation between them and the smaller cells at the base. The latter do not disperse well among reticular dermis collagen bundles, and they show only incomplete maturation.

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Mitotic figures are readily detected, with an overall rate of 3.5/mm2. Scanning magnification Web figure shows the location of three mitotic figures. FIG URE 3.12.4 .

An HMB 45 study shows an unusual pattern of staining of the deep dermal component as well as the junctional component.

A stain for Ki-67 (in brown, double-labeled with Melan-A in red) shows a relatively high proliferating fraction, although not greater than 10%. FIGURE 3.12.5.

FIG URE 3.12. 6 .

S100A6 shows diffuse labeling, a feature favoring a Spitz tumor. FIGURE 3.12.7.

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3.12 DIAGNOSIS

Skin, right lateral knee: Melanocytic tumor of uncertain malignant potential, cannot rule out a tumorigenic and mitogenic melanoma with Spitzoid and nevoid features, arising in association with a junctional dysplastic nevus; see previous discussion and comment.

COMMENT

As noted previously, I cannot rule out a tumorigenic and mitogenic vertical growth phase arising in association with a dysplastic nevus. If interpreted as a melanoma, this lesion would show Clark level IV invasion at a greatest Breslow thickness of not less than 3.5 mm, with the dermal component focally transected at the base. The dermal mitotic rate is relatively low for a melanoma at approximately 3/mm², tumor-infiltrating lymphocytes are sparse, there is

no radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic, or neural invasion. As already noted, the differential diagnosis could include a Spitz nevus/tumor, which is quite atypical and could potentially have competence for at least regional metastasis, or a nevoid melanoma. Based on this differential diagnosis, I recommend an additional excision procedure, to be sure this lesion has been completely removed, with an adequate margin of normal skin, and I believe that consideration of sentinel lymph node sampling would also be appropriate, although many authorities do not believe this is necessarily standard of care for lesions of this type. The differential diagnosis also includes a severely dysplastic nevus, and I also recommend evaluation of this patient’s other risk factors for melanoma and, especially if she should have other clinically atypical nevi and/or a family or personal history of melanoma, periodic surveillance of her skin will likely be indicated.


OVERALL COMMENT


This lesion presents competing criteria, including a somewhat higher mitotic rate and Ki-67 fraction than is usual in Spitz tumors, but not in a range pathognomonic for melanoma. The association with a compound dysplastic nevus could be regarded as an example of a so-called “combined nevus,” alternatively

as a precursor relationship between the nevus and a melanoma. Spitzoid melanomas typically do not have an associated nevus. Although I favor the likelihood that this lesion will have a benign course, I cannot rule out a lesion with potential for metastasis in this case.

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3.13 Atypical Spitz vs. MM

C L I N I C A L I N F O R M AT I O N

Atypical nevus on the right posterior thigh of a 21-year-old woman. R E A S O N F O R C O N S U LTAT I O N

Please evaluate this atypical melanocytic neoplasm. DESCRIPTION

These sections show a punch biopsy of skin containing a portion of a melanocytic lesion that is quite highly cellular and asymmetric in the distribution of lesional cells from side to side. The lesion is comprised in its epidermal component of a predominantly single cell proliferation of somewhat enlarged nevoid to epithelioid melanocytes. The cells extend up into the epidermis in a pagetoid pattern that is quite well developed across the lesion, focally extending at least to the stratum granulosum. Similar cells are present in

the papillary dermis and infiltrating the upper reticular dermis. They tend to be epithelioid and spindle, quite reminiscent of Spitz tumor cells; however, there is variation in size, with small cells alternating with larger cells across the lesion, and they are asymmetrically distributed, with two separate areas at least of expansile proliferation and the dermis. The cells show some evidence of maturation from superficial to deep; however, this is incomplete, with some large cells present in the reticular dermis near the base. Some cells disperse as single cells into the collagen at the base of the tumor. This latter feature, of course, is more characteristic of nevi than of melanomas. Although mitotic figures are rare, at least one abnormal mitotic figure has been seen in the dermal component. In summary, this lesion presents conflicting criteria. Also taking into account the relatively youthful age of the patient, I believe that a Spitz tumor is quite likely a

There is a tumor that is only partly contained within the biopsy specimen. The tumor is not especially well circumscribed or symmetrical. It is transected at the specimen margin. FIG URE 3.13.1 .

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3.13 possibility; however, given the adjacent and overlying pagetoid proliferation, the cytological variability, the incomplete maturation, and the abnormal mitotic figure, I cannot rule out an unusual Spitzoid melanoma and therefore characterize this lesion descriptively as follows:

A junctional component extends beyond the periphery of the dermal tumor and is not well circumscribed. FIG URE 3.13.2.

The lesional cells show only slight evidence of maturation from superficial to deep and disperse only partly as single cells into the reticular dermis. Multinucleated tumor cells are present near the dermal-epidermal junction. Nests in the epidermis are not well defined and are not uniform in size and shape. There is no prominent clefting artifact, and Kamino bodies are not observed. FIG URES 3.13.3 A ND 4 .

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Another piece of tissue on the slide contains a predominantly junctional component, comprised as single cells predominating in many areas and extending up into the epidermis in a pagetoid pattern. Some of the lesional cells are relatively small, rather than the uniform “large spindle and/or epithelioid cells” of characteristic Spitz tumors. FIGURE 3.13.6.

Although mitotic figures were not frequent, an abnormal mitotic figure was observed in the upper third of the dermal component of the tumor. FIG URE 3.13.5 .

COMMENT

A Melan-A study emphasizes the pagetoid proliferation in the epidermis and also illustrates a tendency to differentiation of the dermal component. FIG URE 3.13.7.

DIAGNOSIS

Skin, left posterior thigh: Melanocytic tumor of uncertain malignant potential; see previous discussion and comment.

As noted previously, I somewhat favor an atypical Spitz tumor; however, I cannot rule out a Spitzoid melanoma. It is likely that microstaging attributes developed for other melanomas should not be uncritically applied to Spitzoid melanomas; however, if this lesion were interpreted as a melanoma, it would show a Clark level IV invasion at a greatest Breslow thickness of 1.1 mm. The dermal mitotic rate is low at 1/mm², tumor-infiltrating lymphocytes are focally brisk but overall non-brisk, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic, or neural invasion. This is a partial biopsy, and I recommend complete excision of this lesion and perhaps reevaluation of the entire lesion, which might allow for a more specific diagnosis to be made.


OVERALL COMMENT


The junctional component of this lesion is very concerning for melanoma; however, the dermal component has many Spitzoid features. Even if it is interpreted as a

melanoma, the predicted probability of 8-year survival for a lesion with these attributes would be literally 100%, according to the 1989 “Clark prognostic model” (31).

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3.14 Atypical Spitz vs. Spitzoid Melanoma

C L I N I C A L I N F O R M AT I O N

DESCRIPTION

Lesion on the buttock of a 71-year-old woman. The clinical impression was pyogenic granuloma.

The sections show a polypoid tumor comprised of large spindle and/or epithelioid melanocytes, arranged in nests within the expanded papillary dermis, in a fibrovascular stroma. There is only slight evidence of maturation from superficial to deep, and lesional cells do

R E A S O N F O R C O N S U LTAT I O N

Please review this case.

FIGURES 3.14.1 AND 2.

Low magnification shows a polypoid nodular tumor that is quite symmetrical and moderately cellular. 110

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3.14 not disperse well into the reticular dermis, although the lesion is transected at the base, precluding full evaluation of this feature. Although not prominent, occasional eosinophilic Kamino bodies are present at the interface. These are features quite highly suggestive of a Spitz nevus/tumor; however, the relative failure of maturation is a concerning feature. Scrutiny of the lesion for mitotic activity reveals scattered mitoses, some of which are clearly abnormal and at least one of which is present in the lower third of the lesion. This is an additional concerning feature. However, the mitotic rate is low, and there is no in situ component of a melanoma. Particularly in a patient

of this age group, I am quite concerned about the possibility of a Spitzoid melanoma; however, given the relatively low cellularity and a low mitotic rate, I interpret this lesion descriptively as follows.

There is limited evidence of maturation from larger cells superficially to smaller cells at the base. The lesional cells are large, spindle and/or epithelioid in configuration, and are quite uniform from side to side. FIG URES 3.14. 3 A N D 4 .

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There are nests with clefting artifact at the dermal-epidermal junction, without extensive continuous basal or high-level pagetoid proliferation and without ulceration or “consumption of the epidermis.” FIG URE 3.14.5.

F I G UR E 3 . 1 4 . 6 .

Continued.

There are small eosinophilic Kamino bodies at the junction. FIGURE 3.14.6.

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The cells have abundant amphophilic cytoplasm and large nuclei with regular nuclear membranes, pale chromatin, and prominent nucleoli. Mitoses were present, including one in the lower third of the lesion (not shown). FIG URE 3.14.7 .

DIAGNOSIS

Skin, buttock: Melanocytic tumor of uncertain malignant potential, atypical Spitz tumor versus Spitzoid melanoma; see previous discussion and comment.

COMMENT

I recommend managing this lesion with the differential diagnosis of melanoma taken into

There is limited evidence of maturation to the base. The cells do not disperse well; however, the true base of the lesion is not available for examination. FIGURE 3.14.8.

consideration, and, if interpreted as a melanoma, this lesion would constitute Clark’s level IV invasion at a greatest Breslow thickness of 2.4 mm. The dermal mitotic rate is low at 1/mm², tumorinfiltrating lymphocytes are essentially absent, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic, or neural invasion. Changes extend to the specimen base and margins, and I recommend correlating this report with findings from a re-excision specimen for final definitive microstaging.

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OVERALL COMMENT


Although this lesion may represent an atypical Spitz tumor, the probability of this diagnosis is considerably

diminished in this age group, and the abnormal mitoses, in particular, are a very concerning feature.

4 Deep Penetrating Nevi

R

elatively recently described as well as relatively uncommon, these benign lesions may simulate melanomas and are discussed and illustrated here, including variants. Deep penetrating nevus was first described by Seab et al. in a study of 70 patients from the Armed Forces Institute of Pathology (1). The lesions were most commonly found on the face, upper trunk, or proximal extremities of individuals between the ages of 10 and 30. They were darkly pigmented clinically. Histologically they were characterized by “loosely organized nests of pleomorphic pigmented cells that penetrated deep into the reticular dermis and often for subcutaneous fat.” The lesions violate the “rule of thumb” that pigment in usual forms of common and congenital pattern nevi is confined to the upper third of the lesions in the epidermis and superficial dermis. The differential diagnosis includes malignant melanoma, but also spindle and epithelioid cell nevi and blue nevi (1). Soon after, Cooper et al. described 41 patients with what was termed “deep penetrating” or “plexiform spindle cell” nevus (2). Microscopically, the tumors were described as being wedge-shaped and variably involving the reticular dermis, sometimes involving the subcutis. Involvement of neurovascular structures and a tendency to spread between fibers of the reticular dermis created a fascicular-plexiform architecture. The melanocytes were described as fusiform or epithelioid, lightly to moderately pigmented, with mild to focally prominent nuclear atypia. Mitotic figures were described as “few and present in only a small minority of lesions.” In this study, it was also

indicated that deep penetrating nevus was a frequent participant in combined nevus, being associated with an ordinary nevus in two-thirds of the lesions (2). Subsequent studies have confirmed these observations, including emphasis on the usual absence or rarity of mitoses (3–7). In addition to the previously described features, these lesions may have a junctional component characterized by relatively small uniformly sized and evenly spaced nests along the dermal-epidermal junction. There should not be any evidence of an in situ component of a melanoma above the lesion, and, of course, there is no melanoma in situ component adjacent to the dermal component of the lesion. Many of the descriptions of deep penetrating nevi emphasize the presence of pleomorphism or atypia. In my experience, this atypia is characteristically random rather than uniform; that is, it is confined to a minority of the lesional cells, which may have quite startlingly large, irregular, and hyperchromatic nuclei. The nested and fascicular or plexiform architecture of the lesions is also emphasized. A feature that was emphasized by the late Wallace H. Clark Jr. was the presence of “sustentacular cell differentiation” around the edges of the nests or fascicles. This was recognized by the presence of narrow elongated spindle cells wrapping around the plexiform bundles or nests of spindle to epithelioid melanocytes. In a recent study, histologic and clinical features, including dermoscopic features, were studied in 52 melanocytic proliferations belonging to the morphologic spectrum of blue nevus. Using this approach, deep penetrating nevi were described as “polychromatic” (8). In

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a genomic analysis study, using comparative genomic hybridization, one deep penetrating nevus studied showed no chromosomal aberrations (9). In the series summarized previously, there have been no instances of metastasis and few if any instances of local recurrence. However, “the devil is in the details,” and, just as deep penetrating nevi may simulate melanomas, so, on occasion, one may assume that a melanoma may simulate a deep penetrating nevus. Features that should give rise to concern, in my opinion, include the presence of melanoma in situ, above and especially adjacent to the lesion; ulceration or necrosis; the presence of uniform, rather than random, atypia; confluent sheetlike, rather than nested, fascicular, or plexiform, architecture of the dermal component; and the presence of any mitoses, other than perhaps one or two mitoses per lesion. Ki-67 staining could be useful in assessing proliferation; however, there have been no definitive studies. In most instances one may expect this to be almost completely negative. In summary, these are benign lesions, despite their often considerable depth in terms of Breslow thickness and the presence of cytologic atypia, as well as rare mitoses in them. The differential diagnosis of deep penetrating nevus also includes cellular blue nevus and Spitz nevus; however, these differentials are relatively trivial because each of these diagnoses is benign and should not lead to excessive therapy. There are some lesions with features of deep penetrating nevi, especially those with mitotic activity or with sheets of cells, that are probably best interpreted descriptively as “melanocytic tumor of uncertain malignant potential” or MELTUMP. Other lesions may be described as “atypical deep penetrating nevi.” Microstaging attributes such as Breslow’s thickness, Clark’s levels of invasion, mitotic rate, and ulceration may be used as a guide to therapy; however, most of these lesions are greater than 1 mm in thickness and extend to

NE VI

Clark’s level IV. Like other “blue nevus-like” lesions, perineural “invasion” may be seen and is not an indicator of malignancy. Lymphovascular invasion, if unequivocally demonstrated, should likely lead to a diagnosis of melanoma. Ulceration should be absent and the mitotic rate should be low, or otherwise the lesions would probably be better termed melanomas. Therapeutic considerations should include complete excision and might include a consideration of sentinel lymphadenectomy. However, I do not believe this latter procedure is standard of care for these lesions. In any event, because experience with deep penetrating nevi is still relatively limited and because of occasional difficulties with the differential diagnosis, it seems best to ensure that all of these lesions are completely removed.

References 1 Seab JA Jr, Graham JH, Helwig EB. Deep penetrating nevus. Am J Surg Pathol 1989;13:39–44. 2 Cooper PH. Deep penetrating (plexiform spindle cell) nevus. A frequent participant in combined nevus. J Cutan Pathol 1992 Jun;19(3):172–80. 3 Mehregan DA, Mehregan AH. Deep penetrating nevus. Arch Dermatol 1993;129:328–31. 4 Gonzalez-Campora R, Galera-Davidson H, Vazquez-Ramirez FJ, az-Cano S. Blue nevus: classical types and new related entities. A differential diagnostic review. Pathol Res Pract 1994 Jun;190(6):627–35. 5 Mehregan DR, Mehregan DA, Mehregan AH. Proliferating cell nuclear antigen staining in deep-penetrating nevi. J Am Acad Dermatol 1995;33:685–7. 6 Barr RJ. Deep penetrating nevus. Dermatol Online J 1997 Mar;3(1):7. 7 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 Dec;43(6):529–37. 8 Ferrara G, Soyer HP, Malvehy J, Piccolo D, Puig S, Sopena J, Zalaudek I, Argenziano G. The many faces of blue nevus: a clinicopathologic study. J Cutan Pathol 2007 Jul;34(7):543–51. 9 Maize JC Jr., McCalmont TH, Carlson JA, Busam KJ, Kutzner H, Bastian BC. Genomic analysis of blue nevi and related dermal melanocytic proliferations. Am J Surg Pathol 2005 Sep;29(9):1214–20.

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4.1 Deep Penetrating Nevus vs. Nodular Melanoma

giant cells.” There is a somewhat ill-defined tendency to spindle cell or sustentacular cell differentiation around the periphery of the nests. There is a sprinkling of lymphocytes and melanophages. The lesional

C L I N I C A L I N F O R M AT I O N

A black lesion of the thigh in a 47-year-old woman. R E A S O N F O R C O N S U LTAT I O N

Is this an atypical nevus or a melanoma? DESCRIPTION

These sections show a punch biopsy containing a moderately cellular tumor comprised of spindle shaped to nevoid to epithelioid melanocytes, arranged in nests and fascicles within the reticular dermis. There are some scattered giant cells, consistent with “nevus

Scanning magnification shows an ill-defined tumor in the reticular dermis. These lesions are often pyramidal in shape with their base applied to the epidermis and their apex in the mid reticular dermis. This lesion is more irregular in shape. FIG URE 4.1.1.

The lesion extends to lateral specimen margins. It is poorly circumscribed at its periphery. FIGURE 4.1.2.

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4.1 cells themselves contain moderate pigment, from superficial to deep. Scattered among smaller cells, there are cells with large, irregular, and hyperchromatic nuclei, constituting random cytologic atypia. In the overlying epidermis, there is a population of somewhat similar cells, mostly as single cells, without extensive continuous basal or high-level pagetoid proliferation. Taken together, I agree that these findings are consistent with a fairly typical deep penetrating nevus. A slight concern is the finding of one probable dermal mitosis. This may be a pyknotic cell; however, the finding of a single mitosis was considered to be within acceptable limits for deep penetrating nevi in the original report of this entity. In the absence of other compelling indicators of malignancy, I therefore interpret this lesion as follows:

There are a few enlarged nevoid epithelioid melanocytes in the overlying epidermis (see also Figure 3). There is no continuous basal proliferation, extensive highlevel proliferation, or other evidence of melanoma in situ. FIGURE 4.1.4.

The lesion is comprised of spindle and epithelioid cells arranged in ill-defined nests in the dermis. Confluent sheetlike proliferation is not observed. FIG URE 4.1.3.

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4.1 DIAGNOSIS

Skin, right anterior thigh: Deep penetrating nevus, with atypical features including rare mitotic activity; see previous discussion and comment.

COMMENT The cells in the dermis are arranged in illdefined nests. There is sometimes a tendency to spindle cell differentiation at the periphery of the nests reminiscent of sustentacular cells of nerves. There is random atypia in the form of nuclear enlargement, irregularity, and hyperchromatism. In this particular lesion, one possible mitotic figure was observed; however, this may have represented a pyknotic nucleus. FIG URE 4.1.5.

As noted previously, a rare dermal mitosis may be an acceptable finding in a deep penetrating nevus, and I regard the other characteristics of this biopsy as quite consistent with that diagnosis. Changes extend to specimen margins, and, because of the mitotic activity and also because these are somewhat unusual lesions, I recommend an additional procedure, to be sure this lesion has been completely removed, with a margin of normal skin around the scar of this procedure and any residual lesion.


OVERALL COMMENT


A more cautious interpretation of this lesion might be as “melanocytic tumor of uncertain malignant potential, favor an atypical deep penetrating nevus.” Although the original report of this entity allowed for the presence of a rare mitosis, many experienced

pathologists today are reluctant to accept mitotic activity in these lesions. There have been no formal studies of this question, however, and there are also no controlled studies of the use of Ki-67 or other markers.

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4.2 Deep Penetrating Nevus vs. Epithelioid Blue Nevus

C L I N I C A L I N F O R M AT I O N

This lesion was described as a dark-pigmented macule from the left lower leg of a 33-year-old woman, noted during a routine skin check following removal of a basal cell carcinoma. There is no previous history of melanoma. R E A S O N F O R C O N S U LTAT I O N

I favor either a superficial variant of deep penetrating nevus, or perhaps an epithelioid nevus, but am concerned that perhaps it could be a melanoma. DESCRIPTION

cells and nests along the dermal epidermal junction, with some tendency to upward intraepidermal migration. Similar cells are present in the dermis, where they are arranged mainly in nests, admixed with macrophages. The cells in the dermis contain moderate melanin pigment. Some of the nests are surrounded by spindle cells reminiscent of sustentacular cells. The density of the cellular component in the dermis is relatively low, atypia tends to be random rather than uniform, and, perhaps most reassuring of all, mitotic figures appear to be rare or absent. Therefore, I agree with your diagnosis, characterizing the lesion as follows:

The sections show an excision of a lesion characterized by a junctional component comprised of single

Scanning magnification shows a small, relatively superficial, moderately to heavily pigmented, melanocytic proliferation, mainly in the dermis. FIG URE 4.2.1.

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There is a junctional component comprised of single cells and extending somewhat beyond the lateral border of the dermal component, which is an atypical feature in a deep penetrating nevus. FIG URES 4.2.2 A N D 3 .

The proliferation in the dermis is predominantly nested, the cellularity is relatively low, and mitotic figures are rare or absent. FIG URE 4.2.4.

There is little or no evidence of maturation to the base of the lesion FIGURE 4.2.5.

COMMENT DIAGNOSIS

Skin, left lower leg: Deep penetrating nevus, completely excised; see previous discussion and comment.

The presence of a junctional component is perfectly consistent with the diagnosis of deep penetrating nevus; however, the pagetoid proliferation is an atypical feature. Given the absence of mitoses and the low cellularity of the dermal component, however, I do not believe that it represents melanoma.


OVERALL COMMENT


The slight pagetoid scatter in the overlying epidermis is an atypical feature; however, the lack of an adjacent in

situ melanoma component is reassuring. Complete excision would be recommended if margins were positive.

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4.3 Atypical Deep Penetrating Nevus vs. Nodular Melanoma

and the presence of mitotic figures, although these are not numerous. Because of these atypical features, I cannot rule out the possibility of a lesion with potential for local recurrence, and possibly some potential for metastasis, and therefore characterize this lesion descriptively as follows:

C L I N I C A L I N F O R M AT I O N

Lesion of the shoulder in an 18-year-old male. R E A S O N F O R C O N S U LTAT I O N

Is this a melanoma or an unusual nevus? DESCRIPTION

These sections show a bulky, quite highly cellular, melanocytic tumor measuring more than 4 mm in diameter and about 2.5 mm in depth, transected at the base of the specimen, with a couple of included additional fragments. The tumor presents a somewhat sheetlike pattern of growth in some areas; however, there is an underlying nested architecture, and, in some areas, the pattern is predominantly nested. At the periphery of the nests, there are spindle cells reminiscent of sustentacular cell differentiation as seen in deep penetrating nevi. There are scattered cells with larger, hyperchromatic, and irregular nuclei, constituting random cytologic atypia, which may also be seen in deep penetrating nevi, and there are a few junctional nests, without evidence of wellorganized in situ melanoma or dysplastic nevus pattern. Concerning features in this lesion include the focal, more confluent, or sheetlike pattern of growth

Scanning magnification shows a fairly bulky, highly cellular tumor extending from the epidermis into the reticular dermis, transected at the base of the specimen. FIGURE 4.3.1.

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4.3

There is little or no evidence of maturation of the lesional cells from superficial to deep. Lesional cells, especially superficially, tend to be arranged in a nested pattern. Especially at the base of the lesion, the nests tend to become confluent. This is an atypical feature. FIG URES 4.3.2 A N D 3 .

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There is a junctional component, presenting as a moderately dense proliferation, with single cells and nests, predominantly along the dermal-epidermal junction. FIG URE 4.3.4.

Scattered throughout the lesion, there are atypical cells characterized by large, irregular, and hyper chromatic nuclei. A rare mitotic figure was identified (not shown). FIGURE 4.3.5.

HMB 45 staining is patchy rather than diffuse, which would be more characteristic of a typical deep penetrating nevus. FIGURE 4.3.7.

Immunostains had been done. Ki-67 demonstrates only a few reactive cells in the dermal component. There are positive controls in the epidermis in the form of basal keratinocytes. The lesional cells in the epidermis appear to be negative. FIG URE 4.3.6.

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4.3 COMMENT

Melan-A staining demonstrates a predominantly nested architecture of the dermal component. The junctional component tends to become confluent; however, many of the cell bodies appear to be separated by dendrites. FIGURE 4.3.8.

DIAGNOSIS

Skin, left shoulder: Melanocytic tumor of uncertain malignant potential, favor an atypical deep penetrating nevus, cannot rule out an unusual form of melanoma; see previous discussion and comment.

It is not clear that microstaging attributes developed for usual forms of melanoma can be applied uncritically to lesions of this type. Nevertheless, if this lesion were to be interpreted as a melanoma, it would show Clark level IV invasion at a greatest Breslow thickness of not less than 2.5 mm. The dermal mitotic rate is low at 1/mm2, tumor-infiltrating lymphocytes are very sparse, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic, or neural invasion. The lesion is transected at the base. I recommend additional therapy for this lesion, with the previously described differential diagnosis taken into consideration, and this, in my opinion, should include, at a minimum, a re-excision procedure, with a margin of normal skin around the scar of this procedure and any residual lesion. In addition, many clinicians would consider a sentinel lymph node procedure for a lesion of this type, and I believe that this should be discussed as an option with the patient and his family.


OVERALL COMMENT


The presence of any dermal mitoses in a lesion thought to be a possible deep penetrating nevus should lead to serious consideration of melanoma. In addition, the cells in these lesions should be arranged almost exclusively in nests and/or fascicles, rather than in

confluent sheets. Unlike in common or congenital nevi, these lesions do not show much evidence of maturation from superficial to deep, and deep pigmentation is a characteristic feature.

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4.4 Deep Penetrating Nevus vs. Nodular Melanoma

C L I N I C A L I N F O R M AT I O N

Lesion from the right upper back of a 14-year-old male. R E A S O N F O R C O N S U LTAT I O N

I believe it to be a nevus, probably congenital, with features of a deep penetrating nevus. It is, however, somewhat unusual, so I’d like you to put your eyes on it. As always, any insights you have will be greatly appreciated. DESCRIPTION

The sections show a very unusual lesion that presents considerable and perhaps impossible difficulties of interpretation. The sections show a fairly broad lesion about 6 mm in diameter on the slide and about 2.5 mm in depth, extending from the epidermis well

into the reticular dermis. It is comprised of a rather uniform population of spindle-shaped melanocytes, arranged in ill-defined nests, with a considerable tendency to confluence and formation of sheets. Scattered among a population of smaller cells, there are larger cells with large, irregular, and hyperchromatic nuclei. This pattern of random atypia and the underlying nested architecture, focally with a suggestion of peripheral spindle cell or sustentacular cell differentiation, are quite characteristic of deep penetrating nevi. The increased cellularity is a concerning feature. In addition, the junctional component is considerably more cellular than one usually sees in these lesions, with a tendency to confluence along the dermalepidermal junction, and focal pagetoid extension into

Scanning magnification shows a relatively symmetrical, dome-shaped tumor, forming a nodule that extends from the elevated epidermis into the mid-reticular dermis. The lesion is fairly well circumscribed on each side. FIG URE 4.4.1.

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4.4 the epidermis. Finally, scattered lesional cell mitoses are identified, with some difficulty. This includes occasional lesional cell mitoses close to the base of the lesion. Perineural involvement is identified within the tumor; however, in deep penetrating nevi and related lesions, such as blue nevi, this is not automatically an indicator of malignancy. Focally, the perineural invasion is present well beyond the periphery of the tumor,

suggesting that this is an active and perhaps somewhat more concerning process. There are prominent lymphovascular channels superficially; however, there is no clear evidence of vascular invasion. This lesion presents concerning and conflicting criteria. However, especially in a person of this youthful age, I cannot make a diagnosis of malignant melanoma in this lesion and therefore characterize it descriptively as follows:

The tumor is comprised of nevoid epithelioid cells, arranged in a vaguely nested and fascicular pattern. There is little evidence of maturation from superficial to deep. There is a predominantly nested and fascicular pattern, with a tendency to confluence and sheetlike growth. At the periphery of the nests, there is sometimes a narrow, elongated spindle cell wrapping around the other cells in the nests, a feature that has been termed “sustentacular cell differentiation.” FIGURES 4.4.2 AND 3.

On one side, there is a narrow zone of junctional proliferation, forming a “shoulder.” This proliferation is predominantly nested and predominantly basal. FIG URE 4.4.4.

In the overlying epidermis, there are nests that are reasonably uniform in size, shape, and spacing. There is no extensive continuous basal or high-level pagetoid proliferation that might be characteristic of melanoma in situ. FIGURE 4.4.5.

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Although mitotic figures were rare, they could be found with some difficulty. These figures show a mitotic figure in the upper third of the dermal component of the tumor. FIG URE 4.4.6.

DIAGNOSIS

Skin, right upper back: Melanocytic tumor of uncertain malignant potential, most consistent with an atypical deep penetrating nevus, completely excised; see previous discussion and comment.

COMMENT

This lesion has been completely and relatively generously excised, with closest borders of about 2 mm.

Perineural invasion is noted at the base of the tumor. This is not necessarily a sign of malignancy in a deep penetrating nevus, a blue nevus, or a congenital nevus. Occasional Spitz tumors may also show perineural invasion. FIGURE 4.4.7.

I do not believe this is a usual form of melanoma. Deep penetrating nevi, as you know, are typically benign lesions, although the experience of the full range of behavior these lesions, especially those with mitotic activity, is necessarily limited by their rarity. Some authorities might recommend consideration of a sentinel node sampling procedure for staging in lesions of this type; however, I do not believe that this is necessarily standard of care. Similarly, an additional excision procedure might be contemplated; however, this lesion is relatively widely excised, and periodic surveillance might be reasonable as an alternative.


OVERALL COMMENT


The presence of mitoses is a concerning feature, leading to a cautious interpretation. In addition, there is perineural invasion, which is not

an independent indicator of malignancy in these lesions (or in congenital nevi, blue nevi, and related lesions).

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4.5 Deep Penetrating Nevus vs. Nodular Melanoma

C L I N I C A L I N F O R M AT I O N

Compound nevus (a bit irritated), in a 69-year-old man. R E A S O N F O R C O N S U LTAT I O N

We cannot rule out a melanoma in this lesion. DESCRIPTION

The sections show a moderately cellular, predominantly dermal tumor comprised of plump spindle-shaped melanocytes, with scant cytoplasmic melanin pigment and scattered melanophages, as well as a few lympho-

FIGURE 4.5.1.

Scanning magnification of a plaquelike tumor.

cytes. The cells are placed in a somewhat sclerotic stroma. There is an ill-defined pyramidal architecture to the lesion, and the cells are arranged in nested and fascicular patterns, suggesting the possibility of a deep penetrating nevus. Another consideration would be a Spitz nevus/tumor, although, of course, these are rare in this age group. In any event, lesional cells, to my mind, exhibit significant cytologic atypia, which is relatively uniform rather than the random atypia of most characteristic deep penetrating nevi. Also the plexiform architecture is an atypical feature. Finally, at least one mitotic figure is observed in the dermal component, and there are a few Ki-67 positive cells, indicating that the lesion has proliferative capacity. In a patient of this age group and despite the lack of more characteristic features of melanoma such as an in situ component, I believe this lesion is best regarded as an unusual form of spindle cell melanoma, which I characterize as follows:

The tumor is comprised of spindle cells, arranged in nests and plexiform fascicles. There is only slight, if any, evidence of maturation from superficial to deep. FIG URES 4.5.2 A N D 3 .

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There is substantial nuclear pleomorphism and slight hyperchromatism, relatively uniform rather than confined to randomly scattered cells. At least a single mitotic figure was present, probably morphologically abnormal. FIG URE 4.5.4.

DIAGNOSIS

Skin, right abdomen: Malignant melanoma, nodular type, with spindle cell tumorigenic and mitogenic vertical growth phase, Clark level IV, Breslow thickness not less than 1.1 mm, nonulcerated, focally extending to the specimen base and margins; see previous discussion and comment.

COMMENT

The differential diagnosis for this lesion could include an atypical deep penetrating nevus; however,

FIGURE 4.5.5.

Ki-67 staining was positive in scattered

lesional cells.

as noted previously, given the proliferative activity and atypia of the dermal component, I believe this lesion is best managed as a melanoma. The tumor also has some Spitzoid features and could perhaps be regarded as a “Spitzoid melanoma,” although most of these occur in younger individuals. The dermal mitotic rate is low for melanoma at 1/mm2, and tumor-infiltrating lymphocytes are present and sparse, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites in this material, and there is no evidence of vascular, lymphatic, or neural invasion. There is no associated nevus, and actinic elastosis in the adjacent skin is absent. These would be attributes of a lesion with a very good prognosis, assuming there is no substantial residual tumor and appropriate definitive therapy is accomplished.


OVERALL COMMENT


Although deep penetrating nevi may occur at any age (unlike Spitz nevi/tumors), the likelihood of melanoma is obviously greater with increasing age. As in many of these difficult lesions, the low mitotic rate

and other prognostically favorable attributes in this lesion (except for its thickness and level of invasion) can be consistent with a good prognosis.

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4.6 Atypical Deep Penetrating Nevus vs. Nodular Melanoma

C L I N I C A L I N F O R M AT I O N

The dermatologist’s clinical description was “rule out atypical mole versus benign blue nevus versus possibly deeply pigmented seborrheic keratosis” in a lesion of the back of a 36-year-old man. R E A S O N F O R C O N S U LTAT I O N

lesion may be a form of combined deep penetrating and congenital pattern nevus. Of some concern is the presence of mitotic activity, with at least three mitotic figures observed in multiple section planes. This is an atypical feature; however, I do not believe these changes, taken together, are diagnostic of melanoma, I characterize this lesion descriptively as follows:

We believe the findings fall in the spectrum of a deep penetrating nevus. There is some nuclear atypia, but the lesion lacks mitotic activity and there does appear to be some maturation with progressive descent through the dermis. DESCRIPTION

The sections show a melanocytic tumor that is somewhat pyramidal in shape, with its base applied to the epidermis and its apex in the deep reticular dermis, measuring 2–3 mm in diameter and about the same in depth on the slide. It is comprised of epithelioid to spindle-shaped melanocytes, arranged in nests predominantly, with some tendency to confluence superficially, but with dispersion of the nests and some diminution in size of the cells as they descend into the reticular dermis at the base. Cytologically, there is enlargement, irregularity, and hyperchromatism of randomly scattered nuclei throughout the lesion, consistent with random cytologic atypia. All of these features are consistent with a diagnosis of deep penetrating nevus, including the presence of a somewhat scant junctional component above the lesion. In a few areas, there are foci of more ordinary dermal nevus cells of recurrent genital pattern type, suggesting that this

A moderately to highly cellular tumor, more or less pyramidal in shape, with its base applied to the epidermis, extends from the papillary dermis into the midreticular dermis. FIGURE 4.6.1.

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There are a few nests in the epidermis and in the dermis; however, there is no suggestion of an in situ melanoma pattern. FIG URE 4.6.2.

The lesional cells superficially are epithelioid to spindled in shape, arranged predominantly in nests, without extensive sheetlike proliferation. FIGURE 4.6.3.

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There is some diminution in size of the cells toward the base. Pigmentation is relatively uniform throughout the lesion. FIG URE 4.6.4.

Randomly scattered lesional cell nuclei are large and irregular. There is, however, no extensive uniform atypia. Scattered lesional cell mitoses were identified in multiple sections (not shown), an atypical feature of uncertain significance in deep penetrating nevi. FIGURE 4.6.5.

DIAGNOSIS

Skin, back: Melanocytic tumor of uncertain malignant potential, favor an atypical deep penetrating nevus with mitotic activity; see note.

COMMENT

As noted previously, I cannot rule out the possibility of a lesion with locally recurring and possibly metastatic ability, although I favor a diagnosis of deep penetrating nevus. These are typically benign lesions; however, the presence of mitoses adds some element

of uncertainty. I recommend an additional procedure, to be sure this lesion has been removed, with a margin of normal skin around the scar of this procedure and any residual lesion, with careful histologic checking of margins. Because this lesion is greater than 1 mm in thickness and has dermal mitotic activity, it could have metastatic capability, and the possibility of sentinel lymph node sampling might be considered; however, as noted previously, I do not believe that prognostic and management criteria applicable to ordinary melanomas are necessarily applicable to these unusual lesions.

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4.6
OVERALL COMMENT


Although this is otherwise a rather characteristic deep penetrating nevus, the presence of mitoses leads to a

cautious interpretation. This is a lesion that should be completely excised.

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4.7 Deep Penetrating Nevus vs. Cellular Blue Nevus

C L I N I C A L I N F O R M AT I O N

A 31-year-old man with a heavily pigmented lesion of the abdomen. R E A S O N F O R C O N S U LTAT I O N

Is this a deep penetrating nevus? DESCRIPTION

These sections show an unusual lesion, characterized by a moderately to focally more highly cellular proliferation of elongated, heavily pigmented spindle cells, placed among reticular dermis collagen fiber bundles, extending to the base of the biopsy specimen. Focally, there is an area of increased cellularity surrounding a skin appendage, but, in general, the cells are arranged in loosely oriented fascicles and ill-defined nests. There may be a few slightly enlarged slightly

hyperchromatic nuclei scattered about the lesion, but, in general, nuclei are relatively small and uniform. Mitotic figures are rare or absent. There is an overlying junctional component comprised of single cells and nests, mainly near the tips and sides of elongated rete ridges, with some nests bridging between adjacent rete, presenting some architectural features of melanocytic dysplasia, although cytologic atypia is minimal. Importantly, there is no evidence of in situ melanoma. The pattern of the proliferation and the cytology in this lesion are fairly characteristic of a deep penetrating nevus. An unusual feature is the more considerable breadth than is usually seen in these lesions, with an appearance of scattered foci reminiscent of satellites. However, these are likely components of the main lesion rather than true satellites. In summary, I interpret this lesion as follows:

Scanning magnification, showing three section planes of a pigmented lesion, unevenly distributed in the reticular dermis. FIG URE 4.7.1.

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There is a subtle junctional component. The cells are distributed in a plexiform fascicular pattern reminiscent of a deep penetrating nevus; however, the cytology is more reminiscent of a blue nevus.

FIG URE 4.7.2.

Low magnification images, demonstrating the scattering of spindle-shaped to dendritic heavily pigmented cells, infiltrating among reticular dermis collagen fiber bundles.

FIGURE 4.7.4.

There is a tendency to perifollicular distribution of the spindle cells. The appearances in this area are somewhat reminiscent of an unusual lesion that has been determined “pilar neurocristic hamartoma.”

FIGURE 4.7.5.

FIG URE 4.7.3.

There is an ill-defined nested pattern again, suggesting deep penetrating nevus. Mitotic figures are rare or absent, and there is no high-grade uniform cytologic atypia.

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4.7 COMMENT DIAGNOSIS

Skin, right abdomen: Deep penetrating nevus, with unusual features; see previous discussion and comment.

Unusual features in this lesion include predominantly the discontinuous foci and the considerable breadth. Changes extend to the specimen base. Although these lesions are considered to be benign, experience with them is relatively limited, and I recommend complete excision of this lesion, primarily to rule out the possibility of any additional significant pathology and also to preclude any possibility of persistence or progression of this somewhat unusual lesion.


OVERALL COMMENT


This lesion exhibits overlapping features between deep penetrating nevus and cellular blue nevus. Before the description of these lesions, most of them

were probably considered to represent variants of blue nevi or pigmented Spitz tumors or were incorrectly classified as melanomas.

SECTI O N

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4.8 Deep Penetrating Nevus vs. Nodular Melanoma

C L I N I C A L I N F O R M AT I O N

Biopsy and re-excision of a deeply pigmented lesion of the right knee in a 53-year-old man. R E A S O N F O R C O N S U LTAT I O N

Favoring a deep penetrating nevus, but cytologic atypia is of concern. DESCRIPTION

The sections show, in the biopsy specimen, a lesion comprised of plump spindled to epithelioid cells arranged in fascicles, extending from near the epidermis into the mid-reticular dermis. The cellularity is relatively low, with only some tendency to confluence of nests, and, cytologically, there is atypia, which, however, is randomly confined to a minority of the lesional cells. There is little or no evidence of maturation from superficial to deep; however, this is ordinarily not a prominent feature in deep penetrating nevi. Scrutiny of multiple section planes on the two slides reveals no mitoses. Changes extend to the specimen base, and therefore I agree with the recommendation for complete excision. In summary, I interpret this material as follows. Sections of the re-excision specimen show a biopsy site reaction and extensive residual lesion similar to that previously described, but extending into the subcutis and present in multiple foci. The architecture of the lesion is therefore not the usual pyramidal shape, with the base of the pyramid applied to the epidermis and the apex in the dermis. However,

the cytologic appearances are similar to those in the biopsy, and, again, mitotic figures are rare or absent. Based on these findings one might include the differential diagnosis of a cellular blue nevus; however, as before, the architecture and cytologic features are most consistent with a deep penetrating nevus. These are difficult lesions to interpret definitively because experience with them is relatively limited. The deeper component of this lesion represented in the re-excision demonstrates somewhat greater cytologic atypia than was evident in the biopsy, and I therefore qualify this lesion as follows:

Scanning magnification shows a tumor that tends to be wider near the surface than near its base in the mid-reticular dermis. FIGURE 4.8.1.

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The tumor is transected at the base of the biopsy, however, so that the full silhouette of the lesion cannot be evaluated for symmetry and pattern of infiltration at the base. FIG URE 4.8.2.

The lesion is comprised of relatively large epithelioid to somewhat spindled cells, arranged in illdefined nests and fascicles, infiltrating among reticular dermis collagen fiber bundles. FIGURE 4.8.3.

A re-excision was recommended and performed. There is residual tumor deep to the scar, rather asymmetrically distributed, with a suggestion of satellites, and extending into the subcutis. FIGURE 4.8.5.

The tumor cells contain pigment, and there is nuclear enlargement, irregularity, and hyperchromatism of randomly scattered cells. FIG URE 4.8.4.

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The residual tumor at the base is comprised of cells similar to those in the biopsy. FIG URE 4.8.6.

DIAGNOSIS

Skin, left knee, shave biopsy: Spindle cell mela-

There is no evidence of maturation from superficial to deep, but this is not expected in these lesions. Random atypia, as seen here, is also an expected feature. In this case the atypia tends to become more uniform, and the nests tend to become confluent, both concerning features. The complete lack of mitoses in this lesion is a strongly reassuring feature. FIGURE 4.8.7.

nocytic tumor consistent with deep penetrating nevus, transected at the specimen base. Skin, left knee, re-excision: Biopsy site reaction, and extensive residual atypical spindle cell proliferation, consistent with an atypical deep penetrating nevus; see previous discussion and comment.

COMMENT

Despite the focally severe uniform atypia, as is seen especially in the re-excision specimen, in the absence

of greater degrees of hypercellularity, or mitotic activity, or necrosis or ulceration, I do not believe this lesion can be characterized as a malignancy. It is quite reassuring that this lesion appears to have no mitoses at all. However, as already noted, experience with deep penetrating nevi is somewhat limited, especially with atypical lesions. The lesion appears to be completely excised, with a border less than 1 mm at the base in the subcutis, and one might consider an additional procedure, to be completely certain that it has been removed, or perhaps careful follow-up of the lesional site.


OVERALL COMMENT


Although a few mitoses may be acceptable in deep penetrating nevi, the majority of them have no mitoses at all, and, in my opinion, based on a few anecdotal cases, the presence of any mitoses is a concerning feature. I

have seen a few lesions otherwise consistent with deep penetrating nevi in which separate satellite lesions are present as in this case, which do not appear to have been associated with aggressive behavior to date.

C ASE

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4.9 Deep Penetrating Nevus vs. Nodular Melanoma

C L I N I C A L I N F O R M AT I O N

Lesion of the back of a 52-year-old woman. R E A S O N F O R C O N S U LTAT I O N

We are favoring a Spitz nevus but cannot rule out a melanoma. DESCRIPTION

These sections show an excision of skin containing a cellular nodule comprised of spindle-shaped melanocytes, which are arranged predominantly in nests, extending from near the epidermis into the midreticular dermis. A few slightly enlarged melanocytes may be present in the overlying epidermis, but there

is no evidence of any in situ component of a melanoma. The cells are arranged in nests that tend to be relatively uniform in size, with some slight tendency to confluence but without diffuse sheetlike proliferation. Some of them show a tendency to spindle cell or sustentacular cell differentiation at the periphery, although this is not prominent. Cytologically, there are randomly scattered large, hyperchromatic, and somewhat irregular nuclei; however, this atypia is random rather than uniform. Of note, scattered mitoses are present, including one at least near the base of the lesion. A Ki-67 study demonstrates scattered positive cells. The maximal rate in any one high-power field is less than 5%. Taken together, I believe that

Low magnification shows a fairly broad and deep pigmented melanocytic tumor extending from near the epidermis into the upper third of the reticular dermis. FIG URE 4.9.1.

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4.9 these findings are fairly consistent with the lesion that has been described as deep penetrating nevus. Although the presence of mitoses in these lesions was acknowledged in the first reports, most of them have

no mitoses at all, and the presence of mitotic activity, in my opinion, renders the behavior of these lesions to some extent uncertain. I therefore interpret this lesion descriptively as follows:

Although the tumor is quite highly cellular, the lesional cells are predominantly nested rather than arranged in confluent sheets. FIG URES 4.9.2 A ND 3 .

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4.9

FIG URE 4.9.4.

There is little or no evidence of maturation to the base of the tumor.

FIGURE 4.9.5.

High magnification showing random cytologic atypia of a minority of the lesion cells. A few spindle cells at the periphery of some of the lobules (arrows) have been likened to sustentacular cells of peripheral nerve end organs.

FIGURE 4.9.7.

FIG URE 4.9.6.

There is a relatively inconspicuous junctional component.

Melan-A staining demonstrates relatively low density of the dermal component, without sheetlike proliferation.

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4.9 COMMENT

Only a few Ki-67 positive lesional cells are present in the dermal component. However, at least one dermal mitosis was identified (not shown). FIG URE 4.9.8.

DIAGNOSIS

Skin, right flank: Melanocytic tumor of uncertain potential, favor an atypical deep penetrating nevus; see previous discussion and comment.

I do not believe that prognostic criteria and management strategies developed for routine melanomas should be applied uncritically to lesions of this type. The behavior of deep penetrating nevi with rare mitoses is usually benign; however, a few lesions with features otherwise compatible with deep penetrating nevi, but with mitoses, have anecdotally been found to have competence for metastasis. In these unusual lesions, sometimes metastasis is confined to regional lymph nodes, with subsequent benign follow-up. This present lesion is completely excised, with borders of greater than 2 mm in the section planes available for study. Although one might consider the possibility of a sentinel node procedure, I do not believe that this is necessarily a standard of care for unusual lesions of this type, although it could be considered as an option if desired. As mentioned previously, positive sentinel nodes have been followed by prolonged survivals in at least some of these or related unusual lesions.


OVERALL COMMENT


As noted previously and in other cases, the presence of any mitotic figures is of concern in these lesions, especially if they are in the lower third of the lesion

and especially if they are associated with other atypical features, such as confluent proliferation, and in older individuals.

5 Blue Nevi and Variants: Cellular Blue Nevus, Atypical Cellular Blue Nevus, and Malignant Blue Nevus

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lue nevi (BN) are relatively common and familiar; however, the cellular and atypical variants create problems because they are not commonly seen, and they may present as bulky tumors that simulate high-risk melanomas. The term “blue nevus” is derived from the clinical appearance of the lesions. Blue nevi differ from common nevi in that they typically retain pigment in their cytoplasm throughout the full depth of the lesion, which extends well into the reticular dermis. In addition, blue nevi typically lack a junctional component. Light transmitted from the pigment through the dermis is subject to the so-called Tyndall effect, which results in preferential passage of blue light. Therefore, just as red blood in veins appears blue on inspection from the surface, so does brown pigment in melanocytes in the dermis. Blue nevi can be divided into at least four major categories, namely common blue nevi, cellular blue nevi (CBN), epithelioid blue nevi, and malignant blue nevi (MBN) (1–3). The commonest lesions are small blue macules or papules, which may be termed “common” or “banal” blue nevi. Histologically, these are comprised of narrow, elongated spindle cells that contain relatively abundant melanin pigment, usually insufficient to obscure the nucleus completely. They are arranged in a relatively sparse distribution of fascicles, placed among reticular dermis collagen fiber bundles, which are sometimes thickened. There may be some nuclear variability, but there is no highgrade atypia, and there are no mitoses. There may be a sprinkling of lymphocytes, but usually these are

absent. Like most blue nevi, banal blue nevi lack a junctional component. A second category of blue nevi is termed “cellular blue nevi” (4;5). These lesions characteristically have a component of a banal blue nevus, often at the periphery. In the center of the lesion, the cell density is much greater. The cells tend to be arranged in two major patterns. One of these is a pattern of ill-defined nests of cells with relatively clear cytoplasm, which is often separated by a second pattern of relatively densely packed, more heavily pigmented spindle cells. This mixed pattern is known as the “mixed-biphasic” pattern of cellular blue nevi. Other subtypes described include alveolar, fascicular, or neuronevoid and atypical varieties (5). Architecturally, a common feature of cellular blue nevi is a bulbous expansion of the lesion in the panniculus at its base. This sometimes gives rise to a “dumbbell” silhouette at scanning magnification. Like the vast majority of banal blue nevi, most cellular blue nevi lack mitotic activity and lack high-grade nuclear atypia. Their nuclei are commonly somewhat larger than those of most banal blue nevi. A rare variant with features of common and cellular blue nevus is the “plaque-type” blue nevus. In a few case reports, these have been described as characterized by slow enlargement, sometimes with nodule formation, forming lesions that may become many centimeters in diameter. Histologically, the appearances may range from those of dermal melanocytosis to common or cellular blue nevus (6). Cellular blue nevi, including plaque-type blue nevi, may be regarded as precursors of malignancy (“malignant blue nevi”) (7–9).

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The “epithelioid blue nevus” is a lesion that may have features intermediate between those of cellular blue nevi and malignant blue nevi. In previous studies, epithelioid blue nevi may have been characterized as “fascicular” or “monophasic” variants of cellular blue nevi. These lesions were described in detail by Carney as an association of the Carney complex (myxomas, spotty skin pigmentation, endocrine overactivity, and schwannomas) (3). The lesions are heavily pigmented, poorly circumscribed, dermal lesions comprised of two types of melanocytes: one intensely pigmented, globular, and fusiform (i.e., epithelioid); the other lightly pigmented, polygonal, and spindled (3). Follow-up studies have shown no evidence of malignant behavior in association with epithelioid blue nevi in the context of the Carney syndrome. However, lesions considered to be morphologically identical to epithelioid blue nevi, outside of the syndrome, may have locally recurrent or metastatic potential and have been termed “pigmented epithelioid melanocytomas,” which are regarded as neoplasms of uncertain malignant potential (10). A close relationship between these two lesions is also indicated by the finding of loss of expression of protein kinase A regulatory subunit one alpha in both of them, but not in melanoma or other melanocytic lesions (11). The fourth major category of blue nevi is malignant blue nevi. This, of course, is a contradiction in terms, because ordinarily nevi are benign lesions, and some have argued that these lesions should simply be termed “malignant melanoma” (12). These malignant lesions, however, can often clearly be recognized to have arisen out of a lineage of banal and cellular blue nevus. In addition, there is some evidence that these lesions differ genomically from ordinary melanomas (11;13). A typical presentation is of a focal area of high-grade cellular atypia, often with necrosis and always with mitotic activity, placed within a background lesion that has architectural and cytologic

VARIANTS

features of cellular blue nevus and, often, banal blue nevus (5;14–16). Although these distinctions are often simple to make, there are many examples of lesions that have overlapping features. There are many lesions that otherwise have features of a banal blue nevus that also exhibit areas of slightly increased cellularity. There are few if any negative consequences of “overcalling” a banal blue nevus as a cellular blue nevus, except perhaps that the latter category of lesions could trigger a recommendation for complete excision, which is not necessary for a banal blue nevus. There are lesions termed “atypical cellular blue nevi” (ACBN), which may be characterized by increased cellularity, increased cytologic atypia, or the finding of a few mitoses (5;17). A category of “ancient” blue nevi has been described as having stromal and cellular changes, such as those seen in ancient melanocytic nevi, including large, dilated vessels with pseudoangiomatous features, hyaline angiopathy, myxoid changes, sclerosis or hyalinization of the stroma, variable amounts of edema, and pleomorphic melanocytes, the latter especially a feature that might lead to misdiagnosis as melanoma (18). Series of atypical cellular blue nevi reported in the literature have not been associated with metastasis. However, cases of the much less common malignant blue nevi may have features that could overlap with the diagnosis of atypical cellular blue nevi. Although malignant blue nevi are defined in terms of high-grade cellular atypia, tumor necrosis, and frequent mitoses, there are lesions that lack one or more of these attributes that have metastasized in follow-up, sometimes with fatal results. A recent study has demonstrated that there is “substantial confusion and disagreement” among experienced histopathologists about the definition and significance of cellular blue melanocytic neoplasms (19). Because of this uncertainty, it is often appropriate, in my opinion, when faced with a lesion

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that has attributes of a cellular blue nevus but with increased cellularity, a few mitoses, or possibly a focal area of tumor necrosis or ulceration, to issue a descriptive diagnosis, such as “melanocytic tumor of uncertain malignant potential” (MELTUMP) (20). In such a case, one would describe the lesion and usually be able to indicate whether a benign or malignant diagnosis is favored. However, there are some particularly difficult cases where such an indication is difficult or impossible to make. In any event, management considerations include complete local excision and a discussion of sentinel node sampling. These atypical lesions are tumorigenic and usually mitogenic, so they could have potential competence for metastasis.

References 1 Gonzalez-Campora R, Galera-Davidson H, Vazquez-Ramirez FJ, az-Cano S. Blue nevus: classical types and new related entities. A differential diagnostic review. Pathol Res Pract 1994 Jun;190(6):627–35. 2 Zembowicz A, Mihm MC. Dermal dendritic melanocytic proliferations: an update. Histopathology 2004 Nov;45(5):433–51. 3 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 Mar;20(3):259–72. 4 Rodriguez HA, Ackerman LV. Cellular blue nevus. Clinicopathologic study of forty-five cases. Cancer 1968 Mar;21(3):393–405. 5 Temple-Camp CR, Saxe N, King H. Benign and malignant cellular blue nevus. A clinicopathological study of 30 cases. Am J Dermatopathol 1988 Aug;10(4):289–96. 6 Busam KJ, Woodruff JM, Erlandson RA, Brady MS. Large plaque-type blue nevus with subcutaneous cellular nodules. Am J Surg Pathol 2000 Jan;24(1):92–9. 7 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 Oct;20(5):459–64. 8 Calista D, Schianchi S, Landi C. Malignant blue nevus of the scalp. Int J Dermatol 1998 Feb;37(2):126–7. 9 Ergun SS, Buyukbabany N, Kurul S, Ulay M, Kural YB. Malignant transformation in a cellular blue nevus of long duration. Eur J Dermatol 2001 Apr;11(3):265–7.

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10 Zembowicz A, Carney JA, Mihm MC. Pigmented epithelioid melanocytoma: a low-grade melanocytic tumor with metastatic potential indistinguishable from animal-type melanoma and epithelioid blue nevus. Am J Surg Pathol 2004 Jan;28(1):31–40. 11 Zembowicz A, Knoepp SM, Bei T, Stergiopoulos S, Eng C, Mihm MC, Stratakis CA. Loss of expression of protein kinase a regulatory subunit 1alpha in pigmented epithelioid melanocytoma but not in melanoma or other melanocytic lesions. Am J Surg Pathol 2007 Nov;31(11):1764–75. 12 Mones JM, Ackerman AB. “Atypical” blue nevus, “malignant” blue nevus, and “metastasizing” blue nevus: a critique in historical perspective of three concepts flawed fatally. Am J Dermatopathol 2004 Oct;26(5):407–30. 13 Maize JC Jr., McCalmont TH, Carlson JA, Busam KJ, Kutzner H, Bastian BC. Genomic analysis of blue nevi and related dermal melanocytic proliferations. Am J Surg Pathol 2005 Sep;29(9):1214–20. 14 Mehregan DA, Gibson LE, Mehregan AH. Malignant blue nevus: a report of eight cases. J Dermatol Sci 1992 Nov;4(3):185–92. 15 Aloi F, Pich A, Pippione M. Malignant cellular blue nevus: a clinicopathological study of 6 cases. Dermatology 1996;192(1):36–40. 16 Granter SR, McKee PH, Calonje E, Mihm MC, Busam K. Melanoma associated with blue nevus and melanoma mimicking cellular blue nevus: a clinicopathologic study of 10 cases on the spectrum of so-called ‘malignant blue nevus.’ Am J Surg Pathol 2001 Mar;25(3):316–23. 17 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 May;25(5):252–8. 18 Cerroni L, Borroni RG, Massone C, Kerl H. “Ancient” blue nevi (cellular blue nevi with degenerative stromal changes). Am J Dermatopathol 2008 Feb;30(1):1–5. 19 Barnhill RL, Argenyi Z, Berwick M, Duray PH, Erickson L, Guitart J, Horenstein MG, Lowe L, Messina J, Paine S, Piepkorn MW, Prieto V, Rabkin MS, Schmidt B, Selim A, Shea CR, Trotter MJ. Atypical cellular blue nevi (cellular blue nevi with atypical features): lack of consensus for diagnosis and distinction from cellular blue nevi and malignant melanoma (“malignant blue nevus”). Am J Surg Pathol 2008 Jan;32(1):36–44. 20 Elder DE, Xu X. The approach to the patient with a difficult melanocytic lesion. Pathology 2004 Oct;36(5):428–34.

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5.1 Atypical Cellular Blue Nevus vs. Malignant Blue Nevus

C L I N I C A L I N F O R M AT I O N

A pigmented lesion on the right dorsal wrist of a 50-year-old female. There was no clinical description or clinical diagnosis offered by the surgeon. R E A S O N F O R C O N S U LTAT I O N

At first glance, the histologic features appear to represent a cellular blue nevus. We are concerned about the cytologic atypia, and, in some areas, the cells are forming sheets. In addition, a single mitosis is present near the center of the lesion. Should we be concerned about a type of melanoma or a malignant blue nevus? DESCRIPTION

The sections show an excision of a cellular tumor in skin, comprised of nevoid to epithelioid melanocytes,

arranged in sheets and ill-defined nests and fascicles, and infiltrating from near the epidermis into the subcutis and focally transected at the base. As you note, there is an occasional mitotic figure; however, overall the mitotic rate is very low indeed. There is no spontaneous tumor necrosis or ulceration. There is no overlying in situ component of a characteristic form of melanoma. At the periphery of the lesion, there are pigmented spindle cells infiltrating among reticular dermis collagen fibers, which, taken in isolation, would certainly be consistent with a blue nevus, supporting the diagnosis of a cellular blue nevus. The lesion does not have compelling indicators of malignancy, such as anaplastic nuclear atypia, necrosis, or numerous mitoses. However, it is rather cellular, and this feature,

Scanning magnification of sections of skin containing a bulky tumor spanning the reticular dermis and entering the subcutis. The tumor seems to expand as it enters the fat, giving the lesion a somewhat “dumbbell configuration.” FIGURE 5.1.1.

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5.1 together with the rare mitotic activity, leads me to have some concern about its biological potential. This lesion may therefore be put into the category of “atypical cellular blue nevus,” which is essentially a benign diagnosis or, preferably in my view, into the descriptive

category of a melanocytic tumor of uncertain malignant potential, because it appears to be the case that not all lesions behaving as malignant blue nevi demonstrate all of the characteristics prospectively. I therefore diagnosis this lesion descriptively as follows:

FIG URE 5.1.2.

The lesion is separated from the epidermis by a “grenz” or clear zone.

FIGURE 5.1.3.

Adjacent to the tumor, there is a proliferation of pigmented spindle cells, placed among reticular dermis collagen fiber bundles, indistinguishable from a banal blue nevus. The lesion is quite cellular, with sheetlike proliferation in several areas, including where it honeycombs the fat.

FIGURE 5.1. 5.

FIG URE 5.1.4.

The lesional cells infiltrate and honeycomb the fat at the base of the tumor.

There is variable but sometimes quite dense pigment. The tumor surrounds peripheral nerves, not necessarily an indicator of malignancy in a lesion of this type.

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5.1 DIAGNOSIS

Skin, right dorsal wrist: Melanocytic tumor of uncertain malignant potential, most consistent with an atypical cellular blue nevus; see previous discussion and comment.

COMMENT

As discussed previously, the atypical features include increased cellularity and mitotic activity. The lesion

also involves specimen margins. I consider a lesion of this type to have at least locally recurring potential and cannot entirely rule out the possibility of missed at metastatic capability. I recommend a definitive excision procedure, to be sure this lesion has been completely removed, with a margin of normal skin and subcutaneous tissue around the scar of this procedure and any residual lesion, and I recommend consideration of follow-up for this patient. A sentinel lymph node sampling procedure might also be considered, as a staging procedure primarily; however, I do not believe this is necessarily the standard of care for lesions of this type.


OVERALL COMMENT


Although most cellular blue nevi with a few mitoses have a benign course, unfortunately, it does not seem to be possible to rule out entirely the possibil-

ity of a lesion with metastatic potential in a few of these lesions. In general, they should be completely excised.

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5.2 Cellular Blue Nevus vs. Malignant Blue Nevus

C L I N I C A L I N F O R M AT I O N

The patient is a 69-year-old woman who presented with what grossly appeared to be blue nevi of the forehead and scalp. She has a history of three prior pigmented lesions read as blue nevi. Our specimen from the forehead is adjacent to these lesions; the scalp lesions are new. Another lesion appears to be developing adjacent to a scar from the eyelid. R E A S O N F O R C O N S U LTAT I O N

There is minimal mitotic activity, but the nuclei tend to be disturbingly dysplastic. Our chief concern is

whether one or both of these lesions represent metastatic melanoma. DESCRIPTION

The present material consists of two separate biopsies, with one including two separate, but perhaps contiguous, nodules of tumor. The other contains only a single deposit. All of the tumors are quite similar to one another, consisting of a population of plump spindle-shaped and rounder epithelioid melanocytes, forming tumor nodules that span the thickness of the reticular dermis to extend into the subcutaneous fat.

Scanning and low-power images of a moderately to highly cellular, somewhat asymmetrical tumor extending from near the epidermis into the subcutis. At the periphery of the lesion, there are changes consistent with a banal blue nevus, characterized by narrow, pigmented, spindle cells placed among reticular dermis collagen bundles. FIGURE 5.2.1.

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5.2 There is moderate melanin pigment, which, in some cases, fills the cytoplasm of the cells and is arranged in relatively coarse melanin pigment granules, outlining a dendritic cytoplasm. The tumors tend to lie in the reticular dermis and subcutis, in general sparing the papillary dermis and the overlying epidermis. The lesional cells are relatively large, some with prominent nucleoli, and mitotic figures are readily detected. One of the nodules focally shows a higher mitotic rate, with 1–3 mitoses per high-power field in a focal area. There is focal evidence of high-grade uniform cytologic atypia, but there is no spontaneous lesional cell necrosis. The combination of dendritic spindle cells with heavy pigment and epithelioid cells, coupled with the morphology of some of the lesions, which suggests a secondary “dumbbell” expansion of tumor in the subcutaneous tissue, suggests that these lesions are best placed in the category of blue nevi. The differential diagnosis lies between cellular and malignant blue nevi. The presence of high-grade uniform atypia and a focally high mitotic rate places these lesions at least in the category of atypical cellular blue nevi. However,

the history of persistence and recurrence of lesions at this site suggests further the lesion should be qualified as having uncertain malignant potential. This means that I cannot rule out the possibility of continuing locally aggressive behavior or even of metastasis, although I consider the latter property unlikely. I expect the prognosis for these lesions to be much better than one would consider for the alternative possibilities of metastatic melanoma or usual melanoma with the same thickness of approximately 3 mm. If the more mitotically active lesion were interpreted as a melanoma, other microstaging attributes would include intermediate mitotic rate, essentially absent tumor-infiltrating lymphocytes, and no evidence of radial growth phase regression, ulceration, satellites, or lymphatic or neural invasion. The possibility that these lesions might represent metastasis from another site has also been considered, but I do not consider this likely because of the complexity of lesions, which

In a focal area, the cellularity is greater, and there is substantial although moderate atypia in the form of nuclear enlargement and prominent nucleoli, without marked hyperchromatism or pleomorphism. Mitotic figures were rare or absent in this region. In summary, this lesion may be interpreted as an atypical cellular blue nevus, and, given the lack of mitotic activity, this lesion taken in isolation would not, in my opinion, be likely to be associated with competence for metastasis. FIGURE 5.2.3.

At intermediate magnification, the lesion is seen to be comprised of spindle-shaped cells, some pigmented and some nonpigmented, arranged in a fascicular and somewhat nested pattern, infiltrating the fat at the base of the lesion.

FIGURE 5.2.2.

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5.2 include some areas of lower cellularity consistent with blue nevus rather than the relative monotony that characterizes most metastases. In summary, I interpret this material in the following manner:

Scanning and low-power images of another biopsy containing two foci of highly cellular proliferation of melanocytes in the dermis. There is a narrow zone of separation between the two lesions; however, the dermis in this area appears scarred, and there is a history of prior procedures, so that it is possible that the two foci represent recurrences of a single tumor. FIG URE 5.2.4.

At the periphery of one of the lesions, there is a region of involvement of the reticular dermis by smaller more pigmented cells, more sparsely distributed among reticular dermis collagen fiber bundles, consistent with a banal blue nevus component. FIGURE 5.2.6.

The tumor is comprised of fascicles, with some sheets, and ill-defined nests, infiltrating from near the epidermis into the subcutis, with a suggestion of a bulbous expansion in the latter area (“dumbbell lesion”). There is also a suggestion of a rather ill-defined “nested and biphasic” pattern, fairly characteristic of a cellular blue nevus. At the base of the lesion in the region of bulbous expansion, there is a small satellite of tumor extending into the fat beyond the main tumor. FIG URE 5.2.5.

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5.2

These fields, at intermediate and higher magnification, show rather more severe cytologic atypia than was apparent in the first specimen, characterized by greater nuclear enlargement, pleomorphism, and hyperchromatism, again with prominent nucleoli. FIG URE 5.2.7.

Green circles in the scanning power fields (seen in Web figures) demonstrate the locations of two mitotic figures selected for illustration. In at least one high-power field, not shown, there were two mitotic figures present. Coupled with severe nuclear pleomorphism, this finding is concerning for a malignant blue nevus. However, there is no tumor necrosis or ulceration or “anaplastic” cytologic atypia. FIGURE 5.2.8.

DIAGNOSIS

Skin, left side of forehead and scalp (three lesions): Dermal melanocytic tumors of uncertain malignant potential, most consistent with atypical cellular blue nevi; see previous discussion and following comment.

COMMENT

The appearances previously described (including a review of prior material) are those of multiple cellular

and more banal blue nevi, all occurring within a localized region over a 15-year period. The first two of these lesions apparently represent an original lesion and a persistence at the lesional site. The later two lesions appear to be at noncontiguous but nearby sites. It is possible that these appearances are representative of some kind of localized “field effect,” in which, for some unknown reason, multiple independent primary lesions are arising in a localized area. However, the possibility that these lesions represent some kind of localized persistence and recurrence of a single

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5.2 neoplasm cannot be ruled out from this material. The present material is more cellular, with greater cellular atypia and mitotic activity, than any of the previous lesions. Changes extend close to specimen borders. As discussed with the surgeon, additional procedures

may be indicated at the local site, to reduce the likelihood of persistence and recurrence in the future. Prior to any such extensive local surgery, any additional lesions present should be evaluated histologically, and a metastatic workup should be done.


OVERALL COMMENT


As noted previously, the combination of cellular atypia and mitotic activity, although not perhaps diagnostic of a malignant blue nevus, are concerning, especially

given the history of persistence and/or recurrence at the site over more than a decade.

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5.3 Atypical Cellular Blue Nevus vs. Malignant Blue Nevus

growth pattern and numerous mitotic figures are atypical.

C L I N I C A L I N F O R M AT I O N

Lesion of the left thigh in an 8-year-old girl. R E A S O N F O R C O N S U LTAT I O N

DESCRIPTION

Sections show confluent dermal nests of large, moderately pigmented melanocytes, with scattered melanophages, and little intervening collagen. Frequent mitoses are observed. Although there are features of deep penetrating nevus, the confluent

The previously captioned material presents consider able difficulties of interpretation, particularly in view of the age of the patient. The sections show a wedgeshaped lesion with its apex in the mid to deep reticular dermis, extending up to the epidermis, but without

Low magnification of a fairly bulky, highly cellular tumor, comprised of pigmented melanocytes, extending from near the epidermis into the deep reticular dermis and subcutis to the base of the biopsy. Note the suggestion of a bulbous expansion as the lesion meets the fat. At the base, the tumor cells infiltrate adnexal structures. FIG URE 5.3.1.

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5.3 much evidence of involvement of the epidermis. Epidermal involvement, of course, is fairly characteristic of deep penetrating nevi. The lesional cells are arranged in ill-defined and somewhat confluent nests and sheets, with a fascicular and somewhat Schwannian arrangement in some areas. They show little or no evidence of change or maturation from superficial to deep. Cytologically, the lesional cells tend to have quite large nuclei, with prominent nucleoli in many cells. The atypia is somewhat more uniform than the random atypia (which may be quite severe in individual cells) that is more characteristic of the usual deep penetrating nevus. As you note, mitotic figures are easily detected in the lesion, and, overall, the mitotic rate is intermediate at 4/mm², with an occasional field containing two mitoses in one high-power field. Mitotic figures were described as very rare and usually absent in the original descriptions of deep penetrating nevi, and I regard them as a finding to be treated with great caution, especially in these numbers.

Lesion does not involve the overlying epidermis. There is no evidence of maturation from superficial to deep. The lesional cells are arranged in sheets, with a tendency to a fascicular or plexiform pattern, reminiscent of either deep penetrating nevus or blue nevus. The lesion has an infiltrative pattern into the reticular dermis at the base of the tumor.

An alternative diagnostic consideration for this lesion is that of a cellular blue nevus. There is no background banal blue nevus in this case, which would constitute the best evidence for a blue nevus lesion. If this is a blue nevus, it would be classified in the “monophasic spindle cell” pattern of cellular blue nevi rather than the more usual “mixed biphasic” type. As you know, occasional cellular blue nevi have metastasized to regional lymph nodes, apparently often—though certainly not always—without more distant spread. The age of this patient and the presence of spindle cells in this lesion might bring up the possibility of a Spitz nevus, but I do not believe this

FIG URE 5.3.2.

To the side of the tumor, there are smaller spindle cells infiltrating the reticular dermis. It is not clear whether this represents an associated banal blue nevus compound or simply attenuation of the lesional cells at the periphery of the lesion. FIGURE 5.3.3.

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5.3 lesion fits well into that category. Nevertheless, atypical and malignant Spitz nevi have also been described that had metastasized, in both adults and children. For all of these reasons, I cannot place this lesion in a completely benign diagnostic category. However, it certainly does not fit well into the usual forms of melanoma. In the absence of necrosis, this

There is a tendency to a nested pattern, with intervening spindle cells, akin to the “nested-biphasic” pattern characteristic of cellular blue nevus. A mitotic figure is present near the top of the field (white arrow). FIG URE 5.3.4.

lesion also lacks at least one of the major criteria for malignant blue nevi, although the uniform atypia and mitotic activity might suggest this possibility. Because all of these considerations are difficult to resolve with any certainty, especially in a child of this age, I refrain from making a specific diagnosis but interpret this lesion descriptively as follows:

Two mitotic figures present in the same highpower field. Circles in the Web figure show the location. FIGURE 5.3.5.

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5.3 COMMENT

FIG URE 5.3.6.

Perineural invasion is present within the

tumor.

As noted previously, I am quite concerned that this lesion might have some form of locally aggressive or regional even regionally metastatic potential, and I cannot rule out the possibility of distant metastasis either. I tend to place this lesion most likely in the category of atypical cellular blue nevus versus malignant blue nevus. I recommend managing this lesion with a definitive excision procedure, which should encompass a margin of normal skin around the scar, to rule out additional pathology and ensure the complete removal of this lesion from its site. Based on the uncertain potential of this lesion, the possibility of a sentinel node staging procedure could be discussed with the patient and her family. A negative finding would be of some reassurance, but a positive finding would not necessarily indicate any additional therapy, except for a consideration of a clearance of the remaining nodes. Obviously, I also recommend continuing follow-up for this child. Thank you for the opportunity of reviewing this highly problematic, most unusual material.

DIAGNOSIS

Skin, right leg (thigh): Melanocytic tumor of uncertain malignant potential; see previous discussion and comment.


OVERALL COMMENT


This lesion has overlapping features among the categories of deep penetrating nevus, pigmented Spitz nevus, cellular and malignant blue nevus. The mitotic

activity, cellularity, and atypia raise concern for the possibility of a lesion with metastatic potential.

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5.4 Atypical Cellular Blue Nevus vs. Malignant Blue Nevus

C L I N I C A L I N F O R M AT I O N

A pigmented tumor on the scalp of a 72-year-old man. R E A S O N F O R C O N S U LTAT I O N

We are concerned about the possibility of a malignant blue nevus. DESCRIPTION

and irregularity and some hyperchromatism of lesional cell nuclei. Dermal mitotic figures are identified rather readily; however, the mitotic rate is less than 1/mm2. There is no spontaneous tumor necrosis and no ulceration. Taken together, I consider this to be an atypical melanocytic tumor with features of a deep penetrating nevus; however, there are overlapping and perhaps conflicting criteria, and one might

These sections show an excision of a lesion on the scalp, characterized by a moderately to highly cellular proliferation of plump, spindle-shaped melanocytes, and arranged in ill-defined and nests that tend to become confluent, extending from a broad base near the epidermis to an apex in the deep reticular dermis, with extension focally into the subcutis. Cytologically, there is relatively uniform enlargement

Scanning magnification shows a cellular, moderately pigmented tumor extending from near the epidermis into the subcutaneous tissue. There is no ulcer, and there is no tumor necrosis. FIGURE 5.4.2.

Multiple, blue-black dermal nodules that have slowly increased in number and tendency to confluence over many years (courtesy of Frederick Aronson, MD). FIG URE 5.4.1.

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5.4 also consider epithelioid blue nevus/pigmented epithelioid melanocytoma and unusual forms of cellular blue nevi and related lesions. However, the more confluent rather than predominantly nested growth, the more uniform rather than random atypia, and the deep extension of a very poorly circumscribed base

are features of some concern. In addition, it is not clear whether this is a biopsy that contains essentially the entire lesion or perhaps a biopsy of a larger lesion that could raise the possibility of a plaque-type blue nevus. I therefore interpret this lesion descriptively as follows:

The lesion is, in general, separated from the epidermis by a narrow “grenz” or free zone. It is comprised of plump spindle cells, arranged in fascicles and sheets.

FIGURE 5.4.4.

FIGURE 5.4.3.

The tumor infiltrates into the subcutaneous tissue at the base. Comparison of tumor cells at the surface (Figure 3) and at the base reveals some tendency to diminution of size and dispersion of single cells at the base of the tumor. Superficially, the nuclei are relatively large, but without marked nuclear irregularity or hyperchromatism. FIGURE 5.4.6.

The tumor surrounds nerves but does not clearly infiltrate them. FIG URE 5.4.5.

An apparent mitotic figure, detected with

difficulty.

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5.4 DIAGNOSIS

Skin, scalp: Melanocytic tumor of uncertain malignant potential; see previous discussion and comment.

procedure is necessarily the standard of care for lesions of this type. One’s interpretation of this lesion might be influenced by whether there had been any history of growth or change or, conversely, any history of longstanding stability. I am most interested in any additional history that may become available. ADDED COMMENT

COMMENT

( T H R E E W E E K S L AT E R )

Although, to some extent, I favor a diagnosis of deep penetrating nevus, I cannot rule out the possibility of a lesion with at least locally recurring potential. Although I do not believe that microstaging attributes applicable to ordinary forms of melanoma apply to these unusual lesions, if interpreted as a melanoma, this lesion would extend to Clark level V and a greatest thickness of approximately 2.7 mm. The dermal mitotic rate is low at 1/mm2, tumor-infiltrating lymphocytes are patchy and overall sparse, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular or lymphatic invasion. Focal neural invasion is present, however. Whether this is interpreted as an atypical deep penetrating nevus, an unusual plaque-type blue nevus, a cellular blue nevus, an epithelioid blue nevus, or a pigmented epithelioid melanocytoma, or an unusual form of pigment-synthesizing melanoma, I believe that it may have at least locally persisting and recurring potential and recommend an additional procedure, to be sure this lesion has been completely removed. Consideration of a sentinel node sampling procedure might also be appropriate. However, I do not believe that this

Dr. Frederick Aronson has kindly called with additional history and supplied clinical photographs of this patient’s lesion. He has been followed for multiple pigmented scalp lesions for many years without definite malignant behavior. Previous biopsies have been done, and, in one instance, the lesion was interpreted as melanoma; on other occasions, blue nevus or atypical blue nevus has been the diagnosis. It is not possible to encompass all of the disease in a surgical resection to render him free of the lesion. This present biopsy was done because of an area that seemed a bit more nodular. In the absence of more definitive evidence of melanoma, I agree that resection does not appear appropriate at this time, and the most appropriate diagnosis is melanocytic tumor of uncertain malignant potential, clinically and histologically consistent with a low-grade, but likely at least locally, progressive lesion. The lesion has some features in common with plaque-type blue nevus, except that it is present in the form of multiple nodules rather than a single plaque-nodule. Of interest, the patient is a carrier of the BRCA1 mutation. However there is no suggestion of familial melanoma.


OVERALL COMMENT


The history of persistence and the continued growth of this lesion are concerning for the possibility of more aggressive behavior in the future, which would have been difficult or impossible to predict from a single biopsy early in the course of the disease. Because

of cases like this, it seems reasonable to recommend complete removal of all cellular blue nevi, especially those with any mitotic activity, cellular atypia, or increased cellularity.

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5.5 Malignant Blue Nevus vs. Malignant Melanoma

A 60-year-old white female with a mass in the left neck and a history of a previous excision 25 years ago.

another consultant. We will attempt to retrieve tissue or reports from the prior excision specimen of the neck.

R E A S O N F O R C O N S U LTAT I O N

DESCRIPTION

The necrosis and high mitotic rate with atypical mitotic figures would favor a diagnosis of malignancy. The tumor appears to infiltrate both collagen and muscle. Malignant blue nevus is very rare. We would like this diagnosis to be confirmed by

I have reviewed the previously captioned material and am in complete agreement with your report. The sections show a bulky neoplasm, composed of uniformly atypical large epithelioid and somewhat spindleshaped melanocytes, forming a tumor well over 1 cm

C L I N I C A L I N F O R M AT I O N

Scanning magnification of one of the profiles of the main tumor, showing a bulky tumor located in subcutaneous tissue. The lesion has a relatively circumscribed profile; however, there is infiltration of connective tissue. In other sections, not available at this time, there was infiltration of skeletal muscle. FIG URE 5.5.1.

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5.5 in diameter. Within the tumor, the cells are arranged in an ill-defined fascicular pattern, and there are some fibrous septa separating the tumor into lobules. There are focal areas of confluent tumor necrosis, and mitotic figures are readily detectable, with some few fields containing three mitoses and many fields that contain two mitoses or a single mitosis. At its periphery, the tumor infiltrates reticular dermis and subcutaneous collagen and fat. The striking feature, also noted in your report, is the presence of multiple satellite deposits of much less cellular tumor, composed of epithelioid and dendritic pigmented melanocytes, quite consistent with cellular blue nevus, and also of less cellular proliferations of heavily pigmented dendritic spindle cells, which, taken in an isolation,

would be consistent with banal blue nevus. To my mind, the finding of a nodule in a background of cellular blue nevus is consistent with a neoplasm in the blue nevus lineage, and the presence of spontaneous tumor necrosis and a high mitotic rate (focally greater than 6/mm²), coupled with cytologic atypia— which, although perhaps not severe, is uniform—is diagnostic of malignant blue nevus. The presence of a background of apparently indolent cellular blue nevus, lacking mitoses or much evidence of expansile growth, and the history of excision of a lesion at this site 15 years ago also tend to confirm the diagnosis of malignant blue nevus, which I distinguish from common forms of malignant melanoma. In summary, I interpret this lesion in the following manner:

Scanning magnification of another section. Again, there is a cellular nodule, adjacent to which there are additional satellites. Several such foci are illustrated in the Web figures. FIGURE 5.5.3.

There is moderate to severe uniform cytologic atypia of cells in the nodule. Mitotic figures were readily detected, with some fields containing three mitoses. FIG URE 5.5.2.

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A satellite nodule adjacent to the main tumor has the morphology of a cellular blue nevus, with a “mixed—biphasic” pattern comprised of clear epithelioid cells in nests separated by pigmented spindle cells. FIG URE 5.5.4.

DIAGNOSIS

Skin and subcutaneous tissue of right upper mid neck: Malignant blue nevus.

COMMENT

I do not believe that prognostic attributes developed for common forms of malignant melanoma are necessarily applicable in a malignant blue nevus. In

In this area, also attached to the main tumor, there is a “monophasic spindle cell” pattern of a cellular blue nevus. FIGURE 5.5.5.

particular, the considerable thickness of the lesion (28 mm) may not indicate quite the same ominous prognosis that might be the case in the common melanoma. The mitotic rate is high, and tumorinfiltrating lymphocytes are sparse. I certainly believe that this lesion has potential capacity for distant metastasis. I recommend complete excision of the cellular nodule, as well as removal of the diffuse background cellular blue nevus, if possible. Then, I recommend follow-up for the patient according to protocols for malignant melanoma.


OVERALL COMMENT


This case, like two earlier cases in this chapter, suggests the advisability of complete excision of a cellular blue nevus, if possible. The time course of this disease evidently can be measured in decades rather

than months or years, making it difficult to accrue a representative experience of these tumors and their behavior.

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5.6 Malignant Blue Nevus vs. Pigmented Epithelioid Melanocytoma vs. Pigment Synthesizing Malignant Melanoma C L I N I C A L I N F O R M AT I O N

A pigmented tumor of the left arm in a 67-year-old man. R E A S O N F O R C O N S U LTAT I O N

We consider this to be a cellular blue nevus, completely excised. Our histologic differential diagnosis includes a combined nevus (Spitz’s nevus and blue nevus) with the presence of the large epithelioid cell type seen in this proliferation. DESCRIPTION

Sections show a bulky, melanocytic tumor in the dermis, measuring 8 mm in breadth, with adjacent scar consistent with recent biopsy site. The tumor is

composed of a monotonous proliferation of spindled to epithelioid melanocytes, with abundant coarsely divided melanin pigment and numerous infiltrating melanophages with coarsely granular melanin pigment. Scrutiny reveals, for the most part, few mitoses, but, in more cellular areas, the mitotic rate is slightly increased at 2/mm2 in the superficial third of the lesion. Tumor-infiltrating lymphocytes are present and non-brisk. Tumor-infiltrating macrophages are present. There are features reminiscent of blue nevus, but there is no clear evidence of a benign blue nevus component. Although the differential diagnosis would include a cellular blue nevus of the monophasic spindle-cell type; however, readily detectable mitoses, abnormal mitoses, and marked cellular atypia would

Low magnification images of a moderately to highly cellular tumor comprised of heavily pigmented cells, extending from near the epidermis well into the reticular dermis. FIG URE 5.6.1.

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5.6 lead me to characterize this lesion as a melanocytic tumor of uncertain malignant potential if additional clinical history were not available. In light of subsequent information that the lesion is locally recurrent after a previous procedure years ago (not known at the time of initial submission of this biopsy and not available for review) and given that the patient has heavily pigmented liver metastases, I feel that this lesion must

be construed as malignant cellular blue nevus versus malignant melanoma. Given that the lesion lacks a characteristic intraepidermal component of malignant melanoma and, even though there is no evidence of a banal blue nevus component as is usually seen in cellular blue nevi, I believe that the lesion is best characterized as malignant blue nevus. In summary, I interpret the material in the following manner:

FIG URE 5.6.2.

The tumor is comprised of plump, spindleshaped cells, with abundant amphophilic cytoplasm containing moderate to abundant finely divided melanin pigment.

FIGURE 5.6.3.

In this field there was a suggestion of lymphatic invasion.

FIGURE 5.6.5.

FIG URE 5.6.4.

The nuclear membranes are relatively regular; however, an occasional larger nucleus is present. There are prominent nucleoli.

Near the base of the lesion there was a dumbbell-like extension of tumor and adipose tissue and around the skin appendages.

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5.6 DIAGNOSIS

Skin, right arm: Malignant blue nevus; see previous discussion.

COMMENT

In this region, the location of a mitotic figure is indicated by an arrow. FIG URE 5.6.6.

The diagnosis is based in large part upon the lesion’s behavior as well as the morphology, which is quite difficult or impossible to interpret in isolation. The possibility that this lesion represents a metastasis from another site cannot be entirely ruled out, although I favor a primary at this site. Foci of possible lymphatic invasion and small satellites extending out from the tumor are seen. Although microstaging attributes applicable to ordinary forms of melanoma are probably not applicable to these lesions, the history of local recurrence and the presence of liver metastases at the time of this specimen are obviously dire signs.


ADDITIONAL COMMENT


This patient presented with liver metastasis 10 months after the excision of the putative primary lesion. The lesion was originally diagnosed as a monophasic pattern of cellular blue nevus/malignant blue nevus; today it would likely be better regarded as a pigmented epithelioid melanocytoma, or a pigment synthesizing

melanoma, because of the lack of an associated mixedbiphasic cellular blue nevus pattern or a background of benign blue nevus. Although the existence of liver metastases is clearly ominous, some lesions in these general categories can have a relatively indolent course despite the existence of metastases.

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5.7 Malignant Blue Nevus vs. Atypical Cellular Blue Nevus

C L I N I C A L I N F O R M AT I O N

A heavily pigmented tumor on the scalp of a 53-yearold woman. R E A S O N F O R C O N S U LTAT I O N

We would be grateful for your opinion of this atypical melanocytic lesion. DESCRIPTION

Sections show a quite cellular lesion, comprised of narrow, elongated, spindle cells, placed among reticular dermis collagen fiber bundles. At the periphery, the density is low, but, toward the center, the cellularity is somewhat greater, with more closely packed spindle cells. There is a focal area of ulceration with overlying

scale-crust. Several dermal lesional cell mitotic figures are observed. The differential diagnosis for this lesion includes a blue nevus with focally increased cellularity (cellular blue nevus, monophasic spindle-cell type), a pigmented epithelioid melanocytoma, and a malignant blue nevus. A Ki-67 study shows relatively numerous reactive cells in the dermal component of the lesion, largely limited to the cellular component of it, near the surface. Based on the cytologic atypia, the ulceration, and the mitotic activity, as well as the associated banal blue nevus histology at the periphery and the lack of any in situ component of a usual form of melanoma, I believe that this lesion is best interpreted as a malignant blue nevus, which I characterize as follows:

Scanning magnification of a relatively small, but highly cellular, melanocytic tumor, extending from near the epidermis into the upper reticular dermis. FIG URE 5.7.1.

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Adjacent to the more cellular central part of the tumor, on each side there are pigmented spindle cells, placed among reticular dermis collagen fibers, reminiscent of a banal blue nevus. FIG URE 5.7.2.

FIG URES 5.7.4 A ND 5 .

In the more central part of the lesion, there are intersecting fascicles of clear and pigmented cells, reminiscent of a cellular blue nevus. FIGURE 5.7.3.

Mitotic figures are readily identified in the lesional cells.

DIAGNOSIS

Skin, head: Malignant blue nevus; see previous discussion and comment.

COMMENT

There are no well-characterized prognostic attributes for malignant blue nevi. This lesion is smaller than

most of them. However, the mitotic rate is at least 4/mm². In addition, there is focal neurotropism. The lesion is completely excised in the section plans available for study. However, I recommend definitive management for this lesion, based on the above diagnosis, likely to include an additional excision procedure and the consideration of sentinel lymph node sampling, as well as of close follow-up for the patient.

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OVERALL COMMENT


This lesion is much smaller than most malignant blue nevi. A reasonable alternative would be to interpret it is a “melanocytic tumor of uncertain

malignant potential” (MELTUMP). In either case, in my opinion, it should be managed as an AJCC Stage II melanoma.

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5.8 Malignant Blue Nevus vs. Metastatic or Primary Melanoma

C L I N I C A L I N F O R M AT I O N

DESCRIPTION

Lesion of the scalp in a 50-year-old man. Grossly received were fragments of gray-tan to yellow, partially hemorrhagic tissue, thought to be consistent with portions of cyst wall.

Sections show a bulky, malignant neoplasm, composed in some areas of bland, spindled cells and, in other more cellular areas, with a mixed-biphasic pattern of clear cells and spindle cells, as seen in a cellular blue nevus. In the latter areas, there are scattered mitoses. In another area, however, there is a solid proliferation of uniformly atypical cells, with high-grade atypia and frequent mitoses (greater than 6/mm2), which focally shows five mitoses in one high-power field. In addition, there are areas of tumor necrosis. In summary, I interpret the material in the following manner:

R E A S O N F O R C O N S U LTAT I O N

We think that the overall features are consistent with malignant blue nevus arising within cellular blue nevus.

Scanning magnification of a tumor of the scalp that was received in fragments. The lesion appears to be located in dermis and subcutaneous tissue. The epidermis is not included in the specimen. FIG URE 5.8.1.

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5.8

A more cellular area is present at one pole of the specimen. FIG URE 5.8.2.

FIGURE 5.8.3.

There is an area of pigmented melanocytes consistent with partial regression of the tumor (“tumoral melanosis”). FIGURE 5.8.5.

In the more cellular area, mitotic figures were readily detected, with one high-power field containing five mitoses (not shown). FIG URE 5.8.4.

There is an area of tumor necrosis.

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There are extensive areas demonstrating a mixed-biphasic pattern characteristic of cellular blue nevus. In this area, scattered mitoses were detected (not shown). FIG URE 5.8.6.

DIAGNOSIS

Dermis and subcutaneous tissue of scalp: Malignant dermal melanocytic neoplasm, consistent with malignant blue nevus; see comment.

Elsewhere again, there is a much less cellular area, consistent with a banal or slightly cellular blue nevus. FIGURE 5.8.7.

COMMENT

This lesion is most consistent with a primary malignant blue nevus; however, the more remote possibility of a metastatic lesion cannot be completely excluded. Because the epidermis is not represented on the slide, the presence of a more usual type of melanoma cannot be ruled out. In our group, we recommend definitive excision, with careful control of margins, and follow-up as for high-risk melanoma.


OVERALL COMMENT


I consider the possibility of a metastasis to be very unlikely, given the background cellular blue nevus. The diagnosis of malignancy is not difficult in this lesion, because of the high-grade atypia, necrosis, and frequent mitoses. The presence of a background

blue nevus and cellular blue nevus components again suggests that these lesions have a finite but probably low capacity to progress to a frank malignancy, over a time course that may occupy many years.

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5.9 MELTUMP, Cellular vs. Malignant Blue Nevus

C L I N I C A L I N F O R M AT I O N

A subcutaneous tumor in the temporalis fascia in a 59-year-old man: grossly, a black, fleshy fragment of tissue, measuring 2 cm in greatest dimension. The patient has no known history of cutaneous melanoma. R E A S O N F O R C O N S U LTAT I O N

Although the findings indicate that this is a melanocytic neoplasm, classification is not straightforward because of the lack of atypia, proliferative activity, areas of neurotization, and nesting pattern in the larger specimen. Immunohistochemical stains are strongly positive for multiple melanocytic markers, including Melan-A, HMB 45, MITF, and tyrosinase. Ki-67 staining is less than 1%. Would you please give a formal consult on this case? DESCRIPTION

The accompanying paperwork indicates that the patient has a history of dermal nevus removed from the left temple 15 years earlier. We obtained a slide and a report on this specimen, which, on review, shows a very superficial shave biopsy containing the top of a lesion that has morphological characteristics of a dermal nevus, without atypia, and is transected at the specimen base. Sections of the mass removed recently show a bulky tumor, comprised of nevoid

to epithelioid and spindle-shaped melanocytes, arranged in various patterns, including ill-defined nests, fascicles, and patternless sheets, with densely cellular areas and areas of loose and edematous stroma. In other areas there is dense fascia, apparently infiltrated by pigmented spindle cells. Pigmentation is variable across the lesion but is quite heavy in many areas. In addition, there is extensive hemorrhage and hemosiderin pigment deposition. The tumor marks positively with multiple melanocytic markers, including tyrosinase, HMB 45, Melan-A, and MITF, although, interestingly, S100 appears to be negative. Cytologically, the lesional cells are relatively bland, although there is some variation in nuclear size, shape, and staining intensity, without marked pleomorphism. Mitotic figures are rare and were absent in a formal count of more than 50 highpower fields; however, in scanning the sections, at least one definitive lesional cell mitotic figure was identified. In addition, Ki-67 labels lesional cells, although the proportion is clearly far less than 10%. There is no frank necrosis, although, in some areas, there appears to have been cystic degeneration. The tumor is somewhat circumscribed but appears to have an infiltrative relationship with adjacent fascia and apparently extends to multiple resection margins. In summary, this lesion presents conflicting criteria, and I interpret it descriptively.

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5.9

There are prominent trabeculae, and there is an ill-defined capsule comprised of dense fibrous tissue, infiltrated by tumor cells, having a somewhat mixed-biphasic pattern of somewhat epithelioid clear cells in ill-defined nests, surrounded by more heavily pigmented, more spindledshaped cells. FIGURE 5.9.2.

Scanning magnification of a highly cellular, partly cystic, incompletely encapsulated, bulky tumor in the subcutis. FIG URE 5.9.1.

Toward the center of the tumor, the mass is comprised of somewhat more heavily pigmented, predominantly spindle cells, with cystic degeneration and prominent vessels. Nuclei are relatively bland, and only a rare lesional cell mitosis was observed (not shown). FIG URE 5.9.3.

There were areas of hemorrhage, possibly consistent with fine needle tracks. There was also cystic degeneration; however, there was no definitive spontaneous tumor necrosis. FIGURE 5.9.4.

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FIG URE 5.9.5.

MITF staining was strongly and diffusely Ki-67 staining was focally positive in lesional cells, overall less than 1% reactivity. FIGURE 5.9.7.

positive.

COMMENT

The lesion was also strongly and diffusely positive with Melan-A. However, S100 was negative. FIG URE 5.9.6.

DIAGNOSIS

Subcutaneous tissue, left infratemporal fossa mass: Melanocytic tumor of uncertain malignant potential; see previous discussion and following comment.

In my opinion, this lesion is not a routine primary or metastatic malignant melanoma. The differential diagnosis, to my mind, includes cellular blue nevus, malignant blue nevus, and clear-cell sarcoma. The latter diagnosis could be explored with cytogenetic studies, if desired. I expect that this lesion is likely to have at least locally persisting and recurring potential and cannot rule out the possibility of a lesion with metastatic potential. The lesion previously biopsied and reported as dermal nevus, apparently from the same general area, shows changes consistent with a dermal nevus located in the superficial dermis and transected at the specimen base and does not bear any resemblance whatsoever, cytologically or architecturally, to the present material.

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5.9
OVERALL COMMENT


This is a most unusual lesion. It bears some resemblance to six lesions described as “ancient” blue nevi by Cerroni et al. in 2008 (18). Three of these patients

had been followed up to 10 years without metastases. Nevertheless, a cautious approach to diagnosis and management would seem to be appropriate.

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5.10 Atypical Cellular Blue Nevus vs. Malignant Blue Nevus

C L I N I C A L I N F O R M AT I O N

A lesion on the parietal scalp of a 28-year-old female. R E A S O N F O R C O N S U LTAT I O N

In a few areas, the lesion shows features that suggest to me that it may represent a cellular blue nevus. However, I am concerned about the possibility that it may represent a malignant blue nevus or malignant melanoma. DESCRIPTION

This material is unusually difficult. The sections show a bulky, melanocytic tumor, located in the dermis and the subcutaneous tissue. The tumor presents, in some areas, an organoid appearance, with nests and fascicles of spindle-shaped cells and, in some areas, with dendritic pigmented cells. These attributes are quite characteristic of cellular blue nevi. In other areas, however, there are broad sheets of less differentiated epithelioid

Low magnification of a bulky tumor located in the dermis and subcutis. There are at least two major components visible at scanning magnification: one more superficial and pigmented, the other more deeply located, forming a mass. FIG URE 5.10.1 .

melanocytes, showing significant though not striking nuclear atypia, with prominent nuclear line, and with easily detectable mitoses. In addition, there are a few abnormal mitoses. Although, as you point out, the lesion is reasonably well circumscribed, in some areas, it appears to have an infiltrative relationship with surrounding collagen and adipose tissue. There is no necrosis. Although I would place this lesion, for purposes of categorization, in the cellular blue nevus category, I cannot regard it as a benign lesion. The important features in reaching this conclusion are the extensive epithelioid cell areas, the moderate nuclear atypia, the occasional mitoses, the presence of abnormal mitoses, and the focally infiltrative pattern (with a couple of satellites) at the periphery. On the other

The superficial component itself has at least two major components. At the periphery, there are small spindle cells, placed in the reticular dermis collagen fiber bundles. Toward the center, there is a more densely cellular pigmented population, with a mixed-biphasic pattern. FIGURE 5.10.2.

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5.10 hand, the lesion lacks necrosis, one of the most widely cited diagnostic criteria for so called “malignant blue nevus.” Thus, for diagnostic and therapeutic purposes,

I sign this lesion out descriptively as “dermal spindle and epithelioid cell melanocytic tumor, probably of low malignant potential.”

The more sparsely cellular population at the periphery has the characteristics of a banal blue nevus, albeit with scant pigmentation.

FIGURE 5.10.4.

FIG URE 5.10.3.

The more central portion of the tumor is more heavily pigmented and demonstrates a mixedbiphasic pattern of a cellular blue nevus.

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The more deeply situated tumor is comprised of relatively large epithelioid cells, with a somewhat “rhabdoid” phenotype, showing no evidence of maturation. FIG URE 5.10.5 .

Mitotic figures were readily detected, with a maximal mitotic rate of approximately 2/mm2. FIGURE 5.10.6.

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5.10

Approximately three years later, a liver biopsy demonstrated metastatic pigmented tumor in the liver, consistent with metastasis from this patient’s lesion. The figure shows normal liver cells in the upper left and the metastatic tumor in the lower right of the image. In a section from a needle biopsy of the liver, at the top left, there are benign liver cells. At the bottom right, there is a pigment synthesizing tumor consistent with a metastasis from the patient’s primary lesion of the scalp. FIG URE 5.10.7.

DIAGNOSIS

Skin, parietal scalp: Dermal spindle and epithelioid cell melanocytic tumor, probably of low malignant potential.

COMMENT

Because of the organoid differentiation, I believe that this lesion is certainly not a metastatic melanoma. Furthermore, I do not believe that it is a characteristic primary malignant melanoma,

because of the absence of an in situ component and the presence of background components of cellular and banal blue nevus. It is possible that some consultants might regard this lesion as a benign cellular blue nevus. However, I believe that it may have at least a potential for local recurrence and possibly some low potential for metastasis. As you know, cellular blue nevi have been associated with metastases to regional lymph nodes, followed by long survival. Thus, I regard the prognosis for this patient as excellent, provided that local control is achieved, probably with a complete local re-excision. I do not believe that a formal wide excision, as typically advocated for high-risk primary cutaneous melanoma, is indicated. ADDED COMMENT ( T H R E E Y E A R S L AT E R )

Thank you for your letter with follow-up information and a slide from the previously captioned case. I have reviewed the previous material in some detail. The slide shows a bulky, cutaneous tumor, with attributes of a cellular blue nevus, namely, the bottom-heavy and somewhat dumbbell configuration, the presence of nests of clear spindle cells, embedded in a background of eosinophilic cuboidal cells, and the presence of associated dendritic heavily pigmented cells in the reticular dermis reminiscent of common blue nevi. There are no areas of necrosis, there is no high-grade nuclear atypia, and mitotic figures, although readily observed, are not frequent. I counted mitotic figures at approximately 2–3/mm2 in various areas of the tumor.

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OVERALL COMMENT


The outcome of this case confirms my belief that lesions with morphology of cellular blue nevi, but with mitotic activity, must be treated with some circumspection. However, I do not believe that these should be uncritically termed malignant melanomas. Now that this lesion has metastasized systemically, of course, it must unfortunately qualify as a malignant blue nevus. As with any malignant melanoma, the attributes of the primary lesion are not likely to have much influence on the course of the disease now that it has established systemic metastases. This lesion did not recur locally following complete excision and therefore must have metastasized

systemically prior to its complete removal. This outcome was difficult to predict from histology of the primary tumor; however, as a general “rule of thumb,” any melanocytic lesion (with the exception of a few well-defined lesions, such as Spitz tumors with a low mitotic rate) characterized by a combination of cytologic atypia and dermal mitotic activity should be treated with circumspection, and the possibility of metastatic potential cannot be ruled out. The prognosis, accordingly, should be somewhat guarded in these lesions, and they should be regarded as being of uncertain malignant potential.

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6 Combined Nevi

T

hese lesions combine features of two or more other nevus types, often compounding their difficulties of interpretation. The “clonal nevus,” defined as “a variant of melanocytic nevus that histologically exhibits a localized proliferation of pigmented epithelioid dermal melanocytes within an otherwise ordinary nevus” represents a subset of combined nevi (1). There is considerable overlap with deep penetrating nevi, which are a frequent element of combined nevi, along with blue nevi, epithelioid blue nevi, cellular blue nevi, and Spitz nevi (2–5). It has been proposed that clonal nevi may represent a superficial variant of deep penetrating nevi (6). In a description of 95 cases of combined nevi by Pulitzer et al. (2), the commonest variant, in about 50% of cases, was characterized by plump, pigmented spindle cells, forming fascicles among nests of ordinary nevus cells. Clinically, most of the lesions were darkly pigmented papules or nodules. The clinical diagnosis was nevus, blue nevus, or melanoma. Fifteen percent of the lesions had concomitant histologic features of melanocytic dysplasia. The cytologic features of apparent infiltration by pigmented spindle cells often lead to misdiagnosis of melanoma, a problem that is compounded by features of melanocytic dysplasia, when present (2). In a subsequent study of 41 deep penetrating or “plexiform spindle cell” nevi, it was recognized that these lesions were associated with an ordinary nevus component in two-thirds of the cases (3). Another study emphasized blue nevi as a component of combined nevi (4). The combination of a Spitz nevus and an acquired nevus is unusual but has

been rarely reported (7). Generally speaking, a combination of a lesion characterized by large atypical melanocytes, with mitotic activity, in association with a common nevus is more likely to represent a melanoma, and the diagnosis of a combined nevus and Spitz nevus/tumor should be made rigorously. Among 21 cases in the original report of epithelioid blue nevi by Carney, 7 were part of a combined nevus. In such cases, the Carney complex (myxomas, spotty skin pigmentation, endocrine overactivity, and schwannomas) should be considered (8). In an interesting study that focused on epithelioid blue nevi, Groben et al. identified a morphologic spectrum encompassing a group of combined blue nevi with epithelioid melanocytes and other Spitzoid nevus features. These epithelioid combined nevi (ECN) fell into three phenotypes: the classic or Carney complex pattern or ECN-CC; lesions that showed overlap with deep penetrating nevus, i.e., ECN-DPN; and lesions that had many dermal Spitz nevus features, termed BLue + SpITZ’s nevus, or ECN-BLITZ. Some cases had associated banal congenital nevus. Limited follow-up showed no evidence of malignancy or recurrent disease after excision. Epithelioid combined nevus was thought to be a fitting nosologic designation for all of these lesions (5). An example of a combined nevus with malignant transformation has been described, composed of a cellular blue nevus in the reticular dermis and overlying compound melanocytic nevus, with melanoma in situ in the epidermis (9). This would appear to be an extremely rare phenomenon.

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References 1 Huynh PM, Glusac EJ, Bolognia JL. The clinical appearance of clonal nevi (inverted type A nevi). Int J Dermatol 2004 Dec;43(12):882–5. 2 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. 3 Cooper PH. Deep penetrating (plexiform spindle cell) nevus. A frequent participant in combined nevus. J Cutan Pathol 1992 Jun;19(3):172–80. 4 Gonzalez-Campora R, Galera-Davidson H, Vazquez-Ramirez FJ, Diaz-Cano S. Blue nevus: classical types and new related entities. A differential diagnostic review. Pathol Res Pract 1994 Jun;190(6):627–35. 5 Groben PA, Harvell JD, White WL. Epithelioid blue nevus: neoplasm. Sui generis or variation on a theme? Am J Dermatopathol 2000 Dec;22(6):473–88.

NE VI

6 High WA, Alanen KW, Golitz LE. Is melanocytic nevus with focal atypical epithelioid components (clonal nevus) a superficial variant of deep penetrating nevus? J Am Acad Dermatol 2006 Sep;55(3):460–6. 7 Jin ZH, Kumakiri M, Ishida H, Kinebuchi S. A case of combined nevus: compound nevus and spindle cell Spitz nevus. J Dermatol 2000 Apr;27(4):233–7. 8 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 Mar;20(3):259–72. 9 Requena L, Barat A, Hasson A, Arias D, Gutierrez MC, Martin L, de Castro A. Malignant combined nevus. Am J Dermatopathol 1991 Apr;13(2):169–73.

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6.1 Combined Cellular Blue and Congenital Pattern Nevus vs. Pigmented Epithelioid Melanocytoma C L I N I C A L I N F O R M AT I O N

DESCRIPTION

Biopsy of a lesion of the nail bed in a 40-year-old woman.

These sections show a shave biopsy containing a moderately cellular melanocytic lesion comprised of spindle-shaped melanocytes, arranged in intersecting fascicles and ill-defined nests, extending from near the epidermis through an expanded papillary dermis and forming an expansile nodule in the reticular dermis, extending close to the base of the biopsy specimen. Although there is a minority population

R E A S O N F O R C O N S U LTAT I O N

Please review this unusual lesion.

Scanning magnification views of two profiles of a subungual tumor that had been present for 35 years with slow growth. The overlying nail has apparently been shaved off.

FIGURE 6.1.1.

At the right of the lesion, changes could be interpreted as those of a compound congenital pattern nevus, with junctional nests and nevus cells in the dermis. These, however, are mixed with pigmented spindle cells.

FIG URES 6.1.2 A N D 3 .

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6.1 of mature nevoid cells, the lesional cells for the most part are plump spindle cells, with abundant cytoplasm, in many cases, containing moderate to abundant melanin pigment in the form of rather finely divided pigment granules. Scattered cells have moderately enlarged, somewhat irregular and somewhat hyperchromatic nuclei, many with small nucleoli. Mitotic figures are rare or absent. To my mind, the overall morphology of this lesion with spindle cells placed among somewhat thickened reticular dermis collagen bundles is that of a form of blue nevus. The

lesion is focally cellular, although it does not demonstrate the characteristic mixed-biphasic morphology of usual forms of cellular blue nevi. I do not believe this lesion demonstrates the cellular architecture of the most characteristic lesions of pigmented epithelioid melanocytoma. In the absence of more severe uniform cytologic atypia, mitotic activity, and tumor necrosis, I do not believe that this lesion is likely to have capacity for metastasis, and it does not meet criteria for a malignant blue nevus. In summary, I interpret this material as follows:

The lesion is predominantly comprised of pigmented spindle cells, which are relatively uniform from side to side and from superficial to deep, arranged in fascicles, with moderate cellularity. FIG URE 6.1.4.

Higher-power views of the cytology of the spindle cells. They have relatively large but uniform nuclei, with irregular nuclear membranes, open chromatin, and few if any mitoses. FIGURE 6.1.5.

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6.1 DIAGNOSIS

Skin, left fourth fingernail bed and matrix biopsy: Combined nevus with features of congenital pattern nevus and blue nevus with cellular and epithelioid features, extending to specimen margins focally; see previous discussion and comment.

COMMENT

I note that there is a 35-year history of a slowly expanding blue-black nodule with regular borders,

extending from matrix to nailbed, in this 40-yearold patient. Therefore the lesion, although indolent, appears to have dynamic qualities. I usually recommend complete local excision for cellular blue nevi, because I have seen examples of local persistence and recurrence with increased atypia. However, this lesion is not a characteristic cellular blue nevus. Because the lesional location is cosmetically significant, it may be appropriate to follow the lesional site carefully if there is no evidence at this time of residual or persistent lesion. However, I certainly recommend prompt and complete removal of any recurrent lesion.


OVERALL COMMENT


Like several lesions discussed in the previous chapter, this lesion appears to illustrate an occasional tendency

for indolently progressive behavior of cellular blue nevi over a time span that may be measured in decades.

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6.2 Combined Deep Penetrating and Congenital Pattern Nevus vs. Melanoma C L I N I C A L I N F O R M AT I O N

A two-tone, tan and blue-black lesion of the arm of a 78-year-old woman. R E A S O N F O R C O N S U LTAT I O N

Is this a melanoma arising in a nevus, or a combined nevus? DESCRIPTION

These sections show a shave biopsy of a lesion characterized by two major cell types, with a more superficial component consisting of orderly small nevus cells extending into the reticular dermis from the papillary dermis in a “congenital pattern.” The second component is comprised of larger, spindleshaped cells, with moderately abundant finely divided

FIG URE 6.2.1.

cytoplasmic melanin pigment, and these cells form a plaque that extends into the upper reticular dermis. The cellularity of this latter component is moderate, with retention of a nested architecture, with a tendency to sustentacular cell differentiation at the periphery of the nests, and without denser, more confluent or sheetlike growth. The morphology of this second component is consistent with that of a deep penetrating nevus, or possibly an epithelioid blue nevus. Significantly, I believe that there is blending or maturation of one cell type into another. This is a quite reassuring finding, as is the absence of mitotic activity, supported by the absence of Ki-67 proliferative activity in your immunostains. I therefore regard this lesion as an example of a combined nevus, which I characterize further as follows:

Scanning magnification of an excision biopsy of a plaquelike lesion in chronically sun-damaged skin.

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6.2

The lesion is comprised of two types of cells. At the surface and to the right of the images, there are nevoid melanocytes, placed among collagen fiber bundles in a so-called congenital pattern. Below and to the left, there are larger, more epithelioid melanocytes, with a tendency to arrangement in nests, and with cytoplasmic melanin pigment. These appearances have been termed “inverted Type A pattern.”

FIG URES 6.2.2 A N D 3 .

FIG URE 6.2.4.

Melan-A stains both cell types. HMB45 stains the more pigmented cell population, but not the dermal congenital pattern nevus cells above. FIGURE 6.2.5.

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6.2 DIAGNOSIS

Skin, right upper arm: Combined nevus with features of congenital pattern and deep penetrating nevus, focally extending to the specimen base; see previous discussion and comment.

COMMENT

Reassuringly, Ki-67 staining is essentially negative in both types of lesional cells, with positive internal controls. Mitotic figures were absent.

FIGURE 6.2.6.

Although this is a benign diagnosis, these lesions are unusual, and I recommend consideration of an additional procedure, to obtain a margin of normal skin around any residual lesion. In this present biopsy, excision is complete, with a closest border of about 1 mm laterally; however, tumor cells extend close or to the specimen base in the center of the lesion.


OVERALL COMMENT


The term “clonal nevus” has also been used for lesions of this type; however, currently these lesions are more commonly referred to as combined nevi, with the

pigmented component considered to represent patterns of proliferation like those of either blue nevus or deep penetrating nevus.

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6.3 Combined Deep Penetrating and Congenital Nevus

C L I N I C A L I N F O R M AT I O N

A lesion of the right thigh in an 84-year-old woman. R E A S O N F O R C O N S U LTAT I O N

Please review this lesion. DESCRIPTION

The sections show a moderately to highly cellular melanocytic lesion in the shape of a plaque or a dome, measuring about 5 mm in diameter on the slide and about 1.5 mm in depth, comprised of epithelioid to somewhat spindle-shaped cells, arranged predominantly in nests, with a tendency to fascicular or plexiform features, with nests and single cells in the overlying epidermis, and forming a tumor that extends into the mid-reticular dermis. The lesion has

a somewhat pyramidal shape, coming to an apex in the dermis. At one side of the lesion, there is an area of small or nevoid melanocytes in the dermis, extending into the upper reticular dermis in a so-called congenital pattern. Cytologically, throughout the main part of the lesion, but not in the nevoid area, there are scattered cells with large, irregular, and somewhat hyperchromatic nuclei, constituting random cytologic atypia. Mitotic figures, however, are not seen in random sections or in a formal count of 50 consecutive high-power fields. Taken together, I believe that these appearances are consistent with a deep penetrating nevus, a lesion that can exhibit this degree of random cytologic atypia. The lack of mitotic activity is very reassuring. In summary, I interpret this lesion as follows:

Scanning magnification shows a domed-shaped tumor with a fairly symmetrical silhouette. The tumor extends from the epidermis into the reticular dermis.

FIGURE 6.3.1.

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6.3

To the left of the tumor, there is a collection of smaller, more nevoid cells, showing evidence of maturation and dispersion as single cells into the reticular dermis at the base of the collection. These findings are consistent with an associated, small, congenital pattern nevus.

FIGURE 6.3.2.

Although the tumor closely approaches the epidermis, there is no well-developed in situ or junctional component. FIGURE 6.3.3.

Randomly scattered lesional cells exhibit substantial nuclear enlargement, irregularity, and hyperchromatism. Mitotic figures are absent. FIGURE 6.3.5.

There is some tendency to maturation of the cells of the major part of the lesion, with dispersion of some of them at the base of the tumor. FIG URE 6.3.4.

DIAGNOSIS

Skin, left thigh: Combined nevus, predominantly deep penetrating nevus with a congenital pattern nevus; see previous discussion and comment.

COMMENT

I see no evidence of malignancy in this material. The lesion is completely excised, with generous borders of normal skin.

195 C A SE

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6.3
OVERALL COMMENT


Despite the cytologic atypia in this lesion (as may be seen in deep penetrating nevi), the lack of mitotic activity is very reassuring. As in most unusual or atyp-

ical melanocytic tumors, complete excision is recommended when margins are positive.

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7 Pigmented Epithelioid Melanocytoma

A

lso known as “animal melanoma” or “pigment synthesizing melanoma,” these lesions overlap with epithelioid blue nevi and have somewhat uncertain malignant potential, with competence for local recurrence and for metastasis at least to regional lymph nodes, apparently often without continued progression. Although many melanomas are essentially amelanotic, especially in the vertical growth phase or tumorigenic compartment, there is a group of melanomas that have abundant pigment, often to the extent that nuclear morphology is obscured. There has long been a suggestion that these lesions might differ significantly in their biology from ordinary forms of melanoma. These lesions have been compared to lesions of animals, including equine melanotic disease, a condition in which lesions resembling a blue nevus develop in horses and may indolently progress, causing substantial local morbidity, but metastasizing late in the course of the disease, if ever (8). Lesions resembling this indolent progression from a precursor resembling a blue nevus to a heavily pigment-synthesizing malignancy have been described in humans (9;10). Experimentally induced lesions in guinea pigs were described as undergoing a similar progression (3). It is possible that some of these lesions may be derived from dermal melanocytes, in contrast to usual forms of melanoma, which develop from melanocytes in the epidermis. In any event, these lesions were referred to as “animal type” or “melanophagic” melanomas, to indicate a resemblance to collections of melanophages. In a description of six cases, mostly from the consultation practice of

Martin Mihm Jr., M.D., the lesions were described as blue-black nodules with irregular borders, ranging from 1 to 9 cm. Histologically, the lesions were comprised of confluent dermal sheets of heavily pigmented cells, of which the nuclei were poorly discernible but were large with irregularly thickened membranes, coarse chromatin, prominent nucleoli, and irregular chromatin clearing. Mitoses were infrequent. About half of the cases had an epidermal component. Four patients had recurrent disease, which was fatal in one case, with two others lost to follow-up. It was concluded that the biological behavior of this lesion is difficult to predict on morphologic grounds (4). About five years later, Dr. Mihm’s group described, in association with Aidan Carney, M.D., a lesion that they termed “pigmented epithelioid melanocytoma” (11). This lesion was said to be very similar to those previously described in the literature as “animal-type melanoma” and also to epithelioid blue nevus, which had been described as a part of the Carney complex of myxomas, schwannomas, and endocrine tumors (1;2). Forty-one cases were described, from patients with a variety of ethnic backgrounds, both sexes, and a wide age range. The tumors were widely distributed, but the extremities were the most common sites. The tumors were deeply extending dermal proliferations, with an average thickness of 3.3 mm. The cells were heavily pigmented epithelioid and/or spindled melanocytes. Seven lesions were ulcerated, and one had necrosis. Regional lymph nodes contained metastasis in 46% of cases, and liver metastasis occurred in one case; however, no patients had died in a relatively limited follow-up

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period. Except for the ulcerated lesions, the pigmented epithelioid melanocytomas were indistinguishable from epithelioid blue nevi of the Carney complex. Epithelioid blue nevi were described by Carney in 1996, as a multicentric familial tumor associated with the Carney complex (1;2). Soon after this report, epithelioid blue nevi were described in 33 patients with no evidence of the Carney complex (6). The lesions were described as “symmetric, predominantly dermal melanocytic proliferations arranged as short fascicles, small nests, and single cells.” Histologically, “large polygonal and epithelioid melanocytes with moderate pleomorphism and occasional nuclear pseudoinclusions were admixed with heavily pigmented dendritic and spindled melanocytes and melanophages.” Rare mitotic figures were present in some of the cases. These authors considered the tumors to exist on a morphologic spectrum of epithelioid combined nevi (ECN), with three phenotypes: the classic Carney lesions (ECN-CC), lesions that showed overlap with deep penetrating nevus (ECN-DPN), and lesions with features of dermal Spitz nevi (ECN-BLITZ) (6). There was no evidence of malignancy in this series, a feature shared with epithelioid blue nevi in the Carney complex, which also have shown no evidence of metastasis, contrasting to some extent with the animal-type melanomas and the pigmented epithelioid melanocytomas, which have, on occasion, exhibited metastatic and occasionally lethal potential. More recently, a contrary view has been presented, in a series of 14 cases of animal-type melanoma. These authors suggested the term “pigment synthesizing melanoma.” The lesions were asymmetric dermal tumors comprised of “deeply pigmented, round or short, spindle-shaped dendritic melanocytes with some degree of hyperchromatism and a single nucleolus.” Cytologic atypia was “always present but was not pronounced.” The mitotic rate ranged from 1 to 5/mm2 per 10 high-power fields. In a median

ME L ANO CY TOMA

follow-up of five years, three patients had local satellite recurrences, four had regional lymph node spread, and one had a distant metastasis to the liver; however, there were no deaths. These authors concluded that pigment synthesizing melanoma is a “distinctive, possible low grade variant of melanoma.” In summary, it is difficult to reconcile these various descriptions of what appears to be a group of morphologically indistinguishable lesions. It would seem that epithelioid blue nevi, at least in the Carney complex, are benign lesions. The epithelioid blue nevi described by Groben et al. (6), most of which were described as being combined with other forms of nevi, may or may not correspond to pigmented epithelioid melanocytomas, which have also been described as a part of a combined nevus in 5 of the 41 original cases (11). On the other hand, the animal-type melanomas, the pigmented epithelioid melanocytomas, and the pigment synthesizing melanomas, all of which have been said to be indistinguishable from each other, appear to have a substantial incidence of recurrence and/or metastasis; however, the course appears to be relatively indolent, with only rare deaths having been reported. A recent molecular study by Zembowicz et al. has provided evidence that the pigmented epithelioid melanocytoma appears to be a distinct genetic entity, characterized by loss of the expression of the gene for protein kinase A, regulatory subunit one alpha, a gene that is also involved in the Carney complex (7;12). It seems reasonable therefore to continue to separate these lesions from ordinary forms of melanoma, and in my opinion, these lesions are best regarded as a form of “melanocytic tumors of uncertain malignant potential” (5). Management of these lesions should certainly include complete local excision, the extent of which has not been clearly defined, and in my opinion, margin widths of a definitive excision procedure should not be uncritically based on guidelines for “usual” forms of melanoma. Especially in the thickness ranges

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of these lesions, which are almost always greater than 1 mm and therefore AJCC stage II or greater, they are much less likely to be lethal than usual forms of melanoma. Similarly, sentinel lymph node sampling may be appropriate as a staging procedure; however, there appears to be a substantial survival rate, even following positive sentinel nodes and even after lymph node metastasis. Therefore, I do not consider that a sentinel node dissection is necessarily a standard of care in these cases. However, the duration of follow-up in these cases is, as yet, limited, and it is at least possible that this indolent disease might progress over a more prolonged time course than usual forms of melanoma.

5 6

7

8

References 1 Carney JA and 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, 20:259–272. 2 Carney JA and Stratakis CA. Epithelioid blue nevus and psammomatous melanotic schwannoma: the unusual pigmented skin tumors of the Carney complex. Semin Diagn Pathol 1998, 15:216–224. 3 Clark WH, Jr., Min BH, and Kligman LH. The developmental biology of induced malignant melanoma in guinea pigs and a comparison with other neoplastic systems. Cancer Res 1976, 36:4079–4091. 4 Crowson AN, Magro CM, and Mihm MCJ. Malignant melanoma with prominent pigment synthesis: “animal type” melanoma—a clinical and histological study of six cases with a

9

10

11

12

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consideration of other melanocytic neoplasms with prominent pigment synthesis. Hum Pathol 1999, 30:543–550. Elder DE and Xu X. The approach to the patient with a difficult melanocytic lesion. Pathology 2004, 36:428–434. Groben PA, Harvell JD, and White WL. Epithelioid blue nevus: neoplasm Sui generis or variation on a theme? Am J Dermatopathol 2000, 22:473–488. Groussin L, Kirschner LS, Vincent-Dejean C, Perlemoine K, Jullian E, Delemer B, Zacharieva S, Pignatelli D, Carney JA, Luton JP, Bertagna X, Stratakis CA, and Bertherat J. Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD. Am J Hum Genet 2002, 71:1433–1442. Levene A. Equine melanotic disease. Tumori 1971, 57: 133–168. Levene A. Disseminated dermal melanocytosis terminating in melanoma. A human condition resembling equine melanotic disease. Br J Dermatol 1979, 101:197–205. Tuthill RJ, Clark WH, Jr., and Levene A. Pilar neurocristic hamartoma: its relationship to blue nevus and equine melanotic disease. Arch Dermatol 1982, 118:592–596. Zembowicz A, Carney JA, and Mihm MC. Pigmented Epithelioid Melanocytoma: A Low-grade Melanocytic Tumor With Metastatic Potential Indistinguishable From Animal-type Melanoma and Epithelioid Blue Nevus. Am J Surg Pathol 2004, 28:31–40. Zembowicz A, Knoepp SM, Bei T, Stergiopoulos S, Eng C, Mihm MC, and Stratakis CA. Loss of expression of protein kinase a regulatory subunit 1alpha in pigmented epithelioid melanocytoma but not in melanoma or other melanocytic lesions. Am J Surg Pathol 2007, 31:1764–1775.

S E CTI O N

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7.1 Pigmented Epithelioid Melanocytoma vs. Nodular Melanoma

C L I N I C A L I N F O R M AT I O N

A pigmented tumor on the shoulder of a 90-year-old woman. R E A S O N F O R C O N S U LTAT I O N

Is this a melanoma, or a blue nevus? DESCRIPTION

These sections show a cellular tumor, spanning much of the reticular dermis, and comprised of large epithelioid and somewhat spindle-shaped cells, which, at the base of the lesion, are heavily pigmented. The degree of pigmentation, somewhat paradoxically, decreases as one approaches the surface of the

FIGURE 7.1.1.

lesion; however, the cell type appears to be the same, namely an epithelioid to spindle-shaped cell, with a large nucleus, relatively pale chromatin, and prominent nucleoli. Mitotic figures are rare or absent in the section planes we studied; however, an occasional Ki-67 positive proliferating lesional cell is observed. I agree with your differential diagnosis for this lesion and would add that of pigmented epithelioid melanocytoma (PEM)/epithelioid blue nevus. As you know, epithelioid blue nevi have been described in association with Carney’s syndrome, and also as a sporadic lesion, and they show almost complete histologic overlap with PEM. In summary, I interpret this material as follows:

Low magnification shows an infiltrating tumor, located in the upper reticular dermis. 200

201 CASE 1: PIGMENTED EPITHELIOID MELANOCYTOMA VS. NODULAR MELANOMA

7.1

There are two types of cells: a more heavily pigmented and dendritic cell type and a more epithelioid cell type. The epithelioid cell type is located more superficially in this example. The dermal tumor is separated from the epidermis, in this case, by a free or grenz zone. FIGURE 7.1.2.

The epithelioid cell type is characterized by relatively abundant cytoplasm and by round to oval nuclei, with irregular nuclear membranes and pale chromatin. FIGURE 7.1.3.

Just deep to Figure 3, there is blending with a more heavily pigmented population of cells. FIGURE 7.1.4.

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7.1

At the base of the tumor, there are even more heavily pigmented cells with dendritic cytoplasm, some of which are consistent with melanophages, whereas others represent heavily pigmented lesional cells that are more rounded in shape. FIGURES 7.1.5 AND 6.

203 CASE 1: PIGMENTED EPITHELIOID MELANOCYTOMA VS. NODULAR MELANOMA

7.1

A Melan-A study demonstrates staining of the lesional cells in the upper dermis (compare with Figure 10 as a negative control). FIGURES 7.1.7 AND 8.

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7.1

A Ki-67 study, with positive internal controls in the basal layer of the epidermis, shows little or no reactivity of the dermal tumor cells. FIGURES 7.1.9 AND 10.

COMMENT DIAGNOSIS

Skin, left shoulder: Pigmented epithelioid melanocytoma; see previous discussion and comment.

The possibility of Carney’s syndrome should be considered in association with these lesions; however, it seems unlikely that this would have gone unrecognized in a patient of this age. Pigmented epithelioid melanocytoma is a lesion that is regarded as of uncertain malignant potential; however, the majority of these lesions behave in a benign fashion. This present lesion has been completely excised.


OVERALL COMMENT


In this lesion, the amount of pigment is somewhat less than usual, and the number of macrophages is

correspondingly reduced, allowing good visualization of the PEM cell type.

CASE

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PIGMENTED

EPITHELIOID

MELANOCYTOMA

VS.

V U LVA R

MELANOMA

7.2 Pigmented Epithelioid Melanocytoma vs. Vulvar Melanoma

C L I N I C A L I N F O R M AT I O N

A pigmented tumor of the vulva in a 20-year-old woman. R E A S O N F O R C O N S U LTAT I O N

I would appreciate your opinion.

sections show a tumor in vulvar skin that measures about 8 mm in diameter and 2 mm in depth. It is comprised of sheets of large heavily pigmented cells, with a tendency to nested proliferation in some areas. Similar cells are present as junctional nests and also extending up into the epidermis focally in a pagetoid

DESCRIPTION

The sections show a most unusual lesion, which presents several difficulties of interpretation. The

The adjacent epidermis does not contain a striking in situ melanoma component; however, there is a subtle proliferation of melanocytes along the dermalepidermal junction: see Figure 12. FIGURE 7.2.2.

Low magnification of a bulky, heavily pigmented tumor of the vulva in a 20-year-old woman. FIG URE 7.2.1.

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7.2 pattern, which, however, is not extensive across the lesion. The cells have abundant melanin pigment in their cytoplasm, partly obscuring the nucleus. Most of these nuclei are fairly regular, with quite open chromatin, and with small nucleoli. Mitotic figures appear to be rare or absent, and there is no tumor necrosis or ulceration. The cells are quite monotonous from side to side across the lesion and show little evidence of maturation or other changes from superficial to deep. The differential diagnosis for this lesion could include an atypical special site nevus of the genital type; however, these lesions do not have this heavily pigmented

cellular phenotype. The cytology of this lesion is most characteristic of a lesion called pigmented epithelioid melanocytoma, which overlaps almost completely with epithelioid blue nevi. The latter were first described by Carney as a part of the Carney complex, and I recommend evaluation of this patient with that possibility in mind. However, given the bulk of this lesion, the presence of some degree of cytologic atypia of the lesional cells, and the pagetoid proliferation in the epidermis, I believe that this lesion is best regarded as at least of uncertain malignant potential, and I therefore characterize it descriptively as follows:

At first glance, the tumor is comprised of a uniform population of heavily pigmented cells.

FIGURE 7.2.4.

FIG URE 7.2.3.

Closer inspection reveals that there are two types of pigmented cells: one with more abundant pigment, representing melanophages, and another with less abundant, more finely divided pigment, representing lesional cells.

207 CASE

2:

PIGMENTED

EPITHELIOID

MELANOCYTOMA

VS.

V U LVA R

MELANOMA

7.2

A Melan-A study with red chromagen stains the lesional cells reddish-brown; the melanophages remained greenish-brown in color. FIG URES 7.2.5 A N D 6 .

A CD68 stain shows the reverse of the Melan-A staining pattern: the melanophages are reddishbrown, whereas the lesional cells are greenish brown. FIG URES 7.2.7 A N D 8 .

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7.2

FIGURES 7.2.9 AND 10.

There is a proliferation of melanocytes, without striking atypia, in the epidermis adjacent to the

tumor.

The proliferating melanocytes tend to become confluent, although many of their cell bodies are separated by dendrites. They do not show striking cytologic atypia or pagetoid extension into the epidermis. FIG URES 7.2.11 A ND 1 2 .

209 CASE

2:

PIGMENTED

EPITHELIOID

MELANOCYTOMA

VS.

V U LVA R

MELANOMA

7.2 DIAGNOSIS

Skin, vulva: Melanocytic tumor of uncertain malignant potential, most consistent with a pigmented epithelioid melanocytoma with atypical features; see previous discussion and comment.

COMMENT

As already noted, pigmented epithelioid melanocytomas have been described as lesions of uncertain

malignant potential, with some tendency to involvement of regional lymph nodes; however, most patients have a benign course. I recommend complete removal of this lesion with, at a minimum, a margin of normal skin about the periphery of the scar of this procedure and any residual lesion. Because of the uncertain metastatic potential, some might consider a sentinel lymph node staging procedure; however, I do not believe this is necessarily a standard of care for lesions of this type. A Melan-A stain highlights the lesional cells, indicating that they are melanocytic, whereas the melanophages are labeled by a CD68 stain.


OVERALL COMMENT


Although this lesion presents several features of concern for melanoma, such as the pagetoid scatter and

the failure of maturation, the absence of mitoses is a reassuring finding, especially in so bulky a tumor.

S E CTI O N

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ME L ANO CY TOMA

7.3 Pigmented Epithelioid Melanocytoma vs. Nodular Melanoma

C L I N I C A L I N F O R M AT I O N

The patient is a 17-year-old male with a history of a 0.6-cm pigmented nodular skin lesion on the right neck. R E A S O N F O R C O N S U LTAT I O N

I have enclosed a representative slide from a recent skin excision for your review and opinion. DESCRIPTION

The sections show a nodular polypoid tumor comprised of heavily pigmented cells of two major types, the most

numerous being cells with cytoplasm stuffed with pigment, a somewhat dendritic appearance, and relatively small nuclei consistent with melanophages. The other population of cells, not always easily distinguished from the first, is also comprised of dendritic cells, with lesser degrees of pigment, and with enlarged round to oval nuclei with pale chromatin and prominent nucleoli, consistent with the cells of so-called pigmented epithelioid melanocytoma and also of epithelioid blue nevi. Occasional mitotic figures are seen in these lesional cells and also in a paracrine cell of a blood vessel wall. In addition, there is rather striking

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211 CASE 3: PIGMENTED EPITHELIOID MELANOCYTOMA VS. NODULAR MELANOMA

7.3

FIG URES 7.3.1 A N D 2 .

Scanning magnification images of a heavily pigmented, dome-shaped tumor, filling and expanding

the papillary dermis.

pseudoepitheliomatous hyperplasia and focal ulceration. I consider all of these latter features—the mitoses, hyperplasia, and the ulceration—to be concerning features for possible aggressive behavior. However,

these lesions should not be considered in the same category as ordinary melanomas and are best characterized as of uncertain malignant potential. In summary, I interpret this material as follows:

There is prominent pseudoepitheliomatous hyperplasia of keratinocytes.

FIGURE

FIG URE 7.3.3.

7.3.4.

component.

There is no adjacent intraepidermal

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7.3

FIG URES 7.3.5 A ND 6 .

There is superficial ulceration.

There are two types of cells, the more heavily pigmented cells representing melanophages. The lesional cells are relatively sparsely distributed among the melanophages, having somewhat lesser degrees of pigmentation, and rounded to ovoid nuclei with relatively prominent nucleoli. FIG URES 7.3.7 A ND 8 .

COMMENT DIAGNOSIS

Skin, right neck: Pigmented epithelioid melanocytoma, extending close to the specimen base; see previous discussion and comment.

As noted previously, these lesions overlap with epithelioid blue nevi, which can be associated with the Carney complex, which includes cutaneous myxomas and endocrine tumors, and I recommend some consideration of this possibility. However, pigmented epithelioid melanocytomas can also be sporadic and isolated findings. They have some biological potential for local recurrence and for metastasis, but this is generally much lower than that in

213 CASE 3: PIGMENTED EPITHELIOID MELANOCYTOMA VS. NODULAR MELANOMA

7.3 a characteristic melanoma of comparable microstaging. This present lesion is approximately 3 mm in thickness, extends to Clark level IV, is focally ulcerated, and is tumorigenic and mitogenic. Therefore, the possibility of a lesion with metastatic potential cannot be ruled out, and I recommend an additional

procedure, to be sure it has been completely removed, and consideration of a sentinel lymph node sampling procedure. Even in cases where metastasis has occurred, the prognosis for these lesions can be good. However, continuing follow-up for the patient is obviously also indicated.


OVERALL COMMENT


The presence of ulceration and the mitotic activity (not shown) give rise to concern in this lesion for the possibility of aggressive behavior. However, the

prognosis is likely to be much better than for a routine melanoma of similar thickness.

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7.4 Pigmented Epithelioid Melanocytoma vs. Nodular Melanoma

C L I N I C A L I N F O R M AT I O N

Please find hemotoxylin and eosin stain slides and special stains on this patient. She is a 5-year-old female with a deeply pigmented lesion of the left cheek. R E A S O N F O R C O N S U LTAT I O N

The preferred diagnosis in our department is a deep penetrating nevus of the cheek with Spitzoid features. No malignancy is identified, and the lesion appears completely excised. Your opinion on this case would be greatly appreciated. DESCRIPTION

These sections show a cellular nodular tumor comprised of two main types of cells, which are not always easily distinguishable from one another by routine hematoxylin and eosin stains. One of the cell types

FIG URE 7.4.1.

has relatively dendritic cytoplasm, which is stuffed with relatively coarse melanin pigment granules and represents melanophages. These have relatively small ovoid nuclei with small nucleoli. The other population of cells has larger nuclei, again with regular nuclear membranes and pale chromatin, with larger nucleoli, and with somewhat lesser degrees of pigment that is somewhat more finally divided. These are the lesional cells that are characteristic of cells seen in pigmented epithelioid melanocytomas. There is a bulbous extension at the base of the tumor into the subcutis, reminiscent of a cellular blue nevus, but the mixed-biphasic pattern and the background banal blue nevus usually seen in these lesions are lacking. The appearances are not those of a deep penetrating nevus, which would be characterized by predominantly nested and fascicular differentiation of smaller nevoid cells, with

Multiple sections of a heavily pigmented tumor, extending from the epidermis into the subcutis. 214

215 CASE 4: PIGMENTED EPITHELIOID MELANOCYTOMA VS. NODULAR MELANOMA

7.4

There is a bulbous expansion of tumor into the reticular dermis, reminiscent of a cellular blue nevus. FIG URE 7.4.2.

FIG URES 7.4.4 A N D 5 .

There is pseudoepitheliomatous hyperplasia of the overlying epidermis. FIGURE 7.4.3.

The cytology is similar at the top and at the bottom of the lesion, without evidence of maturation.

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7.4 quite variable nuclei exhibiting hyperchromatism and irregularity of randomly scattered cells. A striking feature in this present lesion is pseudoepitheliomatous hyperplasia, with a scale-crust, suggestive of incipient ulceration. Cytologically as noted, the lesional cells have relatively uniform nuclei. A few mitotic figures

are observed, including two in one high-power field from near the base of the tumor, seen in the melanin bleach preparation. A Ki-67 study does not demonstrate prominent reactivity of the dermal component. In summary, these appearances are reasonably characteristic, and I interpret them as follows:

There are two types of cells: the more heavily pigmented cells are melanophages, whereas the less heavily pigmented cells, with ovoid nuclei and prominent nucleoli, are the lesional cells.

FIGURE 7.4.7.

FIG URE 7.4.6.

tumor.

Similar cells are present at the base of the

217 CASE 4: PIGMENTED EPITHELIOID MELANOCYTOMA VS. NODULAR MELANOMA

7.4

Melanin bleach makes the two cell types more recognizable. There are no mitoses. FIG URE 7.4.8.

DIAGNOSIS

Skin, left cheek: Pigmented epithelioid melanocytoma; see previous discussion and comment.

COMMENT

Pigmented epithelioid melanocytomas are indistinguishable, to a considerable extent, from epithelioid blue nevi, which can be manifestations of the Carney complex, which includes cutaneous myxomas and endocrine tumors, and I recommend some consideration be given to this possibility in this patient. I would not expect epithelioid blue nevi to exhibit

A Ki-67 stain, with positive basal keratinocytes as controls, is negative in the lesional cells. FIGURE 7.4.9.

such extreme pseudoepitheliomatous hyperplasia, however. Pigmented epithelioid melanocytoma is a form of melanocytic tumor of uncertain malignant potential (MELTUMP). Although most lesions are cured by complete excision, some lesions have metastasized to regional nodes and then sometimes been followed by long survivals; however, the possibility of continued aggressive behavior cannot be ruled out. This present lesion appears to have been excised with clear margins and is on the cheek of a young child. I do not believe that therapy designed for usual forms of melanoma should be arbitrarily applied to these lesions and consider that careful observation of the lesional site might be a suitable alternative to any arbitrary re-excision procedure.

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7.4 If there was any suggestion that the lesion had not been completely removed, however, I would recommend its complete removal locally and follow-up. Because these lesions could have metastatic potential, the possibility of sentinel lymph node sampling

should be discussed; however, I do not believe it is necessarily the standard of care for these unusual lesions, and “watchful waiting” could be considered as a reasonable alternative, based on informed consent.


OVERALL COMMENT


Prior to the description of pigmented epithelioid melanocytoma, a lesion such as this might have been

interpreted as a monophasic spindle-cell pattern of cellular blue nevus.

CASE 5: RECURRENT PIGMENTED EPITHELIOID MELANOCYTOMA VS. MELANOMA

7.5 Recurrent Pigmented Epithelioid Melanocytoma vs. Melanoma

C L I N I C A L I N F O R M AT I O N

Re-excision of a lesion, previously diagnosed as a cellular blue nevus, from the scalp of a 78-year-old man. R E A S O N F O R C O N S U LTAT I O N

Is there any evidence of malignancy? DESCRIPTION

These sections show a large portion of skin representing a wide re-excision of a lesion, which apparently represents a clinical recurrence of a lesion previously diagnosed as a cellular blue nevus. Taken together, the sections show a scar consistent with the prior procedure, contiguous with which there is a tumor comprised of plump, elongated spindle cells,

FIG URE 7.5.1.

with prominent, coarsely divided melanin pigment granules in their cytoplasm, and with large ovoid nuclei with fairly irregular nuclear membranes and pale, tan, and somewhat prominent nucleoli. I regard these changes as most consistent with a pigmented epithelioid melanocytoma. However, the original biopsy, which was interpreted as a cellular blue nevus, is not available for review at this time. In any event, mitotic figures appear to be rare or absent in this recurrent lesion, and I expect its potential for metastasis to be low. In addition to the findings in the dermis, there are foci of cellular atypia in the epidermis. In some instances, these appear to represent keratinocytic atypia, namely actinic keratoses, some of them with a lichenoid infiltrate. The Melan-A study demonstrates continuous proliferation of

Low magnification shows a heavily pigmented tumor, located in the dermis. 219

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ME L ANO CY TOMA

7.5 slightly enlarged melanocytes in the epidermis above the recurrent dermal tumor. Because these melanocytes do not extend beyond the lateral borders of the scar, I regard them as most consistent with the so-called recurrent nevus phenomenon, also known as pseudomelanoma. In any event, this proliferation is completely excised.

There is an adjacent scar, consistent with a prior procedure at this site. FIG URE 7.5.2.

The tumor is comprised of heavily pigmented, spindled to epithelioid cells. F I G U R ES 7 . 5 . 3 A N D 4 .

FIG URE 7.5.5.

the surface.

The cells at the base are similar to those near

221 CASE 5: RECURRENT PIGMENTED EPITHELIOID MELANOCYTOMA VS. MELANOMA

7.5

FIG URES 7.5.6 A N D 7 .

There is no atypical intraepidermal proliferation extending into the epidermis beyond the area of

dermal scarring.

There are mildly to moderately atypical, nevoid to epithelioid, single melanocytes in the epidermis limited to the area above the scar. FIG URES 7.5.8 A N D 9 .

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7.5

Melan-A staining highlights the atypical intraepidermal proliferation and also stains the epithelioid melanocytes, while leaving the pigmented melanophages unstained. FIG URES 7.5.10 A ND 1 1 .

DIAGNOSIS

Skin, left scalp: Surgical site reaction, with contiguous pigmented melanocytic spindle cell tumor, clinically recurrent, of uncertain malignant potential, and with atypical intraepidermal melanocytic proliferation, completely excised; see previous discussion and comment.

COMMENT

As noted previously, the spindle cell tumor has features of pigmented epithelioid melanocytoma, a

lesion that is generally considered to be of uncertain malignant potential, which I expect to be low risk in this present case. Alternatively, the lesion may be a recurrent cellular blue nevus of the type that used to be termed “monophasic spindle-cell type.” Most of these, today, I tend to classify as pigmented epithelioid melanocytomas. Nevertheless, because of the history of recurrence, as well as the presence of cytologic atypia in a cellular melanocytic nodule, I recommend careful continuing follow-up, with attention to regional lymph nodes. In addition, the patient has multiple actinic keratoses, and follow-up for the development of potential skin cancers is also clearly indicated.


OVERALL COMMENT


This lesion exemplifies overlapping features between cellular blue nevi and pigmented epithelioid melanocytoma. The atypical intraepidermal melanocytic

proliferation is an interesting associated finding that seems most likely to be attributable to the recurrent nevus phenomenon.

8 Tumorigenic Melanomas of World Health Organization Classification Categories

T

here is considerable variation in the range of appearances of even otherwise common forms of melanoma, and these are discussed here, with inclusion of difficult examples of the major “clinicopathologic subtypes” of nodular, superficial spreading, lentigo maligna, and acral melanomas. Malignant melanoma is, of course, a malignant neoplasm of melanocytes. This simple definition conceals a panoply of variations on the central theme. There has been debate as to the significance of these variations, but it seems clear at the present time that cataloging of the different forms of melanoma is of value for several reasons. First, the different morphological forms differ sufficiently from one another such that a single set of criteria is not sufficient for diagnosing them accurately. Second, some of the subtypes of melanoma have distinctive behaviors that need to be taken into account when planning therapy. For example, lentigo maligna, desmoplastic, and neurotropic melanomas may subtly involve margins and result in a higher incidence of recurrence if this is not recognized prospectively. Third, it is now becoming apparent that the different subtypes of melanoma differ not only in their pathogenesis but also in their underlying genetic basis. These differences will become increasingly important as targeted therapies are developed, which will need to be selected specifically in the context of the genetic pathways involved in a particular lesion. The present classification of melanoma was published in the 2006 World Health Organization (WHO) fascicle on Pathology and Genetics of Skin Tumors (1). It is based on previous classifications, which can be

traced back as far as the original description of melanoma in the English literature by Hutchinson (2). In 1967, two influential papers were published. An Australian Committee of Pathologists, under the leadership of Vincent J. McGovern, described the pathology of two common forms of melanoma, naming them “pagetoid melanoma” and “Hutchinson’s melanotic freckle” (3). In the United States, Wallace H. Clark Jr. described the same patterns of melanoma, using the terms “superficial spreading melanoma” and “lentigo maligna melanoma” (4). In the same year, Mishima published a paper on “melanocytic and nevocytic malignant melanomas,” thereby presciently alluding to a fundamental difference in the evolutional biology of these two forms of melanoma that has relevance to the current evolving genetic classification today (5). An additional form of cutaneous melanoma, acrallentiginous melanoma, was later described (6), and to this group may be added mucosal-lentiginous melanomas of mucous membranes, including the oral and sinonasal cavities, the vulva, and other less common sites (7). In subsequent years, the classification has been revised and refined by additional committees (7;8), and a similar classification was presented by Peter Heenan in the 1996 WHO Histological Classification of Skin Tumors (9), which has now been slightly modified and superseded by the 2006 classification (1). Despite critiques of this evolving classification scheme, it remains in use today. However, the classification has little direct bearing on management and is therefore omitted from many reports. Nevertheless, published guidelines continue to recommend its use (10), in part because

223

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of its informative value for diagnosis and in part because there are subtle differences in morphology that relate to behavior, such as the poor circumscription of lentigo maligna melanomas and the highly infiltrative properties of desmoplastic melanomas. The importance of histologic classification of melanoma may increase in the future with the advent of targeted therapy for melanoma. In a recent seminal study, Boris Bastian’s group from University of California, San Francisco has studied the correlation of the phenotype of features commonly used for classification of melanoma with the underlying genotype (11). Melanomas with BRAF mutations had larger, rounder, and more pigmented tumor cells, and they had more prominent upward pagetoid migration and nest formation, epidermal thickening, and sharper circumscription, and sharper demarcation from the surrounding skin. Using simple combinations of these features, BRAF mutation status could be predicted with up to 90.8% accuracy in the entire cohort and also within the categories of the current WHO classification. It seems likely therefore that this classification can be refined based on the underlying genotype of the tumors and that the revised classification will prove to be useful in designing the algorithm for genetic testing in preparation for diverse targeted therapies as these are developed. The histogenetic classification exemplified in the current WHO classification and in the Bastian studies mostly relate to the junctional or intraepidermal component of the melanomas. However, in parallel with the evolution of this classification, it was realized that most potentially fatal melanomas proceed through two phases of progression, the radial growth phase (RGP) and the vertical growth phase (VGP) (12). Most melanomas arise and their lesional cells proliferate for a time in the epidermis. Proliferation in the epidermis may occur as single cells or as nests and is currently termed “in situ melanoma.”

C L A S S I F I C AT I O N

C AT E G O R I E S

Then, in some cases, lesional cells migrate from the epidermis into the dermis, at first lacking the capacity to proliferate there, as demonstrated in a recent study using the Ki-67 proliferation marker (13). This stage—when melanomas are present in the epidermis and/or the superficial dermis but lack capacity to form a tumor in the dermis—was termed the RGP because, clinically, it represents a stage when the lesion spreads as it were along the radii of an imperfect circle (12). Histologically, however, the proliferation appears horizontal rather than radial. Although not all lesions progress from in situ to invasive melanoma, some of these invasive RGP melanomas may then progress to the next step, where the cells acquire the capacity for proliferation in the dermis. At this stage, single cells in the dermis may begin to form clusters, or nests in the dermis that have migrated from the epidermis may begin to increase in size. In either case, there is the development of clusters or nests of cells in the dermis that are larger than the largest clusters in the epidermis (Figures 1 and 2). This represents the minimal definition of tumor formation or “tumorigenic melanoma.” Proliferation in the dermis occurs through cell division, so that the presence of mitoses or “mitogenic melanoma” is also indicative of a lesion that has the capacity to proliferate in the dermis. Collectively, tumorigenic and/or mitogenic melanomas are referred to as VGP, because the direction of growth has now become perpendicular to the epidermis. Studies have demonstrated that melanomas that lack tumorigenicity or mitogenicity, i.e., pure RGP melanomas, also lack capacity for metastasis (14;15), with only very rare exceptions (16). Because a metastasis represents tumor cells that proliferate and form a mass at a distant site, the inability of melanomas lacking VGP to produce metastases would seem to be easily explained. In terms of this concept, it is VGP that represents the source of metastatic disease and therefore represents the critical diagnostic element of

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C L A S S I F I C AT I O N

C AT E G O R I E S

There is a highly cellular proliferation of nested and single melanocytes in the epidermis. In the dermis, there is a nest or cluster of cells that is larger than the largest intraepidermal nest. This nest therefore constitutes tumorigenic vertical growth phase. FIG URES 8.1 AN D 2 .

a melanoma. However, tumorigenicity is not a component of the AJCC (American Joint Committee on Cancer) staging system, although mitogenicity has been included in the recent revision, in press at the time of this writing (17). There have been many studies of the microscopic criteria for melanoma, but it is difficult to develop a unifying concept. Studying 30 cases of superficial spreading melanoma that had metastasized, Price, Rywlin, and Ackerman in 1976 listed the following criteria, which are still in use today: (1) poor circumscription of the intraepidermal melanocytic component of the lesion, with lateral extension of individual melanocytes; (2) increased number of melanocytes, solitary and in nests, within and above the epidermal basal-cell layer and within adnexal epithelium (pagetoid appearance); (3) marked variation in size and shape of the melanocytic nests; (4) confluence of melanocytic nests, rather than discrete nests; (5) absence of maturation of melanocytes with descent into the dermis; (6) melanocytes with nuclear atypia; (7) melanocytes in mitosis; and

(8) necrosis or degeneration of melanocytes (18). These criteria remain valuable; however, it should be noted that the first four apply to the epidermal component, so that, in nodular melanomas, which lack an extension of the junctional component beside the dermal component, many of the criteria do not apply, accounting for much of the difficulty that occasionally attends this diagnosis (19). In addition, the criteria apply especially to the common superficial spreading subtype, so they are less useful in a lentiginous melanoma. For inclusion of these cases, one may add the criterion of continuous basal proliferation of uniformly atypical melanocytes to supplement the previously described criteria 2 through 4. In many lentiginous melanomas, nests are present in the center of the lesion, and, in these cases, the Price criteria apply.

References 1 LeBoit P, Burg G, Weedon D, Sarasin A. Melanocytic tumors. In: LeBoit PE, Burg G, Weedon D, Sarasin A, editors. Pathology and Genetics of Skin Tumors. Lyon: IARC Press; 2006. p. 49–120. 2 Hutchinson J. Senile freckles. Arch Surg (London) 1892;3:319.

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3 Australian Committee of Pathologists. Moles and malignant melanoma: terminology and classification. Med J Aust 1967;1:123. 4 Clark WH Jr. A classification of malignant melanoma in man correlated with histogenesis and biologic behavior. In: Montagna W, Hu F, editors. Advances in the Biology of the Skin Volume VIII. New York: Pergamon Press; 1967. p. 621–47. 5 Mishima Y. Melanocytic and nevocytic malignant melanomas. Cellular and subcellular differentiation. Cancer 1967;20:632–49. 6 Coleman WP 3d, Loria PR, Reed RJ, Krementz ET. Acral lentiginous melanoma. Arch Dermatol 1980;116:773–6. 7 McGovern VJ, Cochran AJ, Van der Esch, Little JH, MacLennan R. The classification of malignant melanoma, its histological reporting and registration: a revision of the 1972 Sydney classification. Pathology 1986;18:12–21. 8 McGovern VJ, Mihm MC Jr, Bailly C, Booth JC, Clark WH Jr, Cochran AJ, Hardy EG, Hicks JD, Levene A, Lewis MG, Little JH, Milton GW. The classification of malignant melanoma and its histologic reporting. Cancer 1973;32: 1446–57. 9 Heenan PJ, Elder DE, Sobin LH. Histological classification of skin tumors. In: Heenan PJ, Elder DE, Sobin LH, editors. Histological Typing of Skin Tumors. Berlin Heidelberg New York: Springer; 1996. p. 3–10. 10 Cochran AJ, Bailly C, Cook M, Crotty K, McCarthy S, Mihm M, Mooi W, Sagebiel R. Recommendations for the reporting of tissues removed as part of the surgical treatment of cutaneous melanoma. The Association of Directors of Anatomic and Surgical Pathology. Am J Clin Pathol 1998 Dec;110:719–22. 11 Viros A, Fridlyand J, Bauer J, Lasithiotakis K, Garbe C, Pinkel D, Bastian BC. Improving melanoma classification by integrating genetic and morphologic features. Plos Med 2008 Jun 3;5(6):e120.

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12 Clark WH Jr, Ainsworth AM, Bernardino EA, Yang CH, Jr., Reed RJ. The developmental biology of primary human malignant melanomas. Semin Oncol 1975;2:83–103. 13 Gimotty PA, Van BP, Elder DE, Murry T, Montone KT, Xu X, Hotz S, Raines S, Ming ME, Wahl P, Guerry D. Biologic and prognostic significance of dermal Ki-67 expression, mitoses, and tumorigenicity in thin invasive cutaneous melanoma. J Clin Oncol 2005 Nov 1;23(31):8048–56. 14 Elder DE, Guerry D, Epstein MN, Zehngebot L, Lusk E, Van Horn M, Clark WH. Invasive malignant melanomas lacking competence for metastasis. Am J Dermatopathol 1984;6 Suppl:55–61. 15 Guerry DIV, Synnestvedt M, Elder DE, Schultz D. Lessons from tumor progression: the invasive radial growth phase of melanoma is common, incapable of metastasis, and indolent. J Invest Dermatol 1993;100:342S–5S. 16 Gimotty PA, Elder DE, Fraker DL, Botbyl J, Sellers K, Elenitsas R, Ming ME, Schuchter L, Spitz FR, Czerniecki BJ, Guerry D. Identification of high-risk patients among those diagnosed with thin cutaneous melanomas. J Clin Oncol 2007 Mar 20;25(9):1129–34. 17 Balch CM. 2009 AJCC Staging System for Melanoma. 2009, Personal Communication. 18 Price NM, Rywlin AM, Ackerman AB. Histologic criteria for the diagnosis of superficial spreading melanoma: formulated on the basis of proven metastastic lesions. Cancer 1976;38:2434–41. 19 Ruiter DJ, van Dijk MC, Ferrier CM. Current diagnostic problems in melanoma pathology. Semin Cutan Med Surg 2003 Mar;22(1):33–41. 20 Day CL Jr, Harrist TJ, Gorstein F, Sober AJ, Lew RA, Friedman RJ, Pasternack BS, Kopf AW, Fitzpatrick TB, Mihm MC Jr. Malignant melanoma. Prognostic significance of “microscopic satellites” in the reticular dermis and subcutaneous fat. Ann Surg 1981;194:108–12.

C ASE

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WITH

MICROS COP IC

S AT E L L I T E S

8.1 Nodular Melanoma with Microscopic Satellites

C L I N I C A L I N F O R M AT I O N

An irregularly pigmented lesion of the right elbow, which had recently increased in size, in a 46-year-old woman. R E A S O N F O R C O N S U LTAT I O N

Submitted at patient request for a second opinion. DESCRIPTION

Sections of the original biopsy show a cellular proliferation of uniformly atypical epithelioid melanocytes forming a nodular tumor, with filling and expansion

of the papillary dermis and infiltration of the reticular dermis, extending close or to lateral specimen margins and the base of the biopsy. There is a focally brisk, but overall non-brisk, admixture of tumor-infiltrating lymphocytes. In summary I interpret this material as follows. Mitotic figures are readily identified but are not frequent. There are separate clusters of tumor cells at the base of the lesion, consistent with microscopic satellites, and there is a suggestion of lymphovascular invasion.

Scanning magnification demonstrates a nodular tumor that, at first glance, appears relatively symmetrical and is well circumscribed. FIG URE 8.1.1.

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The lesion presents with very large, irregularly sized and shaped nests of uniformly atypical epithelioid melanocytes at the dermal-epidermal junction, and extending into the dermis. There is tumor necrosis in the center of one of the large nests. FIG UR E 8.1.2.

A tripolar mitotic figure is present at the area circled in Figure 7. Mitotic figures were also demonstrable in the dermal component (not shown). FIGURE 8.1.3.

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8.1

F IGUR E 8.1.4.

lymphocytes.

There are focal areas of tumor-infiltrating

At the base of the lesion, smaller cells are present, which infiltrate into the reticular dermis as cords and clusters of cells rather than dispersing as single cells at the base. FIGURE 8.1.5.

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8.1

FIGUR E 8.1.6.

Close to the inked specimen base, there are clusters of cells separated from the main tumor, constituting microscopic satellites.

FIGURE 8.1.7.

An HMB45 stain highlights the tumor cells, but the nevus cells are negative.

F I G U R E 8.1.9.

FIG UR E 8.1.8.

Near one periphery of the lesion, there is a hair follicle around which there are smaller, more nevoid cells, consistent with an associated nevus.

positive.

In a Melan-A study, the nevus cells are also

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8.1 DIAGNOSIS

Skin, left elbow, biopsy: Malignant melanoma, nodular type, Clark level IV, greatest Breslow thickness 2.75 mm, nonulcerated, with tumorigenic and mitogenic vertical growth phase; see previous discussion and comment.

COMMENT

The Melan-A study demonstrates tumor, near the base of the biopsy, considered most likely to represent microscopic satellites.

F IGUR E 8.1.10 .

The dermal mitotic rate is low at 1/mm2, tumorinfiltrating lymphocytes are focally brisk but overall non-brisk, there is no radial growth phase regression, there is no ulcer, and there is no perineural invasion. There is extensive involvement of the reticular dermis suggestive of microscopic satellites versus extensive local infiltration, and there is a suggestion of lymphovascular invasion. The lesion is minimally excised in the original biopsy specimen and completely excised in the re-excision procedure. Submitted sentinel nodes were negative.


OVERALL COMMENT


The presence of microscopic satellites beneath the tumor would be considered to upstage the tumor, although it is not clear that these were considered (in contrast to clinical satellites) when the 2002 AJCC tagging system was developed. By definition, microscopic satellites are discrete tumor nests, greater than 0.05 mm in diameter, that are separated from the

main body of the tumor by normal reticular dermal collagen or subcutaneous fat (20). In case of doubt, as here, the worst-case scenario should probably be followed. If these foci were considered to be a part of the main tumor, which has been advocated by some, the thickness would be 3.3 mm.

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8.2 Balloon Cell Melanoma vs. Nevus

C L I N I C A L I N F O R M AT I O N

A lesion from the thigh of a 24-year-old female, submitted with the clinical history: “rule out dysplastic nevus.” R E A S O N F O R C O N S U LTAT I O N

Is this a balloon cell melanoma, or a nevus? DESCRIPTION

These sections show a shave biopsy of skin containing a moderately to highly cellular proliferation of nevoid melanocytes in the dermis and in the epidermis, where, at the periphery of the lesion, they are present as single cells and nests, mainly along the dermal epidermal junction. There is a prominent admixture of balloon cells in the junctional component, and focally these tend to become confluent and involve at least the lower third of the epidermis in a pagetoid pattern. At the periphery of the lesion, there are some nests that bridge between

adjacent elongated rete ridges, and there is moderate to severe random atypia, consistent with melanocytic dysplasia. Similar cells protrude into the papillary dermis, arranged in small nests, cords and strands, which extend into the reticular dermis, showing only slight evidence of maturation from superficial to deep. Cells in the dermis also demonstrate moderate to severe cytologic atypia in the form of nuclear enlargement, irregularity, and pleomorphism of randomly scattered lesional cells. In addition, mitotic figures are readily detected in the dermal component, with at least one high-power field containing two mitoses. Despite the presence of a suggestion of maturation from superficial to deep, this is incomplete and, because of the presence of dermal atypia with mitotic activity as well as the changes in the epidermis, I believe this lesion is best interpreted as a melanoma, which I characterize as follows:

Two section planes from the same lesion are shown: one demonstrating prominent balloon cell change of the junctional component, the other demonstrating a spindle to epithelioid cell proliferation in the dermis. FIG URE 8.2.1.

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ME L ANOMA

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8.2

There is a proliferation of large epithelioid melanocytes with pale “ballooned” cytoplasm. There is pagetoid extension of the lesional cells into the epidermis, and there is variation in size, shape, and orientation of nests and a tendency to confluence.

FIGURES 8.2.2 A N D 3 .

The other piece of tissue has only scant junctional component. There is a moderately cellular dermal component comprised of spindle to epithelioid cells. These are arranged in anastomosing fascicles, reminiscent of a “variant” or “accretive” pattern of vertical growth phase (see next case). However, the nests are confluent, and the proliferation is therefore best considered tumorigenic. There is little or no evidence of maturation from superficial to deep, and the process is transected at the base of the biopsy. FIG URES 8.2.4 A N D 5 .

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8.2 COMMENT

An occasional mitotic figure is present in the dermal component. In addition, there is moderate to severe lesional cell nuclear atypia in the form of enlargement, irregularity of nuclear membranes, hyperchromatism, and coarsely clumped chromatin. FIG URE 8.2.6.

The differential diagnosis for this lesion could include severe dermal and epidermal dysplasia or possibly an unusual form of spindle and/or epithelioid cell melanocytic nevus/tumor of uncertain malignant potential. As noted previously, however, because of the presence of dermal atypia and mitotic activity in lesional cells that are not characteristic for a Spitz tumor, I believe that this lesion is best interpreted as a melanoma showing at least Clark level IV invasion at a greatest Breslow thickness of not less than 0.7 mm, transected at the base. There is unusual balloon cell change of the junctional component, and the lesion may have arisen in association with a compound dysplastic nevus.

DIAGNOSIS

Skin, left lateral thigh: Malignant melanoma, superficial spreading type, with prominent balloon cell change of the junctional component, and tumorigenic and mitogenic invasive vertical growth phase, Clark level IV, greatest Breslow thickness not less than 0.7 mm, transected at the specimen base; see previous discussion and comment.


OVERALL COMMENT


The combination of cytologic atypia and mitotic activity, in the dermal component of a melanocytic lesion that is not a Spitz tumor, is always concerning for mel-

anoma. Balloon cells are nonspecific and may be seen in nevi as well as in melanomas. The usual architectural and cytologic criteria for diagnosis apply.

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8.3 Melanoma with Accretive Vertical Growth Phase vs. Radial Growth Phase Only C L I N I C A L I N F O R M AT I O N

A lesion on the right side of a 45-year-old female. There was no clinical description or clinical diagnosis offered by the surgeon. R E A S O N F O R C O N S U LTAT I O N

Is this an atypical nevus with epidermal changes secondary to irritation/rubbing, or should one be concerned with the possibility of melanoma or melanoma in situ arising within a nevus? DESCRIPTION

The sections show a skin biopsy containing a fairly broad, moderately cellular, melanocytic lesion about 4 mm in diameter on the slide and characterized at its periphery by single and nested melanocytes, arranged with nests somewhat predominating, predominantly near the dermal epidermal junction,

FIG URE 8.3.1.

with some nests bridging between adjacent rete ridges. In this area, there is generally moderate atypia of some randomly scattered occasional cell nuclei, whereas other lesional cells have smaller nuclei. Toward the center of the lesion, there is a dermal component comprised of nests of similar melanocytes, with little or no tendency to confluent sheetlike proliferation. However, in the overlying epidermis, the proliferation is somewhat more cellular, with a greater tendency to continuous proliferation between rete ridges, and with focal pagetoid extension of a few lesional cells into the epidermis, although generally not beyond the mid-spinous layer. In addition to these concerning findings, one or two mitotic figures are also present in lesional cells in the epidermis, but not in the dermal component. I therefore conclude that the junctional component has to be regarded, at least in part, as melanoma

Low magnification of the plaquelike lesion and low magnification images of its left and right borders are

shown. 235

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8.3 in situ and, because the lesional cells in the dermis resemble those in the epidermis in this area, I interpret the dermal component as representing an accretive vertical growth phase, characterized by

clusters of cells, none of which is larger than the largest intraepidermal cluster, forming a mass that fills and expands the papillary dermis. In summary, I interpret this lesion as follows:

The central portion of the lesion demonstrates two areas where the papillary dermis is filled and expanded by clusters of cells that, individually, are not larger than the largest intraepidermal clusters, but which nevertheless form a mass, constituting accretive, variant, or nontumorigenic vertical growth phase. FIG URES 8.3.2 A ND 3 .

The left-hand border of the lesion demonstrates an increased number of single and nested nevoid epithelioid melanocytes along the dermal-epidermal junction. This histology overlaps with that of a dysplastic nevus; however, the predominance of single cells and the relatively uniform albeit moderate atypia are concerning for a melanoma in situ. FIGURES 8.3.4 A ND 5 .

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The right-hand border of the lesion demonstrates nests that vary in size and shape and tend to become confluent and shows uniform moderate atypia of lesional cells. FIG URE 8.3.6.

The dermal tumor is comprised of uniformly, albeit moderately, atypical melanocytes, which show little evidence of maturation from superficial to deep. FIGURE 8.3.7.

FIG URE 8 . 3 . 6 .

Continued.

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The top and the bottom of one of the nodules demonstrate lack of maturation. The junctional component demonstrates confluent proliferation of uniformly atypical cells.

FIGURES 8.3.8 A ND 9 .

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In this other area of accretive vertical growth phase, again there is little evidence of maturation from superficial to deep. FIG URE 8.3.10 .

A Melan-A stain demonstrates nests in the dermis that are smaller than the largest nests in the epidermis. FIGURE 8.3.11.

DIAGNOSIS COMMENT

Skin, left thigh: Malignant melanoma, superficial spreading type, invasive, nontumorigenic, nonmitogenic accretive vertical growth phase, Clark level III, greatest Breslow thickness 0.93 mm, nonulcerated; see previous discussion and comment.

As noted previously, the dermal mitotic rate is zero, tumor-infiltrating lymphocytes are sparse, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic, or neural invasion. There is evidence of an associated, at least junctional, dysplastic nevus, and actinic elastosis in the adjacent skin is mild to moderate. The lesion appears to be completely excised; however, I, of course, recommend definitive appropriate therapy.

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8.3
OVERALL COMMENT


In “accretive” vertical growth phase, a mass is formed in the dermis by a buildup of nests derived from the epidermis, which are individually smaller than those in the epidermis. In cases such as this, there are, in addition, no mitoses. Therefore the lesional cells have acquired the ability to survive, but not to

proliferate in the epidermis, and the prognosis is correspondingly good, despite the fact that the lesions may become relatively “thick.” Elevated (polypoid or dome-shaped) nevi may be built up above the level of the skin surface by the same mechanism.

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8.4 Melanoma with Accretive Vertical Growth Phase vs. Severely Dysplastic Nevus C L I N I C A L I N F O R M AT I O N

DESCRIPTION

A variegated pigmented lesion from the back of a 58-year-old man.

The sections show a broad, highly cellular lesion, characterized in part by lentiginous and in part pagetoid proliferation of uniformly atypical cells in the epidermis. There is prominent pagetoid scatter and a low level of nesting. In the dermis, there is a nodule formed by accretion of small nests of moderately atypical melanocytes, without mitotic activity.

R E A S O N F O R C O N S U LTAT I O N

Case for review for treatment planning.

FIG URE 8.4.1.

Scanning magnification shows several levels of an excision procedure.

241

There is an extensive area of involvement of the epidermis, with widening of the papillary dermis. FIG URE 8.4.2.

In this area, there is striking high-level pagetoid proliferation of uniform atypical epithelioid melanocytes. FIGURE 8.4.5.

In this area, the pattern of proliferation is more lentiginous, although some pagetoid proliferation is also present. The appearances are reminiscent of junctional melanocytic dysplasia. FIGURE 8.4.6.

In this area, there is pagetoid proliferation of atypical cells in the epidermis, there is widening of the papillary dermis with diffuse hyperplasia and a bandlike lymphocytic infiltrate, and a few clusters of cells are present in the dermis, constituting invasive nontumorigenic and nonmitogenic radial growth phase. FIG URES 8.4.3 A N D 4 .

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There is a nodule that is comprised of multiple clusters of cells, none of which are larger than the largest clusters of cells in the epidermis. The proliferation is therefore nontumorigenic. However, the nodule that has been formed is termed vertical growth phase of the accretive type. The accretive vertical growth phase is only rarely associated with metastasis. FIG URE 8.4.7.

DIAGNOSIS

Skin, back. Malignant melanoma, superficial spreading type, nontumorigenic, nonmitogenic, accretive vertical growth phase, Clark level III, Breslow thickness 0.81 mm; see description and

There is little or no evidence of maturation from superficial to deep. There are no dermal mitoses. FIGURES 8.4.8 AND 9.

comment.

COMMENT

The dermal mitotic rate is zero, tumor-infiltrating lymphocytes are absent, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic, or perineural invasion. There are changes suggestive of an associated junctional dysplastic nevus. Excision is complete.


OVERALL COMMENT


This case is somewhat ambiguous, because the nests in the epidermis are few in number and also very

small. The absence of mitoses in the accretive vertical growth phase is reassuring.

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8.5 Malignant Melanoma, Lentigo Maligna Type, with Nevoid Vertical Growth Phase C L I N I C A L I N F O R M AT I O N

Lesion of the forearm in a 44-year-old man.

R E A S O N F O R C O N S U LTAT I O N

Confirm diagnosis of melanoma.

DESCRIPTION

These sections show an excision of an unusual lesion characterized at its periphery by a poorly circumscribed proliferation in the epidermis of single cells and some few nests that tend to hang down from the interface in a droplet-like pattern, with effaced rete ridges in chronically sun-damaged skin. Toward the center of the lesion, nevoid to epithelioid cells, somewhat similar to those in the epidermis, protrude into the papillary and upper reticular dermis, both as small nests and single files and also as much larger clusters of smaller nevoid cells. In my opinion, all of the cells

demonstrate generally moderate and quite uniform cytologic atypia, with little evidence of maturation from superficial to deep. Elsewhere in the lesion yet again, there is diffuse fibroplasia of the papillary dermis, with focal absence of changes in the dermis and epidermis, consistent with radial growth phase regression. Taking these findings together, I agree with the diagnosis of melanoma, with mixed pagetoid and lentiginous features, most likely of the lentigo maligna type, which can have substantial nevoid differentiation in its invasive component. The diagnosis is based on the combination of the atypical junctional component, the variation in morphology in the dermis, the failure of maturation in the dermis, and the fibroplasia with focal evidence of regression. It is possible that the smaller nested pattern in the dermis could represent a remnant of an associated nevus; however, I do not favor this for the reasons previously given. In summary, I interpret this material as follows:

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Scanning and low magnification images of a highly cellular, asymmetrical melanocytic tumor are shown. There are two major patterns in the dermis. FIGURES 8.5.1 A N D 2 .

One pattern is comprised of uniformly atypical epithelioid to nevoid melanocytes, arranged in fascicles infiltrating among reticular dermis collagen fibers. FIGURES 8.5.3 A N D 4 .

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In the overlying epidermis, there is an in situ proliferation of atypical single cells without nesting and with low-level pagetoid scatter. FIG URE 8.5.5.

These cells do not mature much from superficial to deep, and they do not disperse as single cells into the reticular dermis at the base. FIG URES 8.5.6 A ND 7 .

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Although small, the cells are atypical, and they show little evidence of maturation from superficial to deep. FIGURE 8.5.10.

COMMENT

The other component is comprised of small nevoid cells, arranged in nests that tend to be very large and irregularly distributed and that vary considerably in size. FIGURES 8.5.8 AND 9.

DIAGNOSIS

Skin, left forearm: Malignant melanoma, lentigo maligna type, with nevoid tumorigenic, nonmitogenic vertical growth phase, showing superficial Clark level IV invasion, and greatest Breslow thickness of 0.69 mm; see previous discussion and comment.

The dermal mitotic rate is zero, tumor-infiltrating lymphocytes are essentially absent with patchy noninfiltrating lymphocytes, there is focal radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic, or neural invasion. There is no definitive evidence of an associated nevus, and actinic elastosis in the adjacent skin is moderate.

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8.5
OVERALL COMMENT


Even though mitoses were not identified, the combination of findings in this case requires a diagnosis of melanoma, in my opinion. The invasive component is nevoid, but the lesion is not a nevoid melanoma

because of the scanning magnification appearance, which is highly suggestive of melanoma because of the cellularity, the asymmetry, and the atypical junctional component.

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B L UE

NE VUS

8.6 Nodular Melanoma vs. Malignant Blue Nevus with Lymph Node Involvement vs. Nevus C L I N I C A L I N F O R M AT I O N

DESCRIPTION

A 59-year-old man had a lesion on his left arm for many years, with recent changes.

These sections show, in the original biopsy, a bulky tumor, comprised for the most part of large epithelioid melanocytes, infiltrating from the papillary dermis well into the reticular dermis, to be transected at the base of the biopsy. The cells exhibit uniform cytologic atypia, with readily detectable mitoses, including at least one high-power field that contains three mitoses. The lesional cells are arranged in nests, plexiform fascicles, and sheets. They show little or no evidence of maturation from superficial to deep. All of these findings would be consistent with the diagnosis already rendered of melanoma. An unusual feature, of course, is the lack of any evidence of a junctional component, with the top of the tumor being separated from the epidermis by a narrow grenz

R E A S O N F O R C O N S U LTAT I O N

The biopsy is peculiar in appearance. I wondered about a strange lesion that is not quite melanoma, but I found some scattered mitoses, therefore agreed with the original diagnosis of melanoma. All are negative except for two intracapsular foci. Could the findings in the lymph node represent a precursor lesion? Or is there an alternative diagnosis of the lesion itself (i.e., something in the range of epithelioid blue nevus, or atypical cellular blue nevus)? Or is it possible to have pure intracapsular metastasis? I greatly appreciate your opinion.

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FIG URES 8.6.1 A ND 2 .

Scanning magnification shows multiple sections of a bulky, highly cellular tumor in skin.

zone, which does not show evidence of fibroplasia, to suggest a regressed superficial component. Therefore, the lesion may have arisen in relation to a dermal precursor, and there is suggestive evidence in some foci of the possibility of a preexisting cellular blue nevus, with a so-called mixed-biphasic pattern of relatively clear cells in ill-defined nests separated by more heavily pigmented spindle cells. Be that as it may, I believe that this lesion has to be interpreted as a malignant melanoma and, based on the previous speculation, it could perhaps be considered to be a form of malignant blue nevus. In summary I interpret this lesion as follows. Multiple sections of lymph nodes received for review show, as you described, and also in the originating laboratory’s report, foci of pigmented

spindle cells in the lymph node capsule. These are strikingly positive with S100 and Mart-1, but negative with HMB45. Morphologically, these clusters are small, comprised of cells that are spindled and contain moderately abundant, rather coarse melanin pigment granules. There is some nuclear variability; however, there is no marked nuclear pleomorphism, no nucleoli, and no mitotic activity. I do not believe these findings are diagnostic of metastatic melanoma. I might speculate, because of the pigmentation, that they represent nodal involvement by the putative antecedent cellular blue nevus. Because this is a highly unusual set of circumstances, it is difficult to be entirely certain about the nature and significance of these nodal cells, and I therefore interpret them, to some extent, descriptively as follows.

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8.6

The lesional cells are separated from the epidermis by a grenz or clear zone, and, except for a few single cells, there is no junctional or in situ component. FIG URE 8.6.3.

FIGURE 8.6.3.

Continued.

The lesion is comprised of spindle cells that infiltrate among reticular dermis collagen fiber bundles at the periphery. There is no clear evidence of a background blue nevus component. FIGURE 8.6.4.

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There is no evidence of maturation of the cells from superficial to deep. Cells at the base infiltrate dermal collagen and skin adnexa. Tumor cells are noted around and within nerves (perineural and intraneural invasion).

FIGURES 8.6.5 A ND 6 .

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8.6

Mitotic figures are readily identified, although the overall rate is low at approximately 2/mm2. The mitotic figure demonstrated is present within the green circle on the Web figure. FIG URE 8.6.7.

There is an area within the tumor comprised of more heavily pigmented spindle cells, with suggestion of nested differentiation, suggesting the mixedbiphasic pattern of a cellular blue nevus. F I G U R ES 8 . 6 . 8 A N D 9 .

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In the capsule of a sentinel node, there are two collections of pigmented spindle cells. These are smaller than the pigmented cells within the main tumor. They are strongly positive with Melan-A (Figure 8.6.11) and negative with HMB45 (Figure 8.6.12). Cytologically, they are benign, and likely represent capsular nevus cells. The pigmentation is unusual and could be consistent with a capsular nevus deposit from a preexisting cellular blue nevus component of the primary lesion.

FIGURES 8.6.10–12.

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8.6 DIAGNOSIS

Skin, right arm: Malignant melanoma, tumorigenic and mitogenic vertical growth phase, Clark level at least IV, Breslow thickness not less than 5.4 mm; see previous discussion and comment. Lymph nodes, right axilla: Lymph nodes with several small (0.2 mm) capsular deposits of pigmented spindled melanocytes, of uncertain significance, favor capsular nevi, possibly involvement by cellular blue nevus; see previous discussion and comment.

COMMENT

In the primary lesion, the mitotic rate is low to intermediate at 2.7/mm2, tumor-infiltrating lymphocytes are patchy and sparse, there is no radial growth phase

regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular or lymphatic invasion. Perineural and intraneural invasion is present, and this could represent a risk factor for local recurrence; however, the reportedly negative re-excision procedure is reassuring in this regard. Careful follow-up is, obviously, indicated. There is some evidence (clinically as well as histologically) of a possible associated precursor lesion in the general category of a cellular blue nevus, in which case this lesion could be regarded as a malignant blue nevus. There is moderate actinic elastosis in the adjacent dermis. As noted previously, it is difficult to be entirely certain of the significance of the capsular spindle cells; however, in my opinion, they are most likely benign. Based on the uncertainty, I think that one might consider a “watchful waiting” strategy for the regional lymph nodes, although, if desired for complete reassurance, a completion node dissection might also be considered.


OVERALL COMMENT


Although tumorigenic and mitogenic and thus apparently fully malignant deposits may be found in association with malignant and cellular blue nevi, the deposits in this case were cytologically bland, nonmitogenic, and confined to the capsule, consistent with benign nevus cells. The absence of an in

situ component and the presence of a focal mixedbiphasic pattern suggests that this lesion may be a malignant blue nevus rather than a more usual form of melanoma; the prognostic and therapeutic implications of either diagnosis are the same.

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8.7 Regressed Tumorigenic Melanoma vs. Inflammatory Dermatosis with Pigmentary Incontinence C L I N I C A L I N F O R M AT I O N

Variegated nodule on the left arm of a 75-year-old woman; rule out melanoma. R E A S O N F O R C O N S U LTAT I O N

I am concerned about the possibility of a regressed melanoma. DESCRIPTION

The sections show a most unusual lesion, well described in your report and letter. There is a region in which there is epidermal hyperplasia, with marked pigmentary incontinence, extending over a breadth of nearly a centimeter, and with a central region where there is a marked inflammatory reaction in the dermis, elevating the overlying hyperplastic

epidermis. Within this region, there are some scattered larger cells in a background of small lymphoid cells. The larger cells have somewhat irregular nuclei and prominent nucleoli. Immunostains prepared in your lab and submitted for review show that there is no Mart 1 reactivity in the dermis. There is, however, quite prominent S100 reactivity, some of which, as you note, appears to be extracellular. However, the large cells in question appeared to be more brightly positive. I am indeed concerned that these may represent remnants of a largely regressed tumorigenic melanoma, with a regressed radial growth phase on each side to account for the marked pigmentary incontinence. The appearances are not, of course, diagnostic of melanoma, and I interpret this lesion descriptively as follows:

Scanning magnification shows a nodular lesion characterized by essentially increased cellularity, flanked by a region of pigmentation in the papillary dermis. FIG URE 8.7.1.

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8.7

The pigment in this region is contained within cells with the characteristics of melanophages— large cells with abundant cytoplasm, stopped with coarse, divided melanin pigment granules. FIG URES 8.7.2 A N D 3 .

The area of nodularity is comprised, for the most part, of inflammatory cells, with overlying pseudoepitheliomatous hyperplasia, reminiscent of patterns seen in some melanomas and described as “verrucous melanoma.” FIG URE 8.7.4.

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FIG URES 8.7.5 A ND 6 .

Cells in the nodule are mostly inflammatory, but there is an admixture of larger cells in a region

near the base.

S100 staining reveals an area of ill-defined, diffuse, partly stromal staining in this region where the large cells are present. At higher magnification, a few large cells appear to be positive.

FIGURES 8.7.7 A ND 8 .

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8.7 DIAGNOSIS

Skin, right upper arm: Epidermal hyperplasia, extensive pigmentary incontinence, and nodular dermal inflammation with atypical cells; see previous discussion and comment.

COMMENT

Mart 1 staining does not demonstrate convincing reactivity, although a few cells are lightly decorated, again in the same region of the lesion. FIG URE 8.7.9.

As noted previously, I would be highly concerned that these changes may be attributable to a regressed tumorigenic melanoma. As you say, if interpreted as a melanoma, this lesion could have been quite substantial in thickness, of the order of up to 2.3 mm. There is no ulcer. I recommend managing this lesion with the differential diagnosis of such a melanoma taken into consideration. It is possible, of course, that this lesion could represent a regressed pigmented lesion of another type, such as a basal cell carcinoma; however, to my mind, the architecture of the lesion tends to favor melanoma rather than another type of tumor because of the suggestion of a regressed radial growth phase, as well as a regressed tumorigenic nodule of vertical growth phase. It might be worth doing additional immunostains to try to identify the large cells. One possibility might be MITF, which can give very clean labeling of neoplastic melanocytes, even in a background of other cells. I doubt that HMB45 or tyrosinase would be positive, given the negative Mart reaction.


OVERALL COMMENT


Because of the pigmentary incontinence, a lesion of this type can present clinical features, including variegated pigmentation and border irregularity, that are highly suggestive of melanoma, even in the absence of viable melanoma cells. In other cases, a regressing melanoma may seem to the patient to be “breaking up and going

away,” leading to a false sense of reassurance. As noted previously, a regressed, pigmented basal cell carcinoma, or another neoplasm in which pigment has been transferred from reactive melanocytes, could explain this appearance. However, the overall architecture of this lesion is quite suggestive of a regressed melanoma.

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9 Nevoid Melanoma

T

hese lesions, by definition, closely resemble benign melanocytic nevi at scanning magnification. They have been described as a “triggered trap” (1), because of the danger of misdiagnosis. These very difficult and treacherous lesions are subject to misinterpretation as benign nevi, because of the absence of prominent intraepidermal pagetoid spread and the presence of apparent maturation at the base of the tumor, mimicking benign nevi (2). The concept of nevoid melanoma can also include Spitzoid melanomas when the lesional cells are large; however, these are considered in a separate section in this monograph (2;3). The first use of the term has been attributed to Arnold Levene, who in 1980, in a review article, illustrated a lesion that he described as “verrucous and pseudonevoid in type” and characterized it as “among the more difficult diagnostic pitfalls” (4). The lesion was indolent clinically, resembling a warty intradermal nevus, both clinically and histologically. Closer examination, however, revealed that part of the lesion was composed of cells that were slightly larger and more hyperchromatic than nevus cells and that mitoses were present in this “seemingly innocent dermal infiltration.” There was also the appearance of nuclear crowding, which could be interpreted as maturation in the depths of the nevus. There may also be dispersion of single cells at the base, similar to “congenital pattern” nevi and different from most melanomas (1). Although many nevoid melanomas have a verrucous (or papillomatous) and pseudonevoid

architecture, characterized by epidermal hyperplasia reminiscent of a seborrheic keratosis, not all lesions have this epidermal reaction, and the simpler term “nevoid melanoma,” apparently first used in an extensive study by Schmoeckel in 1985, has remained in common use (5). Although the lesions had been described as “indolent” or “low-grade,” Schmoeckel emphasized that these were fully malignant neoplasms that were capable of causing metastasis and death. He described 33 patients, 15 of whom had developed metastases and 8 of whom had died of disseminated melanoma. He stated that “some” of the following histologic characteristics were always observed: “cellular atypia, mitoses, infiltration of the adnexa, and in the deeper dermis, infiltrative growth, pigmented tumor cells, sharply demarcated tumor nests, and the absence of maturation” (5). Although some other studies have described the presence of maturation at the base of the lesion, the presence of increased cellularity of the dermal component, recognized as a “sheetlike” proliferation rather than the predominantly nested architecture that characterizes most nevi in the dermis, has been appropriately emphasized (1;3;6). Others have also emphasized the frequent presence of continuous proliferation of single cells along the dermal-epidermal junction (4;7). In addition, “lateral intraepidermal spread” may also be present, albeit inconspicuous (by definition) on initial scanning magnification (8). McNutt studied 12 nevoid melanomas by immunohistochemistry. HMB45 staining was strong in the dermal component of the nevoid melanomas,

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whereas, in common acquired and congenital nevi, the upper dermal component stained less than the junctional component of the nevus, and the deepest components of the nevi were negative. The use of a proliferation marker such as Ki-67 was also recommended and described (3). However, stringent criteria for the use of these markers are not available. There is consensus among recent reports that the presence of mitoses is, for all intents and purposes, required for the diagnosis of a nevoid melanoma (6;9). Nevertheless, not all “nevi with mitoses” are nevoid melanomas. A rare mitosis may be present, for example, in nevi removed from pregnant patients (10), and anecdotally, mitoses have been seen, sometimes multiple, in otherwise histologically benign nevi, usually from children or young adults. In addition, of course, dermal mitoses are commonly seen in Spitz nevi/tumors (11). Therefore, as in other areas of pathology, no single diagnostic criterion can be used to rule this difficult diagnosis either in or out. Clearly, there are examples of “gray zone lesions,” in which there may be a rare mitosis, areas of hypercellularity, or slight atypia of the dermal component, in which a nevoid melanoma cannot be ruled out; however, conversely, a specific diagnosis of melanoma cannot be made with confidence. In my opinion, these lesions can best be interpreted descriptively as “melanocytic tumors of uncertain malignant potential (MELTUMP),” and management can be offered, with the differential diagnosis of melanoma taken into consideration (12;13). It seems likely that prognostic factors developed in studies of more usual forms of melanoma are, in general, applicable to nevoid melanomas as well (6;14). However, because these lesions generally have a low mitotic rate, which is predictive of better survival (15), their prognosis may indeed, as has been suspected in the literature, be at least somewhat better than might be

expected in view of their usually relatively considerable thickness.

References 1 McNutt NS. “Triggered trap”: nevoid malignant melanoma. Semin Diagn Pathol 1998 Aug;15:203–9. 2 Wong TY, Duncan LM, Mihm MC Jr. Melanoma mimicking dermal and Spitz’s nevus (“nevoid” melanoma). Semin Surg Oncol 1993 May;9(3):188–93. 3 McNutt NS, Urmacher C, Hakimian J, Hoss DM, Lugo J. Nevoid malignant melanoma: morphologic patterns and immunohistochemical reactivity. J Cutan Pathol 1995 Dec;22(6):502–17. 4 Levene A. On the histological diagnosis and prognosis of malignant melanoma. J Clin Pathol 1980;33:101–24. 5 Schmoeckel C, Castro CE, Braun-Falco O. Nevoid malignant melanoma. Arch Dermatol Res 1985;277:362–9. 6 Zembowicz A, McCusker M, Chiarelli C, Dei Tos AP, Granter SR, Calonje E, McKee PH. Morphological analysis of nevoid melanoma: a study of 20 cases with a review of the literature. Am J Dermatopathol 2001 Jun;23(3):167–75. 7 Suster S, Ronnen M, Bubis JJ. Verrucous pseudonevoid melanoma. J Surg Oncol 1987;36:134–7. 8 Blessing K, Evans AT, Al-Nafussi A. Verrucous naevoid and keratotic malignant melanoma: a clinico–pathological study of 20 cases. Histopathology 1993;23:453–8. 9 Ruhoy SM, Prieto VG, Eliason SL, Grichnik JM, Burchette JL Jr., Shea CR. Malignant melanoma with paradoxical maturation. Am J Surg Pathol 2000 Dec;24(12):1600–14. 10 Foucar E, Bentley TJ, Laube DW, Rosai J. A histopathologic evaluation of nevocellular nevi in pregnancy. Arch Dermatol 1985;121:350–4. 11 Weedon D, Little JH. Spindle and epithelioid cell nevi in children and adults: a review of 211 cases of the Spitz nevus. Cancer 1977;40:217–25. 12 Elder DE, Xu X. The approach to the patient with a difficult melanocytic lesion. Pathology 2004 Oct;36(5):428–34. 13 Xu X, Elder DE. A practical approach to selected problematic melanocytic lesions. Am J Clin Pathol 2004 Jun;121 Suppl: S3–32. 14 Stas M, Van den Oord JJ, Garmyn M, Degreef H, De Weever I, Peeters C. Minimal deviation and/or naevoid melanoma: is recognition worthwhile? A clinicopathological study of nine cases. Melanoma Res 2000 Aug;10(4):371–80. 15 Clark WH Jr, Elder DE, Guerry DIV, Braitman LE, Trock BJ, Schultz D, Synnestvedt M, Halpern AC. Model predicting survival in stage I melanoma based on tumor progression. JNCI 1989;81:1893–904.

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9.1 Nevoid Melanoma vs. Nevus

C L I N I C A L I N F O R M AT I O N

A mole from the left arm of a 63-year-old woman. R E A S O N F O R C O N S U LTAT I O N

Inability to reconcile melanocyte morphology with overall architecture. DESCRIPTION

These sections show a shave biopsy of a lesion characterized by a densely cellular proliferation of nevoid melanocytes, filling and expanding the

FIG URE 9.1.1.

papillary dermis, and located in chronically sundamaged skin. Although the lesional cells are quite mature and nevoid, there is little or no evidence of further maturation from superficial to deep. This pattern of increased cellularity is concerning for the possibility of a nevoid melanoma. Evidence of mitotic activity is required to establish this diagnosis. After scrutinizing multiple high-power fields, I finally found at least one dermal mitosis that appears to be abnormal. I therefore interpret this lesion as follows:

At scanning magnification, this lesion suggests a nevus, although it is somewhat asymmetric. 263

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There is no diagnostic in situ component. Actinic elastosis in the dermis is moderate to severe. The lesion is comparatively well circumscribed, with the last cells in the epidermis being in the form of nests on both sides. FIG URE 9.1.2.

The more central component of the lesion is highly cellular, with confluent sheetlike rather than nested proliferation of small nevoid melanocytes.

FIG URES 9.1.3 A N D 4 .

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9.1

There is little or no evidence of maturation from superficial to deep in the central component of the lesion. The junctional component (Figure 9.1.6) is comprised mostly of single cells; however, there is no extensive continuous basal proliferation or high-level pagetoid proliferation of uniformly atypical cells. The dermal cells are uniformly and mildly atypical. A rare mitotic figure was present (not shown), for a mitotic rate of 1/mm2. FIG URES 9.1.5 A N D 6 .

COMMENT DIAGNOSIS

Skin, left arm: Malignant melanoma, nodular type, with nevoid tumorigenic and mitogenic vertical growth phase, Clark level III, greatest Breslow thickness 0.70 mm, extending close to lateral specimen borders; see previous discussion and comment.

The dermal mitotic rate is low at 1/mm2, tumorinfiltrating lymphocytes are essentially absent, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic, or neural invasion. As noted previously, changes extend to specimen margins.


OVERALL COMMENT


Although, by definition, a nevoid melanoma resembles a nevus at scanning magnification, it is usually possible

to recognize increased cellularity and failure of maturation, as in this case, prompting a search for mitoses.

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9.2 Nevoid Melanoma vs. Nevus

C L I N I C A L I N F O R M AT I O N

A lesion of the right hip in a 48-year-old woman, which has increased in size over several years. R E A S O N F O R C O N S U LTAT I O N

Is this a combined nevus, or a melanoma? DESCRIPTION

As discussed in your report, this is a most unusual and difficult case. At first glance, as you note, the appearances suggest an unusual form of combined congenital pattern and spindle cell nevus, with some features of a cellular blue nevus. There are two major populations of cells, one being a smaller nevoid cell type, which extends into the reticular dermis, while showing no evidence of maturation and remaining cohesive rather than dispersing as single cells, as is more typical of congenital pattern nevi. The other

cell type is comprised of spindle cells, in a desmoplastic stroma, within which population there is a sprinkling of cells with much larger, hyperchromatic, and irregular nuclei. In addition, as you also noted, mitotic figures are rather readily detected, in both the spindle cells and the smaller, more uniform nevoid cells. In the overlying epidermis, there is nested and single-cell proliferation of pigmented epithelioid cells, with some focal tendency to pagetoid extension into the epidermis, although this is not extensive, nor does it extend, in general, to a high level of the epidermis. Taken together, the combination of cytologic atypia, mitotic activity, failure of maturation, and the atypical junctional component, coupled with a history of progressive change over a period of years, leads me to agree with your conclusion that this lesion must be regarded as melanoma, which I would characterize as follows:

Scanning magnification shows a lesion that, at first glance, resembles a nevus; however, the distribution of cells in the dermis is asymmetrical. FIG URE 9.2.1.

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There is an overlying junctional component, which is somewhat atypical but not diagnostic of melanoma in situ. The cells in the dermis in this area are plump spindle cells, arranged in fascicles that tend to become confluent. FIGURE 9.2.4.

The lesion is sharply delimited at its periphery, with no overlying or adjacent in situ component of the characteristic form of melanoma. FIG URES 9.2.2 A N D 3 .

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To the right of this field, there is a somewhat larger plump spindle cell population; to the left, there is a more nevoid population. These latter cells tend to mature, but they fail to disperse into the reticular dermis at the base, remaining distributed in a fascicular or clustered pattern. FIG URE 9.2.5.

The plump spindle cells on the right exhibit considerable nuclear variability. Mitotic figures were detected in both the spindle cells and the small cell type. FIGURE 9.2.6.

The small cells at the base are nevoid; however, they are arranged, for the most part, in solid clusters, although there is some suggestion of dispersion of single cells into the reticular dermis collagen. Nevertheless, a mitotic figure was observed in the cell type. FIG URES 9.2.7 A N D 8 .

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9.2 COMMENT DIAGNOSIS

Skin, right hip: Malignant melanoma, nodular type, with tumorigenic and mitogenic nevoid vertical growth phase, nonulcerated, showing Clark level IV invasion at a greatest Breslow thickness of 2.4 mm; see previous discussion and comment.

The dermal mitotic rate is generally low, although focally as high as 4/mm2, tumor-infiltrating lymphocytes are essentially absent, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic, or neural invasion. This is a most unusual lesion, which may have arisen in association with a preexisting congenital pattern nevus. Actinic elastosis in the adjacent dermis is essentially absent.


OVERALL COMMENT


One might consider the possibility of a cellular and proliferative nodule in a congenital pattern nevus; however, mitoses are observed in both cell types, and

both patterns of proliferation in the lesion are infiltrative rather than circumscribed.

SECTI O N

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9.3 Nevoid Melanoma vs. Nevus

C L I N I C A L I N F O R M AT I O N

A 45-year-old woman with a growing mole on the face; rule out melanoma. R E A S O N F O R C O N S U LTAT I O N

I am concerned about a nevoid melanoma, or a nevus with mitoses. DESCRIPTION

The sections show a melanocytic neoplasm that, at first glance, strongly resembles a nevus, being comprised of epithelioid to nevoid melanocytes superficially, which show some evidence of maturation from superficial

A cellular tumor in skin. Although somewhat asymmetrical, it has an overall architectural configuration suggestive of a congenital pattern nevus.

to deep. At the base of the lesion, indeed, there may be some authentic nevus cells, dispersing as smaller single cells into the reticular dermis collagen. More superficially, however, the cellularity is greater, with a tendency to a sheetlike rather than nested pattern of growth, and as you note, the lesional cell nuclei are relatively large and irregular, with prominent nucleoli, although without especially hyperchromatic chromatin. Of most concern, as you also note, is the presence of mitotic activity. I found several high-power fields in which two mitoses are present, and one of these high-power fields was in the lower third of the lesion. Coupled with the uniform atypia, the partial failure of maturation, and the increased cellularity, I agree that these changes are diagnostic of a nevoid melanoma, and I congratulate you for correctly recognizing this very difficult example, which I characterize as follows:

FIG URE 9.3.1.

There is no significant adjacent or overlying melanoma in situ component. FIGURE 9.3.2.

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9.3

There is evidence of maturation from superficial to deep, in part explaining the nevoid configuration of the lesion at low power. In addition, in some areas of the lesion, there are single cells dispersing among reticular dermis collagen fiber bundles, a pattern more characteristic of nevi than of melanomas (Figure 9.3.6). FIG URES 9.3.3 – 5 .

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Mitotic figures were readily demonstrated throughout the lesion, including some fields with two mitotic figures (e.g. Figure 9.3.7).

FIGURES 9.3.6 A ND 7 .

COMMENT DIAGNOSIS

Skin, face: Malignant melanoma, nodular type, with tumorigenic and mitogenic nevoid vertical growth phase, showing Clark level IV invasion at a greatest Breslow thickness of 1.7 mm; see previous discussion and comment.

The dermal mitotic rate is relatively low at 2/mm2, tumor-infiltrating lymphocytes are essentially absent, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic, or neural invasion. There is some evidence of an associated congenital pattern dermal nevus component. Actinic elastosis in the adjacent skin is moderate to severe. The lesion appears to be completely excised with minimal margins.


OVERALL COMMENT


The increased cellularity and failure of maturation in parts of this lesion are clues to the diagnosis, which is

confirmed by the mitotic activity.

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9.4 Nevoid Melanoma vs. Nevoid Epidermotropic Metastatic Melanoma

C L I N I C A L I N F O R M AT I O N

This is a papule, near a scar from a previously excised melanoma on the knee. R E A S O N F O R C O N S U LTAT I O N

I favor a compound nevus—I highly doubt a metastatic lesion. What you think? DESCRIPTION

The sections show a relatively small papule, comprised of fairly large epithelioid to nevoid melanocytes, arranged in nests and sheets, showing some

FIGURE 9.4.1.

evidence of maturation to a smaller cell type from superficial to deep, but infiltrating the reticular dermis as groups of cells rather than single cells. Cytologically, there is nuclear enlargement and irregularity with fairly prominent nucleoli, especially superficially. In addition, mitotic figures are readily detected. This combination of atypia and mitotic activity almost rules out a nevus; however, “nevi with mitoses” have, of course, been described. In this context, however, I strongly favor a metastasis from the nearby primary and characterize this lesion descriptively as follows:

Scanning magnification shows a relatively cellular, quite symmetrical, plaquelike lesion in the upper dermis. 273

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9.4

FIG URE 9.4.2.

There are a few nests in the epidermis.

Although there is some evidence of maturation, the cellularity of the dermal component is quite high, and there is uniform, albeit moderate, cytologic atypia. There is also a suggestion of involvement of an endothelial-like channel.

An abnormal mitosis is present in one of the cells in a dermal nest. FIGURE 9.4.3.

FIG URE 9.4.4.

D2-40 stain demonstrates a few lymphatic channels, one of which contains large cells, somewhat similar to those of the lesion. This finding could suggest the possibility of an epidermotropic metastasis. However, it is also possible that the large cells within the lumen are lymphatic endothelial cells, lymphocytes, or histiocytes. FIGURE 9.4.5.

DIAGNOSIS

Skin, right knee: Atypical melanocytic lesion,

COMMENT

most consistent with a nevoid focally epider-

According to history supplied in your note, this lesion is near a scar from a previously excised melanoma of the knee. The histologic characteristics of this lesion are entirely compatible with, if not absolutely diagnostic of, a differentiated or nevoid metastatic

motropic metastatic melanoma; see previous discussion and comment.

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9.4 melanoma deposit, no doubt related to this primary tumor. It might be helpful to evaluate characteristics of the primary melanoma to confirm that it was likely to have had capacity for metastasis and, in addition, follow-up will likely provide a more definitive answer over time. Changes extend close to the base of the shave biopsy, and an additional procedure might be considered or careful follow-up of the site, along with consideration of the possibility of additional regional or nonregional disease. In this context, evidence of lymphatic invasion can be diagnostic, and we have obtained a D2-40 stain, which demonstrates a few atypical cells in an endothelial lined lymphatic channel. This is highly concerning for lymphatic involvement and supports the suggestion of a nevoid epidermotropic metastatic melanoma. I recommend careful follow-up for the possibility of additional lesions. I am most interested in any follow-up that may become available in this case. ADDITIONAL COMMENT ( T H R E E W E E K S L AT E R )

This material has been reviewed again, in the light of history from the patient’s oncologist that the prior lesion was squamous cell carcinoma, not melanoma.

Again, the appearances are those of an atypical, predominantly dermal proliferation of epithelioid to nevoid melanocytes, extending from near the epidermis, with a few nests attached to the epidermis. Although there is some evidence of maturation from superficial to deep, this is incomplete, and the nevoid cells at the base do not disperse well as single cells into the reticular dermis. Superficially especially, the cells are large, with large, somewhat irregular nuclei and prominent nucleoli. At least three mitotic figures are identified in superficially located cells in the dermis. This combination of uniform atypia and mitotic activity is, to my mind, diagnostic of melanoma. In addition, there is evidence of lymphatic invasion. If this patient definitely does not have a prior melanoma, I believe this lesion should be interpreted and managed as a primary melanoma, with nevoid features, and its microstaging attributes are as follows: Clark level IV invasion, greatest Breslow thickness 0.37 mm, dermal mitotic rate 2/mm2, with probable focal lymphatic invasion, tumor-infiltrating lymphocytes non-brisk, no radial growth phase regression, no ulcer, no microscopic satellites. The lesion is minimally excised. I recommend reviewing the prior lesion, to be sure that the diagnosis of squamous cell carcinoma is correct.


OVERALL COMMENT


It may be impossible to distinguish an epidermotropic metastasis from a primary melanoma. This is especially so when the lesions are nevoid. However, the appearance of additional lesions over time

resolves the issue if the lesions are, in fact, metastatic. In the meantime, the initially presenting lesion should be treated as a primary melanoma.

SECTI O N

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9.5 Nevoid Vertical Growth Phase vs. Recurrent Nevus

C L I N I C A L I N F O R M AT I O N

A lesion from the left mid-lateral back of a 34-year-old pregnant woman. R E A S O N F O R C O N S U LTAT I O N

The microscopic differential diagnosis appears to include an atypical clonal congenital nevus, with recurrent nevus phenomenon, an atypical congenital nevus with melanoma in site, and invasive melanoma arising in a congenital nevus. We asked the clinician to query the patient carefully, and she indicates that there is absolutely no history of previous surgical intervention or partial removal of the lesion. With that information, we are leaning to a diagnosis of invasive melanoma arising in a congenital nevus. DESCRIPTION

The sections show a rather complex melanocytic lesion that presents considerable difficulties of

interpretation. In the epidermis, there is a proliferation of quite large epithelioid melanocytes, arranged in nests and as single cells, with some cells extending up into the epidermis in a pagetoid pattern, and with continuous proliferation of single cells along the dermal-epidermal junction. Cytologically, the cells have relatively abundant cytoplasm and quite large, somewhat irregular, and somewhat hyperchromatic nuclei, constituting moderate but relatively uniform cytologic atypia. Similar cells extend into the papillary dermis, in relation to a reaction of diffuse fibroplasia, which I consider more likely to be a stromal reaction than a reaction to prior trauma, and the cells infiltrate into the reticular dermis at the base of the lesion extending to the base of the biopsy. Although these cells have some tendency to nevoid maturation, they are quite different from another population of cells, present in the deep papillary and upper reticular dermis and in relation to a hair

Scanning magnification shows a cellular and asymmetric melanocytic proliferation, with diffuse fibroplasia of the papillary and reticular dermis. FIG URE 9.5.1.

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9.5 follicle, which have clear characteristics of dermal nevus cells of congenital pattern type. This dichotomy, I believe, adds to the concern for the atypical

component, and I agree with your conclusion that it must be regarded as malignant melanoma, which I characterize as follows:

There is continuous proliferation of uniformly atypical, large epithelioid cells along the dermal epidermal junction, apparently as a result of confluence of nests.

FIGURE 9.5.3.

FIG URE 9.5.2.

There are similar cells in the expanded and fibrotic papillary dermis.

FIGURE 9.5.5.

There is a population of smaller nevoid cells beneath the larger epithelioid cells in the epidermis and upper dermis. FIG URE 9.5.4.

epidermis.

The epithelioid cells resemble those in the

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9.5

The cells at the base appear to represent mature nevus cells, contrasting with the larger cells above them. FIG URE 9.5.6.

No mitotic figures were identified in the dermal component, and the Ki-67 proliferation rate in the dermis is minimal. FIGURE 9.5.7.

DIAGNOSIS

Skin, left mid lateral back: Malignant melanoma, superficial spreading type, with tumorigenic but nonmitogenic invasive somewhat nevoid vertical growth phase, Clark level IV, greatest Breslow thickness not less than 0.83 mm in the section plans available for my study, with occasional cells transected at the base of the speciAn HMB45 stain demonstrates a continuous basal proliferation in the epidermis, and there is variation or asymmetry in the staining pattern in the dermis, with the larger, more atypical cells preferentially labeled. FIG URE 9.5.8.

men; see previous discussion and comment.

COMMENT

The microstaging attributes previously mentioned relate to cells that may show some nevoid maturation, but they also resemble the cells in the overlying epidermis that, I believe, represent an in situ melanoma component. The dermal mitotic rate is zero (although there are a few cycling Ki-67 positive cells), tumor-infiltrating lymphocytes are sparse, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is

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9.5 no evidence of vascular, lymphatic, or neural invasion. This is a difficult lesion to interpret, but I do not believe that these changes can be ascribed to pregnancy, nor can the lesion be regarded as a benign combined nevus, which could enter the differential diagnosis. The diagnostic features of melanoma in this case, to my mind, reside predominantly in the junctional component.

There are a few cases, however, in which the recurrent nevus phenomenon appears to involve dermal cells. In this lesion, I believe that there are atypical melanocytes present, a short distance beyond the area of fibrosis and also within native collagen of the dermis, favoring a melanoma. However, I have reviewed this material with colleagues who feel that a diagnosis of recurrent nevus could be supported. I therefore amend the previous diagnosis as follows:

ADDITIONAL COMMENT ( T W O W E E K S L AT E R )

This material has been reviewed again, in light of our telephone conversation and evidence that a prior procedure was performed, at or near this site, four years ago (which had initially been denied). There is no additional history available at this time as to the pattern or timing of any subsequent changes, and I gather that it is not completely certain that the previous lesion—identified as “left flank” and interpreted as “intradermal melanocytic nevus”—is the exact same lesion as the present lesion, identified as “skin, left mid-lateral back.” In addition, “recurrent nevus” usually presents within a few weeks or months of the prior procedure, rather than slowly developing over a period of years, as it is more common with recurrent melanoma. In view of this history, however, the possibility of a so-called recurrent nevus phenomenon or pseudomelanoma deserves serious consideration. In this context, one looks for evidence of proliferation, beyond the lateral border of the scar, and also expects the proliferation to be predominantly intraepidermal.

AMENDED DIAGNOSIS

Skin, right mid-lateral back: Melanocytic tumor of uncertain malignant potential, differential diagnosis includes “recurrent melanocytic nevus” versus malignant melanoma, with the previously described microstaging attributes; see previous discussion and comment.

ADDITIONAL COMMENT

As noted previously, I am still concerned about the possibility that this lesion represents an authentic melanoma, with fibrosis that is either reactive or could be attributed to the prior biopsy. I recommend appropriate management with the previous differential diagnosis taken into consideration. This, of course, should certainly include an additional procedure, to be sure this lesion has been completely removed.

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9.5
OVERALL COMMENT


On initially reviewing this material, I was convinced that it had to be interpreted as a melanoma, because of the continuous proliferation in the epidermis and the uniform atypia of the junctional component, with similar cells in the dermis. The mature dermal nevus cells were interpreted as those of an associated or precursor nevus. On receiving the history of a prior procedure at this site, apparently several years ago, the diagnosis becomes less sure. However, it is unusual, in my experience, for the recurrent nevus

phenomenon to be associated with such a prominent dermal component as is present in this case. In addition, recurrent nevus typically occurs within weeks or a few months, rather than years. Therefore, I regard the biologic potential of this lesion as uncertain at best. It is also worth noting that, as in this case, clinicians may not be aware of a procedure that had been performed many years ago, often by a different physician. However, most “recurrent nevi” present within a few months of the initial procedure.

10 Desmoplastic and Neurotropic Melanoma

D

esmoplastic malignant melanoma may be defined as a form of vertical growth phase melanoma that consists of neoplastic spindle cells, each of which is separated by “desmoplastic” collagen fibers. This is the pattern of growth of a sarcoma, and it is of interest to note that, in older literature, the term “melanosarcoma” was commonly used and distinguished from “melanocarcinoma.” Desmoplastic melanoma was first described by Conley, Lattes, and Orr in 1971 as “a rare variant of spindle cell melanoma” (1). In the next few years, there was debate about the essential nature of this lesion. Although some considered the possibility that the tumors were essentially fibroblastic (2;3), it has subsequently become accepted that these lesions are derived from melanocytes, which can function as facultative fibroblasts to synthesize the desmoplastic stroma that separates the individual cells (4). In addition to fibroblastic differentiation, these tumors exhibit schwannian differentiation, in the form of wavy fiber bundles, consisting of elongated spindle cells with serpentine nuclei, and in the form of expression of neural crest markers, including nestin, peripherin, p75NGFR, and CD56/N-CAM (5–7). In some cases, the schwannian differentiation may be so striking as to simulate a neurofibroma or a neuroma, and, in many cases, the tumor involves peripheral nerves in a pattern of “neurotropic melanoma” (8). These lesions are characterized by atypical “neuromalike” patterns and by neurotropism. This phenomenon has also been referred to as “neurosarcomatous transformation” (9). Neurotropism is often found in association with a desmoplastic vertical growth phase,

but it may be found in association with other melanomas as well. In other cases, fibroblastic differentiation is sufficiently predominant that the lesions may be taken for a hyperplastic scar or a fibromatosis (10). In yet other cases, the lymphocytic infiltrate that characterizes these lesions may be a predominant feature, and the lesions may be mistaken for an inflammatory process such as lupus (11). Desmoplastic melanoma usually arises in association with an atypical intraepidermal melanocytic proliferation that is predominantly lentiginous in character. In some cases this proliferation is relatively subtle and not diagnostic of melanoma (8), but in most cases there is an associated in situ component, either of lentigo maligna (12), acral lentiginous (13), or mucosal lentiginous type (14–16). In other cases, a junctional component is lacking. In a series of 45 cases derived from consultation material, and therefore likely biased toward unusual cases, the tumors fell into three groups: (1) desmoplastic melanoma, with an atypical intraepidermal melanocytic component, or “classical desmoplastic melanoma”; (2) desmoplastic melanoma, without an atypical intraepidermal melanocytic component, or “de novo desmoplastic melanoma”; and (3) predominantly nerve-centered superficial dermal and/or subcutaneous malignant tumors, with or without an atypical intraepidermal melanocytic component, but sometimes associated with pigmentary abnormalities in the overlying skin (17). Although the spindle cell pattern in the dermis is a defining feature of desmoplastic melanoma, these lesions commonly have features of nondesmoplastic

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or “epithelial” melanomas as well. In the desmoplastic pattern, the collagen fibers separate individual lesional cells, whereas in the epithelial pattern the cells are, to some extent, cohesive, forming nests, fascicles, or sheets of cells. Recently, it has been recognized that this admixture of epithelial melanoma has prognostic significance. These lesions have been defined as “mixed” (desmoplastic and epithelial) desmoplastic melanomas. The prognosis of these mixed desmoplastic melanomas appears to be significantly worse than that of “pure” desmoplastic melanoma. At the same time, the prognosis of pure desmoplastic melanoma appears in some (but not all) studies to be better than would be expected on the basis of its Breslow thickness and Clark levels of invasion (18–24). This favorable prognosis may be the result of the usually low mitotic rate in a desmoplastic melanoma and, perhaps also, the presence of prognostically favorable tumor-infiltrating lymphocytes. In terms of the 1989 “Clark prognostic model,” melanomas with tumor-infiltrating lymphocytes and low mitotic rates can have excellent prognosis, even in tumors with level IV or V invasion, or with a Breslow thickness that is greater than 1.0 mm (25). Given the considerable difficulties in recognition of the often subtle desmoplastic melanoma vertical growth phase proliferation, it is not surprising that considerable attention has been paid to the development of immunohistochemical markers. S100 appears to be a reliably sensitive marker (26), present in virtually 100% of cases; however, this marker is not specific, staining normal structures, such as fat cells, and also cells that may be present in scars, including proliferating Schwann cells, and probably also reactive fibroblasts (27). Therefore, an S100 stain needs to be interpreted critically, and evidence of infiltration of S100 positive cells, with at least some degree of cytologic atypia, into normal stroma—as opposed to scattered S100 positive cells within the scar of the prior procedure—is necessary to make this diagnosis.

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It has been suggested that the p75 neurotrophin, or nerve growth factor receptor, may have a sensitivity comparable to that of S100 (6), and the neuroectodermal stem cell marker nestin was expressed in 9 of 9 desmoplastic melanomas in a recent study (5). At this time, however, these markers are not in common use for this purpose, and their specificity has not been completely evaluated. Other markers that have been studied, including HMB 45, Melan-A, MITF, tyrosinase, and others, are usually negative in the desmoplastic vertical growth phase compartment of desmoplastic melanomas (28–33). In fact, the finding of one of these markers in a spindle cell proliferation in the dermis should suggest another diagnosis, such as desmoplastic Spitz nevus/tumor, deep penetrating nevus, or blue nevus. It should be mentioned, however, that this limitation is primarily in the identification of infiltrating spindle cells of a desmoplastic melanoma. In a mixed desmoplastic melanoma, or in a melanoma with a junctional component, the “standard” melanoma markers are usually reactive in the epithelial and/or junctional components of the lesion. Therefore, these markers can be of value in the diagnosis of a spindle cell melanoma versus another form of spindle cell tumor (34).

References 1 Conley J, Lattes R, Orr W. Desmoplastic malignant melanoma (a rare variant of spindle cell melanoma). Cancer 1971;28:914–35. 2 Frolow GR, Shapiro L, Brownstein MH. Desmoplastic malignant melanoma. Arch Dermatol 1975;111:753–4. 3 Labreque PG, Hu C-H, Winkelmann RK. On the nature of desmoplastic melanoma. Cancer 1976;38:1205–13. 4 Valensi QJ. Desmoplastic malignant melanoma: a report on two additional cases. Cancer 1977 Jan;39(1):286–92. 5 Shimada S, Tsuzuki T, Kuroda M, Nagasaka T, Hara K, Takahashi E, Hayakawa S, Ono K, Maeda N, Mori N, Illei PB. Nestin expression as a new marker in malignant peripheral nerve sheath tumors. Pathol Int 2007 Feb;57(2):60–7. 6 Radfar A, Stefanato CM, Ghosn S, Bhawan J. NGFR-positive desmoplastic melanomas with focal or absent S-100 staining: further evidence supporting the use of both NGFR and

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S-100 as a primary immunohistochemical panel for the diagnosis of desmoplastic melanomas. Am J Dermatopathol 2006 Apr;28(2):162–7. Huttenbach Y, Prieto VG, Reed JA. Desmoplastic and spindle cell melanomas express protein markers of the neural crest but not of later committed stages of Schwann cell differentiation. J Cutan Pathol 2002 Oct;29(9):562–8. Reed RJ, Leonard DD. Neurotropic melanoma: a variant of desmoplastic melanoma. Am J Surg Pathol 1979;3:301–11. DiMaiao SM, Mackay B, Smith JL, Dickersin GR. Neurosarcomatous transformation in malignant melanoma: an ultrastructural study. Cancer 1982;50:2345–54. Spitz JL, Silvers DN. Desmoplastic melanoma (or is it merely cicatrix?) arising at the site of biopsy within a conventional melanoma: pitfalls in the diagnosis desmoplastic melanoma. Cutis 1995 Jan;55(1):40–4. Hantschke M. [Hypopigmented melanocytic tumors with spindle cells : A review.]. Pathologe 2007 Nov;28(6): 403–10. Egbert B, Kempson R, Sagebiel RW. Desmoplastic malignant melanoma: a clinicohistopathologic study of 25 cases. Cancer 1988;62:2033–41. Arrington JH III, Reed RJ, Ichinose H, Krementz ET. Plantar lentiginous melanoma: a distinctive variant of human cutaneous malignant melanoma. Am J Surg Pathol 1977;1:131–43. Kurihara K, Sanada E, Yasuda S, Yamasaki H. Desmoplastic malignant melanoma of the gingiva. Oral Surg Oral Med Oral Pathol 1992 Aug;74(2):201–5. Kilpatrick SE, White WL, Browne JD. Desmoplastic malignant melanoma of the oral mucosa: an underrecognized diagnostic pitfall. Cancer 1996;78:383–9. Rogers RS, III, Gibson LE. Mucosal, genital, and unusual clinical variants of melanoma. Mayo Clin Proc 1997;72:362–6. Jain S, Allen PW. Desmoplastic malignant melanoma and its variants: a study of 45 cases. Am J Surg Pathol 1989;13:358–73. Baer SC, Schultz D, Synnestvedt M, Elder DE. Desmoplasia and neurotropism: prognostic variables in patients with stage I melanoma. Cancer 1995;76:2242–7. Skelton HG, Smith KJ, Laskin WB, McCarthy WF, Gagnier JM, Graham JH, Lupton GP. Desmoplastic malignant melanoma. J Am Acad Dermatol 1995;32:717–25. Busam KJ, Mujumdar U, Hummer AJ, Nobrega J, Hawkins WG, Coit DG, Brady MS. Cutaneous desmoplastic melanoma: reappraisal of morphologic heterogeneity and prognostic factors. Am J Surg Pathol 2004 Nov;28(11):1518–25. Livestro DP, Muzikansky A, Kaine EM, Flotte TJ, Sober AJ, Mihm MC Jr., Michaelson JS, Cosimi AB, Tanabe KK. Biology of desmoplastic melanoma: a case-control comparison with other melanomas. J Clin Oncol 2005 Sep 20;23(27):6739–46. Scolyer RA, Thompson JF. Desmoplastic melanoma: a heterogeneous entity in which subclassification as “pure” or

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“mixed” may have important prognostic significance. Ann Surg Oncol 2005 Mar;12(3):197–9. Sassen S, Shaw HM, Colman MH, Scolyer RA, Thompson JF. The complex relationships between sentinel node positivity, patient age, and primary tumor desmoplasia: analysis of 2303 melanoma patients treated at a single center. Ann Surg Oncol 2008 Feb:15(2):630–637 Epub Dec 14. de Almeida LS, Requena L, Rutten A, Kutzner H, Garbe C, Pestana D, Gomes MM. Desmoplastic malignant melanoma: a clinicopathologic analysis of 113 cases. Am J Dermatopathol 2008 Jun;30(3):207–15. Clark WH Jr, Elder DE, Guerry DIV, Braitman LE, Trock BJ, Schultz D, Synnestvedt M, Halpern AC. Model predicting survival in stage I melanoma based on tumor progression. JNCI 1989;81:1893–904. From L, Hanna W, Kahn HJ, Gruss J, Marks A, Baumal R. Origin of the desmoplasia in desmoplastic malignant melanoma. Hum Pathol 1983;14:1072–80. Robson A, Allen P, Hollowood K. S100 expression in cutaneous scars: a potential diagnostic pitfall in the diagnosis of desmoplastic melanoma. Histopathology 2001 Feb;38(2):135–40. Skelton H III, Smith KJ, Barrett TL, Lupton GP, Graham JH. HMB-45 staining in benign and malignant melanocytic lesions. A reflection of cellular activation. Am J Dermatopathol 1991;13:543–50. Busam KJ, Iversen K, Coplan KC, Jungbluth AA. Analysis of microphthalmia transcription factor expression in normal tissues and tumors, and comparison of its expression with S-100 protein, gp100, and tyrosinase in desmoplastic malignant melanoma. Am J Surg Pathol 2001 Feb;25(2):197–204. Granter SR, Weilbaecher KN, Quigley C, Fletcher CD, Fisher DE. Microphthalmia transcription factor: not a sensitive or specific marker for the diagnosis of desmoplastic melanoma and spindle cell (non-desmoplastic) melanoma. Am J Dermatopathol 2001 Jun;23(3):185–9. Xu X, Zhang PJ, Elder DE. Tyrosinase expression in malignant melanoma, desmoplastic melanoma, and peripheral nerve tumors. Arch Pathol Lab Med 2003 Sep;127(9):1083–4. Kucher C, Zhang PJ, Pasha T, Elenitsas R, Wu H, Ming ME, Elder DE, Xu X. Expression of Melan-A and Ki-67 in desmoplastic melanoma and desmoplastic nevi. Am J Dermatopathol 2004 Dec;26(6):452–7. Lim E, Browning J, MacGregor D, Davis ID, Cebon JS. Desmoplastic melanoma: comparison of expression of differentiation antigens and cancer testis antigens. Melanoma Res 2006 Aug;16(4):347–55. Pawlik TM, Ross MI, Prieto VG, Ballo MT, Johnson MM, Mansfield PF, Lee JE, Cormier JN, Gershenwald JE. Assessment of the role of sentinel lymph node biopsy for primary cutaneous desmoplastic melanoma. Cancer 2006 Feb 15;106 (4):900–906.

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10.1 Desmoplastic Melanoma vs. Malignant Peripheral Nerve Sheath Tumor C L I N I C A L I N F O R M AT I O N

A “cyst” of the left shoulder in a 45-year-old man. R E A S O N F O R C O N S U LTAT I O N

Please evaluate this atypical spindle cell proliferation. DESCRIPTION

These sections show a malignant neoplasm consisting of elongated spindle cells, infiltrating extensively through the reticular dermis and into the subcutis, extending along septa of the panniculus. The elongated spindle cells have somewhat wavy fiber orientation, with serpentine nuclei suggestive of schwannian differentiation. There are focal areas

of more densely cellular proliferation reminiscent of melanoma. There is, however, no pigment. There is focally quite marked cytologic atypia. Mitotic figures are relatively infrequent but are present, with at least one abnormal figure. There is a patchy lymphocytic infiltrate, a feature commonly seen in desmoplastic melanomas, and there is focal neurotropism. There is no in situ component, which could indicate that the lesion is an example of Jain et al.’s so-called “de novo” or “nerve-centered desmoplastic and neurotropic melanoma” (17). However, the differential diagnosis could include other spindle cell tumors, and immunohistochemistry will be done to further characterize the lesion.

Scanning magnification shows an asymmetric proliferation of cells extending from the reticular dermis into the subcutis. FIG URE 10.1.1.

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The tumor extensively infiltrates the reticular dermis, extending into septa of the panniculus at the base and honeycombing the fat. FIG URE 10.1. 2 .

There is only a subtle, relatively inconspicuous proliferation of single melanocytes in the overlying epidermis. There is no connection between this sparsely cellular and cytologically bland junctional component and the underlying tumor (see S100 stains). FIGURE 10.1.3.

The tumor cells are separated from one another by a desmoplastic fibroblastic response. FIG URE 10.1.4.

FIGURE 10.1.5.

atypia.

In some areas there is significant cytologic

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Neurotropism was not prominent in this lesion. A small nerve in the center of the lesion appears to be involved focally. FIG URE 10.1.6.

There is extensive invasion of septa of the panniculus and extension into fat lobules in a honeycomb pattern, reminiscent of dermatofibrosarcoma protuberans. Ill-defined nodular clusters of lymphocytes are present, a characteristic finding in desmoplastic melanomas. FIGURE 10.1.7.

S100 staining demonstrates lack of connection to the overlying epidermis and a variably cellular proliferation, including some areas where the pattern of proliferation appears epithelial (lesional cells in contiguity, Figure 10) rather than desmoplastic (lesional cells separated by delicate desmoplastic fibrosis, Figure 9). FIG URE 10.1.8–10.

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10.1 DIAGNOSIS

Skin, shoulder: Malignant spindle cell tumor, infiltrating dermis and subcutis, extending close to the specimen base; see previous discussion and comment.

COMMENT

We have performed immunostains to better characterize the lesion. S100 is strongly and brightly positive in essentially 100% of the lesional cells. Melan-A, SMA, and CD34 are negative. These findings, including the negative Melan-A study, support a diagnosis of desmoplastic melanoma. Interpreted as a melanoma, this lesion shows Clark level V

invasion at a greatest Breslow thickness of approximately 10 mm, although it is focally transected at the base of the biopsy. The dermal mitotic rate is less than 1/mm2, tumor-infiltrating lymphocytes are non-brisk, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, perineural invasion is present within the tumor but not outside it, and there is no evidence of vascular or lymphatic invasion. The prognosis for desmoplastic melanomas may be somewhat better than expected for ordinary melanomas of comparable thickness, and this possibility is supported by the low mitotic rate and the presence of prognostically favorable infiltrating lymphocytes. I, of course, recommend definitive local therapy at the lesional site, with careful control of margins in the resection specimen, with S100 staining if appropriate.


OVERALL COMMENT


The diagnosis of desmoplastic melanoma, rather than malignant peripheral nerve sheath tumor, is favored by the strong and diffuse S100 staining. Some authorities have argued that sentinel lymph node biopsy is not necessarily indicated for “pure”

desmoplastic melanoma, because of the low yield of positive findings (34). However, this case is “mixed” and might be expected to have significant potential for metastasis to regional nodes (20).

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10.2 Desmoplastic Vertical Growth Phase vs. Regression in Lentigo Maligna Melanoma C L I N I C A L I N F O R M AT I O N

The patient is a 70-year-old female with a pigmented lesion of the right shoulder, present for several years. We received a 6-cm ellipse of skin, showing variegated tan to brown areas of pigmentation. R E A S O N F O R C O N S U LTAT I O N

I am concerned about a regressed melanoma, with a deeper spindle cell component, and would appreciate your opinion of Breslow thickness and Clark level. DESCRIPTION

The sections show a re-excision specimen of moderately sun-damaged skin. The sections show extensive

FIGURE 10.2.1.

residual melanoma in situ, characterized by basal lentiginous and partly nested proliferation of enlarged epithelioid melanocytes, with more extensive pagetoid proliferation into the epidermis toward the center of the lesion and with moderate pigment. Changes at the periphery are predominantly lentiginous and consistent with lentigo maligna melanoma in situ. There are multiple areas where lesional cells enter the dermis, sometimes in relation to a brisk lymphocytic infiltrate, and there is also extension downward around skin appendages. There are other areas where there is fibroplasia, without melanoma cells in the overlying epidermis, consistent with radial growth phase regression. As you also note, there is a subtle proliferation of spindle cells

A large resection specimen. An apparently superficial tumor can be seen in the top right corner of the image. 288

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10.2 extending from near the junctional component through the reticular dermis to its interface with the subcutis. Although many of the cells appear bland, others have enlarged, somewhat hyperchromatic nuclei. There is a focal patchy sprinkling of lymphocytes. These appearances are concerning on the hematoxylin and eosin sections for a component of desmoplastic melanoma,

and this is supported by reactivity of the cells with S100. They are negative with Melan-A, as one would expect. A few of the more epithelioid cells in the papillary dermis are positive for Melan-A, also an expected staining pattern. Focal neurotropism is present within the area of the desmoplastic vertical growth phase. In summary, I interpret this lesion as follows:

One can appreciate fibroplasia and widening of the papillary dermis to the left of the tumor.

FIGURE 10.2.3.

FIG URE 10.2.2 .

At high magnification, the area of widening and fibroplasia of the papillary dermis is associated with absence of melanoma in the overlying epidermis and in the dermis, consistent with locally complete radial growth phase regression.

The tumor is comprised of uniformly atypical epithelioid melanocytes, filling and expanding the papillary dermis and infiltrating the upper reticular dermis.

FIG URE 10.2.4 .

To the left-hand side of this area of regression, there is an atypical intraepidermal melanocytic proliferation. There are atypical melanocytes in the epidermis, mainly as single cells, with a bandlike lymphocytic infiltrate in the dermis. FIGURE 10.2.5.

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At the periphery of this in situ process, the pattern is predominantly that of single cells in the dermalepidermal junction, and, taken together, the appearances are those of an adjacent radial growth phase component of melanoma of the lentigo maligna type. FIG URE 10.2.6.

This figure, taken from beneath the tumor in Figure 3, demonstrates slightly increased cellularity of the reticular dermis, with a few slightly enlarged nuclei. FIG URES 10.2.7 A ND 8 .

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The S100 staining demonstrates atypical cells in the epidermis. At higher magnification, S100 positive cells are present in the native reticular dermis beneath the tumorigenic component previously illustrated. This is not a region of previous scarring. In addition, S100 positive atypical cells are present at the specimen margin (right of Figures 10 and 11).

FIGURES 10.2. 9 A N D 1 0 .

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The S100 staining demonstrates atypical cells in the epidermis. At higher magnification, S100 positive cells are present in the native reticular dermis beneath the tumorigenic component previously illustrated. This is not a region of previous scarring. In addition, S100 positive atypical cells are present at the specimen margin (right of Figures 10 and 11). FIG URE 10.2.11.

DIAGNOSIS

Skin, left shoulder: Malignant melanoma, lentigo maligna type, with extensive radial growth phase regression and desmoplastic vertical growth phase, tumorigenic but nonmitogenic, Clark level IV, greatest Breslow thickness 3.8 mm; see previous discussion and comment.

Melan-A staining demonstrates that the epithelioid cells near the surface are positive; however, the atypical spindle cells in the reticular dermis are completely negative in the Melan-A stain. FIGURE 10.2.12.

COMMENT

The dermal mitotic rate is zero, tumor-infiltrating lymphocytes are non-brisk, there is focal radial growth phase regression, there is no ulcer, and no microscopic satellites, and there is no evidence of vascular, lymphatic, or neural invasion. The bulk of the thickness of this tumor consists of “pure” desmoplastic melanoma, which tends to have a good prognosis; however, there is a component of epithelioid tumorigenic melanoma, making this a mixed desmoplastic and epithelioid vertical growth phase. The epithelioid component of the melanoma is less than 1 mm in thickness. I therefore

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10.2 expect the prognosis for this lesion to be better than its thickness might otherwise suggest, from the viewpoint

of metastatic potential. The changes do not involve the specimen margins.


OVERALL COMMENT


This case illustrates the subtlety of the desmoplastic component in some melanomas. The S100 stain is crucial for confirming the diagnosis and defining the extent of the infiltrating spindle cell component. Care should be taken, however, not to overinterpret scattered positive cells in an area of scarring—the diagnosis should be based on tumor cells infiltrating

native tissue, as in this case. The expected negativity with Melan A/Mart and other more specific melanoma markers should also be remembered when assessing differentiation, and can in addition be helpful in distinguishing desmoplastic melanomas from desmoplastic nevi, blue nevi, and other potential simulants.

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10.3 Desmoplastic Melanoma vs. Desmoplastic Nevus

C L I N I C A L I N F O R M AT I O N

Lesion of the back in a 33-year-old woman. R E A S O N F O R C O N S U LTAT I O N

We are questioning desmoplastic/spindle cell melanoma. DESCRIPTION

This lesion presents unusual difficulties of interpretation. The sections show a spindle cell lesion consisting of narrow elongated spindle cells, arranged for the most part as single cells separated by delicate collagen fibers constituting a desmoplastic lesion. Focally, especially superficially, there is a slight tendency to clustering. This is more marked in two of the six section planes on the hematoxylin and eosin stained slide, and, in one of these areas of clustering, there are two dermal lesional cell mitoses. Although the overall density of the lesional cells is low, a concerning feature at scanning magnification is their infiltrative quality and also the presence of multiple clusters of

Scanning magnification shows a portion of skin with an ill-defined increase of cellularity. There is no discrete tumor. Although not numerous, there are focal collections of lymphocytes, a feature more often seen in desmoplastic melanoma than nevi.

FIGURE 10.3.1.

lymphocytes, although most of these are quite small. At higher magnification, one observes fairly considerable enlargement, hyperchromatism, and pleomorphism of some of the lesional cell nuclei. In addition, there appears to be subtle evidence of neurotropism, in the form of a few large cells within scattered small cutaneous nerves. Despite the lack of any convincing in situ component of a melanoma, I consider these appearances to be very concerning for a desmoplastic melanoma. The Melan-A study, again, does not demonstrate any prominent in situ component; however, there is focal concentration of slightly enlarged melanocytes. In addition, although the vast majority of the cells in the dermis are negative, there are few scattered positive cells superficially, tending to

There is increased cellularity in the upper dermis, mostly consisting of spindle cells, with similar cells trickling down into the reticular dermis and around the skin appendage. FIGURE 10.3.2.

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10.3 support the diagnosis of a melanocytic tumor. The predominance negativity of the spindle cells, on the other hand, supports the diagnosis of a desmoplastic

melanoma rather than a desmoplastic nevus. I therefore conclude that this lesion must be regarded as a melanoma, which I characterize as follows:

Focally, there is substantial atypia, and in this area two mitotic figures were seen (not shown).

FIGURE 10.3.4.

FIG URE 10.3.3 .

Elsewhere in the lesion, the cellularity is lower; however, atypical spindle cells permeate the reticular dermis, extending to the base of the biopsy.

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S100 staining demonstrates a subtle increase of cellularity, extending throughout the full thickness of the reticular dermis. A Melan-A stain (not shown) highlighted a few prominent melanocytes in the epidermis but was completely negative in the dermal component of the lesion. FIG URE 10.3.5 A ND 6 .

DIAGNOSIS

Skin, back: Malignant melanoma, desmoplastic and neurotropic, with tumorigenic and mitogenic desmoplastic vertical growth phase, Clark level not less than IV, greatest Breslow thickness not less than 1.6 mm, extending to the specimen base; see previous discussion and comment.

COMMENT

As noted previously, this is a very difficult case; however, the finding of two dermal mitoses in

association with cytologic atypia confirms, to my mind, the diagnosis of malignancy. In this material, the lesion extends to Clark level IV, with a greatest Breslow thickness of at least 1.6 mm, and is transected at the base of the biopsy. The dermal mitotic rate is 2/mm2. Tumor-infiltrating lymphocytes are present and sparse. There is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic, or neural invasion. Actinic elastosis in the associated skin is absent or minimal. I recommend definitive management for this lesion based on the previously discussed microstaging attributes.

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OVERALL COMMENT


Although, at first glance, this lesion could represent a desmoplastic nevus, the mitotic activity and the cytologic atypia, in addition to the highly infiltrative and poorly circumscribed characteristics of this lesion, are

very concerning. In addition, the negative reactivity with Melan-A is much more characteristic of a desmoplastic melanoma than of a desmoplastic nevus, supporting the diagnosis of melanoma.

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10.4 Lentigo Maligna Melanoma with Early Vertical Growth Phase, Desmoplastic vs. Spindle Cell, vs. Severe Dermal and Epidermal Dysplasia, vs. Special Site Nevus of the Ear

C L I N I C A L I N F O R M AT I O N

A lesion of the left ear in a 64-year-old man. R E A S O N F O R C O N S U LTAT I O N

I favor a melanoma (Clark II, Breslow 0.65 mm) over that of a severely atypical nevus. What do you think? DESCRIPTION

The sections show a biopsy of a highly cellular melanocytic proliferation in chronically sun-damaged skin, characterized by single and nested melanocytes, arranged with single cells predominating in some areas along the dermal epidermal junction and with some nests that tend to hang down from the

interface. At the periphery of the lesion, the epidermis is thinned and the rete ridge pattern is effaced, whereas, toward the center of the lesion, there is some epidermal hyperplasia and some pagetoid involvement of the epidermis focally. Cells similar to those in the epidermis protrude into the papillary dermis, both as small groups of epithelioid cells and, focally, as spindle cells separated by collagen fibers in a desmoplastic vertical growth phase pattern. S100 and Melan-A studies were performed and support the diagnosis. The spindle cell invasive component is Melan-A positive, suggesting that it should perhaps be regarded as an invasive spindle cell rather than desmoplastic melanoma.

Scanning magnification shows a cellular proliferation of melanocytes in the epidermis with irregular thickening and thinning of the epidermis, and increased cellularity of the upper dermis. Fi gures 10.4.1 A ND 2 .

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The increased cellularity in the dermis is comprised of lymphocytes and larger cells, epithelioid and spindled in configuration, admixed with inflammatory cells, concerning for invasive and possibly desmoplastic melanoma. FIG URES 10.4. 3 A N D 4 .

S100 staining demonstrates the cellularity in the dermis. The spindle and epithelioid cells are positive, consistent with invasive melanoma. FIGURE 10.4.5.

Melan-A stains the same population of cells in the dermis, indicating that they are better regarded as invasive spindle cells, rather than desmoplastic vertical growth phase. FIGURE 10.4.6.

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10.4 DIAGNOSIS

Skin, right ear: Malignant melanoma, lentigo maligna type, with early tumorigenic spindle cell vertical growth phase, Clark’s level IV (superficial),

greatest

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approximately 0.45 mm; see previous discussion and comment.

COMMENT

The desmoplastic vertical growth phase is best seen on the first set of levels. In any event, I believe that

this should be regarded as established tumorigenic, but nonmitogenic, spindle cell vertical growth phase with desmoplastic features, and the re-excision specimen should be examined carefully with the possibility of residual desmoplastic vertical growth phase kept in mind. In this material, the dermal mitotic rate is zero, tumor-infiltrating lymphocytes are sparse, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic, or neural invasion. Changes in the epidermis extend to both margins, and changes in the dermis or around skin appendages extend close or to the specimen base.


OVERALL COMMENT


The possibility of a so-called special site nevus of the ear could be considered, but the asymmetry, confluent epithelial growth, and cytological atypia are features that strongly favor melanoma. In addition, the ear is the single most common site for melanoma in

men, after correction for unit area. Therefore, in my opinion, the diagnosis of a special site nevus of the ear should be made cautiously, if at all, in an atypical melanocytic lesion in a middle-aged or elderly man.

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10.5 Desmoplastic Melanoma vs. Malignant Peripheral Nerve Sheath Tumor C L I N I C A L I N F O R M AT I O N

A tumor of the scalp in a 43-year-old man. R E A S O N F O R C O N S U LTAT I O N

Please review this case. DESCRIPTION

These sections show a most unusual and difficult lesion. In the first biopsy, the sections show a tumor that extends to all margins of the biopsy specimen and measures about a centimeter in greatest dimension. There is a tumor comprised of spindle-shaped cells, arranged in complex patterns, including fascicles and whorls, with a somewhat storiform architecture in some areas. The cells in fascicles tend to have a wavy fiber orientation, with serpentine nuclei, very characteristic of schwannian differentiation and certainly simulating a neurofibroma very well indeed. Scrutiny of the lesion has revealed few, if any, mitotic figures, with none observed in a formal consecutive count of 50 high-power fields. However, one or two rare structures suggestive of a mitosis might be present. These are identifiable only in retrospect. In addition, also more apparent in retrospect, there is some variation in nuclear size and shape, although there is no really marked hyperchromatism. Given that the lesion recurred within a few months as a melanoma, with

quite similar characteristics to the present tumor, I would not characterize this lesion as a neurofibroma; however, if I had seen it prospectively, I very likely would have done so. For the present, I characterize this lesion as follows. Sections of the second specimen, from five months later, show a considerably larger tumor, which measured 3 cm grossly. Histologically, it is comprised of spindle cells similar to those seen in the initial biopsy. Cytologic atypia is somewhat more readily recognized in some areas, although in other areas the cells are quite bland. In addition, mitotic figures are rather readily recognized, with at least one highpower field containing two mitoses. There are, in addition, a few small clusters of lymphocytes, a finding that, as you note, is characteristic of desmoplastic melanoma and was not seen in the first biopsy. This tumor infiltrates fat, collagen, and, focally, skeletal muscle. There is obvious neurotropism within the tumor and at its periphery. Invasive tumor is transected at a green-inked specimen margin. Multiple sections of the overlying and adjacent epidermis show, in some areas, a lentiginous basal proliferation of atypical melanocytes, establishing the diagnosis of a desmoplastic melanoma. In my opinion, this diagnosis could not be made on the original biopsy. In summary, I interpret this present material as follows:

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10.5

FIGURE 10.5.1. A bulky tumor, extending from near the epidermis into the subcutaneous tissue.

There is no overlying in situ component characteristic of any form of melanoma. Most of the cells in the dermis are small spindle cells, placed between delicate collagen fibers. They are arranged in somewhat wavy fiber bundles, ill-defined but quite reminiscent of a neurofibroma. FIGURE 10.5.2.

At the base of the tumor, the spindle cells infiltrate and honeycomb the fat, perhaps suggesting the possibility of a dermatofibrosarcoma protuberans. FIG URE 10.5.3.

Wavy fiber bundles of delicate spindle cells with serpentine nuclei, indistinguishable from a neurofibroma. FIGURE 10.5.4.

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10.5

Toward the surface of the tumor, there was a more cellular area, with spindle cells growing in an epithelial rather than desmoplastic pattern. These findings are unusual in a neurofibroma. FIG URE 10.5.5 .

A vimentin stain emphasizes the placement of individual single spindle cells between collagen fibers but is otherwise not especially helpful diagnostically. FIGURE 10.5.7.

The lesion recurred, as a more cellular spindle cell tumor, about 4 months later. FIGURE 10.5.8.

Perineural and intraneural permeation of lesional cells could be seen in the neurofibroma-like lesion. FIGURE 10.5.6.

One small piece of tissue contained an intraepithelial proliferation of atypical melanocytes, consistent with melanoma in situ. FIGURE 10.5.9.

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10.5

The tumor presents alternating light and dark areas, reminiscent of a malignant peripheral nerve sheath tumor. FIG URE 10.5.10.

DIAGNOSIS

Skin, scalp, initial biopsy: Spindle cell tumor, extending to all specimen margins; see previous discussion and following comment. Skin, scalp, excision of recurrent lesion, 5 months later: Malignant melanoma, mixed desmoplastic and epithelial type with neurotropism, tumorigenic and mitogenic, Clark level V, greatest

Breslow

thickness

approximately

14 mm; see previous discussion and comment.

COMMENT

The architecture of the vertical growth phase is that of a desmoplastic melanoma, with some foci of more

Focally more cellular areas exhibiting an epithelial-like growth pattern, storiform areas, and an area resembling a peripheral nerve structure were seen. FIGURE 10.5.11.

contiguous growth of lesional cells in the epidermis, consistent with a mixed desmoplastic and epithelial melanoma. This feature may be associated with a worse prognosis than that for a pure desmoplastic melanoma, although this may be dependent on other factors, such as mitotic rate. The dermal mitotic rate in this tumor is low, but substantial, in this lesion at approximately 2/mm², and tumor-infiltrating lymphocytes are sparse, there is no radial growth phase regression, there is no ulcer, there are no microscopic satellites, and there is no evidence of vascular or lymphatic invasion. There is prominent neural invasion. The lesion is arising in severely sun-damaged skin, and there is no associated nevus. Changes of in situ melanoma extend close to specimen borders in the epidermis, and invasive melanoma extends to an inked specimen margin in the reticular dermis.


OVERALL COMMENT


Desmoplastic melanoma is notorious for simulating a benign lesion, such as a scar, a neuroma, or a neurofibroma. When there is an exceptionally prominent

lymphocytic response, an inflammatory lesion, such as lupus profundus, may be simulated.

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10.6 Desmoplastic Melanoma vs. Scar in Re-Excision

C L I N I C A L I N F O R M AT I O N

A 48-year-old woman, who had a lesion removed from right upper arm two years ago, now has a nonpigmented growth at left upper arm near/at scar. This was excised and diagnosed at outside hospital as desmoplastic melanoma and then re-excised. R E A S O N F O R C O N S U LTAT I O N

Please confirm diagnosis and presence of clear margins in final excision. DESCRIPTION

Sections of the excision specimen show a bulky tumor that extends from near the epidermis into the deep reticular dermis and subcutis, transected at the base of the specimen. At scanning magnification, there is

Low-power images show a bulky mass, characterized by nodular clusters of lymphoid cells, in a background of fibrous stroma, simulating an inflammatory reaction. FIG URE 10.6.1.

a strong impression of an inflammatory process, with brisk nodular deposits of lymphocytes, some with germinal centers. Closer inspection, however, reveals infiltrating cytologically atypical spindle cells and some areas separated from one another in a pure “desmoplastic” pattern and in other areas growing in contiguity with one another, forming nodules in an epithelial pattern of growth. Mitotic figures are readily recognized, although the overall mitotic rate is not high. Sections of the re-excision specimen showed superficial scarring, consistent with the prior procedure, extending into the subcutis. Deep to this area of cellular scar tissue, there is a region where there are nodular clusters of lymphocytes, drawing attention to infiltrating cytologically atypical spindle cells, similar to those in the excision specimen and present at the base of the

Nodular clusters of lymphocytes are quite prominent, with a suggestion of germinal center formation. The lesion is separated from the overlying epidermis by a narrow zone of uninvolved elastotic dermis. FIGURE 10.6.2.

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10.6 biopsy specimen. The cells are positive with S100 and were negative with MITF and Melan-A.

Scanning magnification of a re-excision specimen shows areas of apparent scarring in the upper dermis and a region of hypercellularity toward the base of the biopsy in the subcutis on the left. FIGURE 10.6.5.

Closer inspection reveals infiltrating cytologically atypical spindle cells among the lymphoid cells. Throughout most of the lesion, many of the spindle cells are separated by collagen fiber bundles in a desmoplastic melanoma pattern. FIG URE

10.6.3.

In other areas there is a nodular proliferation, with lesional cells contiguous with one another, in an epithelial pattern of growth. FIG URE 10.6.4.

Nodular clusters of lymphocytes are quite prominent in this region, and there is evidence of hypercellular desmoplastic proliferation. This is distinguishable from the scar in the upper portion of Figure 5. FIGURE 10.6.6.

Atypical spindle cells are present, infiltrating in the desmoplastic stroma, with associated lymphocytes. They resemble some of the spindle cells in the excision specimen. FIG URE 10.6.7.

F I G U R ES 1 0 . 6 . 8 A N D 9 .

cal spindle cells.

S100 labels the infiltrating atypi-

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10.6 DIAGNOSIS

Skin, right arm, excision: Malignant melanoma with mixed desmoplastic and epithelial vertical growth phase, Clark level V, Breslow thickness 16 mm, present at lateral and deep tissue margins; see microscopic description. Right arm, re-excision: Skin, residual desmoplastic melanoma, adjacent to prior procedure site, present within 1 mm from the deep tissue margin; see note.

COMMENT

Care should be taken not to overcall randomly scattered small S100 positive cells in the scar as desmoplastic melanoma. These may represent small Schwann cells or other reactive cells. A true desmoplastic tumor should be present outside the scar, infiltrating preexisting native tissue, as in Figures 7–9. FIG URE 10.6.10.

The dermal mitotic rate in the excision specimen is low at 1/mm2, tumor-infiltrating lymphocytes are overtly brisk but overall non-brisk, there is no radial growth phase regression, and there is no definitive in situ component. There is no ulcer. Focal neurotropism is noted within the main tumor. Immunohistochemical stains, performed at the outside institution (submitted for review), show atypical spindle cells, which are positive for S100 and MITF, in association with a brisk lymphoid infiltrate. The tumor cells are negative for cytokeratin AE1/AE3, CD34, SMA, p63, desmin, EMA, and HMB 45. The margins of resection are positive for tumor. In the re-excision specimen, stains performed at our institution, using material requested from the outside institution, demonstrate the presence of atypical S100 positive spindle cells less than 0.1 cm from the deep margin in the center of the specimen.

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10.6
OVERALL COMMENT


Residual desmoplastic melanoma can be very subtle, mimicking a scar histologically, and it can be extensively infiltrated with involvement of margins, as in this case. A high index of suspicion is required, with liberal use of S100 staining. Cytologic atypia is usually also present, although mitoses are usually rare or absent. It should be recognized that small S100 positive cells may be present in healing scars, possibly representing trapped Schwann cells or even reactive cells, such as fibroblasts. A clue to the presence of the tumor at the margin is the nodular lymphocytic infiltrate that is commonly associated with the atypical infiltrating cells and a desmoplastic melanoma. Perineural invasion should also be carefully looked for in a re-excision of a desmoplastic

melanoma. The “primary” lesion submitted for review in this case has no connection to the epidermis; however, there was a history of a prior procedure at this site three years before. It therefore could represent a persistent and recurrent desmoplastic melanoma or, alternatively, possibly a so-called nerve-centered desmoplastic melanoma arising in the dermis, possibly in relation to cutaneous nerves. However, neurotropism, although present, was not a prominent feature in this particular tumor. Sentinel lymph nodes were negative, as is often the case in pure desmoplastic melanoma. However, the existence of a mixed epithelial component in this particular tumor is associated with a significantly worse prognosis for distant metastasis.

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11 Metastatic Melanoma: Epidermotropic, Regressed, Nevoid

T

here is a greater range of variation of metastatic melanoma than is generally recognized. In particular, the well-differentiated “nevoid metastatic melanomas” can be misinterpreted as benign nevi, and “epidermotropic metastatic melanomas” can be misinterpreted as primary melanomas. Metastatic melanoma may present as local, regional, or distant disease. About 50% of all melanoma patients who develop metastases first develop regional lymph node metastases (1). In the other 50%, the first metastases are satellite (about 30%), in-transit metastases (about 20%), or distant metastases (about 30%). Local metastasis includes satellites, which are discontinuous foci of tumor in the dermis or subcutis that are located, by definition, within 5 cm of the primary tumor. Similar metastatic lesions that are greater than 5 cm from the primary tumor but still regional (i.e., proximal to the regional draining lymph nodes), are termed “in-transit” metastases. This distinction was originally made in order to differentiate local metastases that might be encompassed in a wide excision, but studies have since shown that such wide margins do not affect survival, presumably because regional or distant metastases are already established at the time of excision of the primary tumor (1–3). They are treated the same in the current AJCC staging system, so that the distinction between satellites and in-transit metastases is without meaning at this time (4). Satellite and in-transit metastases presumably result from lymphatic spread, and their incidence is higher in cases that have demonstrable lymphatic invasion in the primary tumor (5). Microscopic satellites are related lesions that are

defined as discrete tumor nests, greater than 0.05 mm in diameter, that are separated from the main body of the tumor by normal reticular dermal collagen or subcutaneous fat. They may represent local metastases and are associated with worse survival (6) and with regional lymph node metastasis (7). Satellites and in-transit metastases, in turn, may be located in the papillary dermis, the reticular dermis, or the subcutis. Metastases that are located primarily in the papillary dermis often, in my experience, exhibit nevoid differentiation, both at the architectural and histological levels. These lesions typically present as pink or pigmented symmetrical papules in the region of a primary located in a distal extremity, usually the lower limb. Often, the primary is an acral melanoma, located on the foot, or a superficial spreading or lentigo maligna melanoma, located on the calf or leg. The first of these lesions to be biopsied in follow-up may be difficult to diagnose as a melanoma and may be misinterpreted as a nevus. A related group of lesions termed epidermotropic metastases involves the epidermis, above but usually not adjacent to the major focus of the lesion in the papillary dermis (8;9). The most difficult combination of findings is that of epidermotropic nevoid melanoma, which may simulate a benign compound nevus (10). When cytologic atypia is present and moderate to severe, the lesion is no longer nevoid but may be mistaken for a second primary melanoma. The presence of lymphovascular invasion may be helpful in identifying a lesion as a metastasis (11). In some exceptionally difficult lesions, the best diagnosis that can be made is that of a melanocytic

311

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tumor of uncertain potential, which is probably best treated provisionally as a primary melanoma. In those cases where the correct diagnosis is that of an epidermotropic metastasis, the appearance of additional lesion in follow-up may give the correct answer (12). Molecular methods can potentially be applied today to compare the genetic profile of the new lesion with that of the primary tumor (13;14). Such lesions, often on the lower extremity, may be treated by local excisions or by isolation perfusion chemotherapy, for larger lesions that are beyond the scope of simple techniques, sometimes with survivals that last for several years (15;16). Unfortunately, however, distant, metastases usually make their appearance sooner or later (12). Pathological evaluation of regional lymph node metastases not uncommonly presents difficulties of interpretation, especially in sentinel lymph nodes. A frequent question is the distinction between small metastatic deposits and capsular nevi. The latter are identified in about 10% of sentinel lymph node specimens. In one study, interestingly, the nodal nevi were associated with prominent cutaneous nevi in the region, often with congenital features, and nodal nevi were not seen in nonsentinel nodes (17). Micrometastases can usually be distinguished from nodal nevi by a combination of their location, their morphology, and their immunohistochemical profile (18). They are located in the nodal parenchyma or sinus, rather than the capsule or trabeculae of the node. They exhibit cytologic findings more consistent with melanoma, such as enlargement, irregularity, hyperchromatism, and prominent nucleoli, and they tend to be positive with S100 and Melan-A/Mart but negative with HMB 45. Ki-67 reactivity in metastases and p16 reactivity in nevi could also be helpful diagnostically but are seldom used (19).

References 1 Leiter U, Meier F, Schittek B, Garbe C. The natural course of cutaneous melanoma. J Surg Oncol 2004 Jul 1;86(4):172–8.

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2 Heenan PJ. Local recurrence of melanoma. Pathology 2004 Oct;36(5):491–5. 3 Lejeune FJ. The impact of surgery on the course of melanoma. Recent Results Cancer Res 2002;160:151–7. 4 Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A Jr., Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF. New TNM melanoma staging system: linking biology and natural history to clinical outcomes. Semin Surg Oncol 2003 Jul;21(1):43–52. 5 Borgstein PJ, Meijer S, Van Diest PJ. Are locoregional cutaneous metastases in melanoma predictable? Ann Surg Oncol 1999 Apr;6:315–21. 6 Day CL Jr, Harrist TJ, Gorstein F, Sober AJ, Lew RA, Friedman RJ, Pasternack BS, Kopf AW, Fitzpatrick TB, Mihm MC Jr. Malignant melanoma: prognostic significance of “microscopic satellites” in the reticular dermis and subcutaneous fat. Ann Surg 1981;194:108–12. 7 Harrist TJ, Rigel DS, Day CL Jr, Sober AJ, Lew RA, Rhodes AR, Harris MN, Kopf AW, Friedman RJ, Golomb FM, et al. “Microscopic satellites” are more highly associated with regional lymph node metastases than is primary melanoma thickness. Cancer 1984;53:2183–7. 8 Kornberg R, Harris M, Ackerman AB. Epidermotropically metastatic malignant melanoma: differentiating malignant melanoma metastatic to the epidermis from malignant melanoma primary in the epidermis. Arch Dermatol 1978;114:67–9. 9 White WL, Hitchcock MG. Dying dogma: the pathological diagnosis of epidermotropic metastatic malignant melanoma. Semin Diagn Pathol 1998 Aug;15:176–88. 10 Ruhoy SM, Prieto VG, Eliason SL, Grichnik JM, Burchette JL Jr., Shea CR. Malignant melanoma with paradoxical maturation. Am J Surg Pathol 2000 Dec;24(12):1600–14. 11 Gerami P, Shea C, Stone MS. Angiotropism in epidermotropic metastatic melanoma: another clue to the diagnosis. Am J Dermatopathol 2006 Oct;28(5):429–33. 12 Egberts F, Kaehler KC, Brasch J, Schwarz T, Cerroni L, Hauschild A. Multiple skin metastases of malignant melanoma with unusual clinical and histologic features in an immunosuppressed patient. J Am Acad Dermatol 58(5):880–884. Epub Feb 6. 13 Bahrami S, Cheng L, Wang M, Jones TD, Malone JC, Billings SD. Clonal relationships between epidermotropic metastatic melanomas and their primary lesions: a loss of heterozygosity and X-chromosome inactivation-based analysis. Mod Pathol 2007 Aug;20(8):821–7. 14 Massi D, Sardi I, Urso C, Franchi A, Borgognoni L, Salvadori A, Giannini A, Reali UM, Santucci M. Microsatellite analysis in cutaneous malignant melanoma. Melanoma Res 2002 Dec;12(6):577–84.

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15 Hayes AJ, Clark MA, Harries M, Thomas JM. Management of in-transit metastases from cutaneous malignant melanoma. Br J Surg 2004 Jun;91(6):673–82. 16 Lindner P, Doubrovsky A, Kam PC, Thompson JF. Prognostic factors after isolated limb infusion with cytotoxic agents for melanoma. Ann Surg Oncol 2002 Mar;9(2):127–36. 17 Holt JB, Sangueza OP, Levine EA, Shen P, Bergman S, Geisinger KR, Creager AJ. Nodal melanocytic nevi in sentinel

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NE VOI D

lymph nodes: correlation with melanoma-associated cutaneous nevi. Am J Clin Pathol 2004 Jan;121(1):58–63. 18 Fontaine D, Parkhill W, Greer W, Walsh N. Nevus cells in lymph nodes: an association with congenital cutaneous nevi. Am J Dermatopathol 2002 Feb;24(1):1–5. 19 Barnhill RL. The biology of melanoma micrometastases. Recent Results Cancer Res 2001;158:3–13.

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11.1 Epidermotropic Metastatic Melanoma vs. Nodular Melanoma

C L I N I C A L I N F O R M AT I O N

This is a person with a melanoma of the left foot who developed new nodules in the calf. R E A S O N F O R C O N S U LTAT I O N

I believe these are metastases. Do you agree? DESCRIPTION

The sections show two superficial shave biopsies of skin. The two sections are similar. In each of them, there is a plaquelike tumor, comprised of uniform, atypical, large, epithelioid melanocytes with moderately abundant melanin pigment. The cells

extend up to the epidermis and focally blend with basal keratinocytes, in an “epidermotropic” pattern. There is evidence of maturation from superficial to deep, as lesional cells infiltrate the upper reticular dermis. Nevertheless, in the presence of severe uniform atypia and mitotic activity, the appearances are clearly those of melanoma. In addition, there is evidence in at least one of the specimens of lymphatic invasion. This is a finding much more commonly seen in metastatic than in primary melanoma, especially in relatively thin tumors such as these. I therefore agree with your interpretation of these biopsies as follows:

Scanning magnification shows a broad, plaquelike, quite highly cellular tumor, extending from the epidermis into the mid-reticular dermis. FIG URE 11.1.1.

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11.1

At the periphery of the tumor, there is a separate satellite focus, and there is a suggestion of lymphatic invasion (bottom left to middle of figure). FIG URE 11.1.2 .

The lesion consists of large epithelioid cells, arranged in nests, sheets, and fascicles, infiltrating the reticular dermis at the base. There is a suggestion of maturation from superficial to deep, imparting a nevoid configuration to the lesion. FIGURE 11.1.3.

DIAGNOSIS

Skin, calf (two lesions): Malignant melanoma, consistent with epidermotropic metastatic melanoma with differentiation (“nevoid epidermotropic metastatic melanoma”), with lymphatic invasion, both apparently minimally excised.

Multiple mitotic figures were readily detected, including some with abnormal morphology. FIG URE

COMMENT

11.1. 4 .

The presence of two lesions, closely resembling one another, both with atypia and mitotic activity, and both of recent onset, provide additional support for the diagnosis of metastatic melanoma rather than independent primaries.


OVERALL COMMENT


Differentiated nevoid epidermotropic metastases can sometimes simulate a nevus so closely that the diagnosis can only be made after the appearance

of multiple metastases, during subsequent follow-up. Less differentiated lesions may initially be misinterpreted as a primary melanoma.

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11.2 Epidermotropic Metastatic Melanoma vs. Nodular Melanoma

C L I N I C A L I N F O R M AT I O N

DESCRIPTION

An irregular pigment nodule in the popliteal fossa in a 45-year-old woman, with a history of a melanoma of the calf.

The sections show a fairly bulky, dome-shaped tumor, consisting of uniformly atypical nevoid epithelioid cells, expanding and filling the papillary dermis and elevating the epidermis. Although there is no extensive pagetoid proliferation within the epidermis, the lesional cells extend among keratinocytes in the basal layer of the epidermis. There is a focal area of ulceration. There is no adjacent intraepidermal component.

R E A S O N F O R C O N S U LTAT I O N

Rule out metastatic melanoma.

Scanning magnification shows a relatively symmetrical, dome-shaped, highly cellular tumor, extending from the epidermis into the reticular dermis. FIG URE 11.2.1.

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11.2

FIG URE 11.2. 2 .

There is no adjacent intraepidermal

component.

The tumor focally blends with and “consumes” the epidermis, with an area of incipient ulceration and scale-crust formation. FIGURE 11.2.3.

There are nests of melanocytes in the epidermis and extending down the epithelium of the skin appendage. FIG URE 11.2.4 .

FIGURE 11.2.5.

ily detected.

Mitotic figures, such as this one, were read-

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11.2 DIAGNOSIS

Skin, calf: Malignant melanoma, tumorigenic and mitogenic, most consistent with epidermotropic metastatic melanoma; see discussion and comment.

COMMENT

Taken in isolation, these appearances would be consistent with a primary melanoma with a nevoid vertical growth phase; however, the possibility of an epidermotropic metastasis cannot be ruled out histologically and is strongly suggested by the patient’s history of a prior high-risk melanoma in the region. In addition, over time, this patient developed additional regional metastases.

FIGURE 11.2.6. Even though the lesion is nevoid, there is little or no evidence of additional maturation from superficial to deep.


OVERALL COMMENT


In a patient who presents with a newly developed lesion of this type, which is regional to a prior tumorigenic primary melanoma, the possibility of an epidermotropic metastasis needs to be considered. Sometimes, this distinction cannot be made reliably, and, in these

cases, the lesion should be treated, at least provisionally, as a second primary. The diagnosis often becomes apparent when additional metastases appear within a relatively short period. Theoretically, it is possible to address this question by genomic marker studies.

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11.3 Tumoral Melanosis: Regressed Satellite vs. Regressed Primary Melanoma C L I N I C A L I N F O R M AT I O N

Re-excision of a melanoma (Clark level IV, Breslow thickness 2.2 mm) from the back of a 53-year-old man. R E A S O N F O R C O N S U LTAT I O N

Is there a satellite metastasis adjacent to the residual primary? DESCRIPTION

Adjacent to a biopsy site, there is residual melanoma in situ, consistent with a remnant of the primary

melanoma, and, in turn, there is another adjacent region in the papillary and upper reticular dermis where there is a collection of heavily pigmented cells, with abundant coarsely divided pigment that obscures the nucleus. The cells tend to be separate from one another, rather than being arranged in nests or sheets as is more typical for melanoma cells, and have the characteristics of macrophages. Their presence adjacent to the primary melanoma indicates that the most likely pathogenesis of this focal area of “tumoral melanosis” is a regressed, pigmented, satellite metastasis.

A section from a re-excision specimen for a primary melanoma. On the right, there is a biopsy site reaction, with pseudoepitheliomatous hyperplasia of follicular epithelium, inflammation, fibrosis, and hemorrhage. On the left, adjacent to a hair follicle, there is a collection of pigmented cells in the dermis (see Figures 5–9). FIG URE 11.3.1 .

319

Sections show reactive epithelium, hemorrhage, fibrosis, and chronic inflammation in the region of the healing biopsy site, with no contiguous residual melanoma. FIG URE 11.3.2.

Adjacent to a hair follicle, there is a collection of pigmented histiocytes. Although the nuclei are partly obscured by the coarsely defined pigment granules, there is no evidence of cytologic atypia, and the lesional cells tend to be separated rather than growing in nests or sheets. FIGURES 11.3.3 AND 4.

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11.3 DIAGNOSIS

Skin, leg: Residual melanoma in situ adjacent to a scar, with an adjacent focus of tumoral melanosis in the papillary and upper reticular dermis, consistent with a regressed satellite metastasis; see description and comment.

COMMENT

For staging purposes, this focus of melanophages should be regarded as most likely a regressed satellite.

In follicular epithelium and adjacent to the collection of melanophages, there are atypical melanocytes, suggesting the presence of a remnant of in situ radial growth phase melanoma. Therefore, the collection of satellites could represent regressed invasive and tumorigenic primary melanoma versus a regressed satellite metastasis. FIG URE 11.3.5 .


OVERALL COMMENT


It is likely that these foci of melanophages should be regarded as regressed tumor, either from the primary vertical growth phase or from a satellite, as the case

may be, and managed accordingly. However, there are no definitive guidelines for this unusual situation.

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11.4 Metastatic Melanoma with Regression and Tumoral Melanosis

C L I N I C A L I N F O R M AT I O N

DESCRIPTION

Clinically metastatic melanoma proximal to the site of a nodular melanoma, Clark level IV, Breslow thickness 3.6 mm, excised two years previously.

These sections show a tumor in the dermis, comprised of large uniformly atypical epithelioid and somewhat dendritic melanocytes, admixed with a brisk tumor-infiltrating lymphocyte response and prominent tumor-infiltrating macrophages, many of them stuffed with pigment and constituting focal regression of the tumor (so-called tumoral melanosis). In other areas, however, there are mitotically active uniformly atypical tumor cells. These findings are supported by Melan-A and HMB 45 studies. Changes extend close or to the inked lateral margins of the biopsy specimen. The appearances are consistent with metastatic melanoma and are unlikely, in my opinion, to represent a primary tumor.

R E A S O N F O R C O N S U LTAT I O N

Please confirm diagnosis.

Scanning magnification shows an asymmetrical nodule in the dermis and subcutis, consistent with a metastasis. FIG URE 11.4.1.

The tumor is comprised of pigmented cells, admixed with lymphocytes. FIGURE 11.4.2.

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11.4

FIGURE 11.4.3.

The pigmented cells in this field have the appearance of melanophages, namely cells with bland nuclei, stuffed with coarse pigment granules.

FIGURE 11.4.4.

In the region of pigmented cells, as shown in Figure 3, and HMB 45 stain is negative.

FIGURE 11.4.6.

FIGURE 11.4.5 .

In another area, the pigmented cells are dendritic and have more finely granular pigment, consistent with melanoma cells.

In another section plane, similar to that in Figure 4, there are residual HMB 45 positive melanoma cells among the inflammatory cells.

324 SECTI O N

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11.4 COMMENT DIAGNOSIS

Calf, right nodule: Malignant melanoma in dermis, probably metastatic; see microscopic description.

The presence of a dermal melanocytic tumor that is not a member of the blue nevus family should always suggest the possibility of a metastasis, especially, of course, when there is atypia and mitotic activity.


OVERALL COMMENT


Partial regression is relatively common in metastases and can lead to this phenomenon of tumoral melanosis. Complete regression is less common. If there

is doubt whether a lesion is primary or metastatic, follow-up will usually provide the answer if additional metastatic lesions appear.

CA SE

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ME L ANOMA

11.5 Tumorigenic Melanoma with Prominent Capsular and Sinusoidal Nevus Cells vs. Micrometastases in Sentinel Node C L I N I C A L I N F O R M AT I O N

The patient is a 51-year-old female who has had a pigmented lesion on the left shin for many years. A recent biopsy performed demonstrated an invasive melanoma, with a background of nevus. The patient now has a wide excision of the melanoma, as well as sentinel node biopsies.

Sections of the submitted lymph node profiles show, in each of two specimens, focal collections of small nevoid melanocytes present in the capsule of the nodes. In addition, there are foci that appear to protrude into the substance of the nodes, but these appear to be related to sinusoidal collagen and are not present in the nodal parenchyma itself. The

R E A S O N F O R C O N S U LTAT I O N

The issue is the melanocytic lesions found in the sentinel lymph nodes. The cells are positive for Melan-A and negative for HMB 45, whereas the original tumor was HMB 45 positive. In addition, the morphology of these melanocytic cells in the lymph node favors a nevus instead of a metastatic melanoma.

DESCRIPTION

Sections of the primary tumor show a highly cellular proliferation of uniformly atypical, large epithelioid cells, forming an expansile tumor that fills and expands the papillary dermis and infiltrates the reticular dermis, transected at the base of the biopsy specimen. Mitotic figures are readily detected, although the overall rate is low. Sections of the re-excision show the residual lesion, which, at first glance, has attributes of a nevus. However, superficially the cells are quite large and epithelioid, with mitotic activity. These are continuous with the nevoid population at the base, which, however, does not disperse well into the reticular dermis collagen and is consistent with a nevoid tumorigenic vertical growth phase.

Scanning magnification shows multiple section planes of a highly cellular, asymmetrical tumor. FIGURE 11.5.1.

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11.5 cells exhibit no substantial cytologic atypia, react positively with Melan-A and S100, and are negative with HMB 45 and, with perhaps a rare exceptional positive cell, with Ki-67. Therefore I interpret these findings as follows.

There are two mitoses, one of them abnormal in this single high-power field. FIGURE 11.5.3.

In this area, the tumor is comprised of relatively small, epithelioid, somewhat spindle-shaped cells, infiltrating deeply into the reticular dermis. FIG URE 11.5.2.

In another area, there were larger epithelioid cells, which, perhaps paradoxically, had a lower mitotic rate. FIGURE 11.5.4.

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11.5

The lymph node contains cells in the capsule and peripheral sinusoids, which are smaller than those in the primary tumor and lack mitotic activity or severe cytologic atypia. FIG URES 11.5. 5 A N D 6 .

FIGURE 11.5.7 .

The cells stain strongly with Melan-A.

Another area with an unusually dense collection of capsular nevus cells staining strongly with S100. FIGURE 11.5.8.

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11.5

FIG URE 11.5.9.

The cells are negative with HMB 45. FIGURE 11.5.10.

Ki-67 reactivity is negative. COMMENT

DIAGNOSIS

Skin, left shin (biopsy and re-excision reviewed together): Malignant melanoma, tumorigenic and mitogenic vertical growth phase only, with regressed radial growth phase, Clark level IV, Breslow thickness not less than 2.4 mm; see previous discussion and comment. Lymph node profiles: Reactive lymph nodes, with capsular and sinusoidal benign nevus cells, no evidence of metastatic melanoma seen.

Based on the biopsy and the excision reviewed together, the primary tumor in this case demonstrates Clark level IV invasion at a greatest Breslow thickness of 2.4 mm. The dermal mitotic rate is focally very high in the re-excision procedure at 18/mm2. A Ki-67 study also demonstrates a high rate of reactivity, approximating 30% focally. There is no ulcer, there are no microscopic satellites, and there is no evidence of vascular, lymphatic, or neural invasion. There is evidence at the periphery of the tumorigenic vertical growth phase of a regressed radial growth phase. There is no definitive associated nevus. The lesion is completely excised in the re-excision procedure.


OVERALL COMMENT


This case demonstrated much more prominent involvement of the lymph node by capsular nevus cells than one usually sees. However, the lack of cytologic atypia and the location within the capsule and sinusoidal collagen are helpful in distinguishing them

from a metastasis. In addition, the cells do not resemble those of the primary tumor and are negative for HMB 45 and Ki-67. The latter markers are helpful, but not pathognomonic in making this distinction.

12 Nonmelanocytic Melanoma Simulants

L

esions that are proliferations of other cell types may simulate melanoma quite closely. Many of these lesions simulate an amelanotic melanoma, and, in these cases, routine immunohistochemical staining is usually successful in establishing a definitive diagnosis (1–3). The morphologic categories include small round cell tumors, carcinomas, sarcomas (or sarcomalike tumors), and tumors with histologically overlapping features, including lymphoid and hematologic malignancies, melanoma, and sarcomas with epithelioid appearance (1). A screening panel to demonstrate the expression of markers of major lineages should be used first to delineate the broad category of neoplasia. An initial panel might include S100, Melan-A/Mart, LCA, and several keratin markers. For a spindlecell tumor, desmin and SMA might be added, and in particular situations, other markers would be useful, such as CD34 and Factor 13a if there is a question of dermatofibroma or dermatofibrosarcoma protruberans, CD31 if there is a question of angiosarcoma, or HHV8 to rule out Kaposi’s sarcoma. Because of antigenic heterogeneity, including antigen loss and aberrant expression, several epithelial markers in combination may be required to establish the diagnosis (1). The most sensitive keratin marker is 34 beta E12 (CK903) (4). P63 reactivity is useful in identifying a spindle cell (or other) squamous cell carcinoma (4;5). A more difficult and unusual problem is posed by pigmented but nonmelanocytic tumors. This may occur in a nonmelanocytic lesion as a result of colonization of a tumor by reactive melanocytes, which synthesize and transfer melanin pigment to the tumor

cells (6). This phenomenon is commonplace in pigmented seborrheic keratosis and basal cell carcinoma and has been described less often in other tumors, including, for example, mammary carcinoma. Pigmented Paget’s disease, in particular, may simulate a pagetoid melanoma of the superficial spreading type very closely (7), and a similar phenomenon may occur in (pagetoid and/or nonpagetoid) squamous cell carcinoma (8;9). Immunohistochemical markers, including ber-EP4, CK7, CEA, and EMA in addition to keratin, p63, S100, and HMB 45 or Melan-A, and a mucin stain may be helpful in making these distinctions (10–12). Tumoral melanosis is a comparable but unrelated lesion, comprised of pigment-laden melanophages, forming a mass that may simulate a tumorigenic primary melanoma or may actually represent a regressed primary melanoma. In other cases of regressing melanomas, there is, clinically, a variegated pigmented patch that histologically shows fibrosis and pigmentary incontinence in the papillary dermis, similar to the histology of radial growth phase regression, a change more often seen as a focal area within a primary melanoma. When the diagnosis of a completely regressed primary melanoma is contemplated, the diagnosis is confirmed only in those rare cases in which metastatic disease is found in a regional node draining the putative regressed primary. The regressed primary is often found by examination of the skin draining a node in which metastatic melanoma has been the presenting finding (13). In similar cases in which there is no evidence of metastatic disease, it would seem reasonable to work up and follow the patient for this possibility (14).

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Exogenous pigment, such as tattoo pigment, can also simulate a melanocytic tumor but is usually readily recognized. One common diagnostic problem is posed by the use of Monsel’s solution for control of bleeding after a biopsy. This is a ferrous salt that appears to attract and stimulate histiocytes, leading to an accumulation of activated histiocytes with large nuclei, prominent nucleoli, and abundant cytoplasm containing golden-brown pigment. There is also often associated cautery damage to collagen fibers in the dermis. The pigment can be readily identified with an iron stain, and the cells can be identified as CD68 positive, Melan-A negative by immunohistochemistry (15;16). I have seen many cases in which a trainee or even experienced pathologists who have not previously seen this reaction have made an incorrect diagnosis of melanoma in association with a scar, which is especially problematic when the initial biopsy had shown a benign lesion, such as a dysplastic nevus (15;16).

References 1 Bahrami A, Truong LD, Ro JY. Undifferentiated tumor: true identity by immunohistochemistry. Arch Pathol Lab Med 2008 Mar;132(3):326–48. 2 Glusac EJ, McNiff JM. Epithelioid cell histiocytoma: a simulant of vascular and melanocytic neoplasms. Am J Dermatopathol 1999 Feb;21:1–7. 3 Northcutt AD. Epidermotropic xanthoma mimicking balloon cell melanoma. Am J Dermatopathol 2000 Apr;22:176–8. 4 Morgan MB, Purohit C, Anglin TR. Immunohistochemical distinction of cutaneous spindle cell carcinoma. Am J Dermatopathol 2008 Jun;30(3):228–32. 5 Dotto JE, Glusac EJ. p63 is a useful marker for cutaneous spindle cell squamous cell carcinoma. J Cutan Pathol 2006 Jun;33(6):413–7.

S IMUL ANTS

6 Lambert MW, Lambert WC, Schwartz RA, Mesa ML, Brodkin RH, Abbey AH, Potter GK, Little WP Jr. Colonization of nonmelanocytic cutaneous lesions by dendritic melanocytic cells: a simulant of acral-lentiginous (palmar-plantarsubungual-mucosal) melanoma. J Surg Oncol 1985 Jan;28(1): 12–8. 7 Requena L, Sangueza M, Sangueza OP, Kutzner H. Pigmented mammary Paget disease and pigmented epidermotropic metastases from breast carcinoma. Am J Dermatopathol 2002 Jun;24(3):189–98. 8 Stante M, De G, V, Massi D, Chiarugi A, Carli P. Pigmented Bowen’s disease mimicking cutaneous melanoma: clinical and dermoscopic aspects. Dermatol Surg 2004 Apr;30(4 Pt 1):541–4. 9 Shields JA, Shields CL, Eagle RC Jr., Singh AD, Demirci H, Wolf MA. Pigmented conjunctival squamous cell carcinoma simulating a conjunctival melanoma. Am J Ophthalmol 2001 Jul;132(1):104–6. 10 Garijo MF, Val D, Val-Bernal JF. Pagetoid dyskeratosis of the nipple epidermis: an incidental finding mimicking Paget’s disease of the nipple. APMIS 2008 Feb;116(2):139–46. 11 Sellheyer K, Krahl D. Ber-EP4 enhances the differential _diagnostic accuracy of cytokeratin 7 in pagetoid cutaneous neoplasms. J Cutan Pathol 2008 Apr;35(4):366–72. 12 Chiba H, Kazama T, Takenouchi T, Nomoto S, Yamada S, Tago O, Ito M. Two cases of vulval pigmented extramammary Paget’s disease: histochemical and immunohistochemical studies. Br J Dermatol 2000 Jun;142(6):1190–4. 13 High WA, Stewart D, Wilbers CR, Cockerell CJ, Hoang MP, Fitzpatrick JE. Completely regressed primary cutaneous malignant melanoma with nodal and/or visceral metastases: a report of 5 cases and assessment of the literature and diagnostic criteria. J Am Acad Dermatol 2005 Jul;53(1):89–100. 14 Emanuel PO, Mannion M, Phelps RG. Complete regression of primary malignant melanoma. Am J Dermatopathol 2008 Apr;30(2):178–81. 15 Olmstead PM, Lund HZ, Leonard DD. Monsel’s solution: a histologic nuisance. J Am Acad Dermatol 1980;3:492–8. 16 Duray PH, Livolsi VA. Recurrent dysplastic nevus following shave excision. J Dermatol Surg Oncol 1984 Oct;10(10): 811–5.

CA SE

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12.1 Monsel’s Reaction vs. Residual Melanoma

C L I N I C A L I N F O R M AT I O N

DESCRIPTION

Re-excision of a previously biopsied dysplastic nevus in a 33-year-old woman.

This material shows a lesion that represents a re-excision procedure, with scarring in the dermis, and associated pigmented macrophages. This pigment is likely related to the use of Monsel’s solution to control bleeding during the prior biopsy. I see no evidence of any residual melanocytic lesion; however, we will use the block to do an iron stain, an S100, and a Melan-A, to further evaluate this possibility.

R E A S O N F O R C O N S U LTAT I O N

Please review this case.

FIG URE 12.1.1 .

There is a localized area of increased cellularity in the upper dermis in the center of this excision biopsy

specimen.

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S IMUL ANTS

12.1

The process is fairly well delineated from the normal skin at the periphery. FIGURE 12.1.4.

The lesion is comprised of spindle cells, admixed with cells containing relatively coarse granules of golden-brown pigment. FIG URES 12.1.2 A ND 3 .

The overlying epidermis is effaced. Spindle cells predominate superficially, with bland nuclei and intervening collagen fibers. Pigmented cells are present at the base. FIGURE 12.1.5.

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12.1 COMMENT DIAGNOSIS

Skin, right groin/thigh, re-excision: Surgical site reaction with pigmented macrophages, consistent with a reaction to Monsel’s solution,

An iron stain is positive in the pigmented cells, as expected, and S100 and Melan-A stains do not show evidence of residual melanoma, supporting the diagnosis.

completely excised.


OVERALL COMMENT


This reaction can simulate melanoma quite closely; however, the diagnosis is usually readily made, as long as the possibility is considered. Special stains support the diagnosis. The possibility of both residual

melanoma and Monsel’s reaction being present in the same specimen should also be considered in every such case.

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S IMUL ANTS

12.2 Pigmented Carcinoma vs. Nodular Melanoma

C L I N I C A L I N F O R M AT I O N

DESCRIPTION

Lesion of the cheek in an 81-year-old man. R E A S O N F O R C O N S U LTAT I O N

I think this is an ulcerated, infiltrating, poorly differentiated, epithelial malignancy with foci of intracellular pigmentation. The differential diagnosis includes nodular melanoma versus poorly differentiated squamous cell carcinoma.

A bulky tumor in chronically sun-damaged skin. There is no adjacent in situ component. There is a focal ulcer.

These sections show a polypoid tumor in skin, comprised of epithelioid cells, elevating and focally ulcerating the epidermis and infiltrating into the reticular dermis at the base. Cytologically, there is moderate to severe atypia in the form of nuclear

FIG URE 12.2.1.

The tumor is generally separated from the overlying epidermis. There is a focal ulcer. FIGURE 12.2.2.

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12.2 enlargement, some irregularity and hyperchromatism, and prominent nucleoli. Mitotic figures are readily identified. Desmosomes can be identified between some of the tumor cells. An interesting feature is the presence of pigmented cells scattered throughout the tumor. An HMB 45 study demonstrates prominent dendritic infiltrating melanocytes

FIGURE 12.2.3.

tumor.

A sweat duct is partially surrounded by the

within the tumor. These lack substantial cytologic atypia. The neoplastic cells themselves are negative. This therefore represents the phenomenon of population of an epithelial neoplasm by reactive melanocytes, which then synthesize and transfer pigment to the neoplastic cells. In summary, I agree with your interpretation as follows:

FIGURE 12.2.4.

nophages.

Focal pigment is identified, mostly in mela-

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12.2

HMB 45 staining demonstrates strong reactivity at scanning magnification. FIGURE 12.2.6.

There are desmosomes, and there are frequent mitoses, many of them abnormal. FIGURE 12.2.5.

FIG UR E 1 2 . 2 . 6 .

Continued.

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12.2 DIAGNOSIS

Skin, cheek: Malignant epithelial neoplasm most consistent with squamous cell carcinoma, with pigmentation associated with reactive melanocytes; see previous discussion and comment.

COMMENT

The reactivity is seen to be confined to dendritic cells scattered throughout the tumor, which therefore represent benign melanocytes that populated the tumor, presumably derived from the epidermis or from a hair follicle. FIGURE 12.2.7.

The neoplasm appears to be completely excised in the section planes available for study. There is scarring and hemorrhage beneath the lesion, perhaps associated with a prior surgical procedure. The possibility that this lesion is derived from an adnexal neoplasm cannot be ruled out; however, the predominant differentiation at this time appears to be squamous, albeit nonkeratinizing. Because there is no associated in situ component, the more remote possibility of a metastasis from another site might also be considered. Review of any prior material taken from this site might be of assistance in establishing the histogenesis of this lesion more definitively.


OVERALL COMMENT


Other malignancies that may be colonized by reactive melanocytes and may then become pigmented

include basal cell carcinoma, Paget’s disease, mammary carcinoma, and, of course, other tumors.

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S IMUL ANTS

12.3 Tumoral Melanosis Rule Out Regressed Melanoma vs. Other Regressed Pigmented Lesion C L I N I C A L I N F O R M AT I O N

A pigmented nodule from the leg of a 48-year-old woman. R E A S O N F O R C O N S U LTAT I O N

Rule out melanoma. DESCRIPTION

The sections show an irregular, asymmetrical collection of heavily pigmented cells. The pigment is

consistent with melanin and is arranged in coarsely divided pigment granules that stuff the cytoplasm and tend to obscure the nucleus. The nuclei, where visible, are bland, without marked hyperchromatism, pleomorphism, or frequent mitotic activity. The cytology is that of melanophages, and the appearance is that of tumoral melanosis, which likely represents regression of a pigmented lesion at this site. The asymmetry and the location in the dermis are consistent with a malignant tumor, such as a metastatic melanoma.

Scanning magnification shows a heavily pigmented, asymmetric lesion located in the dermis, extending into the upper panniculus, and transected at the base. FIG URE 12.3.1.

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12.3

There is no connection to the epidermis and no in situ proliferation. The upper dermis shows no evidence of scarring (note the intact pattern of actinic elastosis extending above the tumor).

There are densely packed, heavily pigmented cells, morphologically consistent with macrophages (melanophages). The admixture of less heavily pigmented cells with prominent nucleoli, characteristically seen in pigmented epithelioid melanocytoma, is not seen.

FIGURE 12.3.2 .

FIGURE 12.3.4.

Lesion is transected at the base. In this region, the proliferation is very dense.

FIGURE 12.3.5.

FIGURE 12.3.3.

DIAGNOSIS

Skin, leg: Tumoral melanosis, most consistent with a regressed pigmented tumor, most likely metastatic melanoma; see discussion and comment.

The pigmented cells infiltrate around skin appendages and into the fat at the base of the tumor. COMMENT

Although the appearances are most consistent with a regressed pigmented metastatic melanoma, the possibility of another regressed pigmented tumor cannot be ruled out. Neoplasms, such as basal cell carcinoma and squamous cell carcinoma, can become pigmented as a result of being populated by benign melanocytes, which synthesize transferred pigment to lesional cells.

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12.3
OVERALL COMMENT


Although, in my opinion, the appearances are most consistent with regressed melanoma, a regressed pigmented basal cell carcinoma or another pigmented tumor, in which the pigment is derived from

melanocytes that populate the tumor and extend among the tumor cells, synthesizing and transmitting pigment to them, could not be ruled out.

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12.4 Tumoral Melanosis Regressed Melanoma vs. Other Pigmented Tumor

C L I N I C A L I N F O R M AT I O N

A changing multicolored pigmented lesion of the leg in a 79-year-old man. R E A S O N F O R C O N S U LTAT I O N

I am uncertain as to the significance of this marked pigmentary incontinence. DESCRIPTION

These sections show an unusual lesion that, at scanning magnification, has the configuration of a seborrheic keratosis, with hyperkeratosis and keratin tunnels, and an expanded papillary dermis, within which there is dense tumoral infiltrate of heavily pigmented cells, with abundant coarsely divided dark greenish-black pigment in the form of coarsely divided pigmented granules. There is a brisk admixture of lymphocytes, and there is diffuse fibroplasia, which

extends into the skin adjacent to the verrucoid component of the lesion. These changes are highly suggestive of a regressed pigmented lesion, which may well have been a melanocytic tumor having the configuration of a so-called nevoid and verrucoid malignant melanoma. Increasing the level of concern for a possible regressed melanoma is the presence of pagetoid extension of pigmented cells into some fragments of the stratum corneum included with the specimen. Alternatively, another form of pigmented neoplasm, such as a pigmented basal cell carcinoma, could have been present prior to its complete regression, leaving a residue of pigment in macrophages, or so-called tumoral melanosis. In summary, although I see no definitive evidence of malignancy in this material, I am concerned about the possibility of a regressed melanoma or other pigmented lesion and characterize this lesion as follows:

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12.4

FIGURES 12.4.1 AND 2. Scanning and low magnification images of a lesion characterized by verrucous epidermal hyperplasia and pigmented cells in the dermis.

Adjacent to the verrucoid area, there is fibroplasia of the papillary dermis, consistent with regression of a preexisting radial growth phase. FIGURE 12.4.4.

The pigmented cells are loosely arranged and have abundant, coarsely divided pigment granules. Their nuclei may be large, but the chromatin is pale and uniform. There are attributes of melanophages. FIG URE 12.4.3.

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12.4 COMMENT

The lesional cells were negative for Melan-A and were positive for CD68 (not shown). FIGURE 12.4.5.

DIAGNOSIS

Skin, right anterior leg: Pigmented tumor, consistent with tumoral melanosis, of uncertain malignant potential, cannot rule out the possibility of regressed malignant melanoma; see discussion

S100, Melan-A, and HMB 45 studies, done with a red chromagen, were reportedly negative in the pigmented cells, and many of these cells were positive with the macrophage marker CD68. Therefore, the diagnosis of tumoral melanosis was supported. This is consistent with a regressed pigmented lesion, the nature of which cannot be determined; however, a regressed malignant melanoma cannot be ruled out. As briefly discussed previously, tumoral melanosis is often the result of complete or subtotal regression of a tumorigenic, heavily pigmented melanoma or of regression of another pigmented tumor. Therefore, the possibility of a lesion with potential for local persistence and/or recurrence, and for metastasis to regional lymph nodes or beyond, cannot be ruled out. The differential diagnosis could include a pigmented epithelioid melanocytoma. This latter is a tumor of uncertain malignant potential, which is characterized by heavily pigmented, neoplastic melanocytes admixed with melanophages.

and comments.


OVERALL COMMENT


In its silhouette and general architecture, this lesion closely resembles a verrucous melanoma, and, in my

opinion, it should be managed with this differential diagnosis taken into consideration.

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Index

Note: Page numbers followed by “f” refer to figures. ACBN. See Atypical cellular blue nevi (ACBN) Acquired melanocytic nevi morphologic features, 1–2, 3 oncogene mutations in, 33 varieties, 2 Actin stain, 64, 65f Actinic elastosis, 272 in dermis, 91, 264f, 269 Aggressive behavior blue nevi and, 152, 162 deep penetrating nevi and, 140 pigmented epithelioid melanocytomas and, 217 risk factors for, 58 AJCC (American Joint Committee on Cancer) staging system, 225, 311 Amelanotic melanoma, 329f “Ancient” blue nevi, 146 Ancient change acquired nevi with, 2 nevus with, 15 Angiomatoid Spitz nevi cellular tumor, 63f characteristics of, 59 vs. desmoplastic melanoma, 63–66 diagnosis, 66 reticular dermis, 64f Animal melanoma. See Pigmented epithelioid melanocytoma Animal-type melanoma. See Melanophagic melanoma Aronson, Frederick, 162 Atypia characteristics, 13 deep penetrating nevus, 126

melanocytic lesion, 8, 9f, 11f Atypical cellular blue nevi (ACBN) characteristics of, 146, 148–149 dermal mitoses in, 125 dermal nodules, 160, 160f, 161f diagnosis of, 125, 149f, 150 diagnostic consideration for, 157 HMB 45 staining of, 124f vs. malignant blue nevus, 148–150, 156–162, 179–183 Melan-A staining of, 125f melanocytic tumor, 122, 131 metastatic potential, 150 microstaging, 125 mitotic figures of, 157 vs. nodular melanoma, 122–125, 131–134, 138–144 organoid differentiation of, 182 perineural invasion, 159f treatment of, 159, 183 Atypical epithelioid melanocytes cellular proliferation of, 227 dermal epidermal junction, 228f mitotic figures of, 228f pagetoid proliferation, 242f Atypical halo nevus cellular lesion of skin, 16, 16f diagnosis, 17–19, 17f, 18f epithelioid cells morphology, 17f lymphocytic infiltrate simulation, 17f vs. nevoid melanoma, 16–19, 20–22 papular lesion, 20, 21f, 22f Atypical intraepidermal melanocytic proliferation, 289f Atypical melanocytes intraepithelial proliferation of, 303f lentiginous basal proliferation, 301 345

346 INDE X

Atypical nevus. See also Atypical halo nevus clinical features of, 5 diagnosis, 5–7, 5f, 6f, 7f vs. nevoid melanoma, 5–7 Atypical pigmented spindle cell nevus diagnosis, 95 differential diagnosis of, 93 globoid eosinophilic Kamino bodies, 95f hyperkeratotic epidermis of, 94f mitotic figures of, 95f pigmentation of, 94f vs. SSM, 93–96 Atypical single cells, in situ proliferation of, 246f Atypical spindle cells desmoplastic stroma, 307f S100 labels of, 307f Atypical Spitz tumors bland-looking lesional cells in, 74f cellularity of dermal component, 72f characteristics of, 72 D-240 stain of, 91f destruction of epidermis in, 72f diagnosis of, 74f, 81, 84f differential diagnosis of, 60–61 globoid eosinophilic Kamino bodies, 79f histologic features of, 85 HMB 45 staining of, 73f hyperchromatic nuclei of, 80f Ki-67 staining of, 73f, 79 lesional cells of, 90f location for, 85f lymphatic channels within and around, 91f maturation of lesional cells in, 79f mitotic figure of, 73f, 81, 84f, 90f vs. MM, 107–109 molecular studies, 61 nevoid melanocytes, 83f proliferative activity in, 74 re-excision specimen of, 84f single cells of, 72f vs. spitzoid melanoma, 71–74, 78–81, 82–85, 86–88, 89–92, 100–102, 103–106, 110–114

transection of, 84f tumor-infiltrating lymphocytes in, 83f Balloon cell melanoma differential diagnosis for, 234 junctional component of, 232f, 233f mitotic figures of, 232, 234f vs. nevus, 232–234 proliferation of epithelioid melanocytes in, 233f Banal blue nevus, 146, 149f, 151f, 182 Benign nevi, 2, 57, 261, 311 Benign nevus cells, 41f, 255, 328 Blue nevi (BN) categories of, 145 combined nevi and, 185 vs. common nevi, 145 BN. See Blue nevi (BN) BRAF mutations acquired melanocytic nevi, 1 congenital melanocytic nevi, 33 pigmented spindle cell nevus, 61 tumorigenic melanomas, 223, 224 Carney’s syndrome, 146, 204 CBN. See Cellular blue nevi (CBN) Cellular blue nevi (CBN) atypical. See Atypical cellular blue nevi (ACBN) benign, 182 categorization of, 179 cellular area of, 174f characteristics of, 145 clinical recurrence of, 219 congenital pattern nevus vs. pigmented epithelioid melanocytoma, 187–189 contiguous nodules of tumor, 151, 151f cytologic atypia of, 154f diagnosis of, 154–155, 174f vs. malignant blue nevus, 151–155 mitotic figures of, 154, 158f, 181f mixed-biphasic pattern of, 145, 174f, 180f monophasic spindle cell pattern of, 157 nested and biphasic pattern of, 153f, 158f

347 INDE X

superficial component of, 179f treatment of, 155 variant of, 145 Cellular lesion excision procedure, 241f malignant blue nevi, 169f, 170f skin, 16f, 18f Spitz tumor, 103f Cellular nodule characteristics of, 43 cytologic atypia of cells in, 164f diagnosis, 50 differential diagnosis of, 43, 44f, 45f focal necrosis of superficial cells, 50f lesions in intermediate congenital nevus, 49 vs. malignant melanoma, 46–48, 49 management of, 165 melanocytic lesion, 51f, 52f vs. melanoma, 43–45 vs. MELTUMP, 49–53 microstaging, 45 vs. MM in CN in neonate, 49–53 polypoid lesion, 46f, 47f, 48f skin, cellular tumor in, 43f, 44f, 45f staging procedure, 48 treatment, 50–51 Cellular tumor characteristics of, 156f cytologic atypia of, 249 cytologic features of, 100 diagnosis of, 255 heavily pigmented spindle cells of, 253f Ki-67 reactivity of, 328f lateral specimen margins, 117f lesional cells, 251f Melan-A staining of, 327f mitoses in, 326f mitotic figure of, 253f mixed-biphasic pattern of, 250 morphology of, 250 nuclear variability of, 250 punch biopsy of, 117f

dermal precursor, in relation to, 250 scanning magnification of, 250f, 325f spindle and epithelioid cells, 118f spindle cell differentiation, 119f spindle-shaped cells, 326f Clark level IV invasion, 74, 106, 275 Clark prognostic model, 70, 282 Clark, Wallace H., Jr., 223 Clonal nevus, 185, 192 Combined nevi, 106, 192 characteristics of, 185 cytologic features of, 185 diagnosis of, 185 malignant transformation, 185 melanocytic lesion, 193f, 194f Common blue nevi atypical vs. malignant, 179–182 characteristics of, 145 variant of, 145 Comparative genomic hybridization studies, 58, 116 Congenital melanocytic nevi atypical proliferations, 49, 51, 53 cellular and proliferative nodule in, 49 changes in, 28f classification, 33 clinical significance, 33 definition, 33 diagnosis, 29, 48 heterotopic cartilage and bone, benign vs. MM, 54–56, 56f heterotopic differentiation in, 55 histology of, 33, 36 melanoma in, 33–34 mild dysplasia and pseudolymphatics, 27–29 oncogene mutations in, 33 papular lesion in, 27f, 28f, 29f pathogenesis, 1 scanning magnifications, 49f skin appendages in pattern typical of, 52f treatment, 50–51 tumefactions in, 34, 52 Congenital nevus with mitoses diagnosis, 37f, 38, 38f, 40f, 41f, 42

348 INDE X

Congenital nevus with mitoses (continued) differential diagnosis, 38f Ki-67 proliferation rate, 38f melanocytic lesion, 36f, 37f vs. nevoid melanoma, 36–38 vs. nevoid MM, 39–42 skin lesion, 39, 39f, 40f, 41f Cytologic atypia melanocytic lesion, 195 melanocytic proliferation in, 13 nuclear enlargement, 24 pigmented epithelioid melanocytoma, 198 D2-40 staining atypical Spitz tumors, 91, 91f plaquelike lesion, 274f, 275 Dark-pigmented macule cellular and junctional component of, 120f characterization of, 120f, 121f diagnosis, 121f proliferation in dermis, 121f Deep penetrating nevus, 51 atypia in, 126 atypical. See Atypical deep penetrating nevus vs. cellular blue nevus, 135–137 cellular tumor, 117f cellularity, 138 characteristics of, 115 congenital features of, 126 congenital nevus vs. melanoma, 190–192 cytologic appearances, 138 dark-pigmented macule, 120 deeper component of, 138 dermal mitosis, 119 dermal tumor, 129f diagnosis, 119, 128f, 133, 140 differential diagnosis of, 115, 116 epidermal involvement, 157f vs. epithelioid blue nevus, 120–121 genomic analysis study of, 116 junctional component of, 115

junctional proliferation, 127f Ki-67 staining of, 116, 141 maturation of, 140f melanocytic tumor, 141f, 142f, 143f mitotic activity in, 116, 119, 133, 140 mitotic figure in, 128, 128f nests in epidermis of, 127f nevoid epithelioid cells, 127f vs. nodular melanoma, 117–119, 126–130, 138–140 perineural invasion, 128f pigmented lesion, 135f, 136f pigments of, 139f pleomorphism of, 115 re-excision, 138, 139f sentinel node sampling procedure for, 128 spindle and epithelioid cells, 118f spindle cell differentiation in, 119f spindle-shaped melanocytes in, 126 vs. Spitz tumor, 97–99 superficial variant of, 120 therapeutic considerations for, 116 transection at base of biopsy, 139 Dermal atypia, 7, 47, 232 Dermal cells assessment, 2 nuclear atypia, 6f Dermal dysplasia, 1, 10f Dermal-epidermal junction, 5, 8, 31f, 51, 115, 276 Dermal lesional cell mitoses, 93, 294 Dermal melanocytic proliferations, 2, 198, 222, 281, 289f Dermal nevus diagnosis of, 177 history of, 175 Ki-67 staining of, 177f mass of, 176f MITF staining of, 177f morphological characteristics of, 175 scanning magnification of, 176f trabeculae and capsule, 176f Dermal nodules, blue-black biopsy of, 161

349 INDE X

clinical features of, 160, 160f deep extension of, 161 diagnosis of, 162 infiltration into subcutaneous tissue, 161f mitotic figure of, 160, 161f plump spindle cells in, 161 treatment of, 162 Dermal tumor components of, 237f plump spindle-shaped melanocytes, 129f proliferative activity and atypia of, 130 pyramidal architecture, 129 Dermatofibrosarcoma protuberans, 286f, 302f Dermis cellularity in, 299f masses of pale staining cartilage in, 54f nodule in, 14f spindle cell pattern in, 281, 282 Desmoplastic lesions, 294 Desmoplastic malignant melanoma, 281 Desmoplastic melanoma, 223 vs. angiomatoid Spitz nevi, 63–66 atypical epithelioid melanocytes, 289f bulky tumor, 300, 301f cellularity, 295f, 299f collagen fiber bundles in, 306f cytologic atypia, 285f, 296, 297, 301 definitive management for, 296 dermal mitoses in, 296f dermal mitotic rate of, 287, 292f vs. desmoplastic nevus, 294–297 diagnosis of, 287, 295, 301, 302f, 303f, 304f, 308 epithelioid component of, 292 lymphocytic infiltrate, patchy, 284, 285f vs. malignant peripheral nerve sheath tumor, 284–287, 301–304 Melan-A study of, 287, 294, 296 nerve-centered, 309 neurotropism, 286f perineural invasion, 309 prognosis for, 287, 293

proliferation of single melanocytes, 285f pure, 282 range of diversity, 66 re-excision of, 309 residual, 309 as scar, 308f vs. scar in re-excision, 305–309 spindle cell lesion, 294 spindle cells of, 64f, 65f S100 staining of, 286f, 296f Desmoplastic vertical growth phase collagen fibers in, 298 diagnosis of, 292, 296, 300 fibroplasia, 288, 289f focal neurotropism within, 289 lymphocytic infiltrate, 288 Melan-A staining of, 292, 299f vs. regression in lentigo maligna melanoma, 288–293 in situ process, 290f spindle cell proliferation, 288–289 S100 staining of, 292, 293 Dysplastic nevi acquired nevi and, 2 characteristics of, 1 with mitoses. See Dysplastic nevi with mitoses Dysplastic nevi with mitoses cells in superficial dermis, 10f differential diagnosis, 9, 12 melanocytic lesion, 8, 8f, 9f, 10f, 11f vs. nevoid melanoma, 8–12 ECN. See Epithelioid combined nevi (ECN) Epidermis cellular proliferation of melanocytes in, 298f nests in, 274f nevoid epithelioid melanocytes in, 118f Epidermis, changes in lesion, 15f scanning magnification of, 13f severe melanocytic dysplasia, 44f

350 INDE X

Epidermotropic metastatic melanoma, 311 vs. nevoid melanoma, 273–274 vs. nodular melanoma, 314–315, 316–318 Epithelial melanoma, 282, 304 Epithelial neoplasm, 335 Epithelioid blue nevi characteristics of, 146, 198 pseudoepitheliomatous hyperplasia, 217 Epithelioid blue nevus vs. deep penetrating nevus, 120–121 Epithelioid cells epidermis, 25f morphology, 17f Epithelioid combined nevi (ECN) morphologic spectrum of, 198 phenotypes of, 185 Epithelioid melanocytes, 59, 71, 115, 198 Exogenous pigment, 330 Factor 8 stain, 66f Fascicular-plexiform architecture, 115 Fibroblastic differentiation, 281 Focal neurotropism, 170, 289, 308 Focal ulcer, 211, 334f Garment nevus, 33 Giant congenital nevi heterotopic differentiation in, 55 melanoma in, 33 Globoid eosinophilic Kamino bodies, 69f, 76f, 79f, 95f atypical pigmented spindle cell nevus, 95f junctional Spitz pattern, 76f near dermal-epidermal junction, 79f Gray zone lesions, 262 Halo nevi atypia and. See Atypical halo nevus characteristics, 2–3 definition, 2 Heterotopic cartilage, 55f, 56f HMB 45 staining, 5, 7f atypical Spitz tumors, 73f desmoplastic melanoma, 66

nevoid melanoma, 261 nodular melanoma, 230f pagetoid spitz nevus, 76 plaquelike lesion, 191f polypoid nodular tumor, 335, 336f Spitz tumors, 68 spitzoid melanoma, 104, 105f Hyperplastic intradermal nevus, 46 Immunohistochemical stains, 308, 124f In situ melanoma, 2, 224 In-transit metastases, 311 Invasive RGP melanomas, 224 Invasive spindle cell, 298, 299f Invasive tumor, 301 Inverted Type A pattern, 191f Junctional mitoses, 12 Junctional nevi, 1–2 Junctional proliferations, 2, 127f Junctional Spitz pattern, 75, 76f, 104 Juvenile melanomas, 57 Kamino bodies, 57 atypical pigmented spindle cell nevus, 93, 95f atypical Spitz melanoma, 111, 112f atypical Spitz tumor, 78, 79 pagetoid Spitz nevus, 75, 76 pigmented spindle cell nevus, 59 Spitz tumor, 68, 69f Keratin marker, 329 Ki-67 labels lesional cells, 175 Ki-67 positive lesional cells, 144f Ki-67 positive proliferating lesional cells, 200 Ki-67 proliferation marker, 224 Ki-67 staining, 5 atypical Spitz tumors, 73f, 79, 80f deep penetrating nevus, 116 dermal nevus, 177f melanocytic tumor, 67, 82, 169 pagetoid spitz nevus, 75 pigmented epithelioid melanocytoma, 204f, 216f, 217f

351 INDE X

plaquelike lesion, 192f positive cells in dermis, 6f Spitz tumor, 71 spitzoid melanoma, 104, 105f Lentigo maligna melanoma, 223 early vertical growth phase, 298, 299f, 300 regression vs. desmoplastic vertical growth phase, 288–293 vs. special site nevus of the ear, 300 Levene, Arnold, 261 Liver biopsy, 182 Liver metastasis, 168, 197 Local metastases, 311 Lymph node profiles, 325 Lymphatic invasion, 91f, 167f, 311 Lymphocytes ill-defined nodular clusters of, 286f tumor-infiltrating, 3, 60 Lymphocytic infiltrate band-like, 242f, 289f Melan-A positive nevus cells scattered among, 32f melanophages in dermis, 9f patchy, 284f simulation, 17f Malignant blue nevi vs. atypical cellular blue nevi, 148–150, 156–162, 169–170, 179–183 vs. cellular blue nevus, 151–155 cellular lesion, 169f, 170f cellular nodule, 163f, 164f characteristics of, 146 diagnosis of, 163, 164–165 epithelioid and dendritic pigmented melanocytes, 164 vs. malignant melanoma, 163–165 melanocytic tumor, 165f, 166f, 167f vs. MELTUMP, cellular, 175–177 vs. metastatic or primary melanoma, 172–174 satellite nodule adjacent to, 165f tumor necrosis, 164 Malignant dermal melanocytic proliferations, 2

Malignant melanoma (MM) vs. atypical Spitz, 107–109 vs. cellular nodule, 46–48 CN in neonate vs. cellular nodule, 49–53 definition, 223 diagnosis of, 49, 247, 248 differential diagnosis of, 58 lentigo maligna type, with nevoid vertical growth phase, 244–247 vs. malignant blue nevus, 163–165 maturation of, 247f mitotic figure of, 107 nevoid cells arrangement, 247f patterns in dermis, 245f, 246f vs. pigment synthesizing malignant melanoma, 166–168 vs. pigmented epithelioid melanocytoma, 166–168 prognostic attributes developed for, 165 vs. proliferative nodule, 46–48 Malignant neoplasm, 172, 261 characteristics of, 284 Malignant peripheral nerve sheath tumor vs. desmoplastic melanoma, 284–287, 301–304 Mart 1 staining atypical Spitz tumors, 80f lesional cells, 18f papular lesion, 22f regressed tumorigenic melanoma, 259f McGovern, Vincent J., 223 Melan-A staining, 5 confluence of junctional component, 7f dermis cellularity, 299f desmoplastic melanoma, 287, 294, 296 desmoplastic vertical growth phase, 292 lymphocytic infiltrate, 32f melanocytes, 32f, 55f, 56f melanocytic tumor, 143f melanoma with accretive vertical growth phase, 239f nodular melanoma, 230f, 231f pagetoid proliferation in epidermis, 109f pagetoid spitz nevus, 77f pigmented epithelioid melanocytoma, 203f plaquelike lesion, 191f

352 INDE X

Melanocytic dysplasia, 8, 40, 60 Melanocytic lesion atypia of, 8, 9f, 11f, 13, 53 central portion of, 236f circumscribed, 37f congenital pattern, 193 cytologic atypia, 195 dermal component of, 9f, 10f, 235f, 236 diagnosis of, 52, 194 differential diagnosis, 12 epidermal component of, 107 junctional component of, 9f, 10f, 51 Ki-67 proliferation rate, 38f maturation and dispersion, 37f, 107, 194f mitosis in dermal component, 37f mitotic figure, 11f nests of nevoid to epithelioid cells, 6f proliferation, 37f, 235 scanning magnification of, 5f sentinel lymph nodes, 325 squamous dysplasia in, 15f treatment of, 183 well-circumscribed, and fairly symmetrical, 8f Melanocytic neoplasm, 175, 270f Melanocytic nevi acquired, 1–3 congenital, 33–34 Melanocytic proliferation atypical, 48 dermal, 2 diffuse fibroplasia, 276f intraepidermal, 281 Melanocytic tumor, 57 asymmetrical, 89f atypical cells, 124f cellular, 71, 71f, 82f, 169f central part of, 170f characteristics of, 97 components of, 131 cytologic atypia of, 143f dermal and junctional component of, 67f in dermis, 166

diagnosis of, 99, 144, 295 differential diagnosis of, 98, 166, 169 epidermal hyperplasia focally above, 98f heavily pigmented cells, 166f hyperchromatic, 98f hyperkeratosis of, 78f junctional component of, 124f Ki-67 study of, 169 lesional cells of, 142f management of, 170 maturation of, 143f maturation of lesional cells, 123f microstaging, 168 mitoses in, 142 mitotic activity, 131 mitotic figures of, 78–79, 82, 168f, 170f mitotic rate of, 166, 170 pigmented spindle cells, 170f scanning and low magnification images of, 245f sheetlike pattern of growth, 122f spindle to epithelioid melanocytes, 71 symmetry, 98f Melanocytic tumors of uncertain malignant potential (MELTUMP) vs. cellular nodule, 49–53 clinical presentation of, 60 diagnosis of, 60, 147 vs. malignant blue nevus, 175–177 Melanocytoma, 58. See also Pigmented epithelioid melanocytoma Melanoma amelanotic, 197 BRAF mutations, 224 vs. cellular nodule, 43–45 congenital nevi, 33–34 diagnosis of, 76, 244, 249, 329, 333 likelihood of, 130 low grade variant of, 198 melanophagic, 197 microscopic criteria for, 225 mitotic rate for, 130 molecular studies, 61

353 INDE X

Monsel’s reaction, 333 morphological forms, 223 phases of progression of, 224 risk for, 77 subtypes, 223 WHO classification of, 223–224 Melanoma in pregnancy vs. special site genital skin nevus, 23–26 Melanoma with accretive vertical growth phase cellular lesion, 241f diagnosis of, 239f, 243 maturation of, 238f, 239f, 243f Melan-A stain of, 239f melanocytic lesion, 235f nevoid epithelioid melanocytes, 236f nodule, 243f pagetoid proliferation, 242f papillary dermis, 236f, 242f prognosis of, 240 proliferation of, 240 vs. radial growth phase only, 235–240 vs. severely dysplastic nevus, 241–243 Melanophages, 212f, 213, 215f Melanophagic melanoma, 197 Metastasis, 273 deep penetrating nevi, 116 epithelioid blue nevus, 146 location of, 311 Metastatic melanoma diagnosis of, 312 local, 311 with regression and tumoral melanosis, 322–324 variation of, 311 Micrometastases location of, 312 vs. nodal nevi, 312 Microscopic satellites, 231, 311 Mihm, Martin, 197 MITF staining cellular vs. malignant blue nevus, 175, 177f desmoplastic and neurotropic melanoma, 282 desmoplastic melanoma vs. scar in re-excision, 306

Mitogenic melanomas, 106, 224 Mitogenicity, 224, 225 Mitotic figure junctional lesional cell, 11f keratinocytes, 11f superficial dermal lesional cell, 16 Mixed (desmoplastic and epithelial) desmoplastic melanomas, 282, 304 MM. See Malignant melanoma (MM) Modular melanoma, 230f, 231f Monsel’s reaction vs. residual melanoma, 331–333 Neoplasia, 13, 329 Nerve-centered desmoplastic and neurotropic melanoma, 284, 309f Neurofibroma, 302f, 303f Neurosarcomatous transformation, 281 Neurotropic melanoma, 223, 281–282 Neurotropism, desmoplastic melanoma and, 281–282, 286f Nevoid cells cellular nodule vs. melanoma, 44 combined nevi, 194f halo nevus with atypia, 21f malignant melanoma, 246f nevoid melanoma vs. nevus, 266 nodular melanoma with microscopic satellites, 230 pigmented epithelioid melanocytoma vs. nodular melanoma, 214–215 Nevoid malignant melanoma, 341 Nevoid melanocytes atypical Spitz tumors, 83f characteristics of, 54 Nevoid melanoma actinic elastosis in dermis, 264f vs. atypical halo nevus, 16–19, 20–22 vs. atypical nevus, 5–7 cell types, 266 central component of, 264f characteristics of, 261 concept of, 261 definition, 261, 265 dermal mitotic rate of, 265, 269, 272

354 INDE X

Nevoid melanoma (continued) diagnosis of, 265, 269, 272 vs. dysplastic nevus with mitoses, 8–12 evidence for, 12 immunohistochemistry of, 261 junctional component of, 265f, 267f management, 262 maturation of, 265f, 271f mitoses in, 262, 263, 269, 272f vs. nevoid epidermotropic metastatic melanoma, 273–275 vs. nevus, 263–265, 266–269, 270–272 pathology, 262 proliferation marker for, 262 pseudonevoid architecture of, 261 small cells at base, 268f Nevoid vertical growth phase vs. recurrent nevus, 276–280 dermal mitotic rate, 278 diagnosis of, 279 HMB 45 stain of, 278f Ki-67 proliferation rate, 278f melanocytic lesion, 276f melanocytic proliferation, 276f, 277f, 278f microstaging attributes, 278 treatment of, 280 Nevus asymmetric, 263f, 266f vs. balloon cell melanoma, 232–234 vs. nevoid melanoma, 263–265 Nevus with ancient change characteristics, 13 degenerative/senescent change in, 15f diagnosis, 15 lesional cell nuclei, 14f nodule in dermis, 14f vs. tumorigenic melanoma and squamous cell carcinoma in situ, 13–15 Nodular clusters of lymphocytes bulky mass of, 305f germinal center formation of, 305f hypercellular desmoplastic proliferation of, 306f Nodular lesions, 256f Nodular lymphocytic infiltrate, 309

Nodular melanoma atypical epithelioid melanocytes, 227, 228f vs. deep penetrating nevus, 117–119, 126–130, 138–140 diagnosis of, 133, 231 diminution, 133f epithelioid to spindled, 132f HMB 45 stain of, 230f large epithelioid melanocytes, 249 vs. malignant blue nevus with lymph node involvement, 249–255 maturation of, 249 microscopic satellites, 227–231 mitotic figures of, 228f, 231 nests in epidermis and dermis, 132f vs. pigmented carcinoma, 334–337 vs. pigmented epithelioid melanocytoma, 200–204, 210–213, 214–218 tumor-infiltrating lymphocytes, 229f Nodular polypoid tumor characteristics of, 210 mitotic figures in, 210 scanning magnification images of, 211f Nuclear membranes, 57, 167f Nuclear to cytoplasmic ratio, 46 Oncogene-induced senescence, 1–2 Oncogene mutations BRAF, 1, 33 melanomas and nevi, 61 NRAS, 33 Pagetoid spitz nevus diagnosis, 77f Melan-A staining of, 77f pagetoid proliferation in, 76f risk for, 77 vs. spitzoid melanoma, 75–77 Paget’s disease, 329 Papillary dermis broad, plaquelike lesion expanding, 93f diffuse fibroplasia of, 244 fibroplasia in, 30, 30f, 31f

355 INDE X

Papular lesions, 20 dermal and junctional component, 29f dermis, 28f epithelioid cells arranged in nests, 21f Mart 1 staining, 22f mitoses in, 22f nevoid cells maturation, 21f well-circumscribed, 27f Perineural invasion, 127, 159f Pigment synthesizing melanoma. See Pigmented epithelioid melanocytoma Pigment synthesizing malignant melanoma, vs. malignant melanoma, 166–168 Pigmented carcinoma, vs. nodular melanoma, 334–337 Pigmented epithelioid cells, single-cell proliferation of, 266 Pigmented epithelioid melanocytoma, 198 bulbous expansion of tumor in, 215f CD68 stain of, 207f cell types in, 215f cellular nodular tumor, 214f cytology of, 215f, 216 dendritic cell type, 201f diagnosis of, 200, 204, 209 epithelioid blue nevi, 197 epithelioid cell type, 201f Ki-67 study of, 204f, 216f, 217f vs. malignant melanoma, 166–168 management of, 198–199 Melan-A study of, 203f, 207f melanin bleach of, 217f melanophages, 212f vs. nodular melanoma, 200–204, 210–213, 214–218 pagetoid proliferation, 206 pigmented cells with dendritic cytoplasm, 202f prognosis of, 213 proliferation of melanocytes in, 208f pseudoepitheliomatous hyperplasia, 215f, 216 staging procedure, 199 superficial ulceration of, 212f treatment of, 212–213 vs. vulvar melanoma, 205–209

Pigmented lesion diagnosis, 137 junctional component of, 135, 136f perifollicular distribution of spindle cells, 136f proliferation pattern, 135 scattering of, 136f section planes of, 135f Pigmented melanocytes, 156f, 164, 173f Pigmented neoplasm, 341 Pigmented spindle cell nevus (PSCN), 59 differential diagnosis of, 60 nevoid melanoma in, 60 Spitz nevi/tumors, histological differences with, 59 treatment of, 59 Pigmented spindle cells, 145, 149f, 188f, 254f Pigmented tumor diagnosis of, 343 differential diagnosis of, 343 extending from epidermis into subcutis, 214f location of, 160f, 219f metastatic, 182f pigment granules, 342f pigmented basal cell carcinoma, 341 scanning and low magnification images of, 342f vs. tumoral melanosis regressed melanoma, 341–343 vulva, 205f Plaquelike lesion cell types, 190, 191f congenital pattern, 191f D2-40 stain of, 274f, 275 dermal nest, 274f diagnosis of, 192, 274 excision biopsy of, 190f histologic characteristics of, 274–275 HMB 45 staining of, 191f Ki-67 staining of, 192f lymphatic involvement, 274f, 275 maturation of, 274f Melan-A staining of, 191f mitosis in, 274f treatment of, 275 upper dermis, 273f

356 INDE X

Plexiform architecture, 115, 129 Plump spindle cells, 268f Polypoid lesion diagnosis, 48 lesional cell nuclei, 48f mitotic figures, 46, 48f scanning magnification of, 46f separation from epidermis, 47f tumor cells arrangement, 47f Polypoid nodular tumor, 110f amphophilic cytoplasm, 113f components of, 110 cytology of, 334 diagnosis of, 114, 337 HMB 45 study of, 335, 336f Kamino bodies, 112f maturation of, 111f, 113f mitotic activity for, 111 mitotic figures of, 335 nests with clefting artifact, 112f Proliferative nodule vs. malignant melanoma, 46–48 PSCN. See Pigmented spindle cell nevus (PSCN) Pseudoepitheliomatous hyperplasia, 67f, 78f, 211f, 215f, 319f Punch biopsy, 107, 117 Recurrent nevus phenomenon, 220, 279 Recurrent nevus vs. nevoid vertical growth phase, 276–280 Recurrent pigmented epithelioid melanocytoma atypical intraepidermal proliferation of, 221f, 222 characteristics of, 219 diagnosis of, 222 Melan-A study of, 219–220, 222f vs. melanoma, 219–222 tumor composition, 220f Reed nevus, 59 Regional lymph node metastases, pathological evaluation of, 312 Regressed halo nevi benign, 32 diagnosis, 31f, 32f fibroplasia in papillary dermis, 30f lymphocytes and histiocytes, 31f

vs. regressed melanoma, 30–32 Regressed melanoma, 259 diagnosis of, 329 vs. regressed halo nevus, 30–32 tumoral melanosis. See Tumoral melanosis regressed melanoma Regressed pigmented basal cell carcinoma, 259, 340 Regressed pigmented lesions, 259 changes suggestive of, 341 characteristics of, 339f location in dermis, 338f vs. regressed melanoma, 338–340 transection of, 339f Regressed tumorigenic melanoma area of nodularity of, 257f, 258f epidermal hyperplasia, 256 vs. inflammatory dermatosis with pigmentary incontinence, 256–259 Mart 1 staining of, 259f pigment in, 257f pigmentary incontinence in, 256, 259 S100 staining of, 258f Reticular dermis, 29 cellularity of, 290f, 291f ill-defined tumor in, 117f S100 positive cells, 282 S100 staining angiomatoid Spitz nevi, 65f dermis cellularity, 299f desmoplastic melanoma, 286f, 296f desmoplastic vertical growth phase, 292, 293 regressed tumorigenic melanoma, 258f S100A6 of spitzoid melanoma, 105f Satellites metastases, 311 Scalp, tumor of area of tumor necrosis, 173f cellular area, 173f diagnosis of, 174 mixed-biphasic pattern of, 174f scanning magnification of, 172f Schwann cells, 282, 308f, 309

357 INDE X

Schwannian differentiation acquired melanocytic nevi, 2 desmoplastic and neurotropic melanoma, 281 desmoplastic melanoma vs. malignant peripheral nerve sheath tumor, 284, 301 Sentinel lymph node sampling atypical Spitz tumors, 74 deep penetrating nevus, 128 malignant melanoma, 58 pigmented epithelioid melanocytoma, 199 Spitz tumor, 99 Severely dysplastic nevus characteristics of, 9 differential diagnosis of, 106 vs. melanoma with accretive vertical growth phase, 241–243 Skin, biopsy of cellular lesion, 103f melanocytic lesion, 107, 107f, 235f Skin, cellular lesions of dome-shaped, 16f Mart 1 staining, 18f mitotic figures, 18f Skin, cellular tumors in architectural configuration of, 270f mitotic figure of, 45f multiple levels of, 43f nodularity, 44f sheetlike patterns of growth, 44f Skin lesions excision of, 75f junctional component, 40, 40f mitotic figures in, 39, 41f nuclear size and shape variation of, 41f pagetoid proliferation of nevoid, 75f scanning magnification architecture of, 39f, 40f Skin, shave biopsy of, 67, 232 Small congenital nevi, melanoma in, 33 Special site genital skin nevus characteristics, 23–25 diagnosis, 24–25 epithelioid cells maturation, 25f junctional and dermal component, 24, 24f

lesional cells, 24 vs. melanoma in pregnancy, 23–26 mitotic activity, 25 treatment, 26 Special site nevi, 2, 3 ear, 300 skin, genital, 24, 25 Spindle cell lesions, 294 Spindle cell melanoma, 129 diagnosis, 130 nuclear pleomorphism and hyperchromatism, 130 Spindle-cell tumor, 329 Spindle cell vertical growth phase, 300 Spindle-shaped melanocytes atypical cellular blue nevus vs. malignant blue nevus, 160 atypical deep penetrating nevus vs. nodular melanoma, 131 atypical spitz tumor vs. spitzoid melanoma, 82 cellular vs. malignant blue nevus, 175 combined cellular blue nevus vs. pigmented epithelioid melanocytoma, 187 deep penetrating nevus vs. nodular melanoma, 126, 129, 141 Spitz nevi, 1 characteristics of, 57 PSCN, histological differences with, 59 Spitz, Sophie, 57 Spitz tumors atypical, 58, 60 benign, 61 cell maturation in dermis, 68f cellular lesion, 103f characteristics of, 57, 68 vs. deep penetrating nevus, 97–99 diagnosis, 70 differential diagnosis of, 60, 98 epidermis in, 57 globoid eosinophilic Kamino body, 69f melanocytic tumor, 67f, 97f mitotic rate for, 71 pagetoid proliferation, 69f, 70 staging, 99 variants of, 59

358 INDE X

Spitzoid lesions, 57 clinical features of, 58 Spitzoid melanoma ancient change of, 87f atypia of lesional cell nuclei, 88f vs. atypical Spitz tumors, 71–74, 78–81, 82–85, 86–88, 89–92, 100–102, 103–106, 110–114 cellular dermal component of, 104f Clark level IV invasion, 109 cytologic features of, 100 definitive management for, 102 diagnosis of, 88, 102, 106, 109 eosinophilic Kamino bodies at junction in, 112 epidermal spongiosis and subepidermal edema in, 101f evidence of maturation of, 108f extensive ulceration of, 101f, 102 HMB 45 study of, 104 junctional component of, 87f, 108f, 109 Ki-67 study of, 104 lesional cells in dermis, 88f mitotic rate for, 87f, 88, 100–101, 101f, 102, 105f, 106, 109f pagetoid spitz nevus vs., 75–77 polypoid nodular tumor, 110–111 prognosis of, 58, 77, 88, 102 tumor-infiltrating lymphocytes of, 88 Spitzoid neoplasm, 67, 103 Sporadic lesions, 200 Squamous cell carcinoma in situ vs. in situ melanoma, 13–15 characteristics, 15f diagnosis, 15 SSM vs. atypical pigmented spindle cell nevus, 93–96 Sun-damaged skin bulky tumor in, 334f cellular melanocytic proliferation in, 298 re-excision specimen of, 288 S100 and Melan-A studies of, 298 Superficial atypical melanocytic lesions of uncertain significance (SAMPUS), 60 Systemic metastases, 183

Tardive congenital pattern nevi, 33 TILs. See Tumor-infiltrating lymphocytes (TILs) Triggered trap. See Nevoid melanoma Tumefactions, in congenital melanocytic nevi, 34, 52 Tumoral melanosis metastatic melanoma with regression and, 322–324 pigment-laden melanophages, 329 Tumoral melanosis regressed melanoma vs. regressed pigmented lesion, 338–340 vs. regressed pigmented tumor, 341–343 vs. regressed satellite, 319–322 Tumor, dome-shaped nevoid epithelioid cells, 127f spindle-shaped melanocytes, 126 Tumorigenicity, 224, 225 Tumorigenic melanoma, 224 capsular nevus cells, 325–328 vs. inflammatory dermatosis with pigmentary incontinence, 256–259 vs. micrometastases in sentinel node, 325 squamous cell carcinoma in situ vs. nevus with ancient change, 13–15 Tumor-infiltrating lymphocytes (TILs), 2–3, 83f, 296 Upper dermis cellularity in, 294f, 331f plaquelike lesion in, 273f scarring in, 306f Verrucoid malignant melanoma, 341 Vimentin stain, 303f Vulvar melanoma vs. pigmented epithelioid melanocytoma, 205–209 Vulva, tumor of cytology of, 206 differential diagnosis for, 206 heavily pigmented, 205f, 206, 206f nested proliferation, 205 Wedge-shaped lesions, 156