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H. P. Soyer, G. Argenziano, R. Hofmann-Wellenhof, R. H. Johr (Eds.) Color Atlas of Melanocytic Lesions of the Skin

H. P. Soyer G. Argenziano R. Hofmann-Wellenhof R. H. Johr (Eds.)

Color Atlas of Melanocytic Lesions of the Skin With 366 Figures and 26 Tables


H. Peter Soyer, MD, FACD Professor of Dermatology The Queensland Institute of Dermatology School of Medicine University of Queensland Princess Alexandra Hospital Brisbane, QLD 4102 Australia Giuseppe Argenziano, MD Professor of Dermatology  Department of Dermatology  Second University of Naples  Nuovo Policlinico – Edificio 13  Via Pansini 5 I-80131 Naples Italy

Rainer Hofmann-Wellenhof, MD Professor of Dermatology  Department of Dermatology Medical University Graz Auenbruggerplatz 8 A-8036 Graz Austria Robert H. Johr, MD Clinical Professor of Dermatology and Pediatrics Director, Pigmented Lesion Clinic University of Miami, School of Medicine Miami, FL 33136 USA

Library of Congress Control Number: 2007924719 ISBN 978-3-540-35105-4  Springer Berlin Heidelberg New York This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Springer is a part of Springer Science+Business Media © Springer-Verlag Berlin Heidelberg 2007 The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt   from the relevant protective laws and regulations and therefore free for general use. Editor: Marion Philipp, Heidelberg, Germany Desk Editor: Ellen Blasig, Heidelberg, Germany Production: LE-TEX Jelonek, Schmidt & Vöckler GbR, Leipzig, Germany Cover design: Frido Steinen-Broo, EStudio, Calamar, Spain Reproduction and typesetting: am-productions GmbH, Wiesloch, Germany Printed on acid-free paper  24/3180/YL 5  4  3  2  1  0

This book is dedicated to the memory of Paolo Carli an outstanding scientist and a special human being. H. Peter Soyer and Giuseppe Argenziano on behalf of all authors


Melanocytic tumors of the skin deserve special attention because of the following important facts Melanoma is frequent and early detection is critical. â–  A correct interpretation is necessary because the implications may be very serious. â–  It is a dynamically developing field where major progress has been made over the past decade. â– 

This atlas, written in a concise way, is a highly useful presentation that focuses on the full spectrum of pigmented skin tumors. The prominent features include classical clinical as well as histopathological criteria for diagnosis, illustrations of excellent quality, as well as new concepts and practical aspects of management. Of special interest are modern diagnostic techniques with emphasis on dermatoscopy. Case studies and core messages indicating pathways of the diagnostic approach are at the end of each chapter.

All these features characterize the book as an impressive contribution to the literature in the area of melanocytic tumors. My co-workers in Graz, Dr. H. Peter Soyer and Dr. Rainer Hofmann-Wellenhof, as well as Dr. Giuseppe Argenziano from Naples and Dr. Robert Johr from Miami, together with many international contributors who are all experts in their respective disciplines, have produced a splendid piece of work which presents highly relevant information on a complex and challenging subject. This book will greatly assist physicians in providing optimal care for patients with melanocytic skin lesions.

Helmut Kerl Professor & Chairman Department of Dermatology Medical University of Graz Austria


At the beginning of many scientific endeavors there is an idea shared by a small group of enthusiastic people. This was the case with our group, friends and colleagues from Austria, Italy, and the United States. Our idea was to write a color atlas of melanocytic skin lesions, with particular emphasis on the morphological dimension, using a systematic and logical approach. As practicing dermatologists with backgrounds in dermoscopy and dermatopathology, we wanted to describe the many faces of benign and malignant pigmented skin lesions based on clinico-pathological and dermoscopic−pathological correlations. Together with a large group of distinguished dermatologists from around the world, we prepared this atlas.

In 1894 Paul Gerson Unna published the textbook Histopathology of Skin Diseases. His wellknown saying on the relationship between dermatology and histopathology has been slightly modified by us and now reads as follows: “The dermatologist is fortunate in being able to study the clinical and dermoscopic picture with his/ her histologically trained eye and the microscopic picture with his/her clinically and dermoscopically trained eye.� In this spirit we hope that you enjoy reading this atlas and that it will help you in your daily practice.

H. Peter Soyer Giuseppe Argenziano Rainer Hofmann-Wellenhof Robert Johr



The Morphologic Dimension in the Diagnosis of Melanocytic Skin Lesions. . . . . . . . . . . . . . . . . . . . . . . 1 H. Peter Soyer and Elisabeth M.T. Wurm

III.3 Agminated Nevus. . . . . . . . . . . . . . . . . 75 Ulrike Weigert and Wilhelm Stolz

Clinical Examination of Melanocytic Neoplasms Including ABCDE Criteria . . . . . . . . . . 3 Alfred W. Kopf

III.5 Atypical (Dysplastic) Nevus. . . . . . . . 87 Rainer Hofmann-Wellenhof and H. Peter Soyer


Dermoscopic Examination. . . . . . . . . . 7 Ralph P. Braun, Harold S. Rabinovitz, Margaret Oliviero, Alfred W. Kopf, Jean-Hillaire Saurat, Luc Thomas


Combined Nevus . . . . . . . . . . . . . . . . . 97 Horacio Cabo



Melanoma: the Morphological Dimension. . . . . . . . . . . . . . . . . . . . . . . 23 Lorenzo Cerroni

Common Nevus . . . . . . . . . . . . . . . . . 102 Rainer Hofmann-Wellenhof and H. Peter Soyer


II.1 Laser-Scanning Confocal Microscopy. . . . . . . . . . . . . . . . . . . . . . . 39 Salvador González and Allan Halpern

Congenital Melanocytic Nevi. . . . . . 106 A lon Scope, Cristiane BenvenutoAndrade, Ashfaq A. Marghoob


II.2 Automatic Diagnosis . . . . . . . . . . . . . . 47 Josef Smolle

Melanocytic Nevi on the Genitalia and Melanocytic Nevi on Other Special Locations. . . . . . . . 119 Ingrid H. Wolf



Multispectral Image Analysis. . . . . . . 52 Dina Gutkowicz-Krusin and Harold Rabinovitz


Teledermatology. . . . . . . . . . . . . . . . . . 57 Cesare Massone, Elisabeth M.T. Wurm, Rainer Hofmann-Wellenhof, Gian Piero Lozzi, H. Peter Soyer


The Life of Melanocytic Nevi. . . . . . . 61 Harald Kittler

III.2 Acral Nevus. . . . . . . . . . . . . . . . . . . . . . 66 Masaru Tanaka, Masayuki Kimoto, Toshiaki Saida


Blue Nevus. . . . . . . . . . . . . . . . . . . . . . . 78 Gerardo Ferrara and Giuseppe Argenziano

III.10 Halo Nevus . . . . . . . . . . . . . . . . . . . . . 124 A lessandro Di Stefani and Sergio Chimenti III.11 Irritated Nevus and Meyerson’s Nevus. . . . . . . . . . . . 129 Regina Fink-Puches, Iris Zalaudek, Rainer Hofmann-Wellenhof III.12 Melanocytic Lesions in Darker Racial Ethnic Groups. . . . 135 Heather Woolery-Lloyd III.13 Miescher Nevus. . . . . . . . . . . . . . . . . . 139 Steven Q. Wang, Harold H. Rabinovitz, Alfred W. Kopf



III.14 Nevi with Particular Pigmentation: Black, Pink, and White Nevus . . . . . 142 Iris Zalaudek, Robert Johr, Bernd Leinweber III.15 Recurrent Nevus. . . . . . . . . . . . . . . . . 147 Andreas Blum III.16 Spitz Nevus and Its Variants. . . . . . . 151 Gerardo Ferrara, Elvira Moscarella, Caterina M. Giorgio, Giuseppe Argenziano III.17 Syndromes Involving Melanocytic Lesions. . . . . . . . . . . . . . 164 Cheryl G. Aber, Elizabeth Alvarez Connelly, Lawrence A. Schachner III.18 Nail Apparatus Nevus (Subungual Nevus, Nail Matrix Nevus). . . . . . . . 173 Luc Thomas III.19 Unna Nevus. . . . . . . . . . . . . . . . . . . . . 181 Susana Puig and Josep Malvehy IV.1

Epidemiology of Melanoma . . . . . . . 185 Scott Kitchener

IV.2 Acral Melanoma. . . . . . . . . . . . . . . . . 196 Toshiaki Saida, Hiroshi Koga, Yoriko Yamazaki, Masaru Tanaka IV.3 Amelanotic Melanoma. . . . . . . . . . . 204 JĂźrgen Kreusch IV.4

Early Evolution of Melanoma (Small-Diameter Melanoma) . . . . . . 213 Robert J. Friedman, Melanie Warycha, Michele Farber, Dina GutkowiczKrusin, Harold Rabinovitz, David Polsky, Margaret Oliviero, Darrell S. Rigel, Lori Kels, Edward R. Heilman, Alfred W. Kopf


False-Negative Melanomas. . . . . . . . 221 Robert Johr and Giuseppe Argenziano


Genital Melanoma . . . . . . . . . . . . . . . 229 Ingrid H. Wolf


Melanoma of the Face . . . . . . . . . . . . 233 Ulrike Weigert and Wilhelm Stolz


Melanoma of the Trunk and Limbs Including Superficial and Nodular Melanoma. . . . . . . . . . . 237 Josep Malvehy and Susana Puig


Cutaneous Metastatic Melanoma. . . 260 Maria Antonietta Pizzichetta

IV.10 Scalp Melanoma . . . . . . . . . . . . . . . . . 265 Iris Zalaudek, Jason Giacomel, Bernd Leinweber IV.11 Nail Apparatus Melanoma (Subungual Melanoma, Nail Matrix Melanoma). . . . . . . . . . . 270 Luc Thomas V.1

Pigmented Basal Cell Carcinoma. . . 279 Scott W. Menzies


Dermatofibroma. . . . . . . . . . . . . . . . . 286 Domenico Piccolo and Ketty Peris

V.3 Lentigines Including Lentigo Simplex, Reticulated Lentigo and Actinic Lentigo . . . . . . . . . . . . . . 290 Paolo Carli and Camilla Salvini V.4

Squamous Cell Carcinoma Including Actinic Keratosis, Bowens Disease, Keratoacanthoma, and Its Pigmented Variants . . . . . . . . . . . . . . 295 Iris Zalaudek, Jason Giacomel, Bernd Leinweber


Vascular Lesions. . . . . . . . . . . . . . . . . 303 Fezal Ă–zdemir


Seborrheic Keratosis Including Lichen Planus-like Keratosis. . . . . . . 313 Robert Johr

Subject Index. . . . . . . . . . . . . . . . . . . . . . . . . . . 329

List of Contributors

C. Aber Division of Pediatric Dermatology Department of Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine Cedars Medical Center 1295 NW 14th Street, Suite K Miami, Florida 33125 E-mail: E. Alvarez Connelly Division of Pediatric Dermatology Department of Dermatology and Cutaneous Surgery University of Miami, Miller School of Medicine Cedars Medical Center 1295 NW 14th Street, Suite K Miami, Florida 33125 USA E-mail:

A. Blum Associate Professor of Dermatology Seestraße 3a 78464 Konstanz Germany E-mail: R.P. Braun Department of Dermatology University Hospital Zurich 8091 Zurich Switzerland E-mail: H. Cabo Section of Dermatology Instituto de Investigaciones Médicas “A. Lanari” University of Buenos Aires Argentina E-mail:

G. Argenziano Department of Dermatology Second University of Naples Nuovo Policlinico − Edificio 13 Via Pansini 5 80131 Naples E-mail:

P. Carli † Dipartimento di Scienze Dermatologiche Universita’ di Firenze Via degli Alfani, 37 50121 Florence Italy † Deceased

C. Benvenuto-Andrade Research Dermatologist Photomedicine and Telemedicine Laboratory Federal University of Rio Grande do Sul Porte Alegre Brazil E-mail:

L. Cerroni Department of Dermatology Medical University of Graz Auenbruggerplatz 8 8036 Graz Austria E-mail:


List of Contributors

S. Chimenti Department of Dermatology University of Rome “Tor Vergata” PTV − Policlinico di Tor Vergata Viale Oxford 81 00133 Rome Italy E-mail: A. Di Stefani Department of Dermatology University of Rome “Tor Vergata” PTV − Policlinico di Tor Vergata Viale Oxford 81 00133 Rome Italy E-mail: M. Farber Department of Dermatology New York University School of Medicine 550 First Avenue New York, NY 10016 USA E-mail: G. Ferrara Pathologic Anatomy Service Gaetano Rummo General Hospital Via dell’Angelo 1 82100 Benevento Italy E-mail: R. Fink-Puches Department of Dermatology Medical University Graz Auenbruggerplatz 8 8036 Graz Austria E-mail: R.J. Friedman Oncology Section Department of Dermatology New York University School of Medicine 550 First Avenue New York, NY 10016 USA E-mail:

J.S. Giacomel Private Practice 11 Mends Street South Perth Western Australia 6151 Australia E-mail: C.M. Giorgio Department of Dermatology Second University of Naples Via S. Pansini 5 80131 Naples Italy E-mail: S. González Dermatology Service Memorial Sloan-Kettering Cancer Center New York, NY 10022 USA E-mail: D. Gutkowicz-Krusin Electro-Optical Sciences, Inc. 1 Bridge Street Irvington, NY 10533 USA E-mail: A. Halpern Dermatology Service Memorial Sloan-Kettering Cancer Center New York, NY 10022 USA E-mail: E.R. Heilman Department of Dermatology SUNY Health Science Center at Brooklyn Brooklyn, N.Y. USA E-mail:

List of Contributors

R. Hofmann-Wellenhof Department of Dermatology Medical University of Graz Auenbruggerplatz 8 8036 Graz Austria E-mail: R.H. Johr Pigmented Lesion Clinic School of Medicine University of Miami Miami, FL 33136 USA E-mail: M. Kimoto Department of Dermatology Keio University School of Medicine 35 Shinanomachi, Shinjyuku-ku Tokyo 160-8582 Japan E-mail: S. Kitchener Primary Care Skin Cancer Medicine Unit School of Medicine University of Queensland Herston Road Herston 4006 Australia E-mail: H. Kittler Department of Dermatology Medical University of Vienna Waehringer Guertel 18−20 1090 Vienna Austria E-mail: H. Koga Department of Dermatology Shinshu University School of Medicine 3-1-1 Asahi Matsumoto 390-8621 Japan E-mail:

A.W. Kopf The Ronald O. Perelman Department of Dermatology New York University School of Medicine 550 First Avenue New York, NY 10016 USA E-mail: J. Kreusch Dermatological Practice Skin Cancer Diagnostic Center Moislinger Allee 95 23558 Luebeck Germany E-mail: juergen.kreusch B. Leinweber Department of Dermatology Medical University of Graz, Austria Auenbruggerplatz 8 8036 Graz Austria E-mail: G.P. Lozzi Department of Dermatology University of L’Aquila, Italy Via Vetoio − Coppito 2 67100 L’Aquila Italy E-mail: J. Malvehy Melanoma Unit Department of Dermatology Hospital Clinic Villarroel 170 08036 Barcelona Spain E-mail: A.A. Marghoob Section of Dermatology Memorial Sloan-Kettering Cancer Center 160 East 53rd Street, 2nd floor New York, NY 10022 USA E-mail:



List of Contributors

C. Massone Department of Dermatology Medical University Graz Auenbruggerplatz 8 A-8036 Graz Austria E-mail:

D. Piccolo Department of Dermatology University of L’Aquila Via Vetoio − Coppito 2 67100 L’Aquila Italy E-Mail:

S.W. Menzies Sydney Melanoma Diagnostic Centre 2nd Floor, Gloucester House Royal Prince Alfred Hospital Missenden Road Camperdown NSW 2050 Australia E-mail:

M.A. Pizzichetta Division of Medical Oncology C Oncology Prevention Centro di Riferimento Oncologico National Cancer Institute Via Pedemontana Occidentale 12 33081 Aviano –PN Italy E-mail:

E. Moscarella Department of Dermatology Second University of Naples Via S. Pansini 5 80131 Naples Italy E-mail: M. Oliviero Department of Dermatology University of Miami School of Medicine Miami, FL 33324 USA E-mail: F. Özdemir Department of Dermatology Medical Faculty Ege University 35100 Bornova Izmir Turkey E-mail: K. Peris Department of Dermatology University of L’Aquila Via Vetoio − Coppito 2 67100 L’Aquila Italy E-Mail:

D. Polsky Department of Dermatology New York University School of Medicine 550 First Avenue New York, NY 10016 USA E-mail: H.S. Rabinovitz Skin and Cancer Associates 201 N.W. 82nd Avenue Plantation, FL 33324 USA E-mail: D.S. Rigel Department of Dermatology New York University School of Medicine Adjunct Clinical Professor Department of Dermatology Mount Sinai School of Medicine New York, NY USA E-mail: S. Puig Melanoma Unit Department of Dermatology Hospital Clínic Villarroel 170 08036 Barcelona Spain E-mail:

List of Contributors

T. Saida Department of Dermatology Shinshu University School of Medicine 3-1-1 Asahi Matsumoto 390-8621 Japan E-mail: C. Salvini Department of Dermatological Sciences University of Florence Via della Pergola 58−60 50121 Florence Italy E-mail: J.-H. Saurat Pigmented Skin Lesion Unit Department of Dermatology University Hospital Geneva 24 rue Micheli Du Crest 1211 Geneva 14 Switzerland E-mail: L.A. Schachner Division of Pediatric Dermatology University of Miami, Miller School of Medicine Department of Dermatology and Cutaneous Surgery 1600 NW 10th Avenue Rosenstiel Bldg. Room 2023A Miami FL 33136 USA E-mail: L. Schneider-Kels Department of Dermatology New York University School of Medicine 550 First Avenue New York, NY 10016 USA E-mail: A. Scope Section of Dermatology Memorial Sloan-Kettering Cancer Center 160 East 53rd Street, 2nd floor New York, NY 10022 USA E-mail:

J. Smolle Institute of Medical Informatics, Statistics and Documentation Medical University of Graz Billrothgasse 18a/7 8010 Graz Austria E-mail: H.P. Soyer The Queensland institute of Dermatology School of Medicine University of Queensland Princess alexandra Hospital Brisbane, QlD 4102 Australia E-mail: W. Stolz Abteilung für Dermatologie, Allergologie und Umweltmedizin Krankenhaus München Schwabing Kölner Platz 1 80804 Munich Germany E-mail: M. Tanaka Department of Dermatology Tokyo Women’s Medical University Medical Center East 2-1-10 Nishi-Ogu, Arakawa-ku Tokyo 116-8567 Japan E-mail: L. Thomas Department of Dermatology Hotel Dieu 69288 Lyon Cedex 02 France E-mail: S.Q. Wang Department of Dermatology Mayo Mail Code 98 420 Delaware Street S.E. Minneapolis, MN 55455 USA E-mail:



List of Contributors

M. Warycha Department of Dermatology New York University School of Medicine 550 First Avenue New York, NY 10016 USA E-mail:

E.M.T. Wurm Department of Dermatology Medical University of Graz Auenbruggerplatz 8 8036 Graz Austria E-mail:

U. Weigert Abteilung f端r Dermatologie, Allergologie und Umweltmedizin Krankenhaus M端nchen Schwabing K旦lner Platz 1 80804 M端nchen Germany E-mail:

Y. Yamazaki Department of Dermatology Shinshu University School of Medicine 3-1-1 Asahi Matsumoto 390-8621 Japan E-mail:

I.H. Wolf Department of Dermatology Medical University Graz Auenbruggerplatz 8 8036 Graz Austria E-mail: H. Woolery-Lloyd Department of Dermatology and Cutaneous Surgery School of Medicine University of Miami Miami, FL 33136 USA E-mail:

I. Zalaudek Department of Dermatology Medical University Graz Auenbruggerplatz 8 8036 Graz Austria E-mail:

Chapter I.1

The Morphologic Dimension in the Diagnosis of Melanocytic Skin Lesions


H. Peter Soyer and Elisabeth M.T. Wurm

Contents I.1.1 A Color Atlas of Melanocytic Lesions of the Skin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 I.1.2

The Benign/Malignant Threshold in Morphology. . . . . . . . . . . . . . . . . . . . . . . . . . 1

I.1.3 A New Era of “Clinicoimaging” Diagnosis in Dermatology. . . . . . . . . . . . . . . . 2 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

I.1.1 A Color Atlas of Melanocytic Lesions of the Skin The book in your hands has been designed basically as an atlas entitled Color Atlas of Melanocytic Lesions of the Skin and focuses on the morphologic dimension of melanocytic skin lesions. It encompasses all the classical methods of morphology such as the clinical and dermoscopic examination and dermatopathology, as well as the most up-to-date diagnostic approaches such as laser scanning in-vivo microscopy, multispectral image analysis, automatic diagnosis, and teledermatology. With the exception of the chapters on automatic diagnosis and on multispectral analysis, all chapters focus on the morphologic dimension, albeit in its various facets, thus justifying the title of this book. The core of this book represents an atlas with clinical, dermoscopic, and histopathologic images of the many faces of melanocytic nevi, the various types of melanomas, as well as the variable features of non-melanocytic pigmented skin tumors. Each of these well-illustrated entities are presented following the same ductus characterized by definition, clinical and dermo-

scopic features, relevant clinical differential diagnosis, histopathology, as well as practical aspects of management. Core messages recapitulate the most pertinent facets of each entity. This introductory chapter, therefore, can be considered a plea for recognition of the significance, and the unchanging importance, of the human eye and the human neural network for achieving diagnosis in the protean field of melanocytic skin lesions. We currently are on the edge of the development of new technologies, such as imaging technologies and molecularbiologic tests, for identifying individuals at risk and for refining the benign/malignant threshold. These new technologies are challenging the currently well-accepted morphologic methods including histopathology. However, the present reality, even in high-tech countries, is that dermatologists are, and most probably will remain, at the forefront of diagnosing and treating skin cancers as well as managing melanocytic skin lesions.

I.1.2 The Benign/Malignant Threshold in Morphology The boundary between benignity and malignancy is not as sharp as our established categories would like them to be. Dermoscopic – but also histopathologic – diagnoses, not to mention clinical diagnosis, are subjective as well as objective. In 1962 these facts were well depicted for the histopathologic diagnosis by Rambo who stated that “pathologists are physicians and human beings. They […] traditionally have been regarded to be more scientific than many of their colleagues. A mystic perversion of this assumption prevails among those clinicians who


H. P. Soyer, E. M.T. Wurm

believe that the pathologist, given only a piece of the patient’s tissue, has all the other ingredients necessary to produce a statement of absolute truth at the end of his report. More dangerous to the mankind is a pathologist with the same concept…” [1]. Even today it is not easy at all to find references which indicate that expert pathologists sometimes have great difficulties in recognizing, for example, the threshold separating carcinoma in situ or melanoma in situ from atypia or dysplasia. Interestingly, many dermoscopists reveal more insight with regard to their diagnostic limitations. In a recent issue of the “Archives of Dermatology” an article by Skvara et al. entitled “Limitations of dermoscopy in the recognition of melanoma” focuses on the limitations of dermoscopy in the diagnosis of very early, and mainly featureless, melanomas [2]. The authors report that baseline dermoscopic patterns of 262 melanocytic nevi and 63 melanomas, which were followed by digital dermoscopy and finally excised because of changes over time, did not differ substantially from each other. Suffice it to say that histopathology represented the gold standard in this study.

I.1.3 A New Era of “Clinicoimaging” Diagnosis in Dermatology In 2005 June Robinson, the editor of the “Archives of Dermatology,” wrote in an editorial titled “Biotechnology succeeds in revolutionizing medical sciences” the following statement: “Given the unique visual learning patterns of our discipline, it is not surprising that we eager­ ly adapt emerging bioimaging techniques. [...] We are beginning to move away from clinicopathologic diagnosis into an era of ‘clinicoimaging’ diagnosis” [3]. The introduction of these new ‘clinicoimaging’ techniques in the near future certainly will have a major impact on the current dermatologic practice, although there will be a need to define new quality standards in order to integrate these techniques into the daily workflow. We should not forget, however, that all of these new “clinicoimaging” techniques have, like every other purely morphologic meth-

od, limitations due to methodologic drawbacks, and sometimes even due to personal restraints. In addition, we are presently also on the edge of a period of radical change in histopathology, as DNA and RNA can be analyzed by advanced technologies even from archival paraffin-embedded material, allowing us to make diagnostic leaps and bounds [4]. This “new biology” will certainly also affect the benign/malignant threshold in pathology, and a more functional approach to establish the risk associated with sharply defined categories will substitute the fanciful separation of benign from malignant [4, 5]; thus, one can easily foresee that in the future the conventional morphologic methods will probably be substituted by these new “clinicoimaging” techniques and by novel microbiologic methods. Until then, a combined approach linking the most legitimate and effective morphologic methods, namely, clinical examination, dermoscopy, and histopathology, will strengthen the validity of classical morphology [6, 7]. In this spirit this introductory chapter, and this atlas, has been written.

References 1. Rambo ON. The limitations of histologic diagnosis. Progr Radiat Ther 1962; 2: 215–224 2. Skvara H, Teban L, Fiebiger M, Binder M, Kittler H. Limitations of dermoscopy in the recognition of melanoma. Arch Dermatol 2005; 141: 155–160 3. Robinson JK, Callen JP. Biotechnology succeeds revolutionizing medical sciences. Arch Dermatol 2005; 141: 133–134 4. Quirke P, Mapstone N. The new biology: histopathology. Lancet 1999; 354: SI26–SI31 5. Foucar E. Carcinoma-in-situ of the breast: Have pathologists run amok? Lancet 1996; 347: 707–708 6. Soyer HP, Massone C, Ferrara G, Argenziano G. Limitations of histopathologic analysis in the recognition of melanoma: a plea for a combined diagnostic approach of histopathologic and dermoscopic evaluation. Arch Dermatol 2005; 141: 209–211 7. Bauer J, Leinweber B, Metzler G, Blum A, HofmannWellenhof R, Leitz N, Dietz K, Soyer HP, Garbe C. Correlation with digital dermoscopic images can help dermatopathologists to diagnose equivocal skin tumours. Br J Dermatol 2006;155: 546–551

Chapter I.2

Clinical Examination of Melanocytic Neoplasms Including ABCDE Criteria


Alfred W. Kopf

Contents I.2.1

Clinical Recognition of Melanoma. . . . . . . . . 3

I.2.2 ABCDE Criteria and Other Diagnostic Methods . . . . . . . . . . . . . . . . . . . . . 3

I.2.1 Clinical Recognition of Melanoma The clinical recognition of melanoma in its early phases of progression is exceedingly important since the total surgical removal of such ­lesions is almost invariably curative. When the clinical recognition is delayed, the opportunity for distant metastases increases and the prognosis is guarded since treatment of such metastases is problematic. Since dysplastic nevi and melanomas can ­occur on any area of the cutaneous surface, it is mandatory that a complete cutaneous examination be performed on every patient regardless of age. All new patients should have a complete cutaneous examination either at the initial visit or in the near future. The frequency for an established patient depends on their history. Those patients with a history of actinic keratosis, dysplastic nevi, non-melanoma skin cancer or melanoma should be seen every 6 months for a complete cutaneous examination. The examining room should have proper ­illumination and the temperature should be comfortable for the patient, who should be ­completely undressed except – maybe – for the examination gown, which should be provided. The examiner should have available a simple magnifying lens, an instrument for dermoscopy, and an ultraviolet lamp (“Woods light”) for special examinations such as looking for areas of hyper- or hypopigmentation on the skin.

Ideally, the patient should lie in a horizontal position on the examining table. The entire anterior and posterior cutaneous surface of the patient is examined with the patient assuming a supine, then a prone, position. Intertriginous areas, including the axillae, groin, and interdigital webs of the hands and feet, plus the nail apparatus, are included in the complete cutaneous examination. Finally, examination of the scalp is best accomplished by the use of a hair blower that parts the hair down to the skin of the scalp for viewing.

I.2.2 ABCDE Criteria and Other Diagnostic Methods The acronym ABCDE was created as a simple mnemonic to alert both the general community and health care workers of some of the key features of melanoma. The acronym stands for: A = Asymmetry. No matter where the lesion is bisected, the one half will not match the other in silhouette and/or lesion content. B = Border irregularity. The perimeter of the lesion is uneven, undulating, ragged, notched, or blurred. C = Color. Multiple shades of tan, brown, black, red, white, and blue are admixed, producing a mottled appearance. D = Diameter >6 mm. The largest diameters of most melanomas will exceed 6 mm at a point in their evolution that can be identified. This is not an inviolate rule, and currently a significant portion of melanomas are diagnosed by experts when these cancers are 6 mm or less in diameter.


A.W. Kopf

E = Evolving. While common melanocytic nevi evolve slowly and reach a final stage of growth usually within the first few decades of life, melanomas usually undergo constant change in size, shape, shades of color, symmetry, symptoms (especially pruritus, scaliness, oozing, bleeding), or surface alterations [erosion, ulceration, papule, and/or nodule formation and the development of areas of hypopigmentation and depigmentation (a clinical correlate of spontaneous regression)]. Another easy mnemonic are the three Cs of melanoma standing for: color, contour, and change. The diagnostic method of the Glasgow 7point checklist for diagnosis of melanoma includes: (a) change in size; (b) irregular shape; (c) irregular color (major criterion); (d) diameter at least 7 mm; (e) inflammation; (f) oozing/bleeding; and (g) change in sensation (minor criterion). The features described above are suggestive of melanoma (especially superficial spreading melanoma), but they also appear in benign lesions (such as atypical nevi), thus causing diagnostic difficulties. Nodular melanomas, on the other hand, often appear as small and symmetric round nodules, smaller than 6 mm in diameter, the only hint of malignancy being a clinical history of evolution and change. These limitations to specificity and sensitivity of naked-eye examination can be reduced by dermoscopy as a useful aid in the in-vivo differentiation of such lesions (see Chap. I.3). Furthermore, total cutaneous photography can be performed for patients who have many melanocytic nevi (especially when atypical). Baseline total-cutaneous photographs (Fig. I.2.1) are very helpful in identifying significant changes in pre-existing lesions and identifying new melanocytic neoplasms on subsequent followup clinical examinations. Last but not least, patients should be instructed and encouraged to regularly perform self-examination of their skin (Fig. I.2.2).

Fig. I.2.1.  Illustrations for different views taken of total-body photographs. Sites photographed are bound by dashed lines or solid-line rectangles. Top: On anterior and posterior surfaces of body, all demarcated areas (shaded and unshaded) are photographed. On lateral aspects of body, only shaded areas are photographed

Clinical Examination of Melanocytic Neoplasms


Chapter I.2

Core Messages ■ It is mandatory that a complete cutaneous examination be performed on every patient regardless of her/his age. ■ The examination should include examination of intertriginous areas including axillae, groin, and interdigital webs of hands and feet, as well as nail apparatus and scalp. ■ Features of melanoma can be memorized by the acronym ABCDE: Asymmetry; Borders; Color; Diameter; and Evolution.

■ The diagnostic method of the Glasgow 7-point checklist for diagnosis of melanoma includes: (a) change in size; (b) irregular shape; (c) irregular color (major criterion); (d) diameter at least 7 mm; (e) inflammation; (f) oozing/ bleeding; and (g) change in sensation (minor criterion). ■ Patients should be encouraged to regularly perform a self-examination of their skin.

Fig. I.2.2.  Self-examination of the skin (continuation see next page)

A.W. Kopf


Fig. I.2.2.  (continued)

Chapter I.3

Dermoscopic Examination Ralph P. Braun, Harold S. Rabinovitz, Margaret Oliviero, Alfred W. Kopf, Jean-Hillaire Saurat, Luc Thomas

Contents I.3.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . .   7 I.3.2 Physical Aspects. . . . . . . . . . . . . . . . . . . . . . . .   7


I. Menzies Method. . . . . . . . . . . . . . . . . . . . . . . . 20 I. Three-Point Checklist. . . . . . . . . . . . . . . . . . . 21

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

I.3.3 Equipment for Dermoscopy. . . . . . . . . . . . . .   8 I.3.4 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . .   9 I.3.4.1 Colors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   9 I.3.4.2 Blood Vessels. . . . . . . . . . . . . . . . . . . . . . . . . . .  9 I.3.5 Dermoscopic Structures. . . . . . . . . . . . . . . . . 11 I.3.5.1 Pigment Network. . . . . . . . . . . . . . . . . . . . . . . 11 I.3.5.2 Dots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 I.3.5.3 Globules. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 I.3.5.4 Branched Streaks. . . . . . . . . . . . . . . . . . . . . . . 12 I.3.5.5 Streaks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 I.3.5.6 Structureless Areas . . . . . . . . . . . . . . . . . . . . . 13 I.3.5.7 Blotches. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 I.3.5.8 Regression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 I.3.5.9 Blue-White Veil . . . . . . . . . . . . . . . . . . . . . . . . 13 I.3.5.10 Milia-like Cysts . . . . . . . . . . . . . . . . . . . . . . . . 13 I.3.5.11 Comedo-like Openings (Crypts, Pseudofollicular Openings). . . . . . 13 I.3.5.12 Fingerprint-like Structures . . . . . . . . . . . . . . 14 I.3.5.13 Moth-Eaten Border. . . . . . . . . . . . . . . . . . . . . 14 I.3.5.14 Fissures and Ridges (“Brain-like” Appearance). . . . . . . . . . . . . . . 14 I.3.5.15 Leaf-like Areas. . . . . . . . . . . . . . . . . . . . . . . . . 14 I.3.5.16 Spoke-Wheel-like Structures. . . . . . . . . . . . . 14 I.3.5.17 Large Blue-Gray Ovoid Nests . . . . . . . . . . . . 14 I.3.5.18 Multiple Blue-Gray Globules. . . . . . . . . . . . . 14 I.3.6 Differential Diagnosis of Pigmented Lesions of the Skin. . . . . . . . . 15 I.3.7 ABCD Rule of Dermatoscopy [11, 12] . . . . . 19 I.3.7.1 Asymmetry. . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 I.3.7.2 Border. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 I.3.7.3 Colors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 I.3.7.3 Dermoscopic Structures. . . . . . . . . . . . . . . . . 19 I. Seven-Point Checklist. . . . . . . . . . . . . . . . . . . 20

I.3.1 Introduction Dermoscopy (also known as epiluminescence microscopy, dermatoscopy, amplified surface microscopy) is an in-vivo method that has been reported to be a useful tool for the early recognition of melanoma and the differential diagnosis of pigmented lesions of the skin [1, 2]. Its use increases diagnostic accuracy between 5 and 30% over clinical visual inspection, depending on the type of skin lesion and the experience of the physician. This was confirmed by two recent evidence-based publications from a meta-analysis of the literature [3].

I.3.2 Physical Aspects Light is either reflected, dispersed, or absorbed by the stratum corneum due to its refraction index and its optical density, which is different from air; thus, deeper underlying structures cannot be adequately visualized. The use of ­immersion liquids renders the skin surface translucent and reduces reflections, so that underlying structures will become visible. The application of a glass plate flattens the skin surface and provides an even surface. Optical magnification is used for examination. Taken together, these optical means allow the visualization of certain epidermal, dermo-epidermal, and dermal structures. As immersion liquid we recommend the use of 60° alcohol (ethanol) which can


R. P. Braun, H. S. Rabinovitz, M. Oliviero et al.

be applied directly on the skin using an eye dropper bottle [4]. The advantages are that ethanol results in the best image quality and the least air inclusions. It evaporates immediately, does not have to be wiped off, and does not stain the patient’s clothing or underwear. In areas close to the eyes or to the mucosa, as well as for the examination of the nail apparatus, we recommend instead the use of a gel (ultrasound gel, cosmetic gel, etc.). A cosmetic gel does not burn the eyes and, most importantly, it fills out very nicely the gap between the convex nail surface and the handheld device. As an alternative to the immersion technique, some devices use polarized light in order to reduce the surface reflections. This technique allows a faster examination of the patient, but if the patient has dry skin the use of immersion liquid is still required.

I.3.3 Equipment for Dermoscopy As mentioned, dermoscopy requires optical magnification and liquid immersion. Specially designed handheld devices with 10–20 times magnification are commercially available (Dermatoscope Delta 20, Heine, Herrsching, Germany; DermoGenius Basic, Biocam, Regensburg, Germany; Dermlite (3Gen, San Juan Capistrano, Calif.); see Fig. I.3.1). All devices mentioned above are devices of the second generation which have improved optics and illumi-

nation (LED) compared with the older devices [1]. The optic is designed in such a way that a lesion can be examined at distance from the skin. This is an advantage, because the examination is much faster and it is more comfortable for both, the physician and the patient, if the lesion is, for example, on the face or the genital area. Photographic documentation can be performed in different ways [1]: The digital camera is directly attached to a handheld dermatoscope (coupling adapters are available for most handheld devices). In this case, the camera uses the optics and the illumination of the handheld dermatoscope. Since the optics of the handheld devices are not designed to fit a camera, the dermoscopic image is always a bit blurred towards the periphery, but this is the most inexpensive way of taking dermoscopy images. Dermoscopy attachments (lenses) are directly attached to digital cameras. Their optics and illumination are designed to fit digital cameras and they provide the best image quality. These lenses can only be used with digital cameras and not for the examination of patients. There are many different attachments available, but we mainly use the Dermlite Foto attachment (3GEN; Fig. I.3.1) or a Dermaphot lens (Heine, AG) which can be attached to digital SLR cameras. The attachments can be used with different cameras and the resolution depends on the digital camera used. This solution enables conveniently taking images of excellent quality. Fig. I.3.1.  A choiceof handheld dermatoscopes of the latest generation (from left to right): DermoGenius Basic (Biocam); Delta 20 (Heine); Dermlite II pro HR (3GEN); and Dermlite Foto (3GEN) on a Coolpix 4500 (Nikon)

Dermoscopic Examination

Storage and retrieval remain tricky for both ways of photo documentation mentioned above, and by the end of the day one finds himself with a camera full of images which have to be attributed to patients and stored in a way that they can be easily retrieved. Systems for digital dermoscopy consist of a video camera which is linked directly to a computer. The lesion can be examined “live” on the computer screen. These systems offer physicians many more features than the previous solutions, such as the possibility of easy storage and retrieval of lesions, which is important for followup examinations of suspect lesions. This is a big advantage, because when the patient leaves the office, all images (lesions) are correctly stored and there is no additional work to be done. Some systems offer even the possibility of computerassisted diagnosis and/or teledermoscopy. Since these systems use a video camera, the resolution is not as good as with a digital consumer camera and a dermoscopy attachment, but the image quality is very good on the computer screen. Systems for digital dermoscopy offer many more features and can make life much easier, but their disadvantages are their high cost and their lack of portability.

I.3.4 Dermoscopic Criteria The use of dermoscopy allows the identification of many different structures, colors, and blood vessels not seen by naked-eye examination.

I.3.4.1 Colors Colors play an important role in dermoscopy. Common colors are light brown, dark brown, black, blue, blue-gray, red, yellow, and white. The most important chromophore of the skin, especially in melanocytic neoplasms, is melanin. The color of melanin as seen with dermoscopy depends on its localization in the skin. For

Chapter I.3

example, melanin appears black in the stratum corneum and the upper epidermis, light to dark brown in the epidermis, gray to blue-gray in the papillary dermis, and steel blue in the reticular dermis. Melanin appears to be blue when it is localized within the deeper parts of the skin, because the portions of the visible light with longer wavelengths (red end of visible spectrum) are more dispersed than the portions with shorter wavelengths (blue-violet end of the spectrum). The color red is associated with either an increased number or dilatation of blood vessels, trauma, or neo-vascularization (see vascular pattern). The color white is often due to regression and/or scaring (see Regression).

I.3.4.2 Blood Vessels In recent publications, blood vessels have gained much more importance and their morphological aspect enables the clinician in many cases to make the diagnosis, especially in non-pigmented lesions and lesions of non-melanocytic origin. The following types of blood vessels have been described: red lagoons; hairpin vessels; dotted vessels; “comma”-like vessels; glomerular vessels; string of pearls; crown vessels; corkscrew vessels; and arborizing vessels (Table I.3.1) [5]. An atypical vascular pattern, also called irregular (polymorphous) vessels, may include linear, dotted, or globular red vessels, irregularly distributed within the lesion. Some of the vascular patterns may be due to neo-vascularization. For the evaluation of blood vessels, there has to be as little pressure as possible on the lesion during the examination, because otherwise the vessels are simply compressed and will not be visible. The use of ultrasound gel for immersion helps to reduce the pressure. An excellent alternative is the use of non-contact polarized light examination as used in some handheld dermatoscopes.


R. P. Braun, H. S. Rabinovitz, M. Oliviero et al. Table I.3.1.  Vascular architecture of pigmented skin lesions. (From [5])

Morphological aspect


Red lagoons

Sharply demarcated globular structures, red, violaceous, brownish, bluish, or black

Hemangiomas or angiokeratomas

Hairpin vessels

Elongated vessels resembling hairpins

Fine and surrounded by whitish halo, seborrheic keratosis, or keratinizing tumor


Irregular and thick melanoma or Spitz nevus Dotted vessels

Small vessels resembling the head of a pin

Vertical vessels seen in Spitz ­nevus or melanoma Observed also in psoriasis and squamous cell carcinoma

Comma-like vessels

Resembling the shape of a comma

Compound or dermal nevus

Clusters of glomerular vessels

Small- and fine-coiled vessels

Bowen’s disease

String of pearls

Globular vessels following a serpiginous distribution

Crown vessels

Radial wreath-like or individual Sebaceous gland hyperplasia vessels at the periphery of the tumor; white-yellow globules in the center of the tumor

Corkscrew vessels

Irregular and thick-coiled vessels

Melanoma including melanoma metastasis

Arborizing vessels

Resembling the branches of a tree

Basal cell carcinoma

Irregular poly­ morphous vessels

Multiple vessels with different shapes including comma, dotted irregular lines, corkscrew, glomerular, and others


Observed in melanoma and stasis dermatitis Clear cell acanthoma

Dermoscopic Examination

Chapter I.3

I.3.5 Dermoscopic Structures In this chapter we use the nomenclature as proposed by the Consensus Netmeeting on Dermoscopy with some revisions [6].

I.3.5.1 Pigment Network The pigment network is a honeycomb-like network that consists of pigmented “lines” and ­hypopigmented “holes.” The reticulation (network) represents the rete ridge pattern of the epidermis. Its histopathological correlation is either melanin pigment in keratinocytes, or in melanocytes along the dermo-epidermal junction. The hypopigmented holes in the network correspond to tips of the dermal papillae and the overlying supra-papillary plates of the epidermis. The pigment network can be classified as typical or atypical. A typical network is relatively uniform, regularly meshed, homogeneous in color, and usually thinning out at the periphery (Fig. I.3.2). An atypical network is non-uniform, with darker and/or broadened lines and “holes” that are heterogeneous in diameter and shape. The lines are often hyperpigmented and may end abruptly at the periphery.

I.3.5.2 Dots Dots are small, round structures of less than 0.1 mm in diameter which may be black, brown, gray, or blue-gray. Black dots are due to pigment accumulation in the stratum corneum and the upper part of the epidermis (see colors). Brown dots represent focal melanin accumulations at the dermo-epidermal junction. Gray-blue granules are due to tiny melanin structures in the papillary dermis. Gray-blue or blue granules are due to loose melanin, fine melanin particles, or melanin “dust” in melanophages, or exist freely in the deep papillary or reticular dermis.

Fig. I.3.2.  Clinical picture of a benign compound nevus. Dermoscopy shows a regular pigment network (reticular architecture) at the periphery and regular globules (globular architecture) in the center of the lesion.

I.3.5.3 Globules Globules are round to oval, well-demarcated structures that may be brown, black, or gray. They have a diameter larger than 0.1 mm and correspond to nests of pigmented melanocytes, clumps of melanin, and/or melanophages situated usually in the lower epidermis, at the dermo-epidermal junction, or in the papillary dermis. Both dots and globules may occur in benign as well as in malignant melanocytic proliferations. In benign lesions, they are regular in size and shape and evenly distributed (frequently in the center of a lesion; Fig. I.3.2). In melanomas, they tend to vary in size, color, and shape and are frequently found in the periphery of lesions.



R. P. Braun, H. S. Rabinovitz, M. Oliviero et al.


Fig. I.3.3.  Clinical image of a lesion which has criteria for melanoma on clinical examination. Dermoscopy shows an irregular pigment network but no other criteria for melanoma. Using the 7-point checklist this lesion would have a score of 2 and would be classified as nonmelanoma

I.3.5.4 Branched Streaks Branched streaks are an expression of an altered, perturbed pigment network in which the network becomes broken up (see ABCD Rule of Dermoscopy; Figs. I.3.3, I.3.4). Their pathological correlations are remnants of pigmented rete ridges and bridging nests of melanocytic cells within the epidermis and papillary dermis. This term is exclusively used in the ABCD rule of dermoscopy and should not be confounded with the term “streaks,” which is used in the 7-point checklist of dermoscopy.

Fig. I.3.4.  Clinical image of a melanoma. Dermoscopy shows atypical pigment network, irregular dots in the periphery, regression areas, irregular pigmentation, and irregular streaks (radial streaming)

I.3.5.5 Streaks Both radial streaming and pseudopods correspond histopathologically to intraepidermal or junctional confluent radial nests of melanocytes. This is why some authors prefer using the term “streaks” interchangeably with radial streaming or pseudopods. Streaks can be irregular (unevenly distributed in melanoma) or regular (symmetrical radial arrangement over the entire lesion); the latter is found particularly in the pigmented spindle cell nevi (Reed’s nevi).

Radial Streaming Radial streaming appears as radially and asymmetrically arranged, parallel linear extensions at the periphery of a lesion (Fig. I.3.4).

Dermoscopic Examination

Pseudopods Pseudopods represent finger-like projections of dark pigment (brown to black) at the periphery of the lesion. They may have small knobs at their tips, and are either connected to the pigment network or directly to the tumor body.

I.3.5.6 Structureless Areas Structureless areas represent areas devoid of any discernible structures (globules, network, etc.). They tend to be hypopigmented, which is due to the absence of pigment or diminution of pigment intensity within a pigmented skin lesion. A structureless or hypopigmented area cannot be lighter than the surrounding skin and does not have signs of granularity (peppering) in its periphery.

I.3.5.7 Blotches A blotch (black lamella) is a diffuse pigmen­ tation of black to dark brown color which obscures underlying structures. It is due to a large concentration of melanin pigment localized throughout the epidermis and/or dermis visually. A blotch can be regular, often in the center of a lesion (junctional nevus), or irregular (melanoma).

I.3.5.8 Regression Regression appears as white scar-like depigmentation (lighter than the surrounding skin) or “peppering” (speckled multiple blue gray granules within a hypopigmented area; see Fig. I.3.4). Histopathologically, regression shows fibrosis, loss of pigmentation, epidermal thinning, effacement of the rete ridges, and melanin granules free in the dermis or in melanophages scattered in the papillary dermis.

Chapter I.3

I.3.5.9 Blue-White Veil Blue-white veil is an irregular, indistinct, confluent blue pigmentation with an overlying white ground-glass haze. The pigmentation cannot occupy the entire lesion and is found mainly in the papular part of the lesion. Histopathologically this corresponds to an aggregation of heavily pigmented cells or melanin in the dermis (blue color) in combination with a compact orthokeratosis. Blue-white veil should not be confused with confluent peppering (granularity) in regression areas of melanomas; the ­latter is the dermoscopy aspect of (histopathological) melanosis. Both entities might have a similar dermoscopy aspect but do not have the same histopathological correlation. The bluewhite veil is, together with pigment-network structures, a highly specific criterion for the diagnosis of melanoma.

I.3.5.10 Milia-like Cysts Milia-like cysts are round whitish or yellowish structures which are seen mainly in seborrheic keratosis. They correspond to intraepidermal keratin-filled cysts and may also be seen in congenital nevi as well as in some papillomatous melanocytic nevi (Fig. I.3.5).

I.3.5.11 Comedo-like Openings (Crypts, Pseudofollicular Openings) Comedo-like openings (pseudocomedos) are seen mainly in seborrheic keratosis (Fig. I.3.5) or in some rare cases in papillomatous melanocytic nevi. Histopathologically they correspond to keratin-filled invaginations of the epidermis.



R. P. Braun, H. S. Rabinovitz, M. Oliviero et al.

I.3.5.12 Fingerprint-like Structures


Some flat seborrheic keratoses (also known as solar lentigines) can show tiny ridges running in parallel and producing a pattern which resembles fingerprints.

I.3.5.13 Moth-Eaten Border Some flat seborrheic keratoses (mainly on the face) have a concave border so that the pigment ends with a curved structure. This has been compared to a moth-eaten garment.

I.3.5.14 Fissures and Ridges (“Brain-like” Appearance) Fissures are irregularly, linear keratin-filled depressions, commonly seen in seborrheic keratosis (Fig. I.3.5). They may also be seen in melanocytic nevi with congenital patterns and in some dermal melanocytic nevi. Multiple fissures might give a “brain-like” appearance to the ­lesion. This pattern has also been named “gyri and sulci” by some authors.

I.3.5.15 Leaf-like Areas Leaf-like areas (maple-leaf-like areas) are seen as brown to gray-blue discrete bulbous blobs, sometimes forming a leaf-like pattern. Their distribution reminds one of the shape of finger pads. In the absence of a pigment network, they are suggestive of pigmented basal cell carcinomas.

I.3.5.16 Spoke-Wheel-like Structures Spoke-wheel-like structures are well-circumscribed brown to gray-blue-brown radial projections meeting at a darker brown central hub. In absence of a pigment network, they are highly suggestive of basal cell carcinoma.

Fig. I.3.5.  Clinical image of a pigmented seborrheic keratosis. Dermoscopy shows multiple milia-like cysts, pseudocomedos, some crypts (fissures), regular hairpin blood vessels, as well as a sharp demarcation

I.3.5.17 Large Blue-Gray Ovoid Nests Ovoid nests are large, well-circumscribed, confluent, or near-confluent pigmented ovoid areas, larger than globules, and not intimately connected to a pigmented tumor body (Fig. I.3.6). When a network is absent, ovoid nests are highly suggestive of basal cell carcinoma.

I.3.5.18 Multiple Blue-Gray Globules Multiple blue-gray globules are round well-circumscribed structures which are, in the absence of a pigment network, highly suggestive of a basal cell carcinoma (Fig. I.3.6). They have to be

Dermoscopic Examination

Chapter I.3





Fig. I.3.6.  a Clinical image of a partially pigmented basal cell carcinoma. b Dermoscopy shows arborized telangiectasia as well as an ovoid nest and multiple blue-gray dots and globules. c Clinical image of a pigmented basal

cell carcinoma. d Dermoscopy shows a spoke-wheel area, a blue-gray ovoid nest, a small area of ulceration, and multiple blue-gray dots and globules

differentiated from multiple blue-gray dots (which correspond to melanophages and melanin dust).

For the first decision (melanocytic vs nonmelanocytic) the following algorithm is used (Fig. I.3.8): Steps 1-2: Are pigment network, aggregated globules, branched streaks, homogenous blue pigmentation, or a parallel pattern (palms, soles, and mucosa) visualized? If this is the case, the lesion should be considered as a melanocytic lesion (Figs. I.3.2, I.3.3, I.3.4). Step 3: If this is not the case, the lesion should be evaluated for the presence of comedo-like plugs, multiple milia-like cysts, and comedolike openings, irregular crypts, light-brown fingerprint-like structures, or “fissures and ridges” (brain-like appearance) pattern; if so, the lesion is suggestive of a seborrheic keratosis (Fig. I.3.5) [7]. Step 4: If such is not the case, the lesion has to be evaluated for the presence of arborizing blood

I.3.6 Differential Diagnosis of Pigmented Lesions of the Skin The Board of the Consensus Netmeeting agreed on a two-step procedure for the classification of pigmented lesions of the skin (see Fig. I.3.7) [6]. The first step is the differentiation between a melanocytic and a non-melanocytic lesion. Once a lesion has been identified to be of melanocytic origin, it has to be determined in a second step whether the lesion is benign, suspicious, or malignant. This can be done with the help of different algorithms, which are discussed later.



R. P. Braun, H. S. Rabinovitz, M. Oliviero et al. Fig. I.3.7.  Two-step procedure for the classification of pigmented skin lesions (modified)


Fig. I.3.8.  Algorithm for the decision of melanocytic vs non-melanocytic lesion according to the proposition of the Board of the Consensus Netmeeting (modified)

vessels (telangiectasias), leaf-like areas, large blue-gray ovoid nests, multiple blue-gray globules, spoke-wheel areas, or ulceration. If present, the lesion is suggestive of basal cell carcinoma (Fig. I.3.6) [8]. Step 5: If such is not the case, one has to look for red or red-blue (to black) lagoons. If these structures are present, the lesion should be considered as hemangioma or an angiokeratoma (Fig. I.3.9).

Step 6: If all the preceding questions were answered with “no,” the lesion should still be considered as melanocytic in order not to miss a melanoma. Once the lesion is identified to be of melanocytic origin, the decision has to be made as to whether the melanocytic lesion is benign, suspect, or malignant. To accomplish this, the following algorithms are most common:

Dermoscopic Examination

Fig. I.3.9.  Clinical picture of a cherry angioma. Dermoscopy shows multiple red lagoons

1. Pattern analysis [9] Pattern recognition has historically been used by clinicians and histopathologists to differentiate benign lesions from malignant neoplasms. A similar process has been found to be useful with dermoscopy, and has been termed “pattern analysis.” It allows distinction between benign and malignant growth features. It was described by Pehamberger and colleagues based on the analysis of more than 7000 pigmented skin lesions [9]. Table I.3.2 shows the typical patterns of some common, pigmented skin lesions using pattern analysis.

2. Revised pattern analysis The revised pattern analysis distinguishes between global patterns and local features [10]. The general appearance of Color, Architectural order, Symmetry of pattern, and Homogeneity (CASH) are important components in benign le-

Chapter I.3

sions from melanoma. Benign melanocytic ­ lesions tend to have few colors, architectural ­order, symmetry of pattern, and homogeneity. Melanoma often has many colors, architectural disorder, asymmetry of pattern, and heterogeneity. The reticular pattern or network pattern is the most common feature in melanocytic lesions. This pattern represents the junctional component of a melanocytic nevus. Another pattern is the so-called globular pattern. It is characterized by the presence of numerous “aggregated globules.” This pattern is commonly seen in a congenital nevus, superficial type. The cobblestone pattern is very similar to the globular pattern but is composed of closer aggregated globules, which are somehow angulated, resembling cobblestones. The homogeneous pattern appears as diffuse pigmentation, which might be brown, gray-blue, gray black, or reddish black. No pigment network or any other distinctive dermoscopy structures are found. An example is the homogenous steel-blue color seen in blue nevi. The so-called starburst pattern is characterized by the presence of streaks in a radial arrangement, which is visible at the periphery of the lesion. This pattern is commonly seen in Reed nevi or Spitz’s nevi. The parallel pattern is exclusively found on the palms and soles due to the particular anatomy of these areas. The combination of three or more distinctive dermoscopic structures (i.e., network, dots, and globules, as well diffuse areas of hyper- and hypopigmentation) within a given lesion is called multicomponent pattern. This pattern is highly suggestive of melanoma but might be observed in some cases in acquired melanocytic nevi and congenital nevi. The term “lesions with indeterminate patterns” are dermoscopic patterns that can be seen in both benign and malignant pigmented lesions. Clinically and dermoscopically one cannot distinguish whether they are melanomas or atypical nevi. In addition to the global features mentioned above, the local features (dermoscopic structures such as the pigment network, dots, and globules, etc.) are important to evaluate melanocytic lesions (Table I.3.3).



R. P. Braun, H. S. Rabinovitz, M. Oliviero et al. Table I.3.2.  Pattern analysis. (Modified after [9])


Lentigo simplex

Junctional nevus

Compound nevus

Dermal nevus

Blue nevus

Regular pigment network without interruptions

Regular pigment network without interruptions

Regular pigment network without interruptions

No criteria for melanocytic lesion

Steel blue areas

Regular border, thins out at the periphery

Regular border, thins out at the periphery

Regular border, thins out at the periphery

No pigment network

No pigment network

Black dots over the grids of the pigment network

Heterogeneous holes of the pigment network

Heterogenous holes of the pigment network

Brown globules

Ill defined

Brown-black globules Brown globules at the center of the lesion

Brown globules

Homogenous colors

White veils are possible

Homogenous colors

Symmetric papular appearance


No pseudonetwork

All criteria for melanocytic lesion possible

“Comma”-shaped blood vessels

Homogenous colors

Color heterogeneity possible Melanoma

Atypical (Clarks) nevus


Seborrheic keratosis

Pigmented BCC

Heterogeneous (colors and structures)

Irregular pigment network with interruptions

No features of melanocytic lesion

No features for a melanocytic lesion

No features for melanocytic lesion

Asymmetry (colors and structures)

Heterogeneous holes

No pigment network

Pigment network usually absent

Maple-leaflike pigmentation

Irregular pigment network

Irregular border

Red, red-blue, or red-black lagoons (globules, saccules)

Milia-like cysts


Abrupt border cut-off

Pseudofollicular openings, comedolike openings (plugs)

Tree-like blood vessels

Rough surface

“Dirty” gray brown to gray-black colors

Irregular border with Heterogeneity abrupt peripheral of colors margin Structureless areas

Gray-white veil

Dermoscopic Examination

Chapter I.3

Table I.3.3.  Patterns of benign and malignant melanocytic lesions

Benign melanocytic lesions

Malignant melanocytic lesions


Centrally located or situated right on the network

Unevenly distributed and scattered focally at the periphery


Uniform in size, shape, and color symmetrically located at the periphery, centrally located, or uniform throughout the lesion as in a cobblestone pattern

Globules which are unevenly distributed and when reddish in color are highly suggestive of melanoma


Radial streaming or pseudopods tend to be symmetrical and uniform at the periphery

Radial streaming or pseudopods tend to be focal and irregular at the periphery

Blue-white veil

Tends to be centrally located

Tends to be asymmetrically located or diffuse almost over the entire lesion


Centrally located or may be a diffuse hyperpigmented area that extends almost to the periphery of the lesion

Asymmetrically located or there are often multiple asymmetrical blotches


Typical network that consists of lightto-dark uniform pigmented lines and hypopigmented holes

Atypical network which may be non-uniform with black/brown or gray thickened lines and holes of different sizes and shapes

Network borders

Either fades into the periphery or is symmetrically sharp

Focally sharp

I.3.7 ABCD Rule of Dermatoscopy [11, 12] The ABCD rule of dermatoscopy, described by Stolz et al. in 1994 [11], was based on an analysis of 157 pigmented skin lesions. It is based on a scoring system for melanocytic neoplasms that differentiates them into benign, suspicious, and malignant categories. This is accomplished by calculating a total dermoscopy score (Table I.3.4).

I.3.7.1 Asymmetry The lesion is bisected by two lines that are placed 90° to each other. The first line attempts to bisect the lesion at the division of most symmetry and the other one is placed 90° to it. Symmetry takes into account the contour, colors, and structures within the lesion. Lesions that are symmetric in both axes are given zero points. Points for asymmetry are multiplied with a weighting factor of 1.3 to calculate the dermoscopy score.

I.3.7.2 Border First the lesion is divided into eight equal pieshaped pieces. Next, one counts the number of segments that have an abrupt perimeter cut-off; thus, the points range from 0 to 8, which have to be multiplied with a weighting factor of 0.1.

I.3.7.3 Colors Number the following colors present: light brown; dark brown; black; red; white; and bluegray. The points will range from 1 to 6, which have to be multiplied with a weighting factor of 0.5.

I.3.7.3 Dermoscopic Structures Number the following five structures: dots; globules; structureless areas; network; and branched streaks. The points range from 1 to 6, which have to be multiplied with a weighting factor of 0.5.



R. P. Braun, H. S. Rabinovitz, M. Oliviero et al. Table I.3.4.  The ABCD rule of dermoscopy. (Modified after [11])


Weight factor

Sub-score range

Complete symmetry




Asymmetry in one axis


Asymmetry in two axes



Eight segments, one point for abrupt cut-off of pigment





One point for each color: white; red; light brown; dark brown; black; blue gray




Differential structures

One point for every structure: pigment network; structureless areas; dots; globules; branched streaks






Total score range:

The individual points are multiplied with weighting factor which is specific for each criterion. The different sub-scores are then added together in order to obtain the total dermoscopy score (TDS). A lesion with a TDS <4.75 can be considered to be benign. A lesion with a TDS >5.45 should be considered to be malignant and should be removed. Lesions with a TDS between 4.75 and 5.45 should be considered to be suspicious and should be either removed or monitored.

I. Seven-Point Checklist In 1998 Argenziano and colleagues described a 7-point checklist based on the analysis of 342 pigmented skin lesions [13]. They distinguished three major criteria (atypical pigment network, blue-whitish veil, atypical vascular pattern) and four minor criteria (irregular streaks, irregular pigmentation, irregular dots/globules, regression structures; Table I.3.5). Each major criterion has a score of 2 points and each minor criterion has a score of 1 point. A minimum total score of 3 is required for the diagnosis of melanoma. The 7-point checklist was the first algorithm which compromised the vascular architecture of a lesion.


Table I.3.5.  The 7-point checklist. (According to [6])


7-point score

Major  Atypical pigment network   Blue-whitish veil  Atypical vascular pattern

2 2 2

Minor  Irregular streaks  Irregular pigmentation  Irregular dots/globules  Regression structures

1 1 1 1

I. Menzies Method In Menzies method for diagnosing melanoma, both of the following negative features have to be absent: single color (tan, dark brown, gray, black, blue, and red, but white is not considered) and “point and axial symmetry of pigmentation” (refers to pattern symmetry around any axis through the center of the lesion). This does not require the lesion to have symmetry of shape.

Dermoscopic Examination

Chapter I.3

Table I.3.6.  The Menzies method. (According to [8]) Negative features


Core Messages ■ Dermoscopy increases diagnostic accuracy by 5–30% ■ Features of skin lesions not seen by naked-eye examination can be visualized with dermoscopy: 1. Colors (brown, black, blue, blue-gray, red, yellow, and white) 2. Blood vessel types (red lagoons, string of pearls, hairpin, dotted, “comma”-like, glomerular, crown, corkscrew, arborizing, or irregular vessels) 3. Architectural criteria (pigment network, dots, globules, branched streaks, streaks, structureless areas, blotches, regression, blue-white veil, milia-like cysts, comedo-like openings, fingerprint-like structures, moth-eaten borders, fissures and ridges, leaf-like areas) ■ Potentially malignant lesions tend to show two of the following three features: asymmetry; atypical network; and blue-white structures (3-step checklist).

  Point and axial symmetry of pigmentation   Presence of a single color Positive features   Blue-white veil   Multiple brown dots   Pseudopods  Radial streaming   Scar-like depigmentation   Peripheral black dots−globules   Multiple colors (five or six)   Multiple blue/gray dots   Broadened network

In addition, at least one or more of the positive features that are described in Table I.3.6 has to be found.

I. Three-Point Checklist The three-point checklist [15] is based on a simplified pattern analysis and is intended for use by non-experts as a screening technique. The three-point checklist does not differentiate between melanocytic and non-melanocytic lesions. Its aim is to identify all potentially malignant lesions, including basal cell carcinoma and melanoma, with a high degree of sensitivity. Remarkably, the sensitivity for detecting malignancy by non-experts using the three-point checklist has reached 96.3%; however, as is true for all screening techniques, the specificity achieved by non-experts was much lower (32.8%) than that achieved by experts (94.2%). The three-point checklist requires the examiner to assess the lesion for only three der­ moscopic criteria: (a) asymmetry; (b) atypical network; and (c) blue-white structures. The presence of two or three features suggests that the lesion under investigation is suspect for ­malignancy.

References 1. Marghoob AA, Braun RP, Kopf AW. Atlas of dermoscopy. New York: Taylor Francis; 2004 2. Braun RP, Rabinovitz HS, Oliviero M, Kopf AW, ­Saurat JH. Dermoscopy of pigmented skin lesions. J Am Acad Dermatol 2005; 52(1):109-121 3. Kittler H, Pehamberger H, Wolff K, Binder M. Diagnostic accuracy of dermoscopy. Lancet Oncol 2002; 3(3):159-165 4. Gewirtzman AJ, Saurat JH, Braun RP. An evaluation of dermoscopy fluids and application techniques. Br J Dermatol 2003; 149(1):59-63 5. Malvehy J, Puig S, Braun RP, Marghoob AA, Kopf AW. Handbook of dermoscopy. First ed. London and New York: Taylor and Francis; 2006 6. Argenziano G, Soyer HP, Chimenti S, Talamini R, Corona R, Sera F, et al. Dermoscopy of pigmented skin lesions: results of a consensus meeting via the Internet. J Am Acad Dermatol 2003; 48(5 Pt 1):679– 693




R. P. Braun, H. S. Rabinovitz, M. Oliviero et al. 7. Braun RP, Rabinovitz H, Krischer J, Kreusch J, Oliviero M, Naldi L, et al. Dermoscopy of pigmented seborrheic keratosis. Arch Dermatol 2002; 138:1556–1560 8. Menzies SW, Westerhoff K, Rabinovitz H, Kopf AW, McCarthy WH, Katz B. Surface microscopy of pigmented basal cell carcinoma. Arch Dermatol 2000; 136(8):1012–1016 9. Pehamberger H, Steiner A, Wolff K. In vivo epiluminescence microscopy of pigmented skin lesions. I. Pattern analysis of pigmented skin lesions. J Am Acad Dermatol 1987; 17(4):571–583 10. Argenziano G, Soyer HP, Giorgio V de, Piccolo D, Carli P, Delfino M, et al. Dermoscopy a tutorial. First ed. Milan: EDRA; 2000 11. Stolz W, Riemann A, Cognetta AB, Pillet L, Abmayr W, Hölzel D, et al. ABCD rule of dermatoscopy: a new practical method for early recognition of malignant melanoma. Eur J Dermatol 1994; 4:521–527

12. Stolz W, Braun-Falco O, Bilek P, Landthaler M, Burgdorf WHC, Cognetta AB. Color atlas of dermatoscopy, 2nd ed. Berlin: Blackwell WissenschaftsVerlag; 2002 13. Argenziano G, Fabbrocini G, Carli P, Giorgio V de, Sammarco E, Delfino M. Epiluminescence microscopy for the diagnosis of doubtful melanocytic skin lesions. Comparison of the ABCD rule of dermatoscopy and a new 7-point checklist based on pattern analysis. Arch Dermatol 1998; 134(12):1563–1570 14. Menzies SW, Crotty KA, Ingvar C, McCarthy WH. An atlas of surface microscopy of pigmented skin lesions: Dermoscopy, 2nd edn. Roseville: McGrawHill; 2003 15. Soyer HP, Argenziano G, Zalaudek I, Corona R, Sera F, Talamini R, et al. Three-point checklist of dermoscopy. A new screening method for early detection of melanoma. Dermatology 2004; 208(1):27– 31

Melanoma: the Morphological Dimension Chapter I.4

Melanoma: the Morphological Dimension


Lorenzo Cerroni

Contents I.4.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . 23 I.4.2 General Remarks. . . . . . . . . . . . . . . . . . . . . . . 25 I.4.2.1 Morphological Observations. . . . . . . . . . . . . 25 I.4.2.2 Ancillary Techniques . . . . . . . . . . . . . . . . . . . 25 I.4.2.3 Particular Morphological Types of Melanoma. . . . . . . . . . . . . . . . . . . . . . . . . . . 25 I.4.3 Special Settings. . . . . . . . . . . . . . . . . . . . . . . . . 26 I.4.3.1 Melanocytic Tumors Biopsied in Newborns or Shortly After Birth. . . . . . . 26 I.4.3.2 Proliferations of Melanocytes Within Chronic Sun-Damaged Skin . . . . . . 27 I.4.3.3 Proliferations of Melanocytes Biopsied Shortly After Sun Exposure. . . . . . . . . . . . . . 28 I.4.3.4 Proliferations of Melanocytes Within Mucosal Epithelium (Genital and Oral Mucosa). . . . . . . . . . . . . . . 28 I.4.3.5 Melanocytic Proliferations at Other Special Skin Sites. . . . . . . . . . . . . . . 29 I.4.3.6 Proliferations of Melanocytes at Sites of Inflammatory Skin Disorders. . . . . . . . . . 30 I.4.4 Particular Histopathological Problems. . . . 30 I.4.4.1 Melanocytic Nevi with Several Cell Populations (“Combined” Nevi). . . . . . . . . . 30 I.4.4.2 Nodular Proliferations of Melanocytes Within Congenital Nevi. . . . . . . . . . . . . . . . . 30 I.4.4.3 Superficial Proliferations of Melanocytes with Prominent Pigmentation. . . . . . . . . . . . 31 I.4.4.4 Proliferations of Melanocytes Associated with Prominent Inflammatory Response and/or Regression . . . . . . . . . . . . . . . . . . . . . . 31 I.4.4.5 Recurrence (Persistence) of Melanocytic Lesions at the Site of a Previous Incomplete Excision (Recurrent Nevi, Recurrent Melanoma). . . 32 I.4.4.6 Atypical Melanocytic Nevi with Degenerative Changes (“Ancient” Melanocytic Nevi). . . . . . . . . . . . 32

I.4.4.7 Melanocytic Proliferations with “Spitzoid” Morphology. . . . . . . . . . . . . 33 I.4.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

I.4.1 Introduction The histopathological diagnosis of melanocytic tumors, including malignant melanoma (hence referred to as melanoma) and benign melanocytic nevi, has been the subject of countless studies published in the literature. Although precise histopathological criteria for distinction of benign from malignant melanocytic proliferations have been established, in some instances a precise diagnosis is not possible, a problem that is reflected by the use of various terms coined during the years, including “melanocytic tumors of uncertain malignant potential (MELTUMP)” or “superficial atypical melanocytic proliferation of uncertain significance (SAMPUS)” among others. Despite uncertainty in given cases, however, histological examination of a tissue specimen is still the gold standard in diagnosis of melanocytic tumors, and the most important prognostic criteria for primary melanoma (tumor thickness, ulceration) are established by the observation of the histopathological specimens as well. Sharing unusual or controversial cases in consultation with dermatopathologists with special expertise in melanocytic tumors is helpful in minimizing the risk of misdiag­noses that may be potentially fatal for the patients.



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It is crucial to remember that under the microscope each single melanocytic lesion should first be analyzed at scanning magnification in order to evaluate properly overall symmetry and lateral circumscription. It is also important to emphasize that a proper biopsy is a pre-requisite for a specific diagnosis. This is true in dermatopathology in general, and even more so in the evaluation of melanocytic lesions. Incomplete biopsies (e.g., punch biopsies, shave biopsies) often do not allow a precise classification of the cases. In a similar manner, biopsies with surgical artifacts (crush artifacts) often cannot be interpreted properly. Finally, optimal preparation of the specimens in the dermatopathological laboratory is crucial as well. All too often we receive specimens in consultation that are either badly cut, or badly stained, or both. A precise diagnosis in these cases is often impossible. A good practice in the histopathological evaluation of melanocytic tumors is to study more than a single section of tissue. Step sections should be prepared routinely, particularly in cases that are controversial histopathologically, or that showed atypical features clinically. In this context, communication between clinicians and dermatopathologists is crucial. In addition, photographic documentation of each lesion deemed to be suspicious clinically should be attached to the referral sheet, in order to avoid mistakes in the grossing of the specimens. In fact, in melanomas arising within melanocytic nevi the specific histopathological changes may be found only focally, and a clinical picture with remarks by the clinicians allows precise identification of the suspicious areas before grossing. The occurrence of melanoma within pre-existing melanocytic nevi is probably underestimated [46]. The histopathological criteria for the diagnosis of melanoma are listed in Table I.4.1. They include general architectural criteria, features of the intraepidermal and dermal components, and cytomorphological features of the melanocytes (Fig. I.4.1) [1, 2]. No single criterion is specific for benign or malignant proliferations of melanocytes, and exceptions to any of these criteria exist; thus, only integration of all criteria can be helpful in establishing the correct diag-

Fig. I.4.1.  Melanoma shows scatter of melanocytes in small nests and as solitary units at all level of the epi­ dermis Table I.4.1.  Histopathological features of melanoma

Asymmetry of the lesion  Overall asymmetry  Asymmetry of pigment distribution  Asymmetry of inflammatory infiltrate Unsharp lateral circumscription Presence of ulceration “Consumption” of the epidermis (thinning of the epidermis with attenuation of the basal and suprabasal layers and loss of the rete ridges adjacent to collections of melanocytes) Solitary melanocytes predominate over melanocytes in nests within the epidermis Pagetoid spread of melanocytes within the epidermis (melanocytes distributed in all layers of the epidermis) Incohesive melanocytes within nests Sheets of melanocytes within the dermis “Pushing” lower margin of dermal complexes of melanocytes Obliteration and/or destruction of adnexal structures Presence of intravascular complexes of melanocytes Perineural growth and/or neurotropism Presence of atypical melanocytes Presence of several mitoses, especially at the base of the lesion

Melanoma: the Morphological Dimension

nosis. In this context, it is important to understand that in most cases application of the histopathological criteria listed in Table I.4.1 allows a precise diagnosis of melanoma, and that exceptions are relatively rare; however, exceptions do exist, and their recognition and precise classification is crucial in order to manage patients adequately. We discuss herein the general aspects of the histopathological diagnosis of melanoma and nevi, as well as some of the histopathological problems that may be encountered in the microscopic evaluation of pigmented lesions of the skin.

I.4.2 General Remarks I.4.2.1 Morphological Observations In recent years, many different studies have addressed specific aspects of melanoma diagnosis and prognosis, and many different suggestions have been proposed as to what information a histopathological report should include. Examples are, among others, presence/absence of tumor-infiltrating lymphocytes, vertical or horizontal growth phase, number of mitoses per unit area, presence of regression, presence of neo-angiogenesis, and details on histopathological classification according to the categories of superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, or acral melanoma [17, 19, 27, 28, 34, 43, 60, 73]. This last classification, in our opinion, is obsolete, and does not convey any meaningful information to physicians and/or patients. In addition, the prognostic value of most of the histopathological features listed above have yet to be validated in large studies, and at present the only accepted prognostic features for TNM classification of the tumors are the maximal thickness and the presence of ulceration [6, 7]. The Clark level needs to be mentioned only in the rare cases of thin melanoma (<1 mm) of levels IV or V. For a precise TNM classification of each case it is crucial that prognostic criteria be evaluated properly (Fig. I.4.2).

Chapter I.4

Fig. I.4.2.  Melanoma growing along a hair follicle within the dermis is shown. Breslow tumor thickness should not be measured in the proximity of adnexal structures (adventitial dermis)

I.4.2.2 Ancillary Techniques The diagnosis of melanoma rests upon careful examination of sections of tissue stained with hematoxylin and eosin. Although many studies addressed the value of immunohistochemical stainings in the diagnosis and classification of melanocytic tumors, there are no compelling data showing that any immunohistochemical marker provides informations that go beyond those already provided by routine histological examination of the specimen. Genetic studies may provide in the near future additional valuable informations, especially in controversial lesions. At present, however, careful examination of routine histopathological sections and accurate clinicopathological correlation are the gold standard in the histopathological diagnosis of benign and malignant melanocytic tumors, and in the assessment of prognostic parameters in primary melanoma [38, 55, 93].

I.4.2.3 Particular Morphological Types of Melanoma In some cases, melanoma deviates from the conventional histopathological features listed in Table I.4.1, and is characterized by peculiar aspects that may render the diagnosis difficult. It is important to be familiar with the different morphological presentations of melanoma in



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Fig. I.4.3.  Desmoplastic melanoma. Note patchy lympho­ cytic infiltrate

order to avoid misdiagnosis in such cases. One relatively common problem is the presence of spindled melanocytes in the context of desmoplasia (desmoplastic melanoma) [2, 20, 84]. Useful diagnostic clues are the presence of features of melanoma in situ in the overlying epidermis, of patchy lymphoid infiltrates within the dermal component, of atypical cells and mitoses, and of neurotropism (Fig. I.4.3). Staining for S100 may be helpful in verifying the lateral and deep extension of the tumor, but other melanocytic markers may be negative in this type of melanoma. Another peculiar variant of melanoma is characterized by the presence of abundant myxoid stroma (myxoid melanoma), a variant that is found more frequently in cutaneous metastases of the disease but that can be observed in primary cutaneous cases as well [2]. In addition, sporadic reports of melanomas with other peculiar histopathological features have been published (balloon cell, signet-ring, spindle cell, melanophagic/animal type, pseudolipoblastic, schwannoid, ganglioneuroblas­­tic, plasmacytoid, Merkel cell-like, etc.; Fig. I.4.4) [2, 9, 40, 41, 51, 56, 57, 58, 94]. In some cases, melanoma may be characterized by the absence of prominent cellular atypia and by predo­ minance of small cells (nevoid cells) [75, 91, 95]. These cases have been termed “nevoid melanoma” or “small cell melanoma,” and represent yet another potential pitfall in the differential diagnosis of cutaneous melanocytic tumors.

Fig. I.4.4.  Balloon-cell melanoma. Note atypical nuclei of the balloon cells and a mitotic figure

I.4.3 Special Settings I.4.3.1 Melanocytic Tumors Biopsied in Newborns or Shortly After Birth Melanocytic tumors biopsied shortly after birth show frequently histopathological criteria of melanoma, but behave almost invariably in a benign fashion, and thus are considered to be benign simulators of melanoma [2, 5, 24, 33, 44, 47, 78]. Two main groups are recognized: the first is characterized by a pagetoid intraepidermal growth of melanocytes which is virtually indistinguishable from that observed in melanoma (Fig. I.4.5). These lesions usually present clinically with plaques characterized by irregular pigmentation. Histopathologically, melanocytes arranged in nests or as solitary units are present within the entire thickness of the epidermis including the horny layer. Although it has been frequently reported that a helpful criterion for differentiation of these cases from melanoma is the monomorphism of intraepidermal melanocytes, in our experience the melanocytes can be polymorphous and display atypical morphological aspects (hyperchromatism, large nuclei). The presence of melanocytes of a congenital nevus without atypical features in the dermis is helpful in establishing the correct diagnosis. The second group is characterized by so-called proliferative nodules in congenital nevi in newborns [2, 3, 21, 24, 78]. These

Melanoma: the Morphological Dimension

Chapter I.4

Fig. I.4.6.  Congenital pseudomelanoma (proliferating nodules within congenital nevi in newborns). Note monomorphous population of large, atypical melanocytes

melanocytes. Children presenting with such lesions, however, should be closely and carefully followed.

I.4.3.2 Proliferations of Melanocytes Within Chronic Sun-Damaged Skin Fig. I.4.5.  Melanocytic nevus biopsied shortly after birth. a Note complexes of a congenital melanocytic nevus in the dermis and prominent intraepidermal component. b Scatter of pleomorphic melanocytes within all layers of the epidermis

lesions simulate a melanoma clinically as well as histopathologically, and are one of the most vexing problems in the realm of melanocytic lesions in newborns. Clinically, there is a nodule within a giant congenital nevus, which may be more or less pigmented than the neighboring nevus. Histopathologically there are sheets of melanocytes larger than those in the surrounding nevus, and there can be mitoses and necrotic melanocytes (Fig. I.4.6). Although the epidermis usually lacks features of melanoma in situ, it is often impossible to distinguish these lesions from a so-called dermal melanoma developing in a giant congenital nevus. Features that are helpful in the diagnosis are the sharp circumscription and the superficial location of the nodule, and the monomorphism of the large

Chronic sun-damaged-skin presents two main problems in diagnosis and differential diagnosis of melanocytic tumors. The first problem is due to the presence in “normal” chronic sun-damaged skin of melanocytes at the dermo-epidermal junction that have enlarged nuclei with atypical morphological features, thus being a possible cause of misdiagnosis of melanoma [2, 24]. In chronic sun-damaged skin melanocytes are seated only at the dermo-epidermal junction, are equidistant from one another, do not show prominent dendritic processes, never form nests, and are relatively monomorphous, that is, all melanocytes have similar morphological features. On the other hand, any junctional or compound melanocytic lesion that develops on severely sun-damaged skin must be considered as a probable melanoma [58]. Melanoma in situ in chronic sun-damaged skin is characterized in the early stages by a slight increase in the number of melanocytes arranged as solitary units at the dermo-epidermal junction and only focally above it. The nuclei are enlarged, but so are the nuclei of “normal” melanocytes in




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chronic sun-damaged skin, and at times the diagnosis may be extremely difficult, especially when only small punch biopsies are available. Of course, benign nevi may be observed in chronic sun-damaged skin; however, such a diagnosis should be made only when the evidence for a benign lesion is compelling (sharp circumscription, absence of increased number of solitary intraepidermal melanocytes at the lateral margins, no pagetoid spread, and, more generally, absence of any criteria suggestive of melanoma).

I.4.3.3 Proliferations of Melanocytes Biopsied Shortly After Sun Exposure

Fig. I.4.7.  Genital melanosis. Note hyperpigmentation of the epidermis without increase in number of melanocytes

Benign melanocytic nevi exposed to UV radiation may show intraepidermal features simulating melanoma in situ (e.g., solitary melanocytes disposed not only at the dermo-epidermal junction but also in upper epidermal layers) [24, 87]; however, intraepidermal melanocytes do not show atypical features, and the dermal component does not reveal any aspect of malignancy. Architectural features return to normality in a few weeks after UV irradiation.

I.4.3.4 Proliferations of Melanocytes Within Mucosal Epithelium (Genital and Oral Mucosa) Two conditions may create diagnostic problems in pigmented lesions within mucosal epithelium, namely, so-called melanosis (oral or genital) and melanocytic nevi arising within the genital skin. Melanosis may occur on the genital, labial, or oral mucosa [10, 24, 79]. Clinically, lesions are often similar to those of melanoma in situ in these regions, being asymmetrical, poorly circumscribed, and irregularly pigmented. Histopathologically, the diagnosis of melanosis can be accepted only if there is no increase of melanocytes at the dermo-epidermal junction, and if there are no melanocytes with long dendrites (Figs. I.4.7, I.4.8). In addition, in genuine melanosis there are neither cellular atypia, nor melanocytes above the dermo-epidermal

Fig. I.4.8.  Genital melanoma in situ. Note slight increase of solitary melanocytes with long dendrites above the dermo-epidermal junction

junction, nor nests of melanocytes [2]. A few melanophages, but no melanocytes, are found in the dermis. Reports of melanoma arising in the background of melanosis most likely represented cases of melanoma misdiagnosed from the beginning. Genital nevi can be located on the vulva, the penis, and the perianal region [2, 24, 26, 41, 44]. Clinically, they can simulate melanoma by showing asymmetry and poor circumscription. Histopathologically, there is an intraepidermal proliferation of melanocytes that can be mistaken for melanoma in situ, with some melanocytes and nests located in the upper layers of the epidermis. Features that allow classification of genital nevi as benign are the

Melanoma: the Morphological Dimension

predominance of nests over solitary melanocytes within the epidermis, the presence of an intradermal component showing discrete nests of melanocytes with maturation with progressive descent into the dermis, and the absence of atypical melanocytes and mitoses [4, 24, 36, 61, 72].

Chapter I.4 Table I.4.2.  Special skin sites for melanocytic nevi

Acral skin (palms and soles, finger, toes, nails) Knees, elbows (extensor surfaces) Ears Mucosal regions (oral and genital mucosa, perianal region) Flexural/intertriginous areas

I.4.3.5 Melanocytic Proliferations at Other Special Skin Sites Melanocytic nevi located on palms and soles may simulate melanoma clinically by being asymmetrical and showing irregular pigmentation. Histopathologically, they often reveal melanocytes arranged in solitary units or small nests within the entire thickness of the epidermis including the horny layer (Table I.4.2) [18, 24, 44, 49]. Features allowing the correct histopathological diagnosis are the sharp circumscription and symmetry of the lesion, the maturation of melanocytes with progressive descent into the dermis, and the absence of atypical melanocytes and mitoses. A helpful clue in distinguishing benign from malignant melanocytic lesions on acral regions is the columnar disposition of melanocytes and melanin within the epidermis and horny layer in nevi, as opposed to the diffuse pattern seen in melanoma [49]. This peculiar architectural feature may be explained by the particular anatomical location. In fact, it has been demonstrated that acral nevi cut perpendicular to the skin marks show involvement of upper layers of the epidermis restricted to the site of the skin marks (that is, columnar arrangement of melanocytes and melanin within the epidermis and horny layer), whereas those cut parallel to skin marks present melanocytes in the epidermis and horny layer throughout the entire length of the lesion [77]. This finding suggests a role of the peculiar anatomy of these regions in the genesis of the atypical histopathological features of acral melanocytic nevi. Pigmented lesions located on the nail may also represent a problem in differential diagnosis between benign and malignant processes [8, 16,

Nipple Navel Milk-line

30]. In fact, longitudinal melanonychia may be due to a lentigo simplex, a benign melanocytic nevus, or a melanoma (besides other non-melanocytic, inflammatory, and neoplastic conditions). It is characterized clinically by a brown or black longitudinal streak within the nail plate. Benign forms can be very difficult to distinguish from melanoma in situ of the nail matrix. A helpful clinical clue is the presence in melanoma of the so-called Hutchinson’s sign, characterized by periungual spread of the pigmentation on the proximal or lateral nail fold. Histopathology of benign lesions may show either features of a benign melanocytic nevus, or just an hyperpigmentation of the epidermis with no increase of melanocytes. By contrast, melanoma in situ shows intraepidermal spread of atypical melanocytes arranged in nests or as solitary units. Finally, atypical clinicopathological features may be observed in melanocytic nevi arising at other skin sites such as the nipple, navel, ears, knee, and elbows (extensor surfaces), intertriginous or flexural areas, and the milkline [2, 13, 24, 31, 53, 54, 58, 74]. A slight degree of architectural atypia (some melanocytes may be present above the basal layer) may be accepted at these locations, and a diagnosis of melanoma should be rendered only when compelling evidence is present. Pagetoid spread in these lesions, if present, is confined only to the center of them and does not extend to the margins.



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I.4.3.6 Proliferations of Melanocytes at Sites of Inflammatory Skin Disorders


Melanocytic nevi arising at sites of inflammatory skin disorders can display atypical morphological features induced by the associated disease [58]. In particular, melanocytic nevi arising at sites of lichen sclerosus are often misdiagnosed as melanoma because of atypical architectural and cytological changes due to the lichen sclerosus [37]. Melanocytic nevi arising in patients with epidermolysis bullosa (at sites of scarring) or at sites of burns’ scars, too, may be misinterpreted as melanoma both clinically and histopathologically. Any inflammatory skin condition may alter the normal architecture of a melanocytic nevus conferring some degree of atypia to it, thus representing a diagnostic pitfall. Finally, both melanocytic nevi and melanoma arising in patients with mycosis fungoides or other cutaneous T-cell lymphomas may display intraepidermal lymphocytes arranged as solitary units or in collections (Pautrier’s microabscesses), thus complicating the histopathological diagnosis.

I.4.4 Particular Histopathological Problems I.4.4.1 Melanocytic Nevi with Several Cell Populations (“Combined” Nevi) Combined nevi are characterized either by the combination of histopathological features of two different benign melanocytic nevi, or by the presence of more than one population of melanocytes within a single lesion [2, 24, 32, 39, 66, 71]. They may simulate melanoma clinically by being asymmetric and revealing markedly irregular pigmentation. Features that allow distinction from melanoma are the sharp circumscription and the overall appearance of the lesion, showing a well-circumscribed hyperpigmented spot surrounded usually by a less-pigmented area. Histopathologically, there are several types of combined nevi, characterized by the combination of any morphological expres-

sion of congenital and/or acquired nevi. A typical variant presents with epithelioid and spindle cells of a Spitz’s nevus together with a dysplastic nevus. Another type features small melanocytes admixed with large balloon cells, simulating balloon cell melanoma. Combined nevi can be distinguished from melanoma by the absence of features of melanoma in situ in the intraepidermal portion of the neoplasm, the maturation of melanocytes with progressive descent into the dermis, and the absence of nuclear atypia (with the exception of cells of Spitz’s nevi). Combined nevi show overlapping features with many other variants of benign nevi, including proliferating nodules in congenital nevi and cellular blue nevi among others. A particular variant of combined nevus is represented by the so-called deep penetrating nevus [24, 59, 76]. This melanocytic nevus can simulate melanoma histopathologically by virtue of a dense nodular proliferation of melanocytes extending into the subcutaneous fat and showing some atypical features and rare mitoses; however, the neoplasm is sharply circumscribed, top-heavy, and lacks intraepidermal features of melanoma in situ. Deep penetrating nevi may be characterized by a plexiform pattern with populations of melanocytes with different morphological features. Difficulties in the correct interpretation of these lesions are well illustrated by the description of deep penetrating nevus-like melanocytic tumors with metastases [42].

I.4.4.2 Nodular Proliferations of Melanocytes Within Congenital Nevi This is a variation on the theme of combined melanocytic nevi. Some congenital nevi display nodular aggregates of large melanocytes within the dermal component [24, 45, 92]. The overlying epidermis does not show any sign of melanoma in situ. Differentiation between benign nevi (proliferative nodules in melanocytic nevi) and occurrence of melanoma within a pre-existent melanocytic nevus (so-called dermal melanoma) is one of the most vexing problems in pathology of melanocytic tumors [15, 62, 86]. Histopathological features that favor a diagno-

Melanoma: the Morphological Dimension

Chapter I.4

sis of benignancy are the blending of the two components of the lesions, the absence of prominent necrosis within the nodular component, and the presence of only a few mitoses; however, in given cases a precise diagnosis may be impossible.

I.4.4.3 Superficial Proliferations of Melanocytes with Prominent Pigmentation A variant of melanocytic nevi is characterized clinically by small lesions with prominent pigmentation, located mostly on skin exposed intermittently to the sun (“hypermelanotic nevi”) [28, 29]. Histopathologically, there is marked elimination of melanin through the epidermis and the horny layer (so-called pigmented parakeratosis), thus mimicking melanoma; however, lesions are small, symmetrical, and sharply circumscribed. Melanocytes are arranged mostly at the dermo-epidermal junction, and there are neither atypical features nor mitoses. Hypermelanotic nevi have been termed in the past also “new nevi of midlife” and “nevoid lentigo.” Besides benign hypermelanotic nevi, in the past years we have come across several specimens of melanoma simulating histopathologically the picture of the “hypermelanotic nevi” (Fig. I.4.9). These lesions are larger and less well circumscribed than the benign counterpart, and focally melanocytes above the dermo-epidermal junction can be observed. Evaluation of cytomorphological features is often problematic due to the prominent pigmentation, but in most instances melanocytes with large nuclei can be observed. In these cases clinicians made invariably a confident clinical diagnosis of melanoma, and review of clinical images taken prior to the surgical excision, when available, confirmed the diagnosis. These tumors represent a subset of melanomas in which the clinical diagnosis is much easier than the histopathological diagnosis, and in which accurate clinicopathological correlation is crucial for a precise diagnosis [50]. Dermatopathologists should be alert when a confident diagnosis of melanoma is made by a reliable clinician.

Fig. I.4.9.  Melanoma shows architectural features of melanocytic nevi. Note scatter of melanocytes above the dermo-epidermal junction and normal architecture of the rete ridges with concentric fibroplasia

I.4.4.4 Proliferations of Melanocytes Associated with Prominent Inflammatory Response and/or Regression Halo nevi are defined as melanocytic nevi surrounded by an area of depigmentation caused by an immunological reaction directed against the melanocytes of the nevus [2, 24, 90]. Clinically, they are easily diagnosed as benign. Histopathology, however, may pose problems in the classification of such lesions. The presence of a dense infiltrate of inflammatory cells in a melanocytic lesion, in fact, may be confused with the immune response caused by a melanoma (a “halo nevus” variant of so-called minimal deviation melanoma has been described in 1990 by Reed and coworkers) [69]. The inflammatory cells may at times obscure completely the nests of melanocytes, and atypical nuclear features can be observed in single cells. Features that favor benignancy are the distribution of lymphocytes throughout the entire neoplasms in a symmetrical fashion (in melanoma, by contrast, there is a tendency for focal aggregation of reactive lymphocytes), and the benign aspect of melanocytes with nests situated mainly at the dermo-epidermal junction and predominating over solitary melanocytes. Once completely regressed, halo nevi can be very difficult to differentiate from completely regressed melanoma.



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Features that favor benignancy in completely regressed pigmented lesions are the size (i.e., regressed melanoma are larger as a rule) and shape, halo nevi being usually dome-shaped in contrast to melanoma, which presents with flat macules.


I.4.4.5 Recurrence (Persistence) of Melanocytic Lesions at the Site of a Previous Incomplete Excision (Recurrent Nevi, Recurrent Melanoma) Recurrent (persistent) nevi may simulate melanoma clinically by being asymmetric, poorly circumscribed, and irregularly pigmented [2, 24, 35, 44, 52 ,64]. They occur after incomplete excision of a benign melanocytic nevus, usually after “shaving” biopsies that fail to remove cells in the deeper part of the lesion. Complete clinical history and review of the original sections are crucial for the diagnosis, in order to rule out the possibility of a melanoma recurring after incomplete excision. Recurrent nevi are characterized histopathologically by the proliferation of melanocytes above a scar. Intraepidermal melanocytes are arranged mainly as solitary units disposed in all levels of the epidermis, thus simulating melanoma; however, the atypical growth of melanocytes is strictly confined to the area where scar tissue is present in the dermis (by contrast, melanocytes of recurrent melanoma extend beyond the lateral margins of the scar). Complexes of the pre-existing nevus are often detectable below the scar and/or at the side of the lesion. In contrast, in recurrent melanoma atypical intraepidermal complexes of melanocytes are observed also beyond the dermal margins of the scar, and complexes of a dermal melanocytic nevus are not found. In addition, intraepidermal pagetoid spread of melanocytes is usually more pronounced. As already mentioned, in all cases review of the original section is crucial for the final diagnosis. In this context, a particular pitfall is represented by melanocytic tumors recurring after laser vaporization (or other types of surgical treatment without histo-

pathological verification of the clinical diagnosis). In such cases, the diagnosis relies only on the histopathological features discussed above, and a note should be added in the report mentioning that an accurate diagnosis is hindered by the lack of correlation with the primary lesion. A particular type of melanocytic nevus with dermal fibrosis and epidermal changes similar to those observed in persistent/recurrent nevi is characterized by the absence of history of previous surgical excision. The dermatopathological features, which at times may be mistaken for melanoma, most likely are caused by chronic irritation and/or repeated traumatic events. Diagnostic clues are the presence at the lateral edges of the lesion of conventional complexes of nevoid melanocytes, the restriction of the fibrotic changes to the center of it, and the absence of prominent pagetoid spread. These particular nevi are often located on the back of young adults.

I.4.4.6 Atypical Melanocytic Nevi with Degenerative Changes (“Ancient” Melanocytic Nevi) Ancient nevi have been described recently as benign histopathological simulators of melanoma [24, 48]. They are characterized by the presence of dilated, sometimes thrombosized blood vessels, hyalinized collagen, fibrosis and sclerosis, and by the finding of atypical melanocytes and the presence of mitotic figures. The term “ancient nevus” has been derived from the socalled ancient schwannoma, which shows similar degenerative aspects and atypical features. Criteria that favor benignancy in ancient nevi are the absence of changes of melanoma in situ within the epidermis, and the presence of melanocytes of a conventional melanocytic nevus beneath the atypical melanocytes. Due to the presence of different populations of melanocytes, ancient nevi show overlapping histopathological features with combined melanocytic nevi.

Melanoma: the Morphological Dimension

Chapter I.4

I.4.4.7 Melanocytic Proliferations with “Spitzoid” Morphology Since the original description by Sophie Spitz [83], spitzoid melanocytic tumors (that is, melanocytic proliferations characterized by predominance of large spindle and/or epithelioid melanocytes) have been one of the most commonly discussed problems in dermatopathology [2, 9, 24, 31, 41, 54, 57, 58, 63, 71]. Although one of the patients described originally by Spitz died of metastatic melanoma, it has been clearly demonstrated that most Spitz nevi are completely benign. “Conventional” Spitz nevi are symmetrical, sharply circumscribed, superficial proliferations of large spindle and/or epithelioid melanocytes, commonly associated with epithelial hyperplasia, some scatter of melanocytes above the dermo-epidermal junction (usually confined to the center of the lesion), and presence of dull pink intraepidermal globules that have been termed “Kamino bodies.” A melanocytic nevus with predominance of pigmented spindle cells has been termed “pigmented spindle cell nevus” or “Reed nevus,” and its relationship to Spitz nevi has been debated [12, 67, 70, 81]. Besides “conventional” Spitz nevi and variants, in the past years several publications have addressed the problem of atypical melanocytic tumors with spitzoid morphology [11, 14, 65, 68, 80, 82, 89]. These tumors arise often in children or adolescents, are usually mainly dermal and asymmetrical, lack a prominent pagetoid spread within the epidermis, and in a distinct proportion of cases are associated with the presence of deposits of melanocytes within the parenchyma of regional lymph nodes (Fig. I.4.10). Terminology of these lesions is a matter of debate, and different terms have been used, including atypical spitzoid tumors, malignant Spitz nevi, Spitz nevi with lymph node metastases, and Spitz tumors with uncertain malignant potential, among others. Atypical Spitz tumors are different from “conventional” Spitz’s nevi, which are characterized by a symmetrical, dome-shaped architecture, a prominent junctional component, and a superficial dermal component. Instead, they are tumors characterized often by only focal involvement of the epidermis, and by confluent nests and sheets of melanocytes in the

Fig. I.4.10.  Atypical Spitz tumor. a Note asymmetrical, mainly dermal melanocytic tumor. b Spitzoid melanocytes admixed with inflammatory infiltrates

dermis. In some cases lymph node deposits of melanocytes have been found by diagnostic sentinel lymph node biopsy [35, 85], and a few of these patients have died of metastatic melanoma. The vast majority of patients, though, seem to have a good prognosis without further manifestations of the disease, in spite of the presence of clusters of cells within the lymph nodes. The exact classification of these cases is still a matter




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of debate, and it has been recently proposed that they may represent a type of low-grade melanoma with better prognosis than conventional melanoma of similar thickness [22, 23, 88]. In fact, there are no criteria that allow to distinguish cases with lymph node involvement and/ or progression to systemic disease from those that do not show any evidence of extracutaneous spread [25]. Whatever the personal interpretation of these intriguing tumors, in our opinion the patients should be carefully followed, as the unlucky possibility of a melanoma cannot be ruled out on morphological grounds alone.

approach to the evaluation of controversial melanocytic lesions is provided in Table I.4.3. Some melanocytic tumors with particular morphological features (so-called atypical spitzoid tumors) may represent a special variant of melanoma with better prognosis than conventional melanoma.


Core Messages ■ Accurate examination of routinely stained sections of tissue and clinicopathological correlation represent the gold standard in histopathological diagnosis of benign and malignant melanocytic tumors. ■ Optimal biopsies are a pre-requisite for accurate histopathological diagnoses; punch biopsies and shave biopsies often cannot be interpreted accurately. Sections should be carefully processed and stained, as poor quality of the histopathological specimens hinders a precise diagnosis. ■ Besides paying attention to histopathological criteria for diagnosis, dermatopathologists should be aware of special settings and particular histopathological presentations that may have an influence on the diagnosis (e.g., specific skin site, age, association with other skin disorders, etc.). ■ Although precise criteria for histopathological diagnosis allow a correct diagnosis and classification of the vast majority of melanocytic tumors, a small number of lesions defies precise interpretation and cannot be classified with certainty histopathologically (e.g., benign nevi simulating melanoma, and melanoma mimicking a benign nevus). ■ Sharing cases in consultation with dermatopathologists with special expertise in melanocytic tumors allows minimization of the number of cases that cannot be classified with certainty.

I.4.5 Conclusion Histopathological examination is the gold standard for diagnosis and classifications of benign and malignant melanocytic tumors. Differentiation of specific entities is usually easily achieved on morphological grounds, but occasionally histopathological criteria alone may not allow a precise categorization of a given tumor. Dermatopathologists should pay special attention to particular settings such as lesions biopsied in newborns, or arising at special body sites, or associated with inflammatory diseases, or presenting with particular morphological aspects (e.g., prominent pigmentation, presence of several population of melanocytes, etc.). A rational Table I.4.3.  Stepwise evaluation of controversial/atypical melanocytic tumors

Clinicopathological correlation (including clinical features of the lesion, age, personal and/or familial history of melanoma, skin type and/or other predisposing factors, previous surgery, trauma, recent exposure to UV light, etc.) Evaluation of conventional histopathological criteria Presence/absence of signs of chronic sun damage Anatomical location (special skin site?) Expert consultation Uncertainty should be clearly documented in the histopathological report  

Melanoma: the Morphological Dimension

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Melanoma: the Morphological Dimension 59. Mehregan DA, Mehregan AH (1993) Deep penetrating nevus. Arch Dermatol 129:328–331 60. Mihm MC Jr, Clark WH Jr, From L (1971) The clinical diagnosis, classification and histogenetic concepts of the early stages of cutaneous malignant melanomas. N Engl J Med 284:1078–1082 61. Mihm MC Jr, Googe PB (1990) Problematic pigmented lesions. Lea and Febiger, Philadelphia 62. Okun MR, Mattia A di, Thompson J, Pearson H (1974) Malignant melanoma developing from intradermal nevi. Arch Dermatol 110:599–601 63. Paniago-Pereira C, Maize JC, Ackerman AB (1978) Nevus of large spindle and/or epithelioid cells (Spitz’s nevus). Arch Dermatol 114:1811–1823 64. Park HK, Leonard DD, Arrington JH; Lund HZ (1987) Recurrent melanocytic nevi: clinical and histologic review of 175 cases. J Am Acad Dermatol 17:285–292 65. Piepkorn M (1995) On the nature of histologic observations: the case of the Spitz nevus. J Am Acad Dermatol 32:248–254 66. Pulitzer DR, Martin PC, Cohen AP, Reed RJ (1991) Histologic classification of the combined nevus: analysis of the variable expression of melanocytic nevi. Am J Surg Pathol 15:1111–1122 67. Reed RJ (1985) The histological variance of malignant melanoma: the interrelationship of histological subtype, neoplastic progression, and biological behaviour. Pathology 17:301–312 68. Reed RJ (1999) Atypical spitz nevus/tumor. Hum Pathol 30:1523–1526 69. Reed RJ, Webb SV, Clark WH, Jr (1990) Minimal deviation melanoma (halo nevus variant). Am J Surg Pathol 14:53–68 70. Requena L, Sanchez Yus E (1990) Pigmented spindle cell nevus. Br J Dermatol 123:757–763 71. Rogers GS, Advani H, Ackerman AB (1985) A combined variant of Spitz’s nevus. How to differentiate them from malignant melanomas. Am J Dermatopathol 7 (Suppl):61–78 72. Ronan SG, Eng AM, Briele HA, Walker MJ, Gupta TK (1990) Malignant melanoma of the female genitalia. J Am Acad Dermatol 22:428–435 73. Rongioletti F, Smoller BR (2005) Unusual histological variants of cutaneous malignant melanoma with some clinical and possible prognostic correlations. J Cutan Pathol 32:589–603 74. Saad AG, Patel S, Mutasim DF (2005) Melanocytic nevi of the auricular region. Histologic characteristics and diagnostic difficulties. Am J Dermatopathol 27:111–115 75. Schmoeckel C, Castro CE, Braun-Falco O (1985) Nevoid malignant melanoma. Arch Dermatol Res 277:362–369

Chapter I.4 76. Seab JA, Graham JH, Helwig EB (1989) Deep penetrating nevus. Am J Surg Pathol 13:39–44 77. Signoretti S, Annessi G, Puddu P, Faraggiana T (1999) Melanocytic nevi of palms and soles: a histological study according to the plane of section. Am J Surg Pathol 23:283–287 78. Silvers DN, Helwig EB (1981) Melanocytic nevi in neonates. J Am Acad Dermatol 4:166–175 79. Sison-Torre EQ, Ackerman AB (1985) Melanosis of the vulva. A clinical simulator of malignant melanoma. Am J Dermatopathol 7 (Suppl):51–60 80. Smith KJ, Barrett TL, Skelton HG III, Lupton GP, Graham JH (1989) Spindle cell and epithelioid cell nevi with atypia and metastasis (malignant Spitz nevus). Am J Surg Pathol 13:931–939 81. Smith NP (1987) The pigmented spindle cell tumour of Reed: an underdiagnosed lesion. Semin Diag Pathol 4:75–87 82. Spatz A, Calonje E, Handfield-Jones S, Barnhill RL (1999) Spitz tumors in children: a grading system for risk stratification. Arch Dermatol 135:282–285 83. Spitz S (1948) Melanoma of childhood. Am J Pathol 24:591–609 84. Su LD, Fullen DR, Lowe L, Wang TS, Schwartz JL, Cimmino VM, Sondak VK, Johnson TM (2004) Desmoplastic and neurotropic melanoma. Cancer 100:598–604 85. Su LD, Fullen DR, Sondak VK, Johnson TM, Lowe L (2003) Sentinel lymph node biopsy for patients with problematic spitzoid melanocytic lesions: a report on 18 patients. Cancer 97:499–507 86. Swetter SM, Ecker PM, Johnson DL, Harvell JD (2004) Primary dermal melanoma: a distinct subtype of melanoma. Arch Dermatol 140:99–103 87. Tronnier M, Wolff HH (1995) UV-irradiated melanocytic nevi simulating melanoma in situ. Am J Dermatopathol 17:1–6 88. Urso C (2005) A new perspective for Spitz tumors? Am J Dermatopathol 27:364–366 89. Walsh N, Crotty K, Palmer A, McCarthy S (1998) Spitz nevus versus spitzoid malignant melanoma: an evaluation of the current distinguishing histopathologic criteria. Hum Pathol 29:1105–1112 90. Wayte DM, Helwig EB (1968) Halo nevi. Cancer 22:69–90 91. Wong TY, Suster S, Duncan LM, Mihm MC Jr (1995) Nevoid melanoma: a clinicopathological study of seven cases of malignant melanoma mimicking spindle and epithelioid cell nevus and verrucous dermal nevus. Hum Pathol 26:171–179 92. Xu X, Bellucci KSW, Elenitsas R, Elder DE (2004) Cellular nodules in congenital pattern nevi. J Cutan Pathol 31:153–159




L. Cerroni 93. Zalaudek I, Argenziano G, Ferrara G, Soyer HP, Corona R, Sera F, Cerroni L, Carbone A, Chiominto A, Cicale L, Rosa G de, Ferrari A, Hofmann-Wellenhof R, Malvehy J, Peris K, Pizzichetta MA, Puig S, Scalvenzi M, Staibano S, Ruocco V (2004) Clinically equivocal melanocytic skin lesions with features of regression: a dermoscopic-pathological study. Br J Dermatol 150:64–71 94. Zembowicz A, Carney JA, Mihm MC (2004) Pigmented epithelioid melanocytoma. A low-grade melanocytic tumor with metastatic potential indistinguishable from animal-type melanoma and epithelioid blue nevus. Am J Surg Pathol 28:31–40

95. Zembowicz A, McCusker M, Chiarelli C, Dei Tos AP, Granter SR, Calonje E, McKee PH (2001) Morphological analysis of nevoid melanoma: a study of 20 cases with a review of the literature. Am J Dermatopathol 23:167–175

Chapter II.1

Laser-Scanning Confocal Microscopy Salvador González and Allan Halpern

Contents II.1.1 Fundamentals and Imaging Parameters for Reflectance-Mode Laser Scanning Confocal Microscopy . . . . . . . . . . . . . . . . . . . 39 II.1.2 In-Vivo Confocal Microscopy of Normal and Diseased Skin. . . . . . . . . . . . . . . . . . . . . . 40 II.1.3 In-Vivo Reflectance Confocal Microscopy Features of Melanocytic Skin Lesions. . . . . 40 II.1.3.1 Melanocytic Nevi. . . . . . . . . . . . . . . . . . . . . . . 40 II.1.3.2 Cutaneous Melanoma. . . . . . . . . . . . . . . . . . . 42 II.1.4 Accuracy Studies on Confocal Diagnoses of Melanocytic Malignancy. . . . . . . . . . . . . . 43 II.1.5 Potential Clinical Applications and Current Limitations of Reflectance Confocal Microscopy . . . . . . . . . . . . . . . . . . . 44 II.1.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Early detection is critical to the successful treatment and survival of patients with melanoma. A dermatologist’s sensitivity in detecting melanoma by visual clinical examination is reported to be in the range of 65% to 80% [26, 42]. Dermoscopy, which provides a magnified image of a lesion, can improve diagnostic accuracy to as high as 85% for clinicians who are highly trained in the use of dermoscopy [8]. However, sensitivity is still unacceptably low for a life threatening disease. Therefore, development of non-invasive high-resolution techniques for imaging melanocytic lesions in situ in the patient is highly desirable since they may increase diagnostic ac-


curacy. These techniques may include optical coherence tomography [40], high-frequency ultrasound [23], magnetic resonance imaging [24], and reflectance-mode laser scanning confocal microscopy (RCM) [12, 17, 28, 36]. Of these, RCM offers the highest resolution imaging comparable to routine histology.

II.1.1 Fundamentals and Imaging Parameters for Reflectance-Mode Laser Scanning Confocal Microscopy Confocal microscopy, first introduced to the scientific community by Marvin Minsky in 1957, is an optical technique that produces “optical sections” of an object under observation [27]. Over time, developments in light sources and computer technologies have enabled imaging human and animal skin in vivo [33, 36]. Briefly, a RCM involves the use of a light source, a condenser, objective lenses, and a detector. The light source illuminates a small skin area that will be imaged onto the detector passing through a small aperture (pinhole). The pinhole aperture is matched in size to the illuminated spot. As a result, the detector receives light from only a thin in-focus plane in the tissue. Light from out-of-focus planes is rejected at the pinhole. The point source of light, the illuminated spot in the sample, and the pinhole aperture lie in optically conjugate focal planes – hence the name “confocal.” To create a two-dimensional image, the illumination spots are raster-scanned over the area of interest within the tissue and an image is produced point – by-point (i.e., pixel – by-pixel), a process that is known as “optical sectioning.”


S. González, A. Halpern

Several parameters that have been optimized for high resolution, in-vivo confocal microscopy include the use of near-infrared wavelengths, high numerical aperture water-immersion objective lenses, low illumination power (about 40 mW), and detection apertures equivalent to 1–5¥ lateral resolution [34].


II.1.2 In-Vivo Confocal Microscopy of Normal and Diseased Skin Real-time RCM images are acquired en-face (i.e., in the horizontal tissue plane) and resolved in gray scale with the image contrast derived from naturally occurring differences in optical index of refraction within the tissue [9, 36]. Bright regions of an RCM image generally correspond to regions of high refraction index in the tissue. Since water is the major constituent of living cells, the nominal refractive index of most human tissue is similar to that of water, about 1.33. Rajadhyaksha and coworkers [36] have shown that melanin (refraction index of approximately 1.7) provides strong contrast in RCM images. In normal skin, the stratum corneum is seen to be composed of islands of corneocytes within skin folds. Hair follicles and sweat duct openings can be identified. Going deeper, stratum granulosum and stratum spinosum consist of polygonal cells with large, centrally placed nuclei surrounded by a grainy cytoplasm. Cells of these strata are arranged in a characteristic pattern with a honeycombed appearance. Below, basal keratinocytes can be seen as bright, highly refractile, round or oval cells located on the borders of the dermal papilla. The high refractivity of basal keratinocytes stems from the presence of melanin and melanosomes, with endogenous variation among skin phototypes and anatomic locations. The melanin in basal keratinocytes is typically located in a supranuclear position, often referred to as “melanin caps” implying their protective function. En-face dermal papillae openings are seen as dark round areas surrounded by a bright crown of basal keratinocytes and melanocytes. A reticular collagen network and small capillaries can be seen in the center of dermal papillae.

Non invasive, in-vivo RCM has previously been used to explore a variety of non-melanocytic and melanocytic benign and malignant neoplasms as well as inflammatory skin conditions. In-vivo cytoarchitectural features of psoriasis [18], contact dermatitis [3, 4, 16, 20, 38], bacterial [17] and fungal infections [21, 25, 29], actinic keratoses [2], basal and squamous cell carcinomas [1, 10, 19, 29, 37], as well as melanocytic nevi and melanomas [6, 14, 22, 30–32, 39] have been evaluated by RCM. In particular, our group and others are investing significant time and effort to develop the utility of this technique for the non-invasive evaluation of contact dermatitis, basal cell carcinoma, and melanocytic lesions. Recent studies of the accuracy of RCM evaluation for predicting histopathology suggest a promising future for the clinical use of RCM [4, 14, 32]. In melanocytic lesions, the endogenous contrast provided by melanin and melanosomes facilitates recognition of the relevant structures involved in the differentiation of benign versus malignant tissue and, thus, make RCM imaging a promising non-invasive tool in the differential diagnosis of benign and malignant pigmented skin lesions.

II.1.3 In-Vivo Reflectance Confocal Microscopy Features of Melanocytic Skin Lesions In 2001, Langley and colleagues [22] reported the first descriptive study on RCM features of melanocytic lesions. These confocal features are based on the cytoarchitectural analysis of the skin, including melanocyte and keratinocyte morphology, pattern, and distribution (Table II.1.1).

II.1.3.1 Melanocytic Nevi Common melanocytic nevi are recognized by the distribution of melanocytes on the skin. They present populations of small, monomorphous round to oval bright (refractile) cells with frequently visible, centrally positioned, nuclei (Fig. II.1.1) [5, 22], and preserved keratinocyte cell borders within the overlying epidermis. In

Laser-Scanning Confocal Microscopy

Fig. II.1.1.  Routine hematoxylin-and-eosin (H&E)-stain­ ed histology (left) and reflectance confocal microscopy (right) images of a benign compound nevus. Confocal image obtained at the level marked in the H&E figure

Chapter II.1

shows a rim of monomorphous refractive cells around dermal papillae (asterisk), corresponding to small melanocytes and melanin-rich keratinocytes in the basal layer (edged papillae). Scale bar = 100 µm

Table II.1.1.  Reflectance confocal microscopy features of melanocytic skin tumors

Melanocytic lesion


Melanocytic nevi

Uniform population of small bright cells with central nuclei in the basal layer level Preserved honey-combed pattern in suprabasal layers Occasionally small and fine dendritic projections Regular distribution and morphology of the dermal papillae Edge papillae Clusters of refractile cells at dermal level (dense)

Dysplastic nevi

Heterogeneous population of cells in terms of morphology and brightness Focal loss of cell demarcation Bright granular structures Fine dendrites

Cutaneous melanoma

Pleomorphic bright cells within the epidermis, some of them ascending the epidermis (pagetoid infiltration) Disarray of keratinocytes Focal/total loss of the honeycombed pattern Coarse branching dendrites Bright grainy structures Irregular dermal papillae distribution Non-edge papillae Dermal cerebriform clusters and/or sparse clusters



S. González, A. Halpern


Fig. II.1.2.  Dysplastic nevus. Confocal image (right) taken at the level marked in the routine pathology image (left) shows heterogenous brightness of the epidermis,

irregular distribution of dermal nests (asterisk), and nonedged dermal papillae (arrow). Scale bar = 100 µm.

some benign melanocytic tumors, superficial epidermal layers may show the presence of small round to oval cells with bright cytoplasm and dark outlines giving rise to a cobblestone appearance. Dermal papillae are uniformly distributed and are seen circumscribed by a rim of monomorphous refractive cells that have been termed by Pellacani and coworkers edge papillae [30]. These bright cells at the dermal–epidermal junction correspond to small melanocytes and melanin-rich keratinocytes, lacking cytological atypia and heterogeneous brightness [30]. In the dermis, common nevi frequently present isolated bright cells or groups of cells seen as round to oval clusters typically distributed throughout the lesion and sometimes forming central conglomerates (Fig. II.1.1) [22, 30]. Atypical nevi may be difficult to diagnose under RCM since they present intermediate characteristics when compared with nevi and melanoma [22]. They usually show a greater variability in melanocyte size and shape than banal nevi, although cells still tend to be rounded or oval rather than dendritic. In some instances, medium to large cells with refractile cytoplasm and peripheral nuclei, corresponding to a mild cytological atypia, are also visualized. Focal loss of keratinocyte demarcation within the overlying epidermis and bright granules

within the epidermis, probably representing melanin bodies, are also seen in atypical nevi. En-face view of dermal–epidermal junction in atypical nevi often demonstrate an irregular dermal papillae distribution and the papillae often lack the normal demarcating rim of refractile cells (non-edge papillae; Fig. II.1.2) [30].

II.1.3.2 Cutaneous Melanoma The RCM imaging of melanoma commonly shows large pleomorphic, atypical bright cells at various levels within the epidermis (pagetoid spread) and, sometimes, in the dermis [22, 30]. These cells are oval, stellate, or fusiform in shape, possess coarse branching dendritic processes, and present eccentrically placed large nuclei [22, 30, 39]. The presence of these bright polymorphic cells ascending in the epidermis accompanied by loss of keratinocyte demarcation is highly suggestive of melanoma (Fig. II.1.3) [30, 32]; however, some benign lesions may present dendritic cells arranged in small nests or as single cells located within the upper epidermis, raising the suspicion of a malignant process. In these lesions, the keratinocytic background usually maintains the characteristic honeycomb pattern suggestive of a benign diagnosis. Additionally, presence of bright grainy particles,

Laser-Scanning Confocal Microscopy

Chapter II.1

Fig. II.1.3.  Melanoma. Confocal image shows the presence of enlarged (atypical) melanocytes (arrow) around a hair follicle, within a background of keratinocyte disarray. Scale bar = 100 µm.

probably melanin, also can be noticed in many melanomas [22, 39]. At the dermal–epidermal junction level, dermal papillae look smaller and more irregular in melanoma than in common nevi. At the dermal level, melanomas may demonstrate clusters of cells with a cerebriform appearance composed of aggregates of low-re­ fractile polygonal or elongated cells with fine dust-like granular structures [31]. Additionally, low-refractile cells seen in isolation or small groups with well-defined demarcation, called “sparse cell clusters,” may be seen. These criteria also apply for clinically amelanotic melanoma as shown in several previously reported cases [7, 13]. Presumably, the contrast observed in these lesions is due to either the presence of non-melanized melanosomes in the cytoplasm, an endogenous source of contrast due to their size (0.6–1.2 µm), and/or the presence of some clinically inapparent melanin in pre-melanosomes [7, 35]. Additionally, RCM imaging has been successfully used to map and evaluate response to topical therapies in these lesions [7, 11, 13]. A limitation for the use of RCM in melanoma diagnosis is imaging depth. Lesion depth has been shown to be a very important prognostic factor for patients diagnosed with melanoma; however, available instruments can only image

down to 200–350 µm, and the presence of refractive structures in the dermis, such as inflammatory cells and collagen bundles, may decrease contrast and preclude melanocyte visualization; thus, although RCM has been shown to be useful for the differential diagnosis of intraepidermal processes, limited information about dermal cells and structures can be obtained, limiting the use of this technique for deeper lesions.

II.1.4 Accuracy Studies on Confocal Diagnoses of Melanocytic Malignancy In 2004, Gerger et al. [14] at the Medical University of Graz published the first study of the sensitivity and specificity of RCM for detection of melanocytic skin tumors based on a review of previously selected confocal images. This study included 117 melanocytic skin tumors (90 benign nevi and 27 melanomas) under RCM using Wellman confocal criteria [22] and found sensitivity and specificity for melanoma of 88.15 and 97.60%, respectively. The authors concluded that three characteristics – cytomorphology, architecture, and keratinocyte cell borders – have the highest diagnostic sensitivity for melanoma using reflectance confocal microscopy. A sig-




S. GonzĂĄlez, A. Halpern

nificant criticism of this study is that the analysis of each case was performed on confocal images that appear to have been selected by an observer who was not blinded to the clinical/ histological appearance of the lesion. Another study performed by Pellacani et al. [32] from University of Modena and Reggio Emilia assessed the significance of various RCM features for melanoma identification in a series of 102 melanocytic lesions (37 melanomas, 49 acquired nevi, 16 Spitz nevi) presenting equivocal clinical/dermoscopic findings. Among epidermal features, the presence of disarranged keratinocyte pattern as well as the presence, morphology, and distribution of pagetoid cells was significantly associated with melanoma. At the dermalâ&#x20AC;&#x201C;epidermal junction, the visualization of non-edge papillae was associated with malignancy. Finally, cerebriform clusters and isolated cells with eccentric dark nuclei within the dermal compartment were seen only in melanomas, whereas small to medium dense clusters were more typically observed in acquired nevi.

II.1.5 Potential Clinical Applications and Current Limitations of Reflectance Confocal Microscopy The RCM has the potential to inform clinical care by facilitating non-invasive in-vivo diagnosis of both benign and malignant pigmented and non-pigmented skin lesions. Unlike an invasive biopsy, the RCM technique permits repeated evaluation of the cellular architecture of an area of skin to monitor the progression or resolution of lesions over time. It holds signifi-

cant potential for the direction of invasive biopsies to more accurately pre-selected lesions and to the most histologically concerning areas within large complex lesions. Specifically, in the realm of pigmented lesions, RCM holds significant promise as: 1. A guide for performing biopsies by helping to determine which areas have features suspicious for malignancy, thus reducing sampling error [39] 2. A tool for monitoring the histological response of lesions to novel non-invasive therapy [13, 15, 41] 3. A tool for mapping out the extent of involvement prior to excision [7, 13, 41]

II.1.6 Conclusion A major limitation of the RCM technology is the limited imaging depth of the technique, which prevents accurate imaging below the superficial dermis. This limitation is greatest in lesions that are hyperpigmented or hyperkeratotic, leading to intensity attenuation secondary to light absorption and scattering. Efforts to improve imaging depth with RCM include the use of more powerful light sources, optimal immersion media, and image deconvolution algorithms. Lack of contrast in minimally pigmented skin also poses a challenge, which might be solved by the future development of exogenous contrast agents. As these technical issues are being addressed, considerable additional progress is needed in the consistent interpretation of the en-face images derived from the current generation of RCM instruments.

Laser-Scanning Confocal Microscopy


Core Messages ■ Reflectance confocal scanning microscopy has proven, in principle, that noninvasive skin imaging with single cell resolution is readily achievable. ■ Significant technical and practical barriers need to be addressed prior to the common application of this technique in clinical practice. ■ The apparent advantages of ascertaining quasi-histological information noninvasively dictate that this, or some similar high-resolution optical technique, will find its way into clinical practice in the not-too-distant future. ■ The current generation of RCM instruments provides images of sufficient quality to justify clinical research in image interpretation and diagnostic accuracy. ■ Future iterations of the technology, used in concert with improved macroscopic imaging techniques, will likely change the nature of dermatological practice. ■ Clinical care will benefit from bedside non-invasive “histopathology” just as the interpretation of invasive biopsies will benefit from the advent of molecular diagnosis.

References   1. Agero AL, Busam KJ, Scope A, Benvenuto-Andrade C, Gill M, Marghoob A, González S, Halpern AC (2006) Reflectance confocal microscopy of pigmented basal cell carcinoma. J Am Acad Dermatol 54:6338–6343   2. Aghassi D, Anderson RR, Gonzalez S (2000) Confocal laser microscopic imaging of actinic keratoses in vivo: a preliminary report. J Am Acad Dermatol 43:42–48   3. Astner S, Gonzalez E, Cheung AC Rius- Díaz F, Doukas AG, Farinelli W, González S (2005) Non-invasive evaluation of the kinetics of allergic and irritant contact dermatitis. J Invest Dermatol 124:351– 359

Chapter II.1   4. Astner S, Gonzalez E, Cheung A, Rius-Diaz F, Gonzalez S (2005) Pilot study on the sensitivity and specificity of in vivo reflectance confocal microscopy in the diagnosis of allergic contact dermatitis. J Am Acad Dermatol 53:986–992   5. Busam KJ, Charles C, Lee G, Halpern AC (2001) Morphologic features of melanocytes, pigmented keratinocytes, and melanophages by in vivo confocal scanning laser microscopy. Mod Pathol 14:862–868   6. Busam KJ, Charles C, Lohmann CM, Marghoob A, Goldgeier M, Halpern AC (2002) Detection of intraepidermal malignant melanoma in vivo by confocal scanning laser microscopy. Melanoma Res 12:349–355   7. Busam KJ, Hester K, Charles C, Sachs DL, Antonescu C, González S, Halpern A (2001) Detection of clinically amelanotic malignant melanoma and assessment of its margins by in vivo confocal scanning laser microscopy. Arch Dermatol 137:923–929   8. Carli P, Giorgio V de, Argenziano G, Palli D, Giannotti B (2002) Pre-operative diagnosis of pigmented skin lesions: in vivo dermoscopy performs better than dermoscopy on photographic images. J Eur Acad Dermatol Venereol 16:339–346   9. Carlsson K (1991) The influence of specimen refractive index, detector signal integration, and nonuniform scan speed on the imaging properties in confocal microscopy. J Microsc 163:167–178 10. Charles CA, Marghoob AA, Busam KJ, Clark-Loeser L, Halpern AC (2002) Melanoma or pigmented basal cell carcinoma: a clinical–pathologic correlation with dermoscopy, in vivo confocal scanning laser microscopy, and routine histology. Skin Res Technol 8:282–287 11. Chen C, Elias M, Busam K, Rajadhyaksha M, Marghoob AA (2005) Multi-modal in vivo optical imaging, including confocal microscopy, facilitates pre-surgical margin mapping for clinically complex lentigo maligna melanoma. Br J Dermatol 153:1031–1036 12. Corcuff P, Leveque JL (1993) In vivo vision of the human skin with the Tandem scanning microscope. Dermatology 186:50–54 13. Curiel-Lewandrowski C, Williams CM, Swindells KJ, Tahan SR, Astner SA, Frankenthaler R, González S (2004) Use of in vivo confocal microscopy in malignant melanoma: an aid in diagnosis and assessment of surgical and non-surgical therapeutic approaches. Arch Dermatol 140:1127–1132 14. Gerger A, Koller S, Kern T, Massone C, Steiger K, Richtig E, Kerl H, Smolle J (2005) Diagnostic applicability of in vivo confocal laser scanning microscopy in melanocytic skin tumors. J Invest Dermatol 124:493–498 15. Goldgeier M, Fox CA, Zavislan JM, Harris D, González S (2003) Noninvasive imaging, treatment, and microscopic confirmation of clearance of basal cell carcinoma. Dermatol Surg 29:205–210




S. González, A. Halpern 16. Gonzalez S, Gonzalez E, White WM, Rajadhyaksha M, Anderson RR (1999) Allergic contact dermatitis: correlation of in vivo confocal imaging to routine histology. J Am Acad Dermatol 40:708–713 17. Gonzalez S, Rajadhyaksha M, Gonzalez-Serva A, White WM, Anderson RR (1999) Confocal reflectance imaging of folliculitis in vivo: correlation with routine histology. J Cutan Pathol 26:201–205 18. Gonzalez S, Rajadhyaksha M, Rubinstein G, Anderson RR (1999) Characterization of psoriasis in vivo by reflectance confocal microscopy. J Med 30:337–356 19. Gonzalez S, Tannous Z (2002) Real-time, in vivo confocal reflectance microscopy of basal cell carcinoma. J Am Acad Dermatol 47:869–874 20. Hicks SP, Swindells KJ, Middelkamp-Hup MA, Sifakis AM, González E, González S (2003) Confocal histopathology of irritant contact dermatitis in vivo and the impact of skin color (black vs white). J Am Acad Dermatol 48:727–734 21. Hongcharu W, Dwyer P, Gonzalez S, Anderson RR (2000) Confirmation of onychomycosis by in vivo confocal microscopy. J Am Acad Dermatol 42:214– 216 22. Langley RG, Rajadhyaksha M, Dwyer PJ, Sober AJ, Flotte TJ, Anderson RR (2001) Confocal scanning laser microscopy of benign and malignant melanocytic skin lesions in vivo. J Am Acad Dermatol 45:365–376 23. Mansotti L (1987) Basic principles and advanced technical aspects of ultrasound imaging. In: Guzzardi R (ed) Physics and engineering of medical imaging. Boston: Martinus Nijhoff, pp 263–317 24. Markisz JA, Aquilia MG (1996) Technical magnetic resonance imaging. Stanford: Appleton and Lange 25. Markus R, Huzaira M, Anderson RR, González S (2001) A better KOH prep? In vivo diagnosis of tinea with confocal microscopy. Arch Dermatol 137:1076–1078 26. Miller M, Ackermann AB (1992) How accurate are dermatologists in the diagnosis of melanoma? Degree of accuracy and implicants. Arch Dermatol 128:559–560 27. Minsky M (1988) Memoir on inventing the confocal scanning microscope. Scanning 10:128–138 28. New KC, Petroll WM, Boyde A, Martin L, Corcuff P, Leveque JL, Lemp MA, Cavanagh HD, Jester JV (1991) In vivo imaging of human teeth and skin using real-time confocal microscopy. Scanning 13:369–372 29. Nori S, Rius-Diaz F, Cuevas J, Goldgeier M, Jaen P, Torres A, González S (2004) Sensitivity and specificity of reflectance-mode confocal microscopy for in vivo diagnosis of basal cell carcinoma: a multicenter study. J Am Acad Dermatol 51:923–930 30. Pellacani G, Cesinaro AM, Longo C, Grana C, Seidenari S (2005) Microscopic in vivo description of cellular architecture of dermoscopic pigment network in nevi and melanomas. Arch Dermatol 141:147–154

31. Pellacani G, Cesinaro AM, Seidenari S (2005) In vivo assessment of melanocytic nests in nevi and melanomas by reflectance confocal microscopy. Mod Pathol 18:469–474 32. Pellacani G, Cesinaro AM, Seidenary S (2005) Reflectance-mode confocal microscopy of pigmented skin lesions: improvement in melanoma diagnostic specificity. J Am Acad Dermatol 53:979–985 33. Rajadhyaksha M, Anderson R, Webb R (1998) Video-rate confocal scanning laser microscope for imaging human tissues in vivo. Appl Optics 38:1–12 34. Rajadhyaksha M, González S, Zavislan J, Anderson RR, Webb RH (1999) In vivo confocal scanning laser microscopy of human skin II: advances in instrumentation and comparison to histology. J Invest Dermatol 113:293–303 35. Rajadhyaksha M, Gonzalez S, Zavislan JM (2004) Detectability of contrast agents for confocal reflectance imaging of skin and microcirculation. J Biomed Opt 9:323–331 36. Rajadhyaksha M, Grossman M, Esterowitz D, Webb RH, Anderson RR (1995) In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast. J Invest Dermatol 104:946–952 37. Sauermann K, Gambichler T, Wilmert M, Rotterdam S, Stucker M, Altmeyer P, Hoffmann K (2002) Investigation of basal cell carcinoma [correction of carcionoma] by confocal laser scanning microscopy in vivo. Skin Res Technol 8:141–147 38. Swindells K, Burnett N, Rius-Diaz F, González E, Mihm MC, González S (2004) Reflectance confocal microscopy may differentiate acute allergic and irritant contact dermatitis in vivo. J Am Acad Dermatol 50:220–228 39. Tannous ZS, Mihm MC, Flotte TJ, Gonzalez S (2002) In vivo examination of lentigo maligna and malignant melanoma in situ, lentigo maligna type by near-infrared reflectance confocal microscopy: comparison of in vivo confocal images with histologic sections. J Am Acad Dermatol 46:260–263 40. Tearney GT, Brezinski ME, Southern JF, Bouma BE, Hee MR, Fujimoto JG (1995) Determination of the refractive index of highly scattering human tissue by optical coherence tomography. Optics Lett 20:2258–2260 41. Torres A, Niemeyer A, Berkes B, Marra D, Schanbacher C, Gonzalez S, Owens M, Morgan B (2004) 5% imiquimod cream and reflectance-mode confocal microscopy as adjunct modalities to mohs micrographic surgery for treatment of basal cell carcinoma. Dermatol Surg 30:1462–1469 42. Wolf IH, Smolle J, Soyer HP, Kerl H (1998) Sensitivity in the clinical diagnosis of malignant melanoma. Melanoma Res 8:425–429

Chapter II.2


Automatic Diagnosis Josef Smolle

Contents II.2.1 Basic Aims and Requirements. . . . . . . . . . . . 47 II.2.2 Clinical Images. . . . . . . . . . . . . . . . . . . . . . . . . 47 II.2.3 Digital Dermoscopy . . . . . . . . . . . . . . . . . . . . 48 II.2.4 Other Methods. . . . . . . . . . . . . . . . . . . . . . . . . 48 II.2.4.1 Spectral Analysis. . . . . . . . . . . . . . . . . . . . . . . 48 II.2.4.2 In-Vivo Confocal Laser Scanning Microscopy. . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 II.2.4.3 Optical Coherence Tomography. . . . . . . . . . 49 II.2.4.4 Levels of Evidence. . . . . . . . . . . . . . . . . . . . . . 49 II.2.4.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

II.2.1 Basic Aims and Requirements Diagnosis of melanocytic skin tumours is traditionally based on the subject of evaluation of images by an expert in the discipline. Despite increasing refinement of subjective criteria – introducing some degree of “objectivity” – there is a continuous demand for truly objective diagnostic features. This means features independent of the subjective judgement of a human observer, or, more drastically, features created and interpreted by a machine. The essential prerequisite for any approach for an automatic melanocytic lesion diagnosis is a set of digital data which can be used for automated analysis. In most approaches, this data set represents a digitized image which may have been acquired by any number of methods, ranging from clinical photography to three-dimensional reconstruction of confocal laser scanning

microscopic images. The entire undertaking may serve two different goals: On the one hand, digital data processing may be used to enhance visually recognizable criteria – which finally are still evaluated by a human observer. On the other hand, digital data processing should directly result in a diagnostic suggestion generated by the machine independently of the human observer. The latter approach is the more fascinating one, although it has not yet revealed its full potential.

II.2.2 Clinical Images Some efforts have been made to use clinical images for automatic diagnosis. Usually colour is taken as the main source of data, although colour itself is hardly a reliable parameter. Usually, some kind of distribution (or texture) analysis has to be considered. Chen et al., for example, showed that not the presence of melanoma-specific colour pixels per se, but colour clustering is the more reliable feature [3]. A preliminary report by Manousaki and coworkers [15] deals with subtle colour features: Intensity values of each of the three colour channels were plotted as the third dimension of the plane clinical photograph, and the surface of the plot was analysed by methods of fractal mathematics including fractal dimensionality and lacunarity. A major problem is often the identification of relevant features. Chang and colleagues therefore proposed a systematic heuristic approach to feature selection particularly applicable to clinical images [2]. Clinical images of individual lesions are usually inferior to dermoscopic images with respect to automated classification [22]. Clinical imag-


J. Smolle

es, however, are gaining some importance as whole-body screening tools. The detection and demarcation of pigmented lesions alone is a sophisticated task [9] which is an essential prerequisite for any subsequent detailed analysis and automatic diagnosis.

II.2.3 Digital Dermoscopy


At present, dermoscopic digital images seem to be the most promising source for automatic melanoma diagnosis. This may be due in part to the fact that standardization is more easily achieved than in clinical imaging, and due in part to the higher magnification and pixel resolution. The potential target structures are manifold: Stoecker and coworkers identified asymmetric structureless areas (â&#x20AC;&#x153;blotchesâ&#x20AC;?) [28], whereas Seidenari et al. based their classification algorithm on average colour values within square pixel blocks [25]. Following the method of a preliminary study by Kahofer et al. [13], Gerger and coworkers used tissue counter analysis [27] to diagnose melanoma in dermoscopy images [6]. Rubegni et al. [23] and Oka et al. [18] developed advanced diagnostic systems based on dermoscopic images, one as a built-in-module of a digital dermoscopy device, and the other as a classification program accessible via the Internet. Particular emphasis has been put on the possibility of sequential dermoscopic images. Visual analysis of consecutive images taken a few months apart has been shown to increase the proportion of true melanomas within the set of lesions which were finally excised [10], and facilitated the detection of melanomas which did not display the usual diagnostic features (socalled featureless melanomas) [14]. Automatic comparison of sequential images would be a valuable undertaking in the future.

II.2.4 Other Methods There are a growing number of imaging methods for melanocytic lesions. Although most of them have not yet been proven to be reliable for automatic diagnostic procedures, there are promising preliminary results.

II.2.4.1 Spectral Analysis Spectral analysis is a method beyond simple three-channel colour analysis. Spectral analysis creates a three-dimensional data cube of twodimensional images, with each plane of the cube representing a particular wavelength [4]. Depending on the attempted wavelength resolution, up to several hundred two-dimensional images would be possible. Usually, however, analysis is limited to a small number of wavelengths which had turned out to be of discriminatory power. In 2001, Farkas and Becker reported automatic detection of the melanoma component in a complex melanocytic skin lesion based on spectral analysis. Pseudo-colour images clearly denoted the malignant portion of the lesion [4]. Spectral intracutaneous analysis (SIA) is based on eight narrow-width wavelength images between 400 and 1000 nm and facilitates the demonstration of melanin, haemoglobin and collagen within skin lesions [16]. Melanomas usually present peculiar patterns which might be suitable for automatic diagnosis. Murphy et al. [17] applied fibre-optic diffuse reflectance spectroscopy to melanocytic skin lesions and found a remarkably high degree of diagnostic accuracy. Another highly sophisticated approach is Raman spectroscopy. This type of laser-induced spectral analysis is based on molecular vibrations and therefore represents to some degree the chemical composition of a lesion. Gniadecka et al. [7] applied this method to freshly excised tissue specimens obtained by punch biopsy and achieved a diagnostic accuracy comparable to automatic dermoscopy analysis.

II.2.4.2 In-Vivo Confocal Laser Scanning Microscopy In-vivo confocal laser scanning microscopy facilitates non-invasive examination of superficial skin layers at the cellular level [5]. Qualitative and semiquantitative diagnosis of melanoma is largely based on the architectural arrangement of keratinocytes in the spinous layer and on the size, shape and distribution of pigmented cells [5]. Digital image processing has been used to

Automatic Diagnosis

enhance visibility of criteria [8]. Recently, Ono et al. introduced three-dimensional reconstruction of in-vivo confocal laser scanning microscopy image stacks [19]. Experimental studies examining the diagnostic significance of tissue counter and wavelet analysis [30] are on the way (M. Wiltgen et al., pers. commun.).

II.2.4.3 Optical Coherence Tomography Optical coherence tomography provides vertical sections through the skin [1]. Resolution is somewhere between ultrasound imaging, on the one hand, and confocal laser scanning microscopy, on the other. It has been used to evaluate histological features underlying certain dermoscopic criteria. Since the method, in addition to imaging, provides quantitative information on the refractive index and the scattering coefficient of the lesion, it might contribute to automatic diagnosis. Initially, ultrasound imaging was used to determine lesion thickness in melanomas in which the diagnosis had been determined by other criteria [24]. More sophisticated technical variants of the method, however, can produce quantitative data related to tissue architecture. Rallan et al. assessed attenuation characteristics of melanocytic skin lesions using reflex transmission imaging [20]. In a pilot study, high diagnostic accuracy was achieved when these data were accompanied by digital analysis of clinical images. Subsequently, the authors demonstrated the diagnostic utility of the quantitative parameters per se [21]. Another approach to lesion interpretation is surface scanning. The method is based on the observation that the skin surface of malignant lesions may differ significantly from those of normal skin. Mathematical morphology facilitates the extraction of skin lines from common white-light clinical images. The skin-line texture seems to hold promising diagnostic information [26]. There is an increasing body of methods which reveal functional features – instead of, or in addition to, image data. Stücker and coworkers showed an increase of blood flow by laser Dop-

Chapter II.2

pler flowmetry in malignant, as compared with benign, melanocytic lesions [29]. This increase in blood flow was more pronounced than the increase in vessel density at the histological level – clearly indicating a functional difference in addition to the morphological finding of neovascularization. This finding may in some way correspond to increased pO2 levels in melanomas compared with nevi. pO2 imaging can be performed with the SkinCam system [12]. An astounding approach is the measurement of electric tissue impedance. Impedance differs significantly between benign and malignant lesions, and combining impedance measurements with digital image analysis provides high diagnostic accuracy [11].

II.2.4.4 Levels of Evidence In view of the impressive body of studies – just a few of them have been cited in this chapter – one may wonder why automatic melanoma diagnosis has not yet become a routine application. The studies are technically sound and usually provide a sensitivity close to 95 or 100%, together with a specificity which is considerably higher than that of more conventional procedures. One has to consider, however, that the level of evidence may still be insufficient to justify routine application in everyday practice. The possible levels of evidence may be classified as follows: 1. Statistical difference between two diagnostic groups by univariate or multivariate analysis 2. Classification generated in, and applied to, a single selected set of lesions 3. Classification generated in a learning set and applied to an independently selected test set 4. Application to an independent, nonselected (e.g. randomly or consecutively sampled) test set 5. Application to an independent, nonselected, consecutively sampled test set acquired in different institutions 6. Application in everyday routine work in numerous institutions



J. Smolle

Many studies start with level I and reach level II or even level III. In contrast, the number of studies providing levels IV, V or VI is small. Particularly the application to consecutively sampled lesions in routine diagnostic work is still quite uncommon, but is an essential prerequisite for general acceptance as a truly useful diagnostic tool.

II.2.4.5 Conclusion


Automatic analysis of digital dermoscopic images is at the threshold of routine application as an additional diagnostic procedure for melanocytic skin lesions. Confocal laser scanning microscopy and spectral imaging techniques hold promise for the future. An automatic procedure will add information to the diagnostic decision process similarly as an expert second opinion. Ultimately, the number of unnecessarily removed benign lesions will be reduced.


Core Messages ■ Automatic diagnostic procedures of melanocytic skin lesions can be applied to a broad range of morphological and functional imaging techniques. ■ At present, automatic analysis of digital dermoscopy images is the most advanced approach. ■ In-vivo confocal laser scanning microscopy and spectral imaging techniques hold considerable promise for the future. ■ An automatic diagnostic procedure, once, will serve as an expert second opinion.

References   1. (2005) Possible histopathologic correlates of dermoscopic features in pigmented melanocytic lesions identified by means of optical coherence tomography. Exp Dermatol 14: 56–59   2. Chang Y, Stanley RJ, Moss RH, Van Stoecker W (2005) A systematic heuristic approach for feature selection for melanoma discrimination using clinical images. Skin Res Technol 11: 165–178   3. Chen J, Stanley RJ, Moss RH, Van Stoecker W (2003) Colour analysis of skin lesion regions from melanoma discrimination in clinical images. Skin Res Technol 9: 94–104   4. Farkas DL, Becker D (2001) Applications of spectral imaging: detection and analysis of human melanoma and its precursors. Pigment Cell Res 14: 2–8   5. Gerger A, Koller S, Weger W, Richtig E, Kerl H, Samonigg H, Krippl P, Smolle J (2006) Sensitivity and specificity of confocal laser-scanning microscopy for in vivo diagnosis of malignant skin tumors. Cancer 107: 193–200   6. Gerger A, Stolz W, Pompl R, Smolle J (2003) Automated epiluminescence microscopy-tissue counter analysis using CART and 1-NN in the diagnosis of melanoma. Skin Res Technol 9: 105–110   7. Gniadecka M, Philipsen PA, Sigurdsson S, Wessel S, Nielsen OF, Christensen DH, Hercogova J, Rossen K, Thomsen HK, Gniadecki R, Hansen LK, Wulf HC (2004) Melanoma diagnosis by Raman spectroscopy and neural networks: structure alterations in proteins and lipids in intact cancer tissue. J Invest Dermatol 122: 443–449   8. Gruber MJ, Wackernagel A, Richtig E, Koller S, Kerl H, Smolle J (2005) Digital image enhancement for in vivo laser scanning microscopy. Skin Res Technol 11: 248–253   9. Guillard G, Lagarde JM (2005) Skin lesions segmentation and quantification from 3D body’s models. Skin Res Technol 11: 123–131 10. Haenssle HA, Krueger U, Vente C, Thoms K-M, Bertsch HP, Zutt M, Rosenberger A, Neumann C, Emmert S (2006) Results from an observational trial: digital epiluminescence microscopy followup of atypical Nevi increases the sensitivity and the chance of success of conventional dermoscopy in detecting melanoma. J Invest Dermatol 126: 980–985 11. Har-Shai Y, Glickman Y, Siller G, McLeod R, Topaz M, Howe C, Ginzburg A, Zamir B, Filo OP, Kenan GP, Ullmann Y (2005) Electrical impedance scanning for melanoma diagnosis: a validation study. Plast Reconstr Surg 116: 782–790 12. Hartmann P, Ziegler W, Lübbers DW (1996) Fluorescence life time imaging of the skin pO2: instrumentation and results. Adv Exp Med Biol 428: 605– 611

Automatic Diagnosis 13. Kahofer P, Hofmann-Wellenhof R, Smolle J (2002) Tissue counter analysis of dermatoscopic images of melanocytic skin tumors: preliminary findings. Melanoma Res 12: 71–75 14. Kittler H, Guitera P, Riedl E, Avramidis M, Teban L, Fiebiger M, Weger RA, Dawid M, Menzies S (2006) Identification of clinically featureless incipient melanoma using sequential dermoscopy imaging. Arch Dermatol 142: 1113–1119 15. Manousaki AG, Manios AG, Tsompanaki EI, Panayiotides JG, Tsiftsis DD, Kostaki AK, Tosca AD (2006) A simple digital image processing system to aid in melanoma diagnosis in an everyday melanocytic skin lesion unit. A preliminary report . Int J Dermatol 45: 402–410 16. Moncrieff M, Cotton S, Claridge E, Hall P (2002) Spetrophotometric intracutaneous analysis: a new technique for imaging pigmented skin lesions. Br J Dermatol 146: 448–457 17. Muryph BW, Webster RJ, Turlach BA, Quirk CJ, Clay CD, Heenan PJ, Sampson DD (2005) Towards the discrimination of early melanoma from common and dysplastic nevus using fiber optic diffuse reflectance spectroscopy. J Biomed Optics 10: 064020 18. Oka H, Iyatomi H, Hashimoto M, Tanaka M (2006) Reply to “Digital dermoscopy analysis and internetbased program for discrimination of pigmented skin lesion dermoscopic images”. Br J Dermatol 154: 570–571 19. Ono I, Sakemoto A, Ogino J, Kamyia T, Yamashita T, Jimbow K (2006) The real-time, three-dimensional analyses of benign and malignant skin tumors by confocal laser scanning microscopy. J Dermatol Sci 43: 135–141 20. Rallan D, Dickson M, Busch NL, Harland CC, Mortimer P, Bamber JC (2006) High-resolution ultrasound reflex transmission imaging and digital photgraphy: potential tools for the quantitative assessment of pigmented lesions. Skin Res Technol 12: 50–59

Chapter II.2 21. Rallan D, Bush NL, Bamber JC, Harland CC (2006) Quantitative discrimination of pigmented lesions using three-dimensional high-resolution ultrasound reflex transmission imaging. J Invest Dermatol 127: 189–195 22. Rosado B, Menzies S, Harbauer A, Pehamberger H, Wolff K, Binder M, Kittler H (2003) Accuracy of computer diagnosis of melanoma. A quantitative meta-analysis. Arch Dermatol 139: 361–367 23. Rubegni P, Burroni M, Sbano P, Andreassi L (2005) Digital dermoscopy analysis and Internet-based program for discrimination of pigmented skin lesion dermoscopic images. Br J Dermatol 152: 395–396 24. Salmhofer W, Rieger E, Soyer HP, Smolle J, Kerl H (1996) Influence of skin tension and formalin fixation on sonographic measurement of tumor thickness. J Am Acad Dermatol 34: 34–39 25. Seidenari S, Pellacani G, Grana C (2005) Pigment distribution in melanocytic lesion images: a digital parameter to be employed for computer-aided diagnosis. Skin Res Technol 11: 236–241 26. She Z, Fish PJ (2003) Analysis of skin line pattern for lesion classification. Skin Res Technol 9: 73–80 27. Smolle J (2000) Diagnostic assessment of cutaneous melanoma and common nevi using tissue counter analysis. Analyt Quant Cytol Histol 22: 299–306 28. Stoecker VW, Gupta K, Stanley RJ, Moss RH, Shrestha B (2005) Detection of asymmetric blotches (asymmetric structureless areas) in dermoscopy images of malignant melanoma using relative color. Skin Res Technol 11: 179–184 29. Stücker M, Springer C, Paech V, Hermes N, Hoffmann M, Altmeyer P (2006) Increased laser Doppler flow in skin tumors corresponds to elevated vessel density and reactive hyperemia. Skin Res Technol 12: 1–6 30. Wiltgen M, Gerger A, Wagner C, Bergthaler P, Smolle J (2004) Evaluation of the influence of image compression on the automatic discrimination of histological images of skin lesions. Meth Inform Med 43: 141–149


Chapter II.3

Multispectral Image Analysis Dina Gutkowicz-Krusin and Harold Rabinovitz

Contents II.3.1 Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . 52


II.3.2 Analysis of Multispectral Images of Skin Lesions from the MelaFind Database . . . . . . . . . . . . . . . . . . . . . 52 II.3.3 Examples of Wavelength-Dependent Lesion Parameters. . . . . . . . . . . . . . . . . . . . . . 54 II.3.4 Lesion Classification Based on Multispectral Images. . . . . . . . . . . . . . . . . 55

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

II.3.1 Background There are several multispectral imaging systems developed or under development to aid physicians in the diagnosis of melanoma. These systems use illumination of the skin in different spectral bands in the visible and near infrared (IR). One such system, MelaFind, is still under development; it acquires images in ten different spectral bands from 430 to 950 nm [2]. Another system, SpectroShade, has been described and evaluated in a prospective study by Tomatis et al. [6]. This system acquires images in 15 bands ranging from 483 to 950 nm. Yet another system, SIAscope, uses eight bands from 400 to 1000 nm to illuminate the lesion and surrounding skin [5]. One of the purposes of multispectral imaging is to improve differentiation of cutaneous melanoma from other pigmented skin lesions that present a challenge to clinicians. The specific approach to this problem varies from sys-


tem to system, but all rely on the fact that the longer the wavelength of light, the deeper light penetrates into the skin [1]; thus, multispectral imaging samples the three-dimensional morphology of a pigmented skin lesion and of the surrounding skin. Unfortunately, the resulting sequence of two-dimensional images is not easy to interpret due to absorption and multiple scattering of light in the skin. Different interpretations are possible, and are, in fact, used by different systems. Here, we focus on the approach used by MelaFind. The next section briefly describes the methods of analysis of multispectral images used by MelaFind. The dependence of lesion parameters on the wavelength of illumination is illustrated in section II.3.3. The diagnostic performances of the multispectral imaging systems are compared and discussed in section II.3.4.

II.3.2 Analysis of Multispectral Images of Skin Lesions from the MelaFind Database For every lesion, MelaFind acquires ten dermoscopic images in seven spectral bands in the visible and three in the near IR (isopropyl alcohol is used for refractive index matching) [2]. Each image is 1280¥1024 pixels, with the pixel size in the lesion plane of 20¥20 µm. An example of such a sequence of images is shown in Fig. II.3.1, for a superficial spreading invasive melanoma with Breslow thickness of 0.5 mm. It is noteworthy that the lesion appears almost uniformly dark in the blue (430 nm) and green (500 nm) spectral bands, due to strong absorption by melanin. In the red bands (650 and 700 nm), the images show much more complex morphology

Multispectral Image Analysis

Chapter II.3

Fig. II.3.1.  An example of a MelaFind multispectral sequence of images of invasive melanoma together with RGB image of this lesion and its mask

of the lesion. Since light in the IR is only weakly absorbed by melanin, the presence of dark areas in these images indicates an invasive lesion. Figure II.3.1 also shows an RGB dermoscopic image of this lesion that would be used in visual evaluation by physicians.

The first step in the image analysis is calibration. MelaFind automatically calibrates every image in a multispectral sequence to measure the absolute reflectance (the fraction of the incident light that is reflected) for every pixel. The next step is automatic image quality control,




D. Gutkowicz-Krusin, H. Rabinovitz

which consists of software filters (algorithms) that check the images for artifacts such as bubbles or too much hair, overexposure, movement, etc. Only images that pass these filters are accepted for further processing, i.e., segmentation. MelaFind’s automatic segmentation algorithms have been described elsewhere [2, 3]. For superficial lesions, the mask (i.e., pixels that belong to the lesion) is found from the image in the blue band; however, for deeper lesions, such as dermal or blue nevi, the green band is selected automatically. The same mask is then used to find the lesion in all the other spectral bands. An example of such an automatically obtained mask is shown in Fig. II.3.1. Given this mask, various lesion properties can be computed as a function of the wavelength of illumination [4]. For example, one can compute the mean lesion reflectances by averaging the calibrated image intensity over the pixels in the lesion mask, for each spectral band independently. Not surprisingly, many lesion parameters depend strongly on wavelength. This is due in part to different absorption of light of different wavelengths by the common chromophores present in the skin: melanin; hemoglobin; collagen; etc. But it is also due to different morphology of the lesion at different depths into the skin. This is seen clearly in Fig. II.3.1.

Not only do the parameters depend on wavelength, but also the ability of a parameter to differentiate melanomas from other pigmented skin lesions may vary with wavelength. One way to measure such ability is to determine how significantly different are the distributions of this parameter for a population of melanomas and a population of other pigmented skin lesions [6]. Another way is to determine the maximum diagnostic accuracy that can be achieved with this parameter at a given wavelength. This is the methodology used here.

II.3.3 Examples of WavelengthDependent Lesion Parameters Multispectral imaging allows determination of the mean lesion reflectance as a function of wavelength. Average values of the mean lesion reflectance, Rm, for a population of 221 melanomas (MM) and a population of 1234 lowgrade dysplastic nevi (LGDN) from the MelaFind dermoscopic image database are listed in Table II.3.1. It can be seen that on the average, melanomas are darker (have lower value of reflectance) than LGDN in every spectral band. The average reflectance is lowest (about 6%) in the blue band due to strong absorption by sur-

Table II.3.1.  Population averages of the mean lesion reflectance (Rm) vs wavelength (221 melanomas and 1234 lowgrade dysplastic nevi). MM melanoma, LGDN low-grade dysplastic nevi

Wavelength (nm)

Average Rm for MM

Average Rm for LGDN

Significance of difference (p)

Diagnostic accuracy (%)

430 (blue band)










500 (green band)















650 (red band)





700 (red band)




















Multispectral Image Analysis

Chapter II.3


Table II.3.2.  Population averages of lesion asymmetry vs wavelength (221 melanomas and 1234 low-grade dysplastic nevi). MM melanoma, LGDN low-grade dysplastic nevi

Wavelength (nm)

Average asymme- Average asymme- Significance of try for MM try for LGDN difference (p)

Diagnostic accuracy (%)

430 (blue band)










500 (green band)















650 (red band)





700 (red band)




















face melanin; in the red band the average reflectance increases to 40–50% due in part to weaker absorption by melanin and in part to high prevalence in the sample of thin and in-situ melanomas. This table also shows that with the large data set used, the differences in average values are statistically very significant (p-values are very small). The diagnostic accuracy of the mean lesion reflectance, also shown in Table II.3.1, increases with wavelength and is highest in the infrared; however, distributions of mean lesion reflectance are very broad with a significant overlap. At 950 nm, there are only 25 (of 1234) LGDN with Rm greater than Rm for all melanomas. Population averages of the lesion asymmetry parameter are shown in Table II.3.2. For both populations, these averages are highest in the blue band (430 nm) and decrease monotonically with increasing wavelength. Table II.3.2 also shows that the differences in these averages are statistically significant, again due in part to the large number of cases. The lesion asymmetry parameter has high diagnostic accuracy that varies with wavelength and has a maximum in

the red band (700 nm). Again, the distributions of asymmetry have significant overlap. At 700 nm, there are only 27 LGDN with asymmetry parameter lower than that of the most symmetric melanoma.

II.3.4 Lesion Classification Based on Multispectral Images In addition to different image processing methods used by different multispectral systems, the methods of classification differ as well. The results for the independent test sets are summarized in Table II.3.3. Direct comparison of these results is not appropriate because of the different lesion types used in these studies. For example, only 11% of melanomas were in situ in the study by Tomatis et al. [6], whereas in the MelaFind study over 50% of melanomas were in situ (D. Gutkowicz-Krusin, in preparation). Nevertheless, these results indicate the level of diagnostic performance that could be achieved with multispectral imaging.


D. Gutkowicz-Krusin, H. Rabinovitz Table II.3.3.  Diagnostic performance of multispectral systems on independent test sets. MM malignant melanoma, PSL pigmented skin lesions




No. of spectral No. of MM bands

Specificity (%)





SpectroShade [6]






SIAscope [5]






Core Messages

Sensitivity (%)

MelaFind 10 (D. Gutkowicz-Krusin, in preparation)

■ Multispectral imaging provides information about pigmented skin lesions that is not available to the human eye. This information helps to differentiate melanomas from other pigmented skin lesions. ■ The diagnostic performance of multispectral systems depends both on the image processing methods and on the lesion classification algorithms used. ■ Comparison among multispectral systems, as well as with any other imaging systems, is difficult at this time because there is no standardized testing set.  

No. of other PSL

References 1. Anderson RR, Parrish JA (1981) The optics of human skin. J Invest Dermatol 77:13–19 2. Elbaum M, Kopf AW, Rabinovitz H, Langley R et al. (2001) Automatic differentiation of early melanoma from nevi with multi-spectral digital dermoscopy: feasibility study. J Am Acad Dermatol 44:207–218 3. Gutkowicz-Krusin D, Elbaum M, Szwajkowski P, Kopf AW (1997) Can early malignant melanoma be differentiated from atypical melanocytic nevus by in vivo techniques? Part II: Automatic machine vision classification. Skin Res Technol 3:15–22 4. Gutkowicz-Krusin D, Elbaum M, Jacobs A, Keem S et al. (2000) Precision of automatic measurements of pigmented skin lesion parameters with a MelaFind(TM) multispectral digital dermoscope. Melanoma Res 10:563–570 5. Moncrieff M, Cotton S, Claridge E, Hall P ((2003) Spectrophotometric intracutaneous analysis: a new technique for imaging pigmented skin lesions. Br J Dermatol 146:448–457 6. Tomatis S, Carrara M, Bono A, Bartoli C et al. (2005) Automated melanoma detection with a novel multispectral imaging system: results of a prospective study. Phys Med Biol 50:1675–1687

Chapter II.4

Teledermatology Cesare Massone, Elisabeth M.T. Wurm, Rainer Hofmann-Wellenhof, Gian Piero Lozzi, H. Peter Soyer

Contents II.4.1 Introduction and Definition . . . . . . . . . . . . . 57 II.4.2 Mobile Teledermatology. . . . . . . . . . . . . . . . . 58 II.4.3 Teledermoscopy. . . . . . . . . . . . . . . . . . . . . . . . 58 II.4.4 Teledermatopathology . . . . . . . . . . . . . . . . . . 58 II.4.2 Teledermatology on the Web. . . . . . . . . . . . . 59

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

II.4.1 Introduction and Definition Telemedicine is a new tool in medicine that utilizes modern telecommunication technology to exchange expert medical information. This can be performed either between patients and doctors or between two or more distant medical centers [4]. Dermatology is perhaps the most visual specialty in medicine, making it ideally


suited for modern telemedicine techniques, as has been shown in a number of recent studies investigating feasibility and reliability of teledermatology [1, 3]. Teledermatology offers an obvious method for improving access and decreasing costs of medical service, by eliminating the necessity of traveling for patients, physicians, and nurses [1, 3]. Technical systems employed in teledermatology include real-time videoconferences and store-and-forward systems. Real-time videoconferencing has been shown to be an effective substitute for in-person consultation, but it is time-consuming and expensive. Store-and-forward systems, in which medical information and images are first stored and then are transmitted to a distant expert, are a fast and low-cost alternative (see Fig. II.4.1). They have been found to be accurate and ef­ fective, either when images are sent by E-mail or presented on a Web-based system [1, 3, 5, 16]. Fig. II.4.1.  Scheme of data transmission in store and forward (SAF) teledermatology


C. Massone, E.M.T. Wurm et al.

There are some requirements which can prove troublesome. Services must be available without fail, ideally 24 h a day, and they must be easy to access, not wasting the time of busy professionals. Most importantly, patients must be confident about the security of their personal information.

II.4.2 Mobile Teledermatology


A new era in telemedicine began with the advent of mobile telecommunication devices. In our understanding mobile teledermatology is defined as medicine at a distance with the participants using mobile devices such as cellular phones or personal digital assistants (PDA). The implementation of modern wireless telecommunication means like Global Positioning Radio System (GPRS) or Wireless Local Area Network (WLAN) and satellite communication has become nearly an everyday reality and thus forms the information-technology basis for mobile teledermatology. Photographs of skin lesions can be easily taken using the new generation of cellular phones or PDAs. The feasibility of this system has been recently proven by Braun et al. and by Massone et al. [7, 12, 13] Mobile teledermatology using PDA and/or cellular phones might become a filtering or triage system allowing a more rational approach to the management of patients with emergent skin diseases. Finally, mobile teledermatology brings an intrinsic peculiar facility: the possibility to cover through the mobile network the transmission of data and images in areas where Internet connection is not available or too expensive (i.e., satellite transmission): in this context, mobile teledermatology will have an exponential grow in the near future, with increasing tasks both from patients and physicians [7, 12, 13].

II.4.3 Teledermoscopy Clinical and dermoscopic images of pigmented skin lesions can be easily transmitted over telecommunication networks (E-mails, specific web applications). Feasibility of teledermoscopy has been established by Piccolo et al. revealing a

good agreement (91% concordance) between the direct, physical examination (face-to-face diagnosis) and the remote diagnosis [17]. The Consensus Net Meeting of Dermoscopy (a virtual meeting of experts from all over the world) was another evident example of the practical applicability of the use of dermoscopy via Internet [6]. In 2003 a pilot study of the dermoscopic–pathological approach using tele­ diagnosis for melanocytic skin neoplasms was conducted by Ferrara et al., and the diagnostic accuracy reached 83% vs gold standard (conventional histopathological diagnosis by experts) [8]. Until now, the validity of teledermoscopy of pigmented skin lesions has been shown by only a few studies [11]; however, teledermos­­copy is a promising area for further research and development and will soon be integrated into the daily office workflow for diagnosis and management of equivocal pigmented skin lesions.

II.4.4 Teledermatopathology Teledermatopathology can be performed with real-time (dynamic) transmission of images or with the store-and-forward (static) option [15]. The first method provides remote consultation via a robotic microscope, which can be controlled by the consulting pathologist. Using the store-and-forward-system each image is captured and transmitted as a single file [15]. In the past years virtual slide system (VSS) has been introduced. With virtual slide system the whole slide can be digitized at a high resolution, which allows the user to view any part of the specimen at any magnification. In this way the limitations imposed by conventional photographs representing small preselected areas can be overcome [9, 20]. Moreover, the acquired images can be stored on a VS server (i.e.,,, which makes them available on the Web, and an integrated VS client enables the users to browse the virtual slide [9, 20]. The feasibility of both storeand-forward and real-time teledermatopathology has been proven already mainly on nonmelanoma skin cancer and on melanocytic


lesions [15, 18]; however, according to these studies, diagnostic efficiency and accuracy in teledermatopathology is limited in the examination of entities that require the distinction of subtle architectural arrangements or cytological features, as in inflammatory skin diseases [15, 18].

Chapter II.4


II.4.2 Teledermatology on the Web Web consultations in dermatology are a very new tool that has become available in the past years [10]. Teledermatological services through the Internet offer many possibilities, including continuing medical education, on-line atlases,

Table II.4.1.â&#x20AC;&#x201A; Some examples of websites that offer opportunities and facilities in dermatology. CME continuing medical education




Discussion forum

Virtual Grand Rounds in Dermatology

Discussion forum


Discussion forum


Discussion forum

DermConsult Website

Educational website


Mailing list


Swiss platform

Cyberambulatory website

Low-cost telemedicine in Brazil


All about dermatology

Archives of Dermatology


American Academy of Dermatology



Case presentations, CME


Case presentations, CME

On-line atlases

On-line atlases


Interactive training programs

Lectures over the Internet


On-line database

Electronic Textbook of Dermatology

Electronic textbooks

Dermatology Resources

Resource lists


C. Massone, E.M.T. Wurm et al.

and databases [1, 2]. Specific Web applications suited for teledermatology, discussion forums, and the DermOnline Community (i.e., www. are other examples in this field [14, 19]. Table II.4.1 illustrates some examples of different websites that offer many opportunities and facilities in dermatology through the Internet.


Core Messages ■ Telemedicine utilizes modern telecommunication technology to exchange expert medical information. ■ Technical systems employed in teledermatology include real-time videoconferences and store-and-forward systems; the latter is the mainly used data transmission system in teledermatology. ■ In mobile teledermatology, mobile devices, such as cell phones and PDAs, are used to transmit medical information. ■ Remote expert consultation with the help of digital dermoscopic images and virtual histopathological slides will probably soon be integrated in the daily office workflow for diagnosis and management of pigmented skin lesions.


References   1. Burg G, ed. (2003) Telemedicine and teledermatology. Current problems in dermatology. Basel: Karger Press   2. McColl I (2003) Dermatology education on the Web. J Telemed Telecare 9: 33–35   3. Eedy DJ, Wootton R (2001) Teledermatology: a review. Br J Dermatol 144: 696–707   4. Loane M, Wootton R (2002) A review of guidelines and standards for telemedicine. J Telemed Telecare 8: 63–71   5. Wootton R, Oakley A, eds. (2002) Teledermatology. London: Royal Society of Medicine Press   6. Argenziano G, Soyer HP, Chimenti S, et al. (2003) Dermoscopy of pigmented skin lesions: results of a

consensus meeting via the Internet. J Am Acad Dermatol 48: 679–693   7. Braun RP, Vecchietti JL, Thomas L, et al. (2005) Telemedical wound care using a new generation of mobile telephones: a feasibility study. Arch Dermatol 141: 254–258   8. Ferrara G, Argenziano G, Cerroni L, et al. A pilot study of a combined dermoscopic–pathological approach to the telediagnosis of melanocytic skin neoplasms. J Telemed Telecare 2004; 10: 34–38   9. Glatz-Krieger K, Glatz D, Mihatsch MJ (2003) Virtual slides: high-quality demand, physical limitations, and affordability. Hum Pathol 34: 968–974 10. Lozzi GP, Soyer HP, Massone C et al. (2007) The additive value of second opinion teleconsulting in the management of challenging case in an out-patient setting: A best practice model? J Eur Acad Dermatol Venereol 21: 30–34 11. Massone C, Di Stefani A, Soyer HP (2005) Dermoscopy for skin cancer detection. Curr Opin Oncol 17: 147–153 12. Massone C, Lozzi GP, Wurm E, et al. (2006 ) Personal digital assistant (PDA) in teledermatology. Br J Dermatol 154: 801–802 13. Massone C, Lozzi GP, Wurm E, et al. (2006) Cellular phones in clinical teledermatology. Arch Dermatol 141: 1319–1320 14. Massone C, Soyer HP, Hofmann-Wellenhof R, et al. (2006) Web-based teleconsulting in dermatology: a two years pilot experience. J Telemed Telecare 12: 83–87 15. Morgan MB, Tannenbaum M, Smoller BR (2003) Telepathology in the diagnosis of routine dermatopathologic entities. Arch Dermatol 139: 637–640 16. Oztas MO, Calikoglu E, Baz K, et al. (2004) Reliability of Web-based teledermatology consultations. J Telemed Telecare 10: 25–28 17. Piccolo D, Smolle J, Wolf IH, et al. (1999) Face-toface diagnosis vs telediagnosis of pigmented skin tumors: a teledermoscopic study. Arch Dermatol 135: 1467–1471 18. Piccolo D, Soyer HP, Burgdorf W, et al. (2002) Concordance between telepathologic diagnosis and conventional histopathologic diagnosis: a multiobserver store-and-forward study on 20 skin specimens. Arch Dermatol 138: 53–58 19. Soyer HP, Hofmann-Wellenhof R, Massone C, et al. (2005) freely available online consultations in dermatology. PLoS Med 2: e87 20. Weinstein RS, Descour MR, Liang C, et al. (2004) An array microscope for ultrarapid virtual slide processing and telepathology. Design, fabrication, and validation study. Hum Pathol 35: 1303–1314

Chapter III.1

The Life of Melanocytic Nevi Harald Kittler

Contents III.1.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . 61 III.1.2 The Life of Congenital Nevi. . . . . . . . . . . . . . 61 III.1.3 The Life of Acquired Nevi. . . . . . . . . . . . . . . . 62 III.1.4 Clark Nevi: Are They Truly Precursors of Melanoma?. . . . . . . . . . . . . . . . . . . . . . . . . . 64

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

III.1.1 Introduction Although melanocytic nevi are very common, their histogenesis is not well understood. The origin of melanocytic nevi and their natural history is still a matter of debate. According to Unna’s “Abtropfung” theory, melanocytic nevi start in the epidermis and drop off into the dermis [1]. In contrast to the theory of “Abtropfung,” the theory of “Hochsteigerung” suggests that melanocytes of neural crest origin migrate up from the dermis into the epidermis [2]. It is possible that both theories are correct and that acquired and congenital melanocytic nevi are fundamentally different. Acquired melanocytic nevi may be interpreted as benign neoplasms triggered by different stimuli, one of them being exposure to UV radiation. They start as a proliferation of epidermal melanocytes, which consecutively “drop off” into the dermis. In contrast to acquired melanocytic nevi, congenital nevi may be interpreted as hamartomas developing from neural crest cells that migrate up from the dermis into the epidermis. Unfortunately, the term congenital nevus has not been


defined consistently. Most authors regard congenital nevi as melanocytic nevi that are present at birth, but in fact congenital nevi may be present but not visible at birth. Melanocytic nevi that are not visible at birth but have clinical or histopathological features of congenital nevi have been termed “tardive” congenital nevi or congenital like nevi. Sometimes it is impossible to differentiate between acquired and small congenital nevi by clinical inspection with the unaided eye or by dermoscopy in particular when anamnestic data are unavailable or unreliable. To complicate matters further, some melanocytic nevi that were reportedly visible at birth lacked typical histopathological criteria of congenital nevi when biopsied. All we know about the life of melanocytic nevi, no matter if acquired or congenital, is based on cross-sectional or cohort studies. At present, it is still impossible to monitor melanocytic nevi in vivo on a cellular level. In the near future new technologies, such as, for example, optical coherence tomography or confocal laser scanning microscopy (see Chap. II.1), may provide new insights into the life of moles on a cellular level, but currently we are still depending on clinical examinations with the unaided eye, or on dermoscopic examinations. Most studies in this field have focused on acquired nevi and only a few studies have investigated the life of congenital nevi.

III.1.2 The Life of Congenital Nevi Congenital nevi enlarge during infancy until they have reached a certain size, but the exact dynamic of this expansion has not been studied over long periods. Rhodes et al. monitored 41



H. Kittler

small- to medium-sized congenital nevi that were present in newborns when examined within 96 h of birth [3]. At the first examination nevus size varied from 1 to 40 mm. The authors measured absolute and relative area expansion of the nevus proportionate to the anatomic region. They observed a proportionate area expansion in most cases studied, but nine congenital nevi showed a disproportionate area expansion during the first 6 months of life. In general, it can be assumed that the velocity of growth of a congenital nevus is correlated with the velocity of overall growth of the human body, which is largest during the first 6 months of age. The same factors that influence human development may also be responsible for the growth of congenital nevi. Mitotic activity of congenital nevi may be increased by stretching of human skin and/or by hormonal growth factors. Expansion of congenital nevi usually stops after the nevus has reached a certain size. Like most mammalian cells, melanocytes of congenital nevi have a protective mechanism against unlimited proliferation called senescence, which is usually driven by telomere attrition. It has been shown recently that the growth arrest of congenital nevi is induced by oncogene driven growth arrest, rather than by telomere attrition [4]. It is assumed that oncogenic mutations in BRAF, a protein kinase, trigger the induction of tumor suppressors, including p16INK4a, and are responsible for the growth arrest of melanocytes of congenital nevi, but it is likely that other mechanisms contribute to this phenomenon as well. Whether oncogene-induced senescence is also responsible for the growth arrest of acquired nevi has yet to be determined.

III.1.3 The Life of Acquired Nevi The life of acquired nevi has been studied in more detail than the life of congenital nevi. It has become common language to divide acquired nevi into common nevi, on one hand, and into “dysplastic” or “atypical” nevi, on the other hand. This terminology has its limitations mainly because it lacks consistent definitions of “common “and “atypical,” and because there is only fair correlation between clinical atypia and

histopathological atypia. It may be more useful to divide acquired nevi into one group that consists of Spitz and Reed nevi, and a second group that summarizes all nevi that are usually called common acquired nevi and “atypical” nevi under the heading Clark nevi. Clark nevi are much more common than Spitz and Reed nevi, and virtually all epidemiological studies on the dynamics of acquired nevi deal with Clark nevi. They appear in childhood and their number is related to genetic factors including skin type and environmental factors, chief among them being UV –exposure [5, 6]. As shown repeatedly, their number is also correlated with melanoma risk, most probably because melanoma and Clark nevi have etiological factors in common, and not because Clark nevi are precursors of melanoma. In a cohort study of 385 individuals we observed that Clark nevi are highly active during childhood and adolescence, but usually remain static in adults [7]. One thousand six hundred twelve Clark nevi were monitored with digital dermoscopy over a median observation period of 1 year. The frequency of enlarging nevi was nearly 60% of all monitored nevi in the youngest age group (0–10 years). It declined to 12% in individuals aged 10–20 years, and finally dropped to 5% and lower in individuals older than 30 years. Although it can be expected that these numbers would be higher for longer follow-up periods, it confirms that the frequency of enlarging Clark nevi in adults is low, and that the velocity of growth of Clark nevi is highest in infancy and adolescence. In our experience there are some individuals that maintain a high growth activity of their Clark nevi, even after the age of 30 years. These individuals tend to have larger Clark nevi than other individuals. It would not be surprising if these patients have an increased risk for melanoma, but an epidemiological study has not been performed to address this question. We have also discovered that Clark nevi have a specific dermoscopic appearance during the initial phase of rapid growth [7]. During this phase they usually show a peripheral rim of brown globules (Fig. III.1.1). Histopathologically, the globules correspond to nests of melanocytes at the dermo-epidermal junction at the

The Life of Melanocytic Nevi

Chapter III.1

Fig. III.1.1.  a–d Incipient Clark nevus in its growth phase monitored over 3 years. The peripheral rim of brown globules (corresponding to nests of melanocytes

at the dermo-epidermal junction) observed in a certain distance of the main body of the nevus is typical for ­enlarging Clark nevi.

periphery of the lesion. When the velocity of nevus growth is extremely high, these nests become confluent at the periphery, forming streaks and pseudopods, typical signs of Reed nevus, which is a type of acquired nevus that enlarges very quickly. Not all enlarging Clark nevi show a peripheral rim of globules. In the lentiginous type of Clark nevus, for example, no nests are formed at the periphery during expansion and the rim is not observed. When the globules in the periphery disappear, the nevus usually has

reached its final size. After reaching their final size, we observed that some Clark nevi become lighter and smaller (Fig. III.1.2). Whether this observed involution corresponds to “Abtropfung” of melanocytes into the dermis is unknown. The observation that immunosuppressed renal transplant recipients may develop a large number of eruptive nevi with a peripheral rim of globules confirms the hypothesis that this morphological feature is a sign of nevus growth [8].



H. Kittler


Fig. III.1.2.  a–d Clark nevus that has reached its final size indicated by disappearance of brown globules at the periphery and subsequent involution of the nevus. Observation period from a–d is 4 years.

III.1.4 Clark Nevi: Are They Truly Precursors of Melanoma? Finally, we also have to address the question as to whether Clark nevi are truly precursors of melanoma. The hypothesis of Clark was based on the assumption of stepwise tumor progression in such a way that common nevi progress to dysplastic nevi and then finally to melanoma [9]. This hypothesis of stepwise tumor progression has gained the status of a paradigm. Retrospective studies of histopathological sections of melanoma seemingly confirmed the association between Clark nevi and melanoma, but a prospective cohort study to determine the risk of a Clark nevus to progress into a melanoma has never been performed [10]. In a cohort study by our group 1812 lesions thought to be Clark nevi at the patients’ first

visit were monitored with digital dermoscopy over a median observation period of 12 months [11]. All patients included in this study had multiple Clark nevi and an increased risk of developing melanoma. We observed a low frequency of changing lesions, even in this high-risk group. Only 5% of lesions enlarged or showed other substantial changes. These lesions were excised to rule out melanoma. Histopathologically, 8 of 75 excised lesions turned out to be early melanoma. No melanoma showed remnants of a Clark nevus histopathologically. It is highly likely that all melanomas were melanomas at the patients’ first visit. It is possible, of course, that a melanoma develops in a Clark nevus, but this happens very rarely. At the Department of Dermatology at the Medical University in Vienna we have monitored more than 10,000 Clark nevi over the past

The Life of Melanocytic Nevi

years, mainly in high-risk patients, and observed only three melanomas that unambiguously developed into a Clark nevus during follow-up. It seems that even in patients with multiple Clark nevi most melanomas develop de novo. This low frequency of melanomas developing in a Clark nevus does not qualify the Clark nevus as a precursor of melanoma. In that sense every melanocytic nevus would qualify as precursor lesion, including all types of congenital nevi, Spitz nevi, Reed nevi, etc. It seems that Clark nevi are no more precursors of melanoma than any other melanocytic nevus in man.


Core Messages ■ Congenital nevi may be interpreted as hamartomas developing from neural crest cells that migrate up from the dermis into the epidermis. ■ Congenital nevi may be present, but not visible, at birth (“tardive” congenital nevi or congenital like nevi). They enlarge during infancy and usually stop growing after they have reached a certain size. ■ Acquired melanocytic nevi, on the other hand, may be interpreted as benign neoplasms triggered by different stimuli (e.g., UV radiation), which consist of melanocytes that consecutively “drop off” into the dermis. ■ Acquired nevi can be divided into two groups: (a) Spitz and Reed nevi; and (b) Clark nevi, which can be further divided into common or atypical Clark nevi. ■ It seems very likely that Clark nevi are no more precursors of melanoma than any other melanocytic nevus.

Chapter III.1

References   1. Krengel S. Nevogenesis: new thoughts regarding a classical problem. Am J Dermatopathol 2005;27:456–65   2. Cramer SF. The origin of epidermal melanocytes. Implications for the histogenesis of nevi and melanomas. Arch Pathol Lab Med 1991;115:115–119   3. Rhodes AR, Albert LS, Weinstock MA. Congenital nevomelanocytic nevi: proportionate area expansion during infancy and early childhood. J Am Acad Dermatol 1996;34:51–62   4. Michaloglou C, Vredeveld LC, Soengas MS et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 2005;436:720–724   5. English DR, Milne E, Simpson JA. Ultraviolet radiation at places of residence and the development of melanocytic nevi in children (australia). Cancer Causes Control 2006;17:103–107   6. Bauer J, Buttner P, Wiecker TS, Luther H, Garbe C. Risk factors of incident melanocytic nevi: a longitudinal study in a cohort of 1,232 young German children. Int J Cancer 2005;115:121–126   7. Kittler H, Seltenheim M, Dawid M, Pehamberger H, Wolff K, Binder M. Frequency and characteristics of enlarging common melanocytic nevi. Arch Dermatol 2000;136:316–320   8. Alaibac M, Piaserico S, Rossi CR et al. Eruptive melanocytic nevi in patients with renal allografts: report of 10 cases with dermoscopic findings. J Am Acad Dermatol 2003;49:1020–1022   9. Elder DE, Clark WH Jr, Elenitsas R, Guerry DT, Halpern AC. The early and intermediate precursor lesions of tumor progression in the melanocytic system: common acquired nevi and atypical (dysplastic) nevi. Semin Diagn Pathol 1993;10:18–35 10. Rhodes AR, Harrist TJ, Day CL, Mihm MC Jr, Fitzpatrick TB, Sober AJ. Dysplastic melanocytic nevi in histologic association with 234 primary cutaneous melanomas. J Am Acad Dermatol 1983;9:563– 574 11. Kittler H, Pehamberger H, Wolff K, Binder M. Follow-up of melanocytic skin lesions with digital epiluminescence microscopy: patterns of modifications observed in early melanoma, atypical nevi, and common nevi. J Am Acad Dermatol 2000;43:467– 476


Chapter II.2

Acral Nevus Masaru Tanaka, Masayuki Kimoto, Toshiaki Saida

Contents III.2.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 III.2.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . 66


melanocytic nevus for the same reason. It is also called longitudinal melanonychia and is thought to be a variant of acral nevus. Subungual nevi are described in Chap. III.18.

III.2.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . . 66 III.2.4 Relevant Clinical Differential Diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 III.2.5 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . . 69


III.2.6 Management. . . . . . . . . . . . . . . . . . . . . . . . . . . 70 III.2.7 Case Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 III.2.7.1 Case 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 III.2.7.2 Case 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 III.2.7.3 Case 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 III.2.7.4 Case 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

III.2.1 Definition The term acral nevus is not uniformly defined in the literature. Some authors refer to acral nevi in broader terms as melanocytic lesions on both the volar and dorsal surfaces of hands and feet; however, recent publications tend to limit the term “acral melanocytic nevus” only to acral volar melanocytic nevus. It would be better to limit the usage this way, in consideration of recent genetic definition of acral melanoma by Bastian et al. [1]. In this atlas, with the above reason, an acquired or congenital benign melanocytic lesion exclusively on the palms and soles (volar skin) should be called an acral nevus. Subungual or ungual nevus is also included in the term acral

III.2.2 Clinical Features Most lesions are small (usually <7 mm in diameter) and flat, with light-brown to dark-brown pigmentations on the palms and soles, except congenital nevi that can be larger and often slightly elevated. The color shade is darker in the center than at the periphery of the lesion. A bluish central area is sometimes observed in correlation with histopathological dermal component in compound type of nevi. Congenital acral nevi, depending on the size of the lesion, are inclined to have a larger dermal component and bluewhite structures are more often observed on dermoscopy as a background in the central area. Most acral nevi are flat; however, compound type of congenital nevi are slightly elevated.

III.2.3 Dermoscopic Criteria The basic dermoscopic global feature for acral nevi is parallel furrow pattern [6, 8]. The parallel furrow pattern is a pattern with linear pigmentation parallel to the skin markings. The linear pigmentation is basically narrow and confined along the furrow. There are some modifications of parallel furrow pattern, namely fibrillar pattern and lattice-like pattern (Fig. III.2.1). The prevalence of these patterns in Japan is reported to be 42, 33, and 19%, respectively [8]; however, up to 10% of acral nevi could show non-typical pattern [6].

Acral Nevus

Chapter III.2

67 Fig. III.2.1.â&#x20AC;&#x201A; Basic parallel patterns for acral melanocytic nevi. The basic dermoscopic global feature in acral nevus is parallel furrow pattern. Modifications of parallel furrow pattern include fibrillar pattern and lattice-like pattern. Parallel furrow pattern is further divided into four variants, namely single dotted line, single line, double dotted line, and double line variants. Linear pigmentations in all patterns, excluding fibrillar pattern, tend to distribute along the furrows. White circles indicate eccrine pores and form a row in the center of each ridge

Fibrillar pattern is a variant of parallel furrow pattern, which is often observed at pressureloaded areas of the sole [5] or at the lateral nail ridges. This variant is attributed to the fact that the horny layer would go obliquely up with tiers of melanin in it. Figure III.2.2 demonstrates the

schematic explanation of the fibrillar pattern. Each fibrillar pattern reveals a different angle between skin markings and linear pigmentations depending on the pressure-loading sites. Lattice-like pattern is also sometimes observed especially on the arch areas as a variant


M. Tanaka, M. Kimoto, T. Saida Fig. III.2.2.  A schematic explanation of fibrillar pattern. Fibrillar pattern is often observed at pressure-loaded area of the soles. When the histopathological section is cut parallel to the streaks of fibrillar pattern, namely almost perpendicularly to the skin markings, the melanin columns in the horny layer are observed obliquely. Nests of nevus cells might be observed mainly at the crista profunda limitans. Most pigment streaks of fibrillar pattern would start from the left side of the furrows and end at the farrows


of parallel furrow pattern [5]. The lattice-like pattern might be due to some differences in skin markings at the arch area. The parallel furrow pattern might be further divided into four variants (Fig. III.2.1), namely single or double; line or dotted line along the sulcus superficialis [8]. The line variants could be observed as a result of pressure loading and oblique melanin columns inclined to the direction parallel to the skin markings. Another explanation of the line variants might be continuous lentiginous proliferation of melanocytes along the crista profunda limitans. Crista dot-

ted pattern is usually seen in combination with parallel furrow pattern, but on rare occasions is seen on its own. Congenital acral nevi that are mainly composed of dermal elements often show homogeneous pattern, sometimes with subtle remaining of parallel furrow pattern due to the presence of nevus cells at the dermal–epidermal junction. Congenital acral nevi sometimes display a combination of parallel furrow, lattice-like, and fibrillar patterns [11], because the lesion is relatively large. Figure III.2.3 shows a congenital acral nevus exhibiting a typical combination of these three patterns.

Acral Nevus

Chapter III.2

nosis of hematoma [10]; however, irregular pigmentation together with lacunas might be a finding of advanced melanoma with hemorrhage.

III.2.5 Histopathology

Fig. III.2.3.  A combination of parallel patterns seen in a congenital acral nevus. This case is a congenital acral nevus exhibiting a typical combination of three patterns, namely parallel furrow (left side), fibrillar (right side), and lattice-like (central part) patterns. Blue-white structures seen in the background of central part correspond to the melanin producing dermal component of nevus cells. Eccrine pores are well recognized as “white dots”

III.2.4 Relevant Clinical Differential Diagnoses The most important differential diagnosis, of course, is melanoma. Clinically, most acquired acral nevi are small and well circumscribed, regular in shape, and usually less than 7 mm [7]. If the distribution of the color has regular tendency, namely dark in the center and light at the periphery, the lesion probably is a melanocytic nevus; however, if there is irregularity of color distribution, further dermoscopic and/or histopathological examination will be needed. If dermoscopic features show parallel ridge pattern and irregular color distribution, the findings are highly specific to the diagnosis of melanoma. Black heel (subcorneal hemorrhage or hematoma) is another differential diagnosis of great importance. Homogeneous areas or lacunas with red-black to red-blue color strongly suggest that the lesion is hemorrhagic [10]. Typical cases of black heel would exhibit a very unique feature on dermoscopy named “pebbles on the ridges,” which is multiple reddish-black, pebble-like droplets with smooth margins chiefly distributed on the ridges of skin markings [6, 8]. Reddish satellites are also a helpful clue for a diag-

Acral nevi tend to be more cellular than common nevi with arrangements in predominantly lentiginous fashion rather than forming nests of nevus cells. The melanocytic proliferation is usually limited on the tips of epidermal rete ridges. The nevus cells proliferate mainly near the crista profunda limitans, but sometimes nevus cells can also be found at the crista profunda intermedia. These nevus cells at the bottom of the epidermis tend to produce melanin granules and transfer them to the surrounding keratinocytes. Since more melanin is inclined to be produced from the nevus cells near the crista profunda limitans, prominent melanin columns are often observed in the horny layer corresponding to the furrows, thus forming parallel furrow pattern on dermoscopy. The nuclei of these nevus cells are oval and uniform, but mild cellular atypism is sometimes observed. Nevus cells of congenital acral nevi tend to proliferate more deeply than those of acquired acral nevi. The nevus cells are present in sweat ducts and glands, in vessel walls, and in the perineurium of nerves. As acral melanocytic nevi often cause diagnostic problems to dermatopathologists because they share histopathological features with melanoma, the most important thing, when a specimen has been taken, is to order a pathological dissection along a perpendicular plane to the skin markings (dermatoglyphics) [9]. Typical features of benignity, namely symmetry, circumscription, and melanin columns in the horny layer, are more frequently observed in lesions cut perpendicularly to dermatoglyphics [9]. Acral melanocytic nevi especially in children might show lentiginous proliferation, confluence of junctional nests, transepidermal elimination of melanocytic nests, and atypical size, shape, and location of the junctional nests [3]. Acral nevi occasionally demonstrate pagetoid spread of melanocytes, but to a minimal de-



M. Tanaka, M. Kimoto, T. Saida

gree [2]. These atypical histopathological features of acral melanocytic skin are also observed in nevi on genital, flexural, and auricular regions, and need careful attention with regard to differential diagnosis of melanoma [4].

III.2.6 Management


A small lesion (<7 mm) of long duration with typical parallel furrow pattern needs no followup. The similarly typical, but recently developed, lesions would require only a short-term dermoscopic follow-up, for about 6 months. Then, if there are no changes in color or size, further follow-up will not be required. Small lesions, but with irregular pigmentation, irregular structure, or any features of concern about malignancy, must be carefully followed up for a long period for any changes in color or size. Digital dermoscopy follow-up is especially recommended in this case. Parallel ridge pattern with irregular shape or pigmentation needs an excisional biopsy and should be histologically assessed [7].

Fig. III.2.4.  Clinical picture of case 1. A dark-brown macule of 4.5¥4.0 mm in size, which has been noticed for 2 years, is seen on the right plantar arch of 19-year-old Japanese man

III.2.7 Case Studies III.2.7.1 Case 1 A 19-year-old Japanese man noticed a brownish macule on his left sole about 2 years previously (Fig. III.2.4). He did not know when the lesion had appeared. As the lesion was gradually increasing in size, he worried about change. Clinically, the brownish macule was 4.5¥4.0 mm in size, and not irregular in shape and color. He had no history of melanoma. Dermoscopically, this lesion showed a typical parallel furrow pattern of double dotted line variant (Fig. III.2.5). There were five parallel pigmented lines at the furrows, and each line was composed of double rows of dots and globules. There were no criteria to suggest that this might be a high-risk lesion; however, the lesion was totally excised and a histopathological diagnosis of melanocytic nevus was established. Melanocytic proliferation was found mainly near the basal layer of the epidermis with some nest formation around the crista profunda limitans.

Fig. III.2.5.  Dermoscopy of case 1. A typical double-dotted-line variant of parallel furrow pattern is recognized. Dark-brown globules are set in array in two rows along the furrows of skin markings

Melanin granules were seen throughout the horny layer forming melanin columns. The horny layer below the furrows lacked melanin granules, which might explain the formation of double dotted line variant.

Comments The double dotted line variant of parallel furrow pattern on dermoscopy often corresponds to histopathological findings of melanocytic nest formation along the shoulders of the crista profunda limitans that is situated beneath the furrow of skin markings.

Acral Nevus

Chapter III.2

cised, and a histopathological diagnosis of melanocytic nevus was obtained. Melanocytic proliferation was found mainly near the basal layer of the epidermis with some nest formation at or around the crista profunda limitans, and melanin granules were seen through the honey layer of stratum corneum.

Comments Fig. III.2.6.  Clinical picture of case 2. A brownish macule composed of linear pigmented streaks is on the right palm of a 62-year-old Japanese woman. It has been noticed for 40 years

The histopathological findings for the parallel furrow pattern of single dotted line variant are nevus cell proliferation just beneath the furrows of skin markings, namely crista profunda limitans. The continuous line variant, as partly seen in the upper half of the picture in this case, might be observed when the melanin columns are obliquely distributed on the specimen cut parallel to the skin markings. This phenomenon also could be explained by the theory of fibrillar pattern.

III.2.7.3 Case 3

Fig. III.2.7.  Dermoscopy of case 2. A typical single dotted line variant of parallel furrow pattern is observed. Linear pigmentations with several dots/globules on the furrows are seen over the light-brown background

III.2.7.2 Case 2 A 62-year-old Japanese woman noticed a brownish macule on her right palm approximately 40 years previously. She felt that the lesion had been getting darker in color since a few years ago. Clinically, the brownish macule was 5.0¥4.0 mm in size, and not irregular in shape and color (Fig. III.2.6). Dermoscopically, the lesion revealed a typical parallel furrow pattern of single dotted line variant; therefore, this lesion fits into the benign categories of acral nevi. There are several parallel pigmented lines that consist of single rows of dots and globules at the furrow (Fig. III.2.7). The lesion was totally ex-

A 27-year-old Japanese woman noticed a small pigmented spot on the sole of her right foot 5 years previously. Since the lesion gradually became prominent in color and size during the past 3 years, she visited a dermatology outpatient clinic for examination. She had no history or family history of melanoma. Clini­­cal examination revealed a 6.2¥5.2-mm dark brown, elliptical macule on her right sole (Fig. III.2.8). The overall color of the lesion seemed homogeneously brown and it was sharply circumscribed. Dermoscopy demonstra­­ted typical fibrillar pattern with linear short pigmentations distributed in the angle of approximately 45° to the skin markings (Fig. III.2.9). A Surgical excision was performed and the specimen was histopathologically examined. Sections were cut 45° to the skin markings. The hematoxylin–eosin staining revealed that melanocytic proliferation was mainly found near the basal layer of the epi­ dermis with some nest formation at or around the crista profunda limitans. These nevus cells were producing melanin and transferring to



M. Tanaka, M. Kimoto, T. Saida

Fig. III.2.8.  Clinical picture of case 3. A 6.2¥5.2-mm small dark-brown spot is noted on the sole of the right foot of a 27-year-old Japanese woman from 5 years previously, which has been enlarged for 3 years

Fig. III.2.10.  Histopathology of case 3. Melanocytic proliferation was found mainly at the crista profunda limitans. Melanin columns are obliquely seen in the stratum corneum at the furrows of skin markings



Fig. III.2.9.  Dermoscopy of case 3.Typical fibrillar pattern with linear short pigmentations is distributed in the angle of approximately 45° to the skin markings. The furrows are recognized as whitish lines of random reflection. Note that most dark pigment streaks are distributed on the right halves of the ridges, reaching furrows at the right end. This is explained by proliferation of nevus cells mainly near the crista profunda limitans; however, there are a few light pigment streaks that are distributed on the left halves of the ridges. This minor pigment distribution is attributed to the nevus cells near crista profunda intermedia

the nearby keratinocytes. Keratinocytes and horny layer corresponding to the furrows have abundant melanin granules. Melanin columns are obliquely seen in the stratum corneum at the furrows of skin markings (Fig. III.2.10).

The dermoscopic fibrillar pattern is well explained by the histopathological distribution of melanin granules in the stratum corneum (Fig. III.2.2). The horny layer of the furrow has scattered reflection and forms linear whitish lines on dermoscopy (Fig. III.2.9). The darker pigment streaks are distributed mainly on the right halves of the ridges of the skin markings, while minor light pigment streaks are also seen on the left halves of the ridges. More melanin granules from nevus cells at the crista profunda limitans would distribute in the stratum corneum below the furrow corresponding to the dark pigment streaks on dermoscopy.

III.2.7.4 Case 4 A 69-year-old Japanese man had noticed a small pigmented macule on his right plantar arch. He insisted that the lesion had existed since his childhood, and had paid no attention to it; however, a dermatologist worried about possible malignancy, because the lesion was irregular in shape and color. Clinical examination revealed a 5.0¥7.0-mm dark-brown, slightly elevated macule on the right plantar arch (Fig. III.2.11). The peripheral lesion seemed slightly blurred on the right side, but had an abrupt edge on the left side. Dermoscopically, the right side of the

Acral Nevus

Fig. III.2.11.  Clinical picture of case 4. A 5.0¥7.0-mm pigmented macule is seen on the right plantar arch of a 69-year-old Japanese man. The lesion has allegedly existed since his childhood

Chapter III.2

Fig. III.2.13.  Histopathology of case 4. Abundant melanin granules were diffusely scattered in the stratum corneum partly forming melanin columns

found near the basal layer of the epidermis and upper dermis. Many nests of nevus cells were seen not only around the crista profunda limitans, but also around the crista profunda intermedia (Fig. III.2.13). These nevus cells were producing large amounts of melanin and transferring them to the nearby keratinocytes. Abundant melanin granules were diffusely scattered in the stratum corneum partly forming melanin columns, which correspond to diffuse black pigmentation on dermoscopy. Fig. III.2.12.  Dermoscopy of case 4. The right side of the lesion revealed parallel furrow pattern, while the left side of the lesion demonstrated irregular, diffuse black pigmentation with irregular black dots and globules. The center of the lesion exhibited blue-white structures

lesion revealed a parallel furrow pattern, while the left side of the lesion demonstrated irregular, diffuse black pigmentation with irregular black dots and globules. The center of the lesion exhibited blue-white structures (Fig. III.2.12). A surgical excision was performed and the specimen was histopathologically examined. Sections were cut perpendicularly to the skin markings. The hematoxylin–eosin staining revealed that prominent melanocytic proliferation was

Comment The diagnostic clue in this case might be parallel furrow pattern shown on the right side of the lesion; however, diffuse irregular black pigmentation with irregular dots and globules are suggestive of melanoma occurring on small congenital nevus. A case like this should be excised and needs to be examined histopathologically. Multiple irregular dots and globules reflect the existence of numerous melanin granules in the stratum corneum. If melanin granules were limited to the honey layer of the furrows forming melanin columns corresponding to the parallel pattern, it would satisfy benign criteria.



M. Tanaka, M. Kimoto, T. Saida


Core Messages ■ Acquired or congenital benign melanocytic lesions exclusively on the palms and soles (volar skin) should be called acral nevi. ■ Acral melanocytic nevi reveal the following main dermoscopic patterns: parallel furrow pattern; lattice-like pattern; and fibrillar pattern. ■ The main clinical differential diagnoses of acral nevi are acral melanomas and subcorneal hematomas.



  1. Bastian BC, Olshen AB, LeBoit PE et al. (2003) Classifying melanocytic tumors based on DNA copy number changes. Am J Pathol 163:1765–1770   2. Boyd AS, Rapini RP (1994) Acral melanocytic neoplasms: a histologic analysis of 158 lesions. J Am Acad Dermatol 31:740–745   3. Evans MJ, Gray ES, Blessing K (1998) Histopathological features of acral melanocytic nevi in children: study of 21 cases. Pediatr Dev Pathol 1:388– 392

  4. Lazova R, Lester B, Glusac EJ et al. (2005) The characteristic histopathologic features of nevi on and around the ear. J Cutan Pathol 32:40–44   5. Miyazaki A, Saida T, Koga H et al. (2005) Anatomical and histopathological correlates of the dermoscopic patterns seen in melanocytic nevi on the sole: a retrospective study. J Am Acad Dermatol 53:230– 236   6. Saida T, Oguchi S, Ishihara Y (1995) In vivo observation of magnified features of pigmented lesions on volar skin using video macroscope: usefulness of epiluminescence techniques in clinical diagnosis. Arch Dermatol 131:298–304   7. Saida T (2000) Malignant melanoma on the sole: how to detect the early lesions efficiently. Pigment Cell Res 13 (Suppl 8):135–139   8. Saida T, Oguchi S, Miyazaki A (2002) Dermoscopy for acral pigmented skin lesions. Clin Dermatol 20:279–285   9. Signoretti S, Annessi G, Puddu P et al. (1999) Melanocytic nevi of palms and soles: a histological study according to the plane of section. Am J Surg Pathol 23:283–287 10. Zalaudek I, Argenziano G, Soyer HP et al. (2004) Dermoscopy of subcorneal hematoma. Dermatol Surg 30:1229–1232 11. Zalaudek I, Zanchini R, Petrillo G et al. (2005) Dermoscopy of an acral congenital melanocytic nevus. Pediatr Dermatol 22:188–191

Chapter III.3


Agminated Nevus Ulrike Weigert and Wilhelm Stolz


III.3.3 Dermoscopic Criteria

III.3.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 III.3.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . 75 III.3.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . . 75 III.3.4 Relevant Clinical Differential Diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 III.3.5 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . . 75 III.3.6 Management. . . . . . . . . . . . . . . . . . . . . . . . . . . 75

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

III.3.1 Definition An agminated nevus consists of multiple pigmented lesions of the same kind, occurring in a cluster or circumscribed group in a localized area of the body.

III.3.2 Clinical Features Agminated nevi are infrequent lesions. Clinically they appear as numerous brown to red macules or papules in different sizes and in a peppered distribution over a certain area of the skin. Pigmented lesions that have been described in the literature as agminated include blue nevi [1], Spitz nevi [2], congenital melanocytic nevi [3], common acquired melanocytic nevi, multiple lentigines [3], and lesions within nevi spili [5]. In most cases, agminated nevi develop in puberty.

Each pigmented lesion within the cluster has to be examined individually. They are usually symmetrical and uniformly pigmented. If the pigment is in the upper dermis, they may have a blue-gray color.

III.3.4 Relevant Clinical Differential Diagnoses A possible differential diagnosis is nevus spilus lacking clinically visible background pigmentation. It commonly appears during late infancy or early childhood. A tan lentiginous background patch on which more darkly pigmented macules and papules are distributed characterizes the lesion. Woodâ&#x20AC;&#x2122;s light examination or UV photography may be helpful to detect the background pigmentation.

III.3.5 Histopathology Dependent on the underlying type of nevus, regularly shaped pigmented or non-pigmented nevus cell nests can be seen at the dermo-epidermal junction or in the dermis.

III.3.6 Management Usually no therapy is needed. If a given lesion appears dermatoscopically irregular, excision is recommended.


U. Weigert, W. Stolz


Core Messages ■ An agminated nevus is an infrequent lesion. ■ It consists of multiple lesions of the same kind, e.g., blue nevi, Spitz nevi, congenital melanocytic nevi, or common acquired melanocytic nevi, occurring in a cluster. ■ Nevus spilus represents a relevant differential diagnosis. ■ If the lesions appear clinically and dermatoscopically regular, no therapy is needed.


Case study 1: Age: 54 years Sex: male Location: upper leg Skin phototype: II Size of lesion (mm): 3¥5 mm

Patient comment: Patient was sent by his wife because a lesion on the upper leg became darker. Questions asked by the physician: How long does the lesion exist? Did you notice any change in shape? Legend: homogenous network of the individual lesions Differential diagnoses: congenital melanocytic nevus, dysplastic melanocytic nevus Diagnosis: agminated melanocytic nevus Management: clinical observation Case study 2: Age: 33 years Sex: female Location: abdomen Skin phototype: III Size of lesion (mm): 10¥14 mm Patient comment: Funny looking newly developed lesion; family doctor sends her to rule out malignancy.

Questions asked by the physician: Did you notice any change in shape? Family history of skin cancer? Number of sunburns? Legend: homogenous pigmentation

Agminated Nevus

Differential diagnoses: dysplastic melanocytic nevus Diagnosis: agminated melanocytic nevus Management: clinical observation

References 1. Velez A, del-Rio E, Martin-de-Hijas C, Furio V, Sanchez Yus E. Agminated blue nevi: case report and review of the literature. Dermatology 1993; 186:144– 148

Chapter III.3 2. Lancer HA, Muhlbauer JE, Sober AJ. Multiple agminated spindle cell nevi: unique clinical presentation and review. J Am Acad Dermatol 1983; 8 3. Brunner M, Vardarman E, Megahed M, Ruzicka T. Congenital agminated segmental naevi. Br J Dermatol 1995; 133:315–316 4. Micali G, Nasca MR, Innucenzi D, Lembo D. Agminated lentiginosis: case report and review of the literature. Pediatr Dermatol 1994; 11:241–245 5. Betti R, Inselvini E, Palvarini M, Crosti C. Agminated intradermal Spitz nevi arising on an unusual speckled lentiginous nevus with localized lentiginosis: a continuum? Am J Dermatopathol 1997; 19:524– 527


Chapter III.4

Blue Nevus Gerardo Ferrara and Giuseppe Argenziano

Contents III.4.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 III.4.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . 80 III.4.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . . 80 III.4.4 Relevant Clinical Differential Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 III.4.5 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . . 82 III.4.5 Management. . . . . . . . . . . . . . . . . . . . . . . . . . . 84 III.4.5 Case Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84


References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

III.4.1 Definition According to the original description by Tieche [33], to which little can be added, blue nevus is a dermal-based, benign melanocytic lesion histopathologically made up by variable proportions of oval/spindle and bipolar, usually heavily pigmented dendritic cells (G. Ferrara et al., submitted) [37, 40]. The aggregation of oval/spindle melanocytes with pale cytoplasm into discrete expansile nodules features a “cellular” blue nevus [23, 37]. The definitional color of this lesion is probably due to the Tyndall effect, which involves selective absorption of long-wavelength light by deep dermal melanin and reflection of the shortwavelength blue light from the skin surface. The cell components of blue nevus consist of arrested embryonal melanocytes migrating from the neural crest into the epidermis during embryonic development [40]. Immunohistochemically, they usually express melanoma-associated antigen HMB45, together with S100 protein and Melan A/Mart-1. These cells are the


sole or the main components of several other melanocytic lesions named “dermal dendritic melanocytic proliferations” [40]. Three categories of dermal dendritic melanocytic proliferations have been identified in the classical dermatopathology literature: (a) hamartomatous dermal melanocytoses (Mongolian spot, nevus of Ota, and is nevus of Ito); (b) classic and cellular blue nevus; and (c) malignant blue nevus [40]. In addition, “combined” lesions made up of dermal dendritic melanocytic proliferations admixed with any other benign melanocytic proliferation (congenital non-blue, common acquired, dysplastic/Clark, and Spitz nevi) were considered as well (see also Chap. III.6) [1, 4, 11, 12, 23, 24, 29, 37]. In recent years, a number of additional histopathological variants of dermal dendritic me­ lanocytic proliferations have been described [1, 6, 8–11, 13, 14, 16, 17, 18, 21, 23, 27–30, 35, 38–40]. A comprehensive histopathological classification of these entities is given in Table III.4.1, which groups together several dermal dendritic melanocytic proliferations into a group of non-hamartomatous benign mela­ nocytic lesions which we also refer to as “the blue nevus family.” Such a taxonomic approach implies that each entity merges within another along a spectrum of morphological changes, as suggested by the well-documented occurrence of “mixed” types of nevi, e.g., common and cellular [23], sclerotic and mucinous [28], and sclerotic and hypo-amelanotic (G. Ferrara et al., submitted). Within the benign lesions of the blue nevus family we can also include “atypical” variants [3, 5, 34, 40]. These are defined as blue nevi, most often of the cellular type, in which histopathology shows one or several atypical features,

Blue Nevus

Chapter III.4


Table III.4.1.  A classification of dermal dendritic melanocytic proliferations




Large infiltrative cellular blue nevus

Melanoma arising in blue nevus

  Mongolian spot   Common blue nevus

  Of the scalp

Blue nevus-like (dendritic cell) primary melanoma

  Nevus of Ota

  Cellular blue nevus

  At other sites

Blue nevus-like metastatic melanoma

  Nevus of Ito


Cutaneous neurocristic hamartoma⁄malignant neurocristic tumor


Pigmented epithelioid melanocytomab


Non-hamartomatous (“blue nevus family”)

 With schwannian differentiation (Masson neuronevus)   With prominent vascular network (paraganglioma-like dermal melanocytic tumor)  “Hypochromic” (white) blue nevus/ cellular blue nevus    Myxoid (cystic)    Desmoplastic/sclerotic    Hypomelanotic    Amelanotic   Deep penetrating (polychromous) nevus   Compound (black) blue (Kamino) is nevus   Combined (brown) blue nevus   Atypical blue nevus/ cellular blue nevusa a 

If strict morphological criteria are used, atypical blue nevus and atypical cellular blue nevus have a completely favorable clinical outcome b  Cases of epithelioid blue nevus in Carney complex did not metastasize to date; however, they cannot be morphologically distinguished from cases of metastasizing epithelioid blue nevus and from animal-type melanoma, thereby justifying their inclusion into a unique rubric designated “pigmented epithelioid melanocytoma”

including mitoses (not atypical and up to 3–4/ mm2), ulceration, large size/deep extension, nuclear pleomorphism, focal necrosis. This concept has been criticized in the name of a “dual” (benign vs malignant) concept of nosology [25]. Indeed, if defined according to strict morphological criteria, atypical blue nevi have a completely benign biological behavior [40].

The clinicopathological spectrum of dermal dendritic melanocytic proliferations also encompasses some entities whose nosology and prognosis still remain controversial (large infiltrative cellular blue nevus, cutaneous neurocristic hamartoma, pigmented epithelioid mela­ nocytoma) [9, 17, 22, 23, 27, 38, 40]. The clinicopathological features of such exceptional


G. Ferrara, G. Argenziano

neoplasms have been recently revisited [40]: their illustration is beyond the scope of this book. Finally, some dermal dendritic melanocytic proliferations are overtly malignant [3, 7, 37], but the term “malignant” or “metastasizing” blue nevus is an oxymoron and should be therefore avoided. Melanoma can seldom arise in the context of a cellular blue nevus: preliminary molecular data suggest that it has a different pathway to tumorigenesis than that of conventional melanoma [3].

III.4.2 Clinical Features


Common or classic blue nevus is a small (<1 cm), gray-blue or blue-black macule, papule, or plaque usually located on the head, neck, presacral region, or distal extremities [2, 14, 32, 37, 40]. Exceptional extracutaneous locations have also been described [15, 20, 26]. It is almost invariably acquired during the second decade of life; most patients belong to phototypes III–IV [37]. The cellular variant is a much larger blueblack nodular lesion whose typical location is the gluteal region [23, 37]. The scalp and the extremities are less commonly affected. Unusual clinical features of blue nevi include congenital, familial, eruptive, plaque-like, targetoid, and linear forms [4, 22, 24, 36, 37, 40]. The term “agminated blue nevus” has been used for multiple blue nevi sometimes arising within a Mongolian spot (see also Chap. III.3) [36, 37, 40]. Most lesions belonging to the blue nevus family show demographic and clinical features which are similar to those of common and cellular blue nevi. In particular, “hypochromic” variants of blue nevi (see Table III.4.1) do not seem to be “ancient” blue nevi because of the young age of most of the patients (G. Ferrara et al., submitted) [6, 10, 40]. Remarkably, these variants of blue nevus are rarely recognized as such on clinical grounds: in fact, the paucity of melanin often imparts a grayish or even a grayish-brown color [6, 10, 16, 40]. Epithelioid blue nevus also resembles blue nevus from a clinical point of view, but is histopathologically distinctive [9, 17]. The majority of epithelioid blue nevi are detected as multiple elements associated with other cutaneous le-

sions (lentigines and myxoid neurofibromas) in the clinical context of a Carney (myxoma) syndrome [9]. This is an autosomal-dominant disorder typified by the triad: cutaneous lesions; cardiac myxomas; and hormonal hyperfunction (adrenal hyperplasia, pituitary adenomas, testicular tumors). These alterations are summarized into the acronyms LAMB (Lentigines, Atrial myxomas, Mucocutaneous myxomas, Blue nevi) and NAME (Nevi, Atrial myxomas, Myxoid neurofibromas, Ephelides).

III.4.3 Dermoscopic Criteria The dermoscopic features of common blue nevi are considered to be peculiar enough as to help their clinical recognition [2, 31]. In fact, they are described as showing a homogeneous pattern with a characteristic steel-blue pigmentation – either in a diffuse “structureless” or, less commonly, in a “dotted-globular” pattern [31]. When pressing with the lens plate, a skin folding above the peripheral area of the lesion often appears as a circular whitish line (Fig. III.4.1). Both arborizing vessels and peripheral streaklike extensions are sometimes discernible as typically out-of-focus structures. Indeed, the “blue nevus family” is composed by lesions which are not always “blue” on dermoscopy. Large, often ovoid areas of discoloration due to loss of melanin and/or to stromal response are definitional for “white” blue nevi. These lesions represented 46.8% of all excised blue nevi in a recent series (G. Ferrara et al., submitted) . Much less commonly, a black lamella  –  namely, a homogeneous, black, disc-like area which can be removed by tape stripping – covers most of the surface of blue nevi, thus featuring “black” blue nevi (G. Ferrara et al., submitted) [14]. Finally, a minority of these nevi are either tan (“brown” blue nevi) or variegated (“polychromous” blue nevi) in their dermoscopic color (G. Ferrara et al., submitted) [12]. Interestingly, deep penetrating nevus, an unusual melanocytic neoplasm belonging to the blue nevus family, has been recently described as a polychromous lesion which can undergo rapid dermoscopic changes (G. Ferrara et al., submitted) [18].

Blue Nevus

Fig. III.4.1.  a A nodular lesion located on the dorsum of the foot of a 34-year-old woman. b In dermoscopy only homogeneous bluish pigmentation is visible. Note the network-like structures corresponding to unusual skin markings on the lesion surface. c A V-shaped, dermalbased pigmented lesion. d The superficial portion of the lesion, made by sparse dendritic melanocytes within a

Chapter III.4

dense sclerotic collagen. e The deep portion of the lesion, made by densely packed melanocytes with heavily pigmented dendritic processes. f At a higher magnification, there is intimate relationship among the dendritic melanocytes and the sclerotic collagen of the dermis, which features the classical “dendritic–sclerotic” histotype of blue nevus



G. Ferrara, G. Argenziano

III.4.4 Relevant Clinical Differential Diagnosis


The clinical recognition of a blue nevus is commonly not problematic. A dermoscopic diagnosis of nodular pigmented basal cell carcinoma can be sometimes evoked because of the presence of arborizing vessels. In blue nevus, however, these vessels are typically out of focus. Some adnexal neoplasms (e.g., trichoblastoma, pigmented intradermal poroma) are characterized by a diffuse bluish pigmentation. As a rule, patients report the onset of these lesions as more recent than that expected for a blue nevus. Apocrine hydrocystoma is an adnexal lesion which is typically located in the periocular area. Its consistency is floating or elastic; not uncommonly, patients report its sudden onset. “Hypochromic” variants of blue nevi can be clinically hard to differentiate from dermal nevi or dermatofibromas [6, 10]. Dermoscopy can help their recognition by showing foci of steelblue pigmentation which could not be discerned by the naked eye (G. Ferrara et al., submitted) [16]. Pigmented Spitz/Reed nevus must be differentiated from deep penetrating nevus clinically [11, 30] and from common blue nevus dermoscopically [2, 31]; however, when present, peripheral extensions of blue nevus are different from true radial streaks/pseudopods of pigmented Spitz/Reed nevus because they are typically grayish-blue in color and out of focus. The most important differential diagnosis must be made between blue nevus and melanoma. Dermoscopy can aid the recognition of nodular melanoma by showing subtle differentiating features (vascular pattern, remnants of pigment network, blue-whitish veil) [2]. Exceptional cases of metastatic melanoma can strictly mimic the clinical and dermoscopic features of blue nevus. Anamnestic data are relevant, but not always clear-cut. A peripheral halo of erythema in metastatic melanoma is quite characteristic but inconstant [2, 31]. In these cases, the “golden rule” is to not schedule any follow-up for a nodular lesion and to excise it.

III.4.5 Histopathology The histopathological pattern of common blue nevus is defined as dendritic–sclerotic [19]: this is typified by the presence of elongated, finely branched, heavily pigmented dendritic melanocytes interspersed with some melanophages among thickened bundles of collagen in the mid and the upper dermis. A thick grenz zone usually separates the lesion from the unaffected epidermis (Fig. III.4.2). Not uncommonly, some areas of otherwise typical blue nevi are composed of oval, often plump, melanocytes almost devoid of any pigment. When the pigment loss is sizable, but involves less that 95% of the lesion, the term “hypomelanotic” blue nevus seems to be appropriate (G. Ferrara et al., submitted). Cases in which pigment loss involves at least 95% of the lesion can be labeled as “amelanotic” [6]. A minority of blue nevi show a marked degree of fibrosis (sclerosing blue nevi; G. Ferrara et al., submitted) [16, 40] and/or myxoid changes of the stroma (G. Ferrara et al., submitted) [28, 40]. We have noticed that transition types between hypoamelanotic and sclerosing blue nevi also exist (G. Ferrara et al., submitted) These lesions can therefore be grouped together into “hypochromic” blue nevi. On dermoscopy most “hypochromic” lesions appear as “white” blue nevi (G. Ferrara et al., submitted) [16]. In rare instances, blue nevus is located superficially and some dendritic melanocytes are arranged in single units within the epidermis: these cases have been labeled as “compound blue nevi” [21] or “blue nevi, superficial type, with prominent intraepidermal dendritic melanocytes” [1] or, simply, “Kamino nevi” [14]. On dermoscopy, these lesions often appear as “black” blue nevi (G. Ferrara et al., submitted) [14]. A nevus of another kind is occasionally associated with a blue nevus: such a lesion is termed “combined blue nevus” (G. Ferrara et al., submitted) [1, 2, 11, 12 31, 37]. The present authors and others [12] have noticed that combined blue nevi are often “brown” blue nevi on dermoscopy. The histological pattern of “cellular” blue nevus is defined as spindle/fascicular [19]. It is composed by dendritic melanocytes together

Blue Nevus

Chapter III.4

Fig. III.4.2.â&#x20AC;&#x201A; a A bluish papule located on the arm of a 54-year-old woman. b Dermoscopically the lesion is typified by homogeneous pattern made of bluish to whiteblue structureless pigmentation. c A papular lesion with a slight epidermal hyperplasia and little pigment deposition within the dermis. d A dermal proliferation of

cells embedded within a sclerotic and somewhat myxoid stroma. e Oval to spindle melanocytes within a sclerotic stroma. A few melanocytes with pigmented dendritic processes are still evident. f Same features as described in a at a higher magnification

with islands of epithelioid and plump spindle cells with abundant pale cytoplasm and usually little pigment. Melanophages are found between the cellular islands. The tumor often bulges into the subcutaneous fat as a nodular downgrowth

with a typical clapper-like silhouette [23, 37, 40]. Stromal desmoplasia and balloon-cell changes are rare occurrences [23, 40]. A peculiar lesion which places somewhat in between combined cellular blue and Spitz (Blitz)



G. Ferrara, G. Argenziano

nevus [17, 37] and epithelioid blue nevus [9, 17, 37] is deep penetrating nevus [11, 30, 37]. It is a dermal V-shaped lesion that bulges into the subcutis; typically dendritic and spindle melanocytes are its main components, with some interspersed epithelioid (spitzoid) cells whose morphological hallmark is a finely vacuolated (sebocyte-like) cytoplasm. The dermoscopic appearance of this lesion is often “polychromous” (G. Ferrara et al., submitted).

III.4.5 Management Neither surgical procedures nor further clinical controls are needed for most cases of blue nevi, because their clinical recognition is obvious. In the presence of atypical features (e.g., recent onset and/or recent changes, peripheral halo of inflammation, unusual dermoscopic features) surgical excision is mandatory.

Case Study III.4.1. 

III.4.5 Case Study


A 59-year-old man with a previous history of melanoma of the dorsum (Breslow’s thickness: 1.30 mm) came to our outpatient service because of a 4-mm nodular lesion of the left arm. According to the patient’s report, the lesion had slightly enlarged during the last few months. Dermoscopic examination disclosed a structureless pattern with a homogeneous steelblue pigmentation consistent with blue nevus (Case Study III.4.1); however, in consideration of both the history of melanoma and the recent enlargement of the lesion a surgical excision was performed. Histological examination disclosed an overall architecture of a blue nevus with heavily pigmented dendritic and spindle dermal melanocytes (Case Study III.4.2). Spindle melanocytes, however, showed slightly pleomorphic and enlarged nuclei with a dispersed chromatin pattern and small but evident nucleoli (Case Study III.4.3). A few mitotic figures (up to 2/mm2) were also detected (Case Study III.4.4). Necrosis, ulceration, and lymphocyte infiltration were not present. A diagnosis of atypical blue nevus was thus rendered.

Case Study III.4.2. 

Case Study III.4.3. 

Blue Nevus

Chapter III.4


Case Study III.4.4. 

This case is an example of a nodular lesion promptly excised (and not scheduled for followup protocols) because of its recent enlargement in the presence of a positive anamnesis for melanoma. A histopathological diagnosis of atypical blue nevus was made because of a mild cytological atypia and some mitotic figures within the dermal spindle melanocytes. The histopathological features of atypia shown in this case cannot be detected by means of dermoscopy. In current practice, however, this is not a problem because strictly defined atypical blue nevi behave in a completely benign fashion [4].


Core Messages ■ The clinical recognition of blue nevi is simple in the majority of cases. ■ Dermoscopy can aid their clinical evaluation, inasmuch as it allows the identification of “blue” (common) blue nevi, “white” (hypochromic) blue nevi, “black” (compound) blue nevi, “brown” (combined) blue nevi, and “polychromous” (deep penetrating) blue nevi (G. Ferrara et al., submitted). ■ As with any other nodular lesion, the presence of atypical clinical and/or dermoscopic features must prompt an immediate surgical excision with no follow-up scheduling.

  1. Ackerman AB, Cerroni L, Kerl K. Pifalls in the diagnosis of malignant melanoma. Philadelphia: Lea and Febiger, 1994   2. Argenziano G, Soyer HP, Giorgi V de, et al. Interactive atlas of dermoscopy (Book and CD-ROM). Milan: Edra Medical Publishing and New Media, 2000   3. Ariyanayagam-Baksh SM, Baksh FK, Finkelstein SD, Swalsky PA, Abernethy J, Barnes EL. Malignant blue nevus: a case report and molecular analysis. Am J Dermatopathol 2003;25:21–27   4. Aroni K, Georgala S, Papachatzaki E. Coexistence of plaque-type blue nevus and congenital melanocytic nevi. J Dermatol 1996;23:325–328   5. Avidor I, Kessler E. “Atypical” blue nevus: a benign variant of cellular blue nevus. Presentation of three cases. Dermatologica 1977;154:39–44   6. Bhawan J, Cao S-L. Amelanotic blue nevus: a variant of blue nevus. Am J Dermatopathol 1999;21:225– 228   7. Busam KJ. Metastatic melanoma to the skin simulating blue nevus. Am J Surg Pathol 1999;23:276– 282   8. Busam K, Woodruff JM, Erlandson PRA. Large plaque-type blue nevus with subcutaneous cellular nodules. Am J Surg Pathol 2000;20:527–530   9. Carney JA, Ferreiro JA. The epithelioid blue nevus. A multicentric familial tumor with important associations, including cardiac myxoma and psammomatous melanotic schwannoma. Am J Surg Pathol 1996;20:259–272 10. Carr S, See J, Wilkinson B, Kossard S. Hypopigmented common blue nevus. J Cutan Pathol 1997; 24:494–498 11. Cooper PH. Deep penetrating (plexiform spindle cell) nevus. A frequent participant in combined nevus. J Cutan Pathol 1992;19:172–180 12. Giorgi V de, Massi D, Salvini C, Trez E, Mannone F, Carli P. Dermoscopic features of combined melanocytic nevi. J Cutan Pathol 2004;31:600–604 13. Deyrup AT, Althof P, Zhou M, Morgan M, Solomon AR, Bridge JA, Weiss SW. Paraganglioma-like dermal melanocytic tumor: a unique entity distict from cellular blue nevus, clear cell sarcoma, and cutaneous melanoma. Am J Surg Pathol 2004;28:1579– 1586 14. Ferrara G, Argenziano G, Zgavec B, Bartenjev I, Staibano S, Rosa G de, Soyer HP. “Compound blue nevus”: a reappraisal of “superficial blue nevus with prominent intraepidermal dendritic melanocytes” with emphasis on dermoscopic and histopathologic features. J Am Acad Dermatol 2002;46:85–89




G. Ferrara, G. Argenziano 15. Ferrara G, Boscaino A, Rosa G de. Bronchial blue nevus: a previously unreported entity. Histopathology 1995;26:581–583 16. Gricknik JM. Dermoscopy of melanocytic neoplasms. Sclerotic blue nevi. Arch Dermatol 2003;139: 1522 17. Groben PA, Harvell JD, White WL. Epithelioid blue nevus. Neoplasm sui generis or variation on a theme? Am J Dermatopathol 2000;22:473–488 18. Guadagni M, Nazzari G. Clinical and dermoscopic features of an evolving deep-penetrating nevus. Arch Dermatol 2005;141:1490 19. Harvell JD, White WL. Persistent and recurrent blue nevi. Am J Dermatopathol 1999;21:506–517 20. Jiji V. Blue nevus of the endocervix. Review of the literature. Arch Pathol Lab Med 1971;92:203–205 21. Kamino H, Tam ST. Compound blue nevus: a variant of blue nevus with an additional junctional dendritic component. A clinical, histopathologic, and immunohistochemical study of six cases. Arch Dermatol 1990;126:1330–1333 22. Marano SR, Brooks RA, Spetzler RF, Rekate HL. Giant congenital cellular blue of the scalp of a newborn with an underlying skull defect and invasion of the dura mater. Neurosurgery 1986;18:85–89 23. Massi G, LeBoit PE. “Cellular” blue nevus. In: Massi G, LeBoit PE (eds). Histological diagnosis of nevi and melanoma. Steinkopf Verlag Darmstadt: Berlin, 2004:151–168 24. Misago N, Narisawa Y, Kohda H. A combination of speckled lentiginous nevus with patch-type blue nevus. J Dermatol 1993;20:643–647 25. 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;26:407– 430 26. Papanicolaou SJ, Pierrakou ED, Patsakas AJ. Intraoral blue nevus. Review of the literature and a case report. J Oral Med 1985:40:32–35 27. Pearson JP, Weiss SW, Headington JT. Cutaneous malignant melanotic neurocristic tumors arising in neurocristic hamartomas. A melanocytic tumor morphologically and biologically distinct from common melanoma. Am J Surg Pathol 1996;20:665– 677

28. Rongioletti F, Innocenzi D. Sclerosing “mucinous” blue naevus. Br J Dermatol 2003;148:1250–1252 29. Scolyer RA, Zhuang L, Palmer AA, Thompson JF, McCarthy SW. Combined naevus: a benign lesion frequently misdiagnosed both clinically and pathologically as melanoma. Pathology 2004;36:419–427 30. Seab JA Jr, Graham JH, Helwig EB. Deep penetrating nevus. Am J Surg Pathol 13:39–44 31. Stolz W, Braun-Falco O, Bilek P, Landthaler M,Cog­ netta AB.Color atlas of dermatoscopy. Oxford: Black­well; 1994, p. 75 32. Tannenbaum M. Differential diagnosis in uropathology. III. Melanotic lesions of the prostate: blue nevus and prostatic epithelial melanosis. Urology 1974;4:617–621 33. Tieche M. Uber benigne Melanome (Chromatophorome) der Haut: blaue Naevi. Virchow Arch Patol Anat 1906:186:212–229 34. Tran TA, Carlson JA, Basaca PC, Mihm MC. Cellular blue nevus with atypia (atypical cellular blue nevus): a clinicopathologic study of nine cases. J Cutan Pathol 1998;25:252–258 35. Urso C, Tinacci G. Angiomatoid cellular blue nevus: a variant of blue nevus with an angioma-like appearance. J Cutan Pathol 2005;32:385–387 36. Veles A, Del Rio E, Martin-de-Hijas C, Furiò V, Sanchez Yus E. Agminated blue nevi: case report and review of the literature. Dermatology 1993;186:144– 148 37. Weedon D. Lentigines, nevi and melanoma. In: Weedon D (ed). Skin pathology, 2nd edn. Edinburg: Churchill Livingstone; 2002, pp. 803–858 38. Zembowicz A, Carney JA, Mihm CMJ. Pigmented epithelioid melanocytoma, a low grade melanoma indistinguishable from animal type melanoma and epithelioid blue nevus. Am J Surg Pathol 2004;28:31–40 39. Zembowicz A, Granter SR, McKee PH, Mihm MC. Amelanotic cellular blue nevus: a hypopigmented variant of cellular blue nevus: clinicopathologic analysis of 20 cases. Am J Surg Pathol 2002;26:1493– 1500 40. Zembowicz A, Mihm MC. Dermal dendritic melanocytic proliferation: an update. Histopathology 2004;45:433–451

Chapter III.5

Atypical (Dysplastic) Nevus Rainer Hofmann-Wellenhof and H. Peter Soyer

Contents III.5.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 III.5.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . 88 III.5.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . . 88 III.5.4 Relevant Clinical Differential Diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 III.5.6 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . . 91 III.5.7 Management. . . . . . . . . . . . . . . . . . . . . . . . . . . 92 III.5.8 Case Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 III.5.8.1 Case 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 III.5.8.2 Case 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

III.5.1 Definition Atypical or dysplastic nevus is our preferred term for a group of melanocytic skin tumors which cause endless debate and controversy. Synonyms include atypical mole, BK mole, Clark nevus, and nevus with architectural disorder. In 1978 Wallace H. Clark, Jr. first drew attention to this particular type of nevus by studying numerous melanocytic nevi in patients with concomitant melanomas. In most common definitions of an atypical nevus this nevus type is characterized by a diameter larger than 6 mm, color variegations, and irregularity of the border. As a rule, clinical features of a congenital nevus are not present. The estimated prevalence of clinically atypical nevi ranges from 7 to 18% in populationbased samples. Atypical nevi represent an im-


portant marker for an increased risk of melanoma. The maximum reported increased relative risk of sporadic melanoma varies from 2.4 for one or more atypical nevus to 32.0 for 10 or more atypical nevi. Clinical and dermoscopic follow-up documentations and the histopathological recognition of dysplastic nevi in contiguity with a melanoma prove the role of atypical nevi as a possible precursor of melanoma. The importance of atypical nevi as precursor lesions is tempered by the fact that only a small percentage of melanomas develop in association with a nevus and estimates imply that only 1 in 10,000 atypical nevi per year will progress to melanoma. Multiple molecular biological studies have tried to differentiate atypical nevi from common nevi and melanoma on genetic grounds, but their results are conflicting. The germ-line p16-gene, INK4a (CDKN2A) mutations on chromosome 9p21, which are frequently present in familiar melanoma, have been found more frequently in individuals with a high number of nevi, but there has been no significant correlation with the number of atypical nevi. Investigations of the development of atypical nevi and the expression of 1p36 region with the PITSLRE gene coding for a p58 protein kinase have revealed controversial results. Telomerase activity, another possible genetic marker, was only increased in atypical nevi when tissue sections were histopathologically selected. No differences were found between common nevi and atypical nevi when clinical criteria were used. Taken together, the molecular studies demonstrate that some lesions among the atypical nevi seem to be transitional between common nevi and melanoma, but the majority are not.


R. Hofmann-Wellenhof, H.P. Soyer

III.5.2 Clinical Features


Atypical nevi are flat to elevated or even slightly papillomatous pigmented lesions characterized by various shades of brown coloration. They are commonly situated on the trunk and extremities. Although atypical nevi are found mostly in skin that has been exposed to sunlight, they also may be seen on the buttocks, the volar surfaces, and other covered parts such as genitalia and soles. Their number varies from one or two to several hundred. Multiple atypical nevi in an individual most often display a similar clinical subtype. The most common clinical types are: (a) the “lentiginous type” with a flat surface and homogenous dark brown or brown-black color; (b) the “fried-egg” type with a raised central portion and a flat peripheral annulus; (c) the “targeted” type with concentric annular zones that vary in degree of pigmentation; (d) the “seborrheic keratosis-like” type with a verrucous surface and usually dark-brown color; and (e) the “erythematous” type with a pink color and only remnants of pigmentation. Atypical nevi are larger than 6 mm and often have a papule in the center surrounded by a macula. Different shades of brown are common, but shades of pink, red, and blue-gray may be present as well (Fig. III.5.1). Following the ABCD rule for detection of suspicious melanocytic lesions, atypical nevi often display all criteria of melanoma: asymmetry; irregular borders; multicolor pigmentation; and diameter larger than 6 mm. Many different terms are used for individuals with numerous atypical nevi: dysplastic nevus syndrome; atypical mole syndrome; familial atypical multiple mole melanoma syndrome (FAMMM); and BK mole syndrome. The definition for this syndrome is equally controversial. The common diagnostic criteria for this syndrome are: an individual with more than 100 melanocytic nevi with some nevi being larger than 8 mm and also some atypical nevi. The dysplastic nevus syndrome can be familiar or sporadic. According to Kopf et al. five different types of the dysplastic nevi syndrome can be distinguished: (a) type A, sporadic dysplastic nevi without melanoma; type B, familial dys-

Fig. III.5.1a.  Numerous atypical nevi on the back of a 32-year-old man. The nevi vary in diameter from a few millimeters to 1 cm and differ in shape and color

plastic nevi without melanoma; type C, sporadic dysplastic nevi with melanoma; type D-1, familial dysplastic nevi with one person with melanoma in the family; and type D-2, familial dysplastic nevi with two or more family members with melanoma. The relative risk of developing a melanoma rises in the latter type up 500–1000 times.

III.5.3 Dermoscopic Criteria In our estimation, the real challenge is to recognize, within the many variations of atypical nevi, those that are actually melanomas in situ or early invasive melanomas. Dermoscopy is essential to achieve this distinction. Based on a morphological study of about 800 atypical nevi in 23 patients, we classified atypi-

Atypical (Dysplastic) Nevus

Chapter III.5

Fig. III.5.2.  Different dermoscopic patterns of atypical nevi according to the main structural types. a Reticular; b globular; c homogeneous; d reticular–globular; e reticular–homogeneous; f globular–homogeneous

cal nevi, according to the global dermoscopic patterns, into three types, namely, reticular, globular, and homogeneous. Frequently, combinations of these types are found, the combination of reticular and globular types being most common (Fig. III.5.2).

The most common reticular type is characterized by a more or less prominent pigment network with thin lines and regular meshes. The pigment network is usually evenly distributed throughout the lesion and fades out at the periphery.




R. Hofmann-Wellenhof, H.P. Soyer

Fig. III.5.3.  Different dermoscopic patterns of atypical nevi according to the variation of pigmentation. a Hyper/ hypopigmented; b central hypopigmented; c central hyperpigmented; d eccentric hyperpigmented

The globular type is characterized by a dotted and/or globular pattern composed of numerous dots/globules of variable size and shape (oval, round, or rectangular) more or less evenly distributed throughout the lesion. A combination of the globular and reticular type is common. An interesting morphological presentation of this combined pattern is an annular arrangement of dots/globules at the periphery of an otherwise typical reticulated atypical nevus indicating ongoing growth of the lesion. The least frequent of the three major patterns of atypical nevi is the homogeneous pattern, characterized by a diffuse pigmentation of various shades of brown coloration with only isolated reticular and/or globular areas. An atypical nevus with all three patterns (reticular, globular, homogeneous) requires special atten-

tion because this multicomponent pattern is frequently found in early melanomas. Besides the three structural dermoscopic archetypes of atypical nevi, a number of characteristic dermoscopic variants are caused by variations in pigmentation (Fig. III.5.3). In this context four very distinctive subtypes have been described: 1. Atypical nevus with central hypopigmentation. This is usually a variant of the reticular–homogeneous type with a central hypopigmented area almost devoid of other dermoscopic features accompanied by an annular reticulated periphery. Frequently, the less-pigmented center corresponds to a clinical papule (“fried-egg” type of atypical nevus).

Atypical (Dysplastic) Nevus

2. Atypical nevus with central hyperpigmentation. This type, also called hypermelanotic nevus or black nevus, represents a distinctive variant composed of a broad rim of prominent pigment network lines at the periphery and a central, diffuse, irregularly outlined black hyperpigmentation, also called black lamella. 3. Atypical nevus with multifocal hypo/ hyperpigmentation. This type is characterized by a multifocal hypo/hyperpigmentation leading to patchy appearance of the entire lesion. 4. Atypical nevus with eccentric hyperpigmentation. This type of atypical nevus is of the utmost significance, because its differential diagnosis includes melanoma in situ or even early invasive melanoma. This type displays a hyperpigmented eccentric area that reaches the border of the lesion. Sometimes this area is a blotch, whereas in other instances the reticular pattern is more pigmented. Most of the patients with multiple atypical nevi show one or two prominent dermoscopic types. Nevi belonging not to the predominant types in an individual should be investigated with additional alertness because they may be – similar to the clinical “ugly duckling” sign – a melanoma. Besides the three major patterns and the above-mentioned distinctive subtypes based on the distribution of hypopigmented and hyperpigmented areas, additional dermoscopic criteria may be occasionally found in atypical nevi, such as streaks and blue-white structures. Very rarely milia-like cysts and comedo-like openings are observed in the compound and dermal types of atypical nevi. A delicate vascular pattern characterized by the presence of “commalike” and dotted vessels is a common finding in atypical nevi.

Chapter III.5

III.5.4 Relevant Clinical Differential Diagnoses Superficial spreading melanoma is the main differential diagnosis. In most cases the atypical features of the ABCD rule are more prominent in melanomas with prominent color variegation and striking asymmetry. Dermoscopy is helpful for the differential diagnosis as the melanomaspecific dermoscopic criteria are much more frequent in melanomas than in atypical nevi. Small congenital nevi are another important differential diagnosis. Congenital nevi tend to have a larger diameter than atypical nevi and frequently show prominent hairs. Seborrheic keratosis may cause in special cases some difficulties in the differential diagnosis, but the dull surface and the hyperkeratosis leads to the correct diagnosis.

III.5.6 Histopathology Architecturally dysplastic nevi are larger than common nevi and contain, by definition, a junctional component, which is commonly present as “shoulder,” adjacent on both sites to a central compound part. Some lesions are entirely junctional. Nested melanocytes arranged predominantly at the tips and the sides of uniformly elongated rete ridges form frequently a symmetric silhouette (Fig. III.5.4). Sometimes the nests show a bridging between adjacent rete ridges. Concentric eosinophilic fibroplasia around the rete ridges or lamellar fibroplasia is typically found in the papillary dermis immediately beneath the dermo-epidermal junction. A patchy perivascular lymphocytic infiltrate is common. Cytomorphologically, some of the melanocytes in dysplastic nevi show “random” cytological atypia, which presents as nuclear enlargement, slight irregularity, and hyper­ chromasia with clumping of the chromatin and occasionally prominent nucleoli. The great dilemma of the histopathological diagnosis that has been discussed controversially for decades is the lack of clear morphological parameters to discriminate dysplastic nevi from melanoma, on the one hand, and from common nevi, on the other hand. In few cases a diagnosis



R. Hofmann-Wellenhof, H.P. Soyer Fig. III.5.4.  Histopathology of an atypical nevus. At scanning magnification, the lesion is confined to epidermis and papillary dermis with nests of melanocytes situated at the dermo-epidermal junction of elongated rete ridges. At closer magnification bridging of nests and few single cells in higher layers of the epidermis are visible.

cannot be made with certainty. For such lesions the terms SAMPUS (superficial atypical melanocytic proliferation of uncertain significance) and MELTUMP (melanocytic tumor of uncertain malignant potential) may be used.

III.5.7 Management


The management depends on the appearance of the atypical nevus and the overall number of atypical nevi in a given person. Atypical nevi clinically and dermoscopically simulating melanoma have to be excised. Also lesions with a history of change in size, shape, or color should be excised, or at least a short follow-up in 2 or 3 months, including clinical and dermoscopic documentation, is recommended. When a person presents with only one atypical nevus, excision is justified, even if this nevus lacks suspicious features; however, if an individual exhibits numerous atypical nevi, documentation and regular follow-up is recommended. The recommendation for follow-up periods varies from 3 months for individuals with familiar dysplastic nevus syndrome to once a year in persons with only a few atypical nevi. Individuals should also be instructed to do self-examination and subsequent sun protection.

III.5.8 Case Studies III.5.8.1 Case 1 Patient Comment A 44-year-old woman visited the office of a dermatologist for a routine check of her nevi. Her mother had died of melanoma 3 years previously.

Question Asked By the Physician Did you mention any change in one of your nevi or the development of new nevi?

Clinical Image Including Detailed Description Clinical examination revealed numerous melanocytic nevi on the whole body. The back had more than 60 nevi varying in diameter.

Dermoscopic Image Including Detailed Description Dermoscopy of one of the largest nevi on the back showed a central hyperpigmented reticu-

Atypical (Dysplastic) Nevus

Chapter III.5

Case Study 1

lar–homogeneous type. No melanoma-specific criteria were detectable. Almost all other nevi display variations of this dermoscopic type of atypical nevi.

Clinical Diagnosis Including Relevant Differential Diagnosis The familiar history of melanoma and the clinical presentation with approximately 100 melanocytic nevi, larger than 6 mm in diameter, led to the correct diagnosis of a familiar dysplastic nevus syndrome. The dermoscopic image confirmed this diagnosis.

Performed Management An exact clinical and dermoscopic examination was performed. Subsequently, the nevi were clinical and dermoscopically monitored, and no marked changes in comparison with the previous examination were noticed.

Most of the atypical nevi belonged to the reticular–homogeneous type with central hyperpigmentation. No dermoscopic criteria suspicious for melanoma were detectable in any nevus; thus, a follow-up in 3–6 months was recommended.

Comments Persons with numerous atypical nevi, especially in the case of familiar dysplastic nevus syndrome, bear a significantly higher melanoma risk. Prophylactic excision of these atypical nevi in such patients is not warranted, since the probability that a single lesion will develop into a melanoma is very low and the overall risk of melanoma cannot be reduced; therefore, regular skin examination with clinical and dermoscopic photography is required to excise an eventually developing melanoma at a curable stage. Affected individuals should be advised to perform self-examination and apply sun protection.




R. Hofmann-Wellenhof, H.P. Soyer

Case Study 2

III.5.8.2 Case 2 Patient Comment The wife of a 66-year-old man noticed a change of color in a nevus on the shoulder. The patient presented with eight atypical nevi on the trunk and some dermal nevi.

Questions Asked By the Physician Did you have a previous history of melanoma? Did one of your first-degree relatives suffer from melanoma?

Clinical Image Clinical examination revealed an asymmetric brown to black macule with a diameter of 6 mm and an irregular border. The other nevi were unsuspicious.

Dermoscopic Image The dermoscopic image shows a reticularâ&#x20AC;&#x201C;homogeneous pattern with eccentric hyperpigmentation. Atypical pigment network and irregular streaks were present in the upper and right part of the lesion.

Atypical (Dysplastic) Nevus

Clinical Diagnosis Including Relevant Differential Diagnosis

Chapter III.5


Core Messages

Differential diagnosis included atypical nevus and melanoma. Non-melanocytic lesions were ruled out because of the prominent reticular pattern clearly visible in dermoscopy. The history of change, the irregular streaks, and the atypical pigment network favored the diagnosis of a melanoma.

■ Atypical nevi are defined as acquired melanocytic nevi with a diameter larger than 6 mm, color variegations, and irregular border. ■ They simulate melanoma clinically, dermoscopically, and histopathologically. ■ Atypical nevi are important markers for melanoma, and to a lesser extent are also precursors of melanoma. ■ The dermoscopic classification according to the reticular, globular, homogeneous type and combination of types according to the distribution of pigmentation is useful. ■ Regular total-body examinations with clinical and dermoscopic documentation are recommended. ■ Suspicious and changing atypical nevi have to be excised.

Histopathological Images Scanning magnification revealed the morphological features of a melanoma in situ on the left side and of a predominantly dermal atypical compound nevus on the right side. Higher magnification exhibited numerous atypical melanocytes at all levels of the epidermis featuring melanoma in situ.

Performed Management  

Excision of the entire lesion in local anesthesia was performed. Histopathological examination revealed a melanoma in situ in association with a preexisting nevus.

Comments This rare example of a melanoma in situ in association with a preexisting nevus underscores the importance of reported changes in a given atypical nevus and the usefulness of dermoscopy in detecting suspicious lesions among the great variety of atypical nevi.

References   1. Elder DE. Precursors to melanoma and their mimics: nevi of special sites. Mod Pathol 2006;19 (Suppl 2):S4–S20   2. Roesch A, Burgdorf W, Stolz W, Landthaler M, Vogt T. Dermatoscopy of “dysplastic nevi”: a beacon in diagnostic darkness. Eur J Dermatol. 2006;16:479– 493   3. Hussein MR. Melanocytic dysplastic nevi occupy the middle ground between benign melanocytic naevi and cutaneous malignant melanomas: emerging clues. J Clin Pathol 2005;58:453–456   4. Gandini S, Sera F, Cattaruzza MS, Pasquini P, Abeni D, Boyle P, Melchi CF. Meta-analysis of risk factors for cutaneous melanoma: I. Common and atypical nevi. Eur J Cancer 2005;41:28–44   5. Celebi JT, Ward KM, Wanner M, Polsky D, Kopf AW. Evaluation of germline CDKN2A, ARF, CDK4, PTEN, and BRAF alterations in atypical mole syndrome. Clin Exp Dermatol 2005;30:68–70   6. Culpepper KS, Granter SR, McKee PH. My approach to atypical melanocytic lesions. J Clin Pathol 2004;57:1121–1131




R. Hofmann-Wellenhof, H.P. Soyer   7. Shapiro M, Chren MM, Levy RM, Elder DE, LeBoit PE, Mihm MC Jr, Margolis DJ, Gimotty PA, Ming ME. Variability in nomenclature used for nevi with architectural disorder and cytologic atypia (microscopically dysplastic nevi) by dermatologists and dermatopathologists. J Cutan Pathol 2004;31:523– 530   8. Wang SQ, Kopf AW, Koenig K, Polsky D, Nudel K, Bart RS. Detection of melanomas in patients followed up with total cutaneous examinations, total cutaneous photography, and dermoscopy. J Am Acad Dermatol 2004;50:15–20   9. Naeyaert JM, Brochez L. Clinical practice. Dysplastic nevi. N Engl J Med 2003;349:2233–2240 10. Wetherington RW, Cockerell CJ. The “dysplastic” nevus: an update at 25 years. Adv Dermatol 2003; 19:237–248 11. Bauer J, Garbe C. Acquired melanocytic nevi as risk factor for melanoma development. A comprehensive review of epidemiological data. Pigment Cell Res 2003;16:297–306 12. Kaddu S, Smolle J, Zenahlik P, Hofmann-Wellenhof R, Kerl H. Melanoma with benign melanocytic naevus components: reappraisal of clinicopathological features and prognosis. Melanoma Res 2002;12:271– 278 13. Crowson AN, Magro CM, Sanchez-Carpintero I, Mihm MC Jr. The precursors of malignant melanoma. Recent Results Cancer Res 2002;160:75–84 14. Hofmann-Wellenhof R, Blum A, Wolf IH, Zalaudek I, Piccolo D, Kerl H, Garbe C, Soyer HP. Dermoscopic classification of Clark’s nevi (atypical melanocytic nevi). Clin Dermatol 2002;20:255–258 15. Hussein MR, Wood GS. Molecular aspects of melanocytic dysplastic nevi. J Mol Diagn 2002;4:71–80 16. Tripp JM, Kopf AW, Marghoob AA, Bart RS. Management of dysplastic nevi: a survey of fellows of the American Academy of Dermatology. J Am Acad Dermatol 2002;46:674–682 17. Barnhill RL. Malignant melanoma, dysplastic melano­cytic nevi, and Spitz tumors. Histologic classification and characteristics. Clin Plast Surg 2000;27:331–360

18. Ackerman AB. Mythology and numerology in the sphere of melanoma. Cancer 2000;88:491–496 19. Greene MH. The genetics of hereditary melanoma and nevi. 1998 update. Cancer 1999;86 (11 Suppl): 2464–2477 20. Murphy GF, Mihm MC Jr. Recognition and evaluation of cytological dysplasia in acquired melanocytic nevi. Hum Pathol 1999;30:506–512 21. Cerroni L, Kerl H. Simulators of malignant melanoma of the skin. Eur J Dermatol 1998;8:388–396 22. Slade J, Marghoob AA, Salopek TG, Rigel DS, Kopf AW, Bart RS. Atypical mole syndrome: risk factor for cutaneous malignant melanoma and implications for management. J Am Acad Dermatol 1995;32:479–494 23. Slade J, Salopek TG, Marghoob AA, Kopf AW, Rigel DS. Risk of developing cutaneous malignant melanoma in atypical-mole syndrome: New York University experience and literature review. Recent Results Cancer Res 1995;139:87–104 24. Bergman W, Gruis NA, Sandkuijl LA, Frants RR. Genetics of seven Dutch familial atypical multiple mole-melanoma syndrome families: a review of linkage results including chromosomes 1 and 9. J Invest Dermatol 1994;103(5 Suppl):122S–125S 25. Marghoob AA, Kopf AW, Rigel DS, Bart RS, Friedman RJ, Yadav S, Abadir M, Sanfilippo L, Silverman MK, Vossaert KA. Risk of cutaneous malignant melanoma in patients with “classic” atypical-mole syndrome. A case-control study. Arch Dermatol 1994;130:993–998 26. Kopf AW, Friedman RJ, Rigel DS. Atypical mole syndrome. J Am Acad Dermatol 1990;22:117–118 27. Clark WH Jr, Reimer RR, Greene M, Ainsworth AM, Mastrangelo MJ. Origin of familial malignant melanomas from heritable melanocytic lesions. “The B-K mole syndrome”. Arch Dermatol 1978;114:732–738

Chapter III.6


Combined Nevus Horacio Cabo

Contents III.6.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 III.6.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . 97 III.6.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . . 98 III.6.4 Differential Diagnosis. . . . . . . . . . . . . . . . . . . 98 III.6.5 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . . 98 III.6.6 Management. . . . . . . . . . . . . . . . . . . . . . . . . . . 98

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

III.6.1 Definition There is no consistent and reproducible definition of combined nevus available in the literature. Some authors only refer to an association of a blue nevus and another melanocytic nevus as combined nevus; however, in our understanding, the most comprehensible and logical approach is to define a combined nevus as the association of two distinctive benign melanocytic proliferations in one biopsy specimen. Any combination of two kinds of melanocytic nevi is possible, but since blue nevi, Clark’s nevi, Miescher nevi, Unna nevi, and Spitz nevi are the most common melanocytic skin lesions, they are most likely to collide. A combined blue nevus is then the confluence of a blue nevus with another nevus, in most cases a common acquired melanocytic nevus or congenital melanocytic nevus. On occasion, a special combination can be the association of a blue nevus with a Spitz nevus [2, 9], sometimes also referred to as “blitz”. (The German word “Blitz” means lightning in English)

Combined nevus is a subcategory of the socalled collision tumors or compound tumors. A collision tumor is a side-by-side occurrence of two distinctive neoplastic skin lesions, just casually colliding within the same biopsy specimen [4, 6, 12]. This can be, for example, the confluence of a seborrheic keratosis and a basal cell carcinoma, which is a quite common combination, or the rare combinations of basal cell carcinoma and melanoma in one lesion, or the combination of an angioma and a Clark nevus. Some authors argue that there are collision tumors which might have a pathogenic relationship [3]. Most frequently colliding lesions are represented by a combination of the followings: seborrheic keratosis; basal cell carcinoma; melanoma; melanocytic nevus; hemangioma; squamous cell carcinoma; and dermatofibroma.

III.6.2 Clinical Features The clinical features of combined nevi are variable depending on the two individual nevus types belonging to the same lesion. As a result of the combined features of two nevus cell populations, combined nevi may often be asymmetric and difficult to differentiate from melanoma [5]. For example, it is important to remember what a blue nevus is like clinically to understand the combined blue nevus. The blue nevus can be common or cellular. The common blue nevus is a small nodule (<0.5 cm), slate blue or bluish black in color. It is generally solitary and occurs in any part of the body, although it is most frequently found on the dorsum of the hands and feet, as well as on the scalp and mucosa. Although it most frequently appears in infancy, there are instances of late onsets in adults. The


H. Cabo

cellular blue nevus is a nodule larger than 0.5 cm (2–3 cm), blue or black in color, preferably located in the gluteus or sacrococcygeal region. Very rarely a melanoma can arise within a preexisting cellular blue nevus [2, 9]. Combined blue nevi are usually small lesions typified by a small blue to black spot (corresponding to the blue nevus component) in the context of a larger area of brown color (corresponding to the common nevus) surrounding the blue nevus [7]; the latter is known as the targetoid combined blue nevus type [1].

III.6.3 Dermoscopic Criteria


Dermoscopic criteria also depend on the individual nevus types belonging to the same lesion. These features are described in the corresponding chapters of this book. Combined blue nevi are generally round, symmetric lesions with two colorations: a deep blue color in the central part, and a more superficial light brown or dark brown color at the periphery. In the blue nevus part a homogeneous blue pattern is observed, whereas brown coloration, regular pigment network, brown globules, and brown structureless areas typify the common nevus component. When the combination does not include a blue nevus component, dermoscopic features are less specific and more difficult to interpret [1, 7].

III.6.4 Differential Diagnosis The clinical and dermoscopic features of combined nevi are due to their protean nature and are not at all well described. Differential diagnoses include a number of benign melanocytic proliferations, among them blue nevi, dysplastic nevi, and, Spitz nevi. Most relevant, however, is that combined nevi frequently simulate melanoma clinically by being asymmetric and re-

vealing markedly irregular pigmentation. Features that allow distinction from melanoma are the sharp circumscription and the overall appearance of the lesion, which shows a well-circumscribed hyperpigmented spot usually surrounded by a less-pigmented area. Other rarer differential diagnoses of combined nevi are basal cell carcinomas and cutaneous metastases.

III.6.5 Histopathology Histopathological features depend on the nevi that are combined within the lesion. The most frequent scenario is the association of a common melanocytic nevus and a blue nevus, either common or cellular type. Less frequent are the associations of a blue nevus with a Spitz nevus or a Spitz nevus with a Clark nevus (Spark). Basically the histopathological findings of a combined nevus reflect the morphological features of its components [2, 5, 10, 11]. So, histopathologically there are several types of combined nevi, characterized by the combination of any morphological expression of congenital and/or acquired nevi. Combined nevi can be distinguished from melanoma by the absence of features of melanoma in situ in the intraepidermal portion of the neoplasm, the maturation of melanocytes with progressive descent into the dermis, and the absence of nuclear atypia (with the exception of cells of Spitz’s nevi). Combined nevi show overlapping features with many other variants of benign nevi, including proliferating nodules in congenital nevi and cellular blue nevi, among others.

III.6.6 Management As distinction from melanoma often cannot be clearly made, complete surgical excision is recommended.

Combined Nevus


Core Messages ■ A combined nevus is the combination of two distinctive benign melanocytic proliferations, whereas a combined blue nevus is the combination of a blue nevus with another nevus type. ■ Clinical features, dermoscopic features, and histopathology are protean and depend on the two individual nevus types belonging to one lesion. ■ They frequently simulate melanoma by being asymmetric and heavily pigmented, and therefore should be excised when the diagnosis of combined nevus is not clear-cut.

Chapter III.6   9. Fitzpatrick TB, Jonson RA, Polano MK, Suurmond D, Wolf K. Common melanocytic nevocellular nevi. In: Fitzpatrick TB (ed) Color atlas and synopsis of clinical dermatology, McGraw-Hill, New York, 1992 10. Scolyer RA, Zhuang L, Palmer AA, Thompson JF, McCarthy SW. Combined naevus: a benign lesion frequently misdiagnosed both clinically and pathologically as melanoma. Pathology 2004;36:419–427 11. Strungs I. Common and uncommon variants of melanocytic naevi. Pathology 2004;36:396–403 12. Zaballos P, Llambrich A, Puig S, Malvehy J. Dermoscopy is useful for the recognition of benignmalignant compound tumours. Br J Dermatol 2005; 153:653–656 13. Zabel R, Vinson R, McCollough M. Malignant melanoma arising in a seborrheic keratosis. J Am Acad Dermatol 2000;42:831–833

References   1. Argenziano G. Dermoscopy of melanocytic neoplasms. Targetoid combined blue nevi. Arch Dermatol 2004;140:1576   2. Cabrera H, Garcia S. Aspectos particulares de los nevos melanociticos. In: Cabrera H (ed) Nevos. Editorial Actualizaciones Médicas, 1998, Buenos Aires. Argentina   3. Cascajo C, Riechel M, Sanchez J. Malignant neoplasms associates with seborrheic Keratosis: an análisis of 54 cases. Am J Dermophatol 1996;18:278– 282   4. Cosme Alvarez Cuesta C, Vazquez Lopez F, Perez Oliva N. Dermatoscopy in the diagnosis of cutaneous collision. Clin Exp Dermatol 2004;29:199–200   5. Giorgi V de, Massi D, Salvini C, Trez E, Mannone F, Carli P. Dermoscopic feature of combined melanocytic nevi. J Cutan Pathol 2004;31:600–604   6. Giorgi V de, Massi D, Sestini B, Alfaioli B, Carelli G, Carli P. Cutaneous collision tumour (melanocytic naevus, basal cell carcinoma, seborrheic keretosis): a clinical, dermoscopic and pathological case report. Br J Dermatol. 2005;152:787–790   7. Dermoscopy of melanocytic neoplasms. Combined blue nevi. Arch Dermatol 2004;140:902   8. Ferrara G, Zalaudek I, Cabo H, Soyer HP, Argenziano G. Collision of basal cell carcinoma with seborrhoeic keratosis: a dermoscopic aid to histopathology? Clin Exp Dermatol 2005;30:586–587

Fig. III.6.1.  a Congenital nevus with two cell populations, clinical view. b Congenital nevus with two cell populations, dermoscopy view. Note the blue color in the central part of the lesion



H. Cabo

Fig. III.6.2.  a Combined blue nevus, clinical view. b Combined blue nevus, dermoscopy view. Blue color in central part and light brown color at the periphery


Fig. III.6.3.  a Combined blue nevus, clinical view. b Combined blue nevus, dermoscopy view. Blue-gray pigmentation and light brown color correspond to the two different cell populations

Combined Nevus

Fig. III.6.4.  a Combined blue nevus, histopathology. The upper part of the lesion is composed by pigmented dendritic cells, whereas the lower part shows small nevus cells (hematoxylin–eosin, ¥50). b Combined blue nevus, histopathology. Pigmented dendritic melanocytes intermingled with melanophages typical for a blue nevus (hematoxylin–eosin, ¥312.5). c Combined blue nevus, histopathology. Small nevus cells in the lower half of the lesion characteristic of a classical dermal nevus (hematoxylin–eosin, ¥312.5)

Chapter III.6


Chapter III.7

Common Nevus Rainer Hofmann-Wellenhof and H. Peter Soyer

Contents III.7.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 III.7.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . 102 III.7.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . 102 III.7.4 Relevant Clinical Differential Diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 III.7.5 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . 103 III.7.6 Management. . . . . . . . . . . . . . . . . . . . . . . . . . 103 III.7.7 Case Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

III.7.1 Definition


There is much debate regarding the term common or typical nevus. In our view of melanocytic nevi, you can clinically and dermoscopically differentiate between common/typical and uncommon/atypical or dysplastic nevi. The term common nevus encompasses the flat common nevus, the dermal nevus of the face (Miescher nevus), and the papillomatous dermal nevus of Unna. These two types of nevi are described in Chaps.  III.13 and III.19. Common nevi are the most frequent melanocytic neoplasms. The number of common melanocytic nevi varies in different studies and is age dependent. Common nevi usually develop most frequently at puberty. In Caucasians the mean number of common nevi varies between 30 and 70 in the age between 30 and 40 years, whereas in darker ethnic races common nevi are less frequent. Besides host factors, such as pigmentary traits and hereditary factors, exposure to UV radiation is the most important en-


vironmental factor for the development of common nevi. According to the current model of the natural evolution of common melanocytic nevi, these nevi begin as simplex lentigo, and then develop into junctional and later compound and dermal nevi. Finally, they completely vanish or end as fibrotic papule (Unna’s concept of “Abtropfung”; see Chap. III.1). Epidemiological studies have consistently shown that the total number of melanocytic nevi is one of the strongest risk factors for the development of melanoma. The relative risk calculated in a meta-analysis was 6.3 for persons with more than 100 common nevi compared with persons with less than 15 nevi. The exact role of common nevi as precursors of melanoma is still under debate.

III.7.2 Clinical Features The common nevus is a round or oval macule or flat papule with regular border and homogeneous color. The color can vary from all shades of brown to black (Fig. III.7.1). The diameter is smaller than 6 mm. Common nevi are found mostly in skin that has been exposed to sunlight, but they may be seen on the entire skin.

III.7.3 Dermoscopic Criteria The common nevus displays a regular overall architecture. Most often the global pattern is reticular, but globular or homogenous patterns are also common (Fig. III.7.2). No combinations of these global patterns are observed. The color is equally distributed and uniform. The common nevus lacks specific local criteria.

Common Nevus

Chapter III.7

III.7.5 Histopathology

Fig. III.7.1.  Two common nevi on the chest of a 37-yearold man. The nevi are smaller than 4 mm and are regularly shaped and pigmented

Flat common nevi are small, symmetric, sharply demarcated melanocytic lesions which are confined to the epidermis and papillary dermis. The melanocytes are arranged in a small nest of similar size and shape. The nests are situated predominantly on the tips of the rete ridges. Some equally distributed single melanocytes may be present. Cytomorphologically, the cells are uniform round or ovoid with monomorphous nuclei. A sparse lymphocytic infiltration may be found in the papillary dermis.

III.7.6 Management Common nevi do not require special treatment or follow-up. Individuals should be advised to perform self-examination with special alertness to changes in shape or color. Individuals with more than 100 common nevi should visit a dermatologist once a year for total-body examination.

III.7.7 Case Study Patient comment Fig. III.7.2.  Dermoscopic image of two common flat nevi. The larger nevus has a diameter of 3 mm. Both nevi are symmetric, uniform pigmented, and regularly bordered. The smaller nevus displays a prominent regular pigment network, whereas in the larger nevus there is only a faint network

A 31-year-old woman visited the office of the dermatologist because she noticed two new nevi after the summer vacation.

Questions asked by the physician III.7.4 Relevant Clinical Differential Diagnoses Since in our view lentigo simplex represents a precursor of the flat common nevus, both can be separated only histopathologically. Solar lentigo or actinic lentigo tend to be lighter than common nevi and are more irregularly bordered.

Do you still mention a growth or another change of the new nevi?

Clinical image including detailed description Clinical examination revealed some flat nevi, all with a diameter fewer than 4 mm on the trunk and extremities.



R. Hofmann-Wellenhof, H.P. Soyer

Comments The clinical diagnosis of common flat melanocytic nevus is undemanding. Dermoscopy serves more to calm concerned patients than to confirm the diagnosis. Patients should be advised to perform self-examination and apply sun protection.

Dermoscopic image including detailed description



Core Messages ■ Common flat melanocytic nevi are the most frequently melanocytic neoplasms. ■ Common flat nevus requires no special treatment. ■ More than 100 common melanocytic nevi indicate a significantly higher risk of developing melanoma.

Dermoscopic features of one nevus on the back revealed a uniform pigmented homogeneous pattern. The small depigmented area on the top of the lesion corresponded to the typical hypopigmentation around a hair follicle.

Clinical diagnosis including relevant differential diagnosis The diagnosis of a common flat melanocytic nevus was made without any difficulty. (A flat seborrheic keratosis may be also taken into differential diagnosis, but early seborrheic keratoses, as a rule, tend to have more dull colors and a finely stippled surface.)

Performed management No further treatment was necessary.

References   1. Zhu G, Montgomery GW, James MR, Trent JM, Hayward NK, Martin NG, Duffy DL. A genomewide scan for naevus count: linkage to CDKN2A and to other chromosome regions. Eur J Hum Genet 2007;15:94–102   2. Zalaudek I, Grinschgl S, Argenziano G, Marghoob AA, Blum A, Richtig E, Wolf IH, Fink-Puches R, Kerl H, Soyer HP, Hofmann-Wellenhof R. Age-related prevalence of dermoscopy patterns in acquired melanocytic naevi. Br J Dermatol 2006;154:299–304

Common Nevus   3. Zalaudek I, Hofmann-Wellenhof R, Soyer HP, Ferrara G, Argenziano G. Naevogenesis: new thoughts based on dermoscopy. Br J Dermatol 2006;154:793– 794   4. Elder DE. Precursors to melanoma and their mimics: nevi of special sites. Mod Pathol 2006;19 (Suppl 2):S4–S20   5. Hussein MR. Melanocytic dysplastic naevi occupy the middle ground between benign melanocytic naevi and cutaneous malignant melanomas: emerging clues. J Clin Pathol 2005;58:453–456   6. Gandini S, Sera F, Cattaruzza MS, Pasquini P, Abeni D, Boyle P, Melchi CF. Meta-analysis of risk factors for cutaneous melanoma: I. Common and atypical naevi. Eur J Cancer 2005;41:28–44

Chapter III.7   7. Bauer J, Garbe C. Acquired melanocytic nevi as risk factor for melanoma development. A comprehensive review of epidemiological data. Pigment Cell Res 2003;16:297–306   8. Worret WI, Burgdorf WH. Which direction do nevus cells move? Abtropfung reexamined. Am J Dermatopathol 1998;20:135–139   9. Schmoeckel C. Classification of melanocytic nevi: Do nodular and flat nevi develop differently? Am J Dermatopathol 1997;19:31–34 10. Ackerman AB, Milde P. Naming acquired melanocytic nevi. Common and dysplastic, normal and atypical, or Unna, Miescher, Spitz, and Clark? Am J Dermatopathol. 1992;14:447–453


Chapter III.8

Congenital Melanocytic Nevi Alon Scope, Cristiane Benvenuto-Andrade, Ashfaq A. Marghoob

Contents III.8.1 Introduction and Definition . . . . . . . . . . . . 106 III.8.2 Etiology and Pathogenesis. . . . . . . . . . . . . . 106 III.8.3 Clinical Features . . . . . . . . . . . . . . . . . . . . . . 107 III.8.3.1 Clinical Variants . . . . . . . . . . . . . . . . . . . . . . 109 III.8.4 Dermoscopic Criteria and Other Diagnostic Modalities. . . . . . . . 110 III.8.5 Relevant Clinical Differential Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 III.8.6 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . 111 III.8.7 Management. . . . . . . . . . . . . . . . . . . . . . . . . . 111 III.8.7.1 Clinical Follow-up. . . . . . . . . . . . . . . . . . . . . 114 III.8.8 Case Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 116


hood, described as small (<1.5 cm), medium (1.5–19.9 cm), and large (20 cm or more). Given that most CMN grow in proportion to the anatomic site after early infancy [42], a factor of 1.5 for head lesions and a factor of 3 for all other anatomic areas can be used to estimate their size in adulthood and classify lesions in children. Small CMN are seen in 1:100 newborns, medium in 1:1000, large in 1:20,000, and giant, the subgroup of large CMN with a diameter of 50 cm or more, in 1:500,000. With increasing nevus size, the frequency of complications is higher. These complications include the development of malignancies, namely melanoma and more rarely rhabdomyosarcoma, manifestations of neurocutaneous melanocytosis and greater psycho-social burden for the patient and parents.

III.8.2 Etiology and Pathogenesis


III.8.1 Introduction and Definition Congenital melanocytic nevi (CMN), reported in 1–6% of newborns [31], are defined as benign melanocytic nevi whose presence is determined in utero. This definition encompasses congenital nevi that are visible at birth, as well as the “tardive” congenital nevi, which become apparent shortly after birth [29, 44]. Nevi with congenital features that lack history of being present since infancy are termed congenital nevus-like nevi. Many different definitions have been proposed to distinguish small and large congenital nevi (CMN) [32]; however, the most widely applied classification is based on the greatest diameter they are predicted to attain during adult-

The embryonic origin of melanocytes is the neural crest. As the neural tube is formed, the cells of the neural crest migrate and give rise to multiple progeny, including melanocytes and peripheral neural system cells. Cramer proposed the theory of the melanocytic differen­ tiation pathway [12], summarized in Fig. III.8.1. A corollary of this hypothesis is that developmental anomaly at the neural crest stage may give rise to the presence of excessive melanocytes in both the skin and leptomeninges, as seen in neurocutaneous melanocytosis. Furthermore, nevi in individuals with neurocutaneous melanocytosis and large CMN may contain not only an absolute increase in the number of melanocytes, but also more primitive cells with increased proliferative capacity.

Congenital Melanocytic Nevi

Fig. III.8.1.  Pathway of melanocytic migration and differentiation, based on Cramer’s melanocytic differentiation pathway theory [12]. Melanocytes migrate from the neural crest to the dermis through the sheaths of peripheral nerves. Immature melanocytes in the dermis then migrate to the epidermis and follicular epithelium, differentiating into the mature dendritic melanocytes capable of supplying melanin to the neighboring keratinocytes (i.e., epidermal–melanin unit). Other melanocytes from the neural crest migrate to visceral sites, including the leptomeninges, retina and inner ear

Several molecular pathways have been implicated in the pathogenesis of CMN and its associated complications. Hepatocyte growth factor/ scatter factor (HGF/SF) is a multi-functional cytokine implicated in the control of melanocytic proliferation, migration, and differentiation. Transgenic mice over-expressing HGF/SF develop excessive melanocytosis of the skin and leptomeninges, clinically resembling neurocutaneous melanocytosis [46]. They also are prone to develop melanoma and rhabdomyosarcoma [47]. Another important pathway for the proliferation, migration and differentiation of melanocytes is the stem cell factor (SCF) – c-kit pathway. It was shown that in neural-crest cell cultures, c-kit-expressing cells invariably give rise to melanocytic clones [28]. In CMN, intense c-kit staining was found in proliferative nodules [19], which are rapidly growing benign nodules that arise within CMN in the early neonatal period and often prompt concern of malignancy. The darker pigmentation of proliferative nodules may be the result of stimulation of the Mitogen-activated protein kinase (MAPK) pathway, downstream of

Chapter III.8

c-kit, leading to increased tyrosinase activity [19]. In addition, proliferative nodules display frequent chromosomal aberrations that are different from those found in MM. Losses of chromosome 7 are found in nodular proliferations, whereas frequent losses of chromosomes 9 and 10 tend to be characteristic of MM [2]. Dysregulated activation of N-RAS/BRAF/ MAPK signal transduction pathway has important implications in melanoma progression [43]. Activating mutations in N-RAS have been found in 28–56% of CMN studied [10, 38]. The prognostic significance of N-RAS mutations in CMN remains to be elucidated, but interestingly, NRAS mutations were reported to be associated with as many as one-third of nodular melanomas [23]. Mutations in BRAF were found in 46– 86% of CMN in some small series [40, 53], while not in others [5], suggesting that this mutation may be an acquired event. Nevertheless, despite constitutive oncogene up-regulation, development of melanoma in CMN probably requires loss of the cellular mechanisms of senescence, such as the p16-Rb pathway, as well as immortalization by telomerase activation [6, 36]. It is postulated that large CMN, which contains immature melanocytes, can undergo spontaneous mutations resulting in melanoma, thus accounting for the tendency of melanomas to develop early in life in patients with large CMN. In contrast, smaller CMN, composed of mature, differentiated nevo-melanocytes, may require exogenous influences, such as ultraviolet radiation, to induce mutations; thus, if melanoma is seen in association with small CMN, it usually occurs later in life, similar to melanomas that are associated with acquired nevi.

III.8.3 Clinical Features Typically, CMN are round or oval pigmented lesions with sharply demarcated borders. Their surface may be smooth (Fig. III.8.2), cerebriform, rugose, verrucous, or lobular. CMN often have a diffuse homogeneous brown color; however, some may have a multi-shaded pigment pattern, varying from light to dark brown (Fig. III.8.3). Others may be speckled with “islands” of darker or lighter pigment. Hypertri-



A. Scope, C. Benvenuto-Andrade, A.A. Marghoob

Fig. III.8.2.  Large congenital nevus with smooth surface and homogenous brown color as focal depicted here is relatively easy to follow-up clinically, as change in color or texture can be promptly detected. Hypertrichosis is common and carries no prognostic value


Fig. III.8.3.  Melanoma detection in a large and heterogeneous congenital nevus, as presented here, can be difficult, demanding careful follow-up and consideration for prophylactic removal of specific areas as clinically indicated

chosis, appearing at birth or by late childhood, is common (Fig. III.8.2). Although CMN are usually asymptomatic, some lesions may be associated with pruritus, xerosis, and anhydrosis. Over time, they may develop a nodular surface and become darker or lighter. Less commonly they may lose pigmentation or, in rare cases, regress [13, 48]. Some patients develop leukoderma, which can result in a halo phenomenon, fading of the nevus, and vitiligo-like lesions in distant skin sites [22]. This depigmentation is usually not associated with malignant degeneration.

Patients with large CMN are additionally at risk for neurocutaneous melanocytosis [8]. Melanocytes occur naturally in the central nervous system where they usually remain quiescent. In neurocutaneous melanocytosis, however, there is an error in embryonal neuro-ectodermal morphogenesis, with dysregulated growth and migration of melanoblasts. Melanocytes at the leptomeninges may undergo asymptomatic benign proliferation (asymptomatic neurocutaneous melanocytosis) or elicit neurological signs and symptoms secondary to impaired cerebrospinal fluid circulation, mass effect, or intracranial hemorrhages (symptomatic neurocutaneous melanocytosis). Some of these cells may give rise to melanoma. The incidence of symptomatic neurocutaneous melanocytosis among patients with large CMN is reported to be between 4.5–11% [1]. Based on MRI screening, the incidence of asymptomatic findings in the central nervous system among patients with large CMN has a range between 4.8 and 30%, with notable variability in study design [1, 15, 16]. The rate of development of symptomatic neurocutaneous melanocytosis among patients with a positive MRI is reported to be approximately 7% over 5 years of follow-up [15]. Patients at greatest risk for developing neurocutaneous melanocytosis are those with large CMN on the posterior axis and/or the presence of more than 20 satellite nevi (Fig. III.8.4) [14, 33]. Symptomatic neurocutaneous melanocytosis carries a poor prognosis, even in the absence of malignant proliferation. Neurological signs of cranial hypertension, such as hydrocephaly and seizures, may arise. Patients with large CMN presenting with subtle motor and behavioral or development problems must also be care­fully evaluated for neurocutaneous melanocytosis. CMN can occasionally give rise to melanoma or, less frequently, other malignancies such as rhabdomyosarcoma, liposarcoma, and malignant peripheral nerve sheath tumor [20]. The risk of melanoma seems to correlate, to some degree, with the size of the nevus, with larger lesions carrying the higher risk. Overall, the lifetime risk for developing cutaneous or extracutaneous melanoma in patients with large CMN is between 4.5 and 10% [7, 50]. The risk of developing melanoma in small and medium

Congenital Melanocytic Nevi

Chapter III.8

Fig. III.8.5.  This 13-year-old girl was born with multiple large segmental speckled lentiginous nevi. This case illustrates the clinical overlap between speckled nevus and congenital melanocytic nevus Fig. III.8.4.  Patients with large congenital melanocytic nevi on the posterior axis in the presence of many satellite nevi, as depicted in this figure, are at risk for developing neurocutaneous melanosis

CMN is even less well known but is reported to be between 0 and 4.9% [41]. Unlike melanomas developing in large CMN, which occur before puberty, melanomas occurring in small and medium CMN generally develop at or after puberty. Also, melanomas developing in small or medium CMN often begin at the dermo-epidermal junction and at the peripheral edge of the nevus; thus, they are more readily detectable than melanomas developing in large CMN, which frequently occur below the dermo-epidermal junction. Signs of malignant degeneration occurring within CMN include the sudden appearance of a nodule or a dark pigmented area, itching, pain, bleeding, and ulceration. It is noteworthy that biopsy specimens of proliferative nodules that develop within large CMN, particularly those found during early infancy, may have histopathological features that resem-

ble melanoma and yet have a benign clinical behavior [52]. Previous reports of melanoma risk as high as 42% may have been over-estimated due to this histopathological phenomenon. It is advised that excision biopsies of CMN be read by a dermato-pathologist experienced with pigmented lesions.

III.8.3.1 Clinical Variants Nevus spilus (speckled lentiginous nevus), seen in 0.2% of newborns, is characterized by a tan well-circumscribed patch that is speckled with darker macules or papules (Fig. III.8.5). Histopathologically, the background tan patch consists of lentiginous proliferation of single melanocytes with elongation of the rete ridges and epidermal hyperpigmentation, whereas the speckled component shows junctional melanocytic nests and less frequently dermal nests. In addition, cases of nevus spilus in which the speckled component was histopathologically consistent with atypical [18], Spitz [9, 21], and



A. Scope, C. Benvenuto-Andrade, A.A. Marghoob

blue nevi [11, 24] have been described. There are several reports of melanoma arising in nevus spilus [39, 51], although an increased risk was not confirmed in a case-control study [26]; thus, a reasonable approach, especially for larger lesions, would be careful follow-up, assisted by photography, and monitoring for clinical changes similarly to the approach for larger-sized CMN.

III.8.4 Dermoscopic Criteria and Other Diagnostic Modalities The four most common global dermoscopic patterns seen in CMN are (a) reticular, which can consist of diffuse or patchy network; (b) globular, mostly composed of dense globules of variable sizes. If the globules are large and angulated, the term “cobblestone-like” is used (Fig. III.8.6); (c) reticulo-globular, mostly with central globules and peripheral network (Fig. III.8.7). Globules appearing in the holes of Fig. III.8.6.  This small congenital nevus shows a globular dermoscopic pattern


Fig. III.8.7.  This mediumsized congenital nevus shows a reticular globular dermo­scopic patterns, with hypertrichosis, central bluish globules, and patchy pigment network

Congenital Melanocytic Nevi

the network are termed “target network with globules”; and (d) diffuse homogenous brown pigmentation (occasionally with remnants of network or globules). In large CMN there are often multiple “islands” of pigment; however, each island has an organized and homogeneous dermoscopic appearance. Specific dermoscopic findings that are commonly observed in CMN include hypertrichosis, milia-like cysts, and peri-follicular hypo- or hyperpigmentation. Although milia-like cysts are considered the “classic” dermoscopic sign of seborrheic keratoses, they should not divert the correct diagnosis in the presence of clinical and dermoscopic structures sug­gestive of a congenital nevus. A multi-compo­nent pattern can be seen occasionally, consisting of three or more dermoscopic structures, often distributed asymmetrically. Since me­lanomas are often multicomponent as well, this pattern in CMN should be viewed and managed with caution. In smallto-medium CMN, melanoma usually arises at the dermo-epidermal junction, a level well visualized by dermoscopy, whereas in large/giant CMN, melanoma may originate too deep in the tissue to be appreciated with dermos­copy. Another non-invasive in-vivo imaging tool, reflectance confocal microscopy (see Chap. II.1), was reported to be useful for diagnosis of CMN [34]; however, its current effective depth of imaging only reaches the papillary dermis and the procedure is time-consuming; thus, its use may be limited to small-to-medium CMN, similar to dermoscopy.

III.8.5 Relevant Clinical Differential Diagnosis Small CMN can resemble acquired nevi, melanoma, and pigmented seborrheic keratosis. Medium-sized CMN, particularly ones that are flat, can resemble café-au-lait spot, Becker’s nevus, epidermal nevus, and melanoma. Large and giant CMN are usually readily diagnosed. Nevus spilus should be distinguished from agminated nevus by the lack of the brown background in the latter.

Chapter III.8

III.8.6 Histopathology Histopathological findings that distinguish congenital from acquired nevi are: (a) nevus cells with a band-like arrangement in a thickened papillary dermis reaching the reticular dermis; (b) nevus cells around and/or within epithelial adnexal structures (including hair follicles, sweat and sebaceous glands) as well as around blood vessels and nerves; and (c) presence of nevus cells between the dermal collagen fibers singly or in Indian files. There is direct correlation between the size of the nevus and the depth of nevus infiltration. Medium to large CMN often reach at least the subcutaneous fat, whereas more superficial involvement of the reticular dermis may be seen in small CMN [27]. Also, the dermis is diffusely involved in large CMN, but tends to have patchy nevus cell infiltration in small CMN [27]. The nevus cells in the dermis show the maturation phenomenon – the superficial cells have greater tendency to form nests, whereas the deeper cells are individually dispersed.

III.8.7 Management Management of CMN must be tailored for each patient and lesion. Beyond the melanoma and neurocutaneous melanocytosis risk, there are often psychosocial/developmental concerns which should be reviewed. All of the following aspects should be taken into account: location, size, depth and appearance of the nevus; the likelihood of improved cosmesis; the potential for decreasing melanoma risk; general risks involved with anesthesia and surgery; degree of residual scarring; anticipated functional impairment; and discomfort. Based on these factors, some CMN may not be amenable to surgical excision. To reach a balance between decreasing the risk for developing melanoma through prophylactic removal of as much of the nevus as possible and attaining acceptable cosmetic results is one of the main objectives in the management of CMN (Table III.8.1). Surgical excision is the most commonly used method for treating CMN; however, there is a wide range of available treatment modalities,



A. Scope, C. Benvenuto-Andrade, A.A. Marghoob Table III.8.1.  Absolute and relative indications for treatment of congenital melanocytic nevi

Treatment indications


Absolute  Malignancy develops Complete excision of the malignant tumor. Even a small congenital nevus that develops suspicious changes, becomes symptomatic or is irregular warrants excision  Metastatic melanoma When the primary cutaneous melanoma is not found, the clinician must consider with unknown the possibility that a melanoma may be “hidden” within a congenital nevus. primary A positron emission tomography scan may help in locating the primary focus of melanoma Relative  Prophylaxis of melanoma

Prophylactic removal should be strongly considered for lesions that are thick, rugous, and heterogeneous, making it difficult to detect melanoma within the nevus. Lesions that present in covered areas of the body (scalp, medial buttocks, perianal, and genital) may be clinically difficult to follow. Note: For congenital nevi <1.5 cm in diameter, the risk for developing melanoma is considered low enough not to justify prophylactic removal

 Physician and patient anxiety

Anxiety regarding the risk of melanoma is a factor in the decision to remove a congenital melanocytic nevus of any size. Families should be aware that while melanoma, neurocutaneous melanocytosis, and other complications can develop, the majority of affected individuals will not develop complications and clinical follow-up is an acceptable management option


Up to 30% of patients with large congenital nevi have social and behavioral/ emotional problems [25]. Patients, families, and physicians alike are usually of the opinion that a scar, even if extensive, is more socially acceptable than a large nevus


Fig. III.8.8.  Photographic follow-up of a patient with a heterogeneous congenital nevus of the posterior axis (left) subjected to staged excisions of the nevus starting

at the age of 9 months (center). Recurrence of pigment along the scar edge is common after surgery (right) especially when lesions are excised before the age of 2 years

from dermabrasion and curettage to chemical peel and laser ablation (Table III.8.2). The choice on the best treatment usually relies on the physicians experience and patient’s expectations

[17, 49]. For those patients in whom lesion removal is considered, surgery should be planned taking into account the fact that the best surgical scars result from surgery performed early in

Congenital Melanocytic Nevi

Chapter III.8

Table III.8.2.  Congenital melanocytic nevi treatment options. MM melanoma

Treatment   option



Full-thickness excision

Reduces melanoma risk

Excision of large nevi may leave cosmetically disfiguring scar


Often requires serial excisions, tissue expanders, or skin grafts Requires general anesthesia

Partial-thickness excision

Reduces melanoma risk

Melanoma may develop from residual melanocytes Excision of large nevi may leave cosmetically disfiguring scar Requires general anesthesia


Less potential for scarring than full-thickness excision

Difficult to detect subcutaneous MM

Potential reduction of melanoma risk if done early

Melanoma may develop from residual melanocytes Requires general anesthesia Must be performed within first few weeks of life



May produce good cosmetic result

Repigmentation of scarred skin

Reduces melanoma risk

Case reports of melanoma development after dermabrasion

May produce good cosmetic result

Post-dermabraded skin is thin, fragile, tender, and with reduced hair density

Reduced pigmentation may allow for easier detection of developing melanoma

Should be performed early in life. Procedure becomes less efficacious with time

Unknown to what extent it may or may not reduce melanoma risk

Melanoma may develop from residual melanocytes

Low potential for scarring


Improved recovery time

Unknown mutagenic potential

life. Additionally, the risk of melanoma in patients with large CMN is reported to be higher in the first decade, whereas in smaller CMN the melanomas occur later in adulthood; thus, prophylactic surgery of large CMN should be performed as early as possible. Another important aspect of the surgical treatment for CMN is that very large lesions

Scarring may make it difficult to detect development of MM

may require serial or staged excisions, with or without tissue expanders (Fig. III.8.8). It is often impossible to assure complete removal of all nevus cells, leaving open the possibility for melanoma to develop post-surgically from remaining nevus cells, even decades after the initial surgical procedure [45]; thus, it is recommended that large CMN be removed down to the fascial



A. Scope, C. Benvenuto-Andrade, A.A. Marghoob

layer [3]. While patients should be aware that of all treatment modalities presented in Table III.8.2, surgical excision is the only treatment that attempts to remove all nevus cells [4].

III.8.7.1 Clinical Follow-up


In the great majority of cases, CMN can be clinically followed annually by total-body skin examinations, with or without baseline photography (Fig. III.8.9). Photographs of the nevus, satellite nevi, and/or scars may be of great benefit in assisting the physician with the detection of subtle changes that may indicate melanoma [37]. Dermoscopy is particularly useful to identify small foci of melanoma within a CMN, direct physicians to specific biopsy sites, and prevent biopsy sampling errors that result in false-negative diagnosis of melanoma. Large CMN that are thick and rugous and where surgical excision is not feasible may benefit from periodic positron emission tomography scan surveillance [30]. Individuals with CMN and their families should be counseled about avoiding over-exposure to UV light [35]. Patients at higher risk for neurocutaneous melanocytosis should receive careful follow-up, and consideration for screening brain magnetic resonance imaging (MRI), ideally before the age of 4 months, when myelination obscures subtle melanin deposits in the brain. At this moment there is no effective treatment for leptomeningeal melanocytosis or central nervous system melanoma. Besides the medical follow-up all patients/ families should be offered the opportunity to contact support groups such as Nevus Outreach ( or Nevus Network (

Fig. III.8.9.  The resection of some congenital nevi may not be feasible. This nevus wraps around the entire circumference of body. Surgical excision would result in substantial functional impairment. This patient is being followed periodically with total body skin examinations, palpation of the lesion, and dermoscopy and baseline photographs, in an attempt to detect subtle changes

III.8.8 Case Study At 7 days of age, the child shown in Fig. III.8.10 was referred to Memorial Sloan-Kettering Hospital for consultation for a large truncal CMN. The nevus extended from the neck to below the mid-back and consisted of a brown patch studded with dark brown-black macules and plaques, as well as a 4-mm dark nodule with a crusted erosion, which was compatible with a prolifera-

Congenital Melanocytic Nevi

Chapter III.8

Fig. III.8.10.  At the age of 1 week, a 4-mm violaceousbrown proliferative nodule with a crusted erosion is seen on the background of a heterogeneously pigmented large

congenital nevus (left). At 1 year the nodule had diminished in size, and the nevus has become more darkly pigmented and hairy (right)

tive nodule. In addition, eight satellite nevi were apparent, mostly on the trunk. Dermoscopy of this large CMN showed a diffuse globular pattern with foci of black dots. Given the size, midback location, and presence of satellites, the increased risk for developing melanoma and neurocutaneous melanocytosis were discussed with the parents, albeit emphasizing that most individuals with large CMN do not develop these complications. Moderate sun avoidance was advised. The foreseen changes in contour and color of the nevus as well as possible appearance of additional satellite nevi were also discussed. The nevus was photographed, with close-up and dermoscopy images. As a multidisciplinary approach is essential in such patients, the child was referred to (a) pediatrician for growth and head circumference monitoring; (b) a pediatric neurologist to monitor for neurological abnormalities; (c) MRI of the brain and spine at baseline to assess for neurocutaneous melanocytosis; and (d) a plastic surgeon consultation to discuss possible surgical treatment options. The family was referred to Nevus Out-

reach support group, a non-profit support organization for patients and families with large CMN. At 1 month of age, the nevus became focally more rugous, some of the speckled macules turned into papules, while the proliferative nodule had diminished in size, and there were over 30 visible satellites dispersed over the torso and extremities. The baseline MRI showed an equivocal brain lesion suspicious for neurocutaneous melanocytosis, but there was no change at 6month imaging, and clinically the patient remained asymptomatic. The parents decided to pursue surgery for cosmesis and possible reduction of melanoma risk. A staged excision was undertaken, starting at 5 months of age for the portion with most heterogeneous appearance. The staged surgeries continued over the next few years using tissue expanders. During 5 years of dermatological follow-up, the remaining portion of the nevus was noted to attain overall lighter color, albeit with focal appearance of darker papules as well as new satellites that are being monitored with digital photography.



A. Scope, C. Benvenuto-Andrade, A.A. Marghoob


Core Messages ■ Individuals with CMN can develop medical, cosmetic, and psychological problems. ■ The absolute risk for developing cutaneous melanoma in association with a CMN is low; however, the relative risk is greatest for patients with large CMN. ■ The risk of neurocutaneous melanocytosis and extracutaneous melanoma is greatest for individuals with a large CMN located on the posterior axis (para-vertebral) and in those with many satellite nevi. ■ Cutaneous melanomas arising in large CMN tend to develop early in life and often develop below the dermoepidermal junction, making early diagnosis challenging. In smaller CMN, melanoma tends to develop in adulthood and at the dermo-epidermal junction and thus early detection is more feasible. ■ Surveillance for malignancy entails inspection and palpation to help detect new subcutaneous nodules that may represent dermal melanoma.


References   1. Agero AL, Benvenuto-Andrade C, Dusza SW et al (2005) Asymptomatic neurocutaneous melanocytosis in patients with large congenital melanocytic nevi: a study of cases from an Internet-based registry. J Am Acad Dermatol 53:959–965   2. Bastian BC, Xiong J, Frieden IJ et al (2002) Genetic changes in neoplasms arising in congenital melanocytic nevi: differences between nodular proliferations and melanomas. Am J Pathol 161:1163–1169   3. Bauer BS, Vicari FA (1988) An approach to excision of congenital giant pigmented nevi in infancy and early childhood. Plast Reconstr Surg 82:1012–1021   4. Bauer BS, Margulis A (2004) The expanded transposition flap: shifting paradigms based on experience gained from two decades of pediatric tissue expansion. Plast Reconstr Surg 114:98–106

■ Congenital nevi with a benign dermoscopic pattern can be followed clinically, whereas nevi with a multi-com­ponent pattern or with an uncom­­mon pattern should be viewed with caution. ■ Prophylactic surgery may reduce the risk of cutaneous melanoma; however, melanoma can still develop from residual nevus cells or in extracutaneous sites. ■ Ideal timing for prophylactic surgery of large CMN is early in life. For smaller nevi, one may elect to wait until the patient can participate in the decision-making process. ■ Patients at high risk for neurocutaneous melanocytosis should be evaluated by a pediatric neurologist and/or by MRI scanning (ideally before 4 months of age). ■ All patients should be instructed on the importance of sun avoidance and protection and self-skin examination.

  5. Bauer J, Curtin JA, Bastian BC (2005) Absence of BRAF mutations in melanocytic nevi which develop in utero implicates UV-light as a acusative agent for BRAF mutations. In: 6th World Congress on Melanoma, Vancouver, Canada   6. Bennett DC (2003) Human melanocyte senescence and melanoma susceptibility genes. Oncogene 22: 3063–3069   7. Berg P, Lindelof B (2003) Congenital melanocytic naevi and cutaneous melanoma. Melanoma Res 13:441–445   8. Bittencourt FV, Marghoob AA, Kopf AW et al (2000) Large congenital melanocytic nevi and the risk for development of malignant melanoma and neurocutaneous melanocytosis. Pediatrics 106:736–741   9. Calista D (2005) Spitz naevus arising within congenital naevus spilus. J Eur Acad Dermatol Venereol 19:137–138

Congenital Melanocytic Nevi 10. Carr J, Mackie RM (1994) Point mutations in the Nras oncogene in malignant melanoma and congenital naevi. Br J Dermatol 131:72–77 11. Cox NH, Malcolm A, Long ED (1997) Superficial spreading melanoma and blue naevus within naevus spilus: ultrastructural assessment of giant pigment granules. Dermatology 194:213–216 12. Cramer SF (1988) The melanocytic differentiation pathway in congenital melanocytic nevi: theoretical considerations. Pediatr Pathol 8:253–265 13. Dawson HA, Atherton DJ, Mayou B (1996) A prospective study of congenital melanocytic naevi: progress report and evaluation after 6 years. Br J Dermatol 134:617–623 14. DeDavid M, Orlow SJ, Provost N et al (1997) A study of large congenital melanocytic nevi and associated malignant melanomas: review of cases in the New York University Registry and the world literature. J Am Acad Dermatol 36:409–416 15. Foster RD, Williams ML, Barkovich AJ et al (2001) Giant congenital melanocytic nevi: the significance of neurocutaneous melanosis in neurologically asymptomatic children. Plast Reconstr Surg 107:933– 941 16. Frieden IJ, Williams ML, Barkovich AJ (1994) Giant congenital melanocytic nevi: brain magnetic resonance findings in neurologically asymptomatic children. J Am Acad Dermatol 31:423–429 17. Gosain AK, Santoro TD, Larson DL et al (2001) Giant congenital nevi: a 20-year experience and an algorithm for their management. Plast Reconstr Surg 108:622–636 18. Grinspan D, Casala A, Abulafia J et al (1997) Melanoma on dysplastic nevus spilus. Int J Dermatol 36:499–502 19. Herron MD, Vanderhooft SL, Smock K et al (2004) Proliferative nodules in congenital melanocytic nevi: a clinicopathologic and immunohistochemical analysis. Am J Surg Pathol 28:1017–1025 20. Hoang MP, Sinkre P, Albores-Saavedra J (2002) Rhabdomyosarcoma arising in a congenital melanocytic nevus. Am J Dermatopathol 24:26–29 21. Hofmann-Wellenhof R, Soyer HP, Smolle J et al (1994) Spitz’s nevus arising on a nevus spilus. Dermatology 189:265–268 22. Itin PH, Lautenschlager S (2002) Acquired leukoderma in congenital pigmented nevus associated with vitiligo-like depigmentation. Pediatr Dermatol 19:73–75 23. Jafari M, Papp T, Kirchner S et al (1995) Analysis of ras mutations in human melanocytic lesions: activation of the ras gene seems to be associated with the nodular type of human malignant melanoma. J Cancer Res Clin Oncol 121:23–30 24. Kiene P, Brodersen JP, Folster-Holst R (1995) “Blue” variant of naevus spilus. Hautarzt 46:349–351 [in German]

Chapter III.8 25. Koot HM, de Waard-van der Spek F, Peer CD et al (2000) Psychosocial sequelae in 29 children with giant congenital melanocytic naevi. Clin Exp Dermatol 25:589–593 26. Kopf AW, Levine LJ, Rigel DS et al (1985) Congenital-nevus-like nevi, nevi spili, and cafe-au-lait spots in patients with malignant melanoma. J Dermatol Surg Oncol 11:275–280 27. Krengel S (2005) Nevogenesis: new thoughts regarding a classical problem. Am J Dermatopathol 27:456–465 28. Luo R, Gao J, Wehrle-Haller B et al (2003) Molecular identification of distinct neurogenic and melanogenic neural crest sublineages. Development 130:321–330 29. Mackie RM, Watt D, Doherty V et al (1991) Malignant melanoma occurring in those aged under 30 in the west of Scotland 1979–1986: a study of incidence, clinical features, pathological features and survival. Br J Dermatol 124:560–564 30. Makosz T, Assaf C, Georgieva J et al (2004) Detection of malignant melanoma in a giant congenital naevocytic naevus by positron emission tomography. Br J Dermatol 151:724–726 31. Marghoob AA (2002) Congenital melanocytic nevi. Evaluation and management. Dermatol Clin 20:607–616, viii 32. Marghoob AA (2005) Congenital melanocytic nevi. In: Rigel D (ed) Cancer of the skin. Elsevier, Amsterdam 33. Marghoob AA, Dusza S, Oliveria S et al (2004) Number of satellite nevi as a correlate for neurocutaneous melanocytosis in patients with large congenital melanocytic nevi. Arch Dermatol 140:171–175 34. Marghoob AA, Charles CA, Busam KJ et al (2005) In vivo confocal scanning laser microscopy of a series of congenital melanocytic nevi suggestive of having developed malignant melanoma. Arch Dermatol 141:1401–1412 35. Mehta RR, Bratescu L, Graves JM et al (2002) In ­v itro transformation of human congenital naevus to malignant melanoma. Melanoma Res 12:27–33 36. Michaloglou C, Vredeveld LC, Soengas MS et al (2005) BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436:720–724 37. Nehal KS, Oliveria SA, Marghoob AA et al (2002) Use of and beliefs about baseline photography in the management of patients with pigmented lesions: a survey of dermatology residency programmes in the United States. Melanoma Res 12:161–167 38. Papp T, Pemsel H, Zimmermann R et al (1999) Mutational analysis of the N-ras, p53, p16INK4a, CDK4, and MC1R genes in human congenital melanocytic naevi. J Med Genet 36:610–614



A. Scope, C. Benvenuto-Andrade, A.A. Marghoob 39. Paraskevas LR, Halpern AC, Marghoob AA (2005) Utility of the Wood’s light: five cases from a pigmented lesion clinic. Br J Dermatol 152:1039–1044 40. Pollock PM, Harper UL, Hansen KS et al (2003) High frequency of BRAF mutations in nevi. Nat Genet 33:19–20 41. Rhodes AR, Melski JW (1982) Small congenital nevocellular nevi and the risk of cutaneous melanoma. J Pediatr 100:219–224 42. Rhodes AR, Albert LS, Weinstock MA (1996) Congenital nevomelanocytic nevi: proportionate area expansion during infancy and early childhood. J Am Acad Dermatol 34:51–62 43. Satyamoorthy K, Li G, Gerrero MR et al (2003) Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res 63:756–759 44. Schaffer JV, Orlow SJ, Lazova R et al (2001) Speckled lentiginous nevus: within the spectrum of congenital melanocytic nevi. Arch Dermatol 137:172–178 45. Streams BN, Lio PA, Mihm MC et al (2004) A nonepidermal, primary malignant melanoma arising in a giant congenital melanocytic nevus 40 years after partial surgical removal. J Am Acad Dermatol 50:789–792 46. Takayama H, La Rochelle WJ, Anver M et al (1996) Scatter factor/hepatocyte growth factor as a regulator of skeletal muscle and neural crest development. Proc Natl Acad Sci USA 93:5866–5871


47. Takayama H, LaRochelle WJ, Sharp R et al (1997) Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. Proc Natl Acad Sci USA 94:701–706 48. Tokura Y, Yamanaka K, Wakita H et al (1994) Halo congenital nevus undergoing spontaneous regression. Involvement of T-cell immunity in involution and presence of circulating anti-nevus cell IgM antibodies. Arch Dermatol 130:1036–1041 49. Tromberg J, Bauer B, Benvenuto-Andrade C et al (2005) Congenital melanocytic nevi needing treatment. Dermatol Ther 18:136–150 50. Watt AJ, Kotsis SV, Chung KC (2004) Risk of melanoma arising in large congenital melanocytic nevi: a systematic review. Plast Reconstr Surg 113:1968– 1974 51. Weinberg JM, Schutzer PJ, Harris RM et al (1998) Melanoma arising in nevus spilus. Cutis 61:287– 289 52. Xu X, Bellucci KS, Elenitsas R et al (2004) Cellular nodules in congenital pattern nevi. J Cutan Pathol 31:153–159 53. Yazdi AS, Palmedo G, Flaig MJ et al (2003) Mutations of the BRAF gene in benign and malignant melanocytic lesions. J Invest Dermatol 121:1160– 1162

Chapter III.9

Melanocytic Nevi on the Genitalia and Melanocytic Nevi on Other Special Locations


Ingrid H. Wolf

Contents III.9.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 III.9.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . 119 III.9.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . 120 III.9.4 Relevant Clinical Differential Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 III.9.5 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . 120 III.9.6 Management. . . . . . . . . . . . . . . . . . . . . . . . . . 121 III.9.7 Case Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

III.9.1 Definition The definition involves benign melanocytic nevi, localized on the genitalia or other particular body sites, which often display atypical clinical and/or histopathological features that may mimic melanoma.

III.9.2 Clinical Features Pigmented genital lesions, including melanocytic nevi, melanotic macules, and melanoma, are observed in about 10% of men and women.

Vulvar nevi occur in about 2% of women. Genital melanocytic nevi are more likely noted in younger patients, especially in premenopausal women. The main locations are the vulva including labia minora/majora, the clitoris, and the glans penis. They present as asymmetrical pigmented macules or papules, uniform or variegated in color, usually with a diameter of less than 1 cm (Fig. III.9.1a). Melanocytic proliferations in concurrence with lichen sclerosus et atrophicus involving genital skin are significant. This association is uncommon but may be a challenging diagnostic problem because the changes can lead to an erroneous diagnosis of persistent/recurrent melanocytic nevus or melanoma [5]. Closely related to melanocytic nevi on the genitalia – with similar clinical and histopathological features – are benign atypical melanocytic proliferations which are located on the skin of particular body sites including the milkline, flexural locations [7], and other anatomical areas (Fig. III.9.2; Table III.9.1) [8]. Milkline nevi are found on the lines (mammary streaks) extending from the axilla through the areola- and periumbilical region to the groin and genitalia, bilaterally. Awareness of all these lesions, which belong to the spectrum of pseudomelanomas, is of practical importance, as they may pose problems in differentiating them from melanoma.


I.H. Wolf Table III.9.1.  Site-specific melanocytic nevi

Location Genitalia, scrotum Breast, mammilla, nipple Axilla, inguinal region, perineal/perianal area Popliteal/antecubital fossa Umbilicus Palms and soles Knee Ear Scalp Conjunctiva

III.9.3 Dermoscopic Criteria Melanocytic nevi on the genitalia and on other special sites frequently reveal a regular pigment network (Fig. III.9.1b). Sometimes, however, an atypical brown to black network, and some irregular streaks or blotches at the periphery, are observed [6, 9]. A special honeycomb-like pigmentation may be observed in melanocytic nevi of the areolar region.

III.9.4 Relevant Clinical Differential Diagnosis


Fig. III.9.1.  Melanocytic nevus on the glans penis. a Asymmetrical, poorly circumscribed, mottled lesion in shades of brown and white. b Dermoscopy reveals a pigment network, whitish structures, globules, and parallel lines. c Histopathology: nests of different sizes and shapes with a “dyscohesive” pattern confined to the dermo-epidermal junction. Note dermal melanocytes and fibrosis

Many genital melanocytic nevi are “common” lesions with no real differential diagnosis. In the cases where distinctive atypical findings are present, these melanocytic proliferations can simulate melanoma, Spitz’s nevi, and non-nevoid melanotic macules.

III.9.5 Histopathology Unusual histopathological features are found only in the epidermis, whereas the dermal changes are typical for a benign acquired or congenital melanocytic compound nevus with signs of maturation. Within the epidermis, nests of melanocytes, which can vary markedly in sizes and shapes

Melanocytic Nevi on the Genitalia

Chapter III.9

121 Fig. III.9.2.  The many faces of melanocytic nevi on the vulva (a, b), umbilicus (c), and axilla (d)

and tend to confluence, are found mainly along the dermo-epidermal junction. Clefts around the nests (dyscohesive pattern) are a characteristic finding (Fig. III.9.1c). There may be a predominance of solitary melanocytes that exhibit focal upward pagetoid spread. Individual melanocytes can sometimes feature large nuclei with abundant pale cytoplasm [1–4].

III.9.6 Management The tumors are commonly excised with a small surgical margin, particularly when the clinical and dermoscopic features are suggestive for malignancy. Aggressive surgical treatment in areas in which conservation of tissue is especially important should be avoided.


I.H. Wolf

III.9.7 Case Study Patient Comment An 8-year-old girl presented with a 3¥2-cm long-standing lesion on the left breast, present since birth.

Management The management was digital follow-up and surgical excision.


Core Messages ■ Many melanocytic nevi localized on the genitalia or on other special anatomic locations represent banal either junctional or compound melanocytic nevi. ■ A special group, however, can show atypical features, and it is important not to overdiagnose melanoma. ■ Clinical–pathological correlation is necessary to reach a correct diagnosis.

Question Asked By the Physician Has growth of the lesion been observed recently?

Differential Diagnosis The differential diagnosis was melanoma, nevus, keratosis areola mammae, naeviformis. The diagnosis was atypical melanocytic nevus of the mamilla, “milk-line” nevus.


Case Study III.9.1.  a, b Clinical images were obtained in 1996 and 2001. Follow-up reveals morphological changes. c Higher magnification of image shown in b. d On dermoscopy, note the delicate pigment network

Melanocytic Nevi on the Genitalia

References 1. Ackerman AB, Cerroni L, Kerl H (1994) Pitfalls in histopathologic diagnosis of malignant melanoma. Lea and Febiger, Philadelphia 2. Clark WH Jr, Hood AF, Tucker MA et al (1998) Atypical melanocytic nevi of the genital type with a discussion of reciprocal parenchymal–stromal interactions in the biology of neoplasia. Hum Pathol 29: S1–S24 3. Crowson AN, Magro CM, Mihm MC (2001) The melanocytic proliferations. Wiley-Liss, New York 4. Elder DE (2006) Precursors to melanoma and their mimics: nevi of special sites. Mod Pathol 19: S4–S20

Chapter III.9 5. El Shabrawi-Caelen L, Soyer HP, Schaeppi H et al (2004) Genital lentigines and melanocytic nevi with superimposed lichen sclerosus: a diagnostic challenge. J Am Acad Dermatol 50: 690–694 6. Johr R, Soyer HP, Argenziano G et al (2004) Dermoscopy, the Essentials. Mosby, Edingburgh 7. Rongioletti F, Ball RA, Marcus R et al (2000) Histopathological features of flexural melanocytic nevi: a study of 40 cases. J Cutan Pathol 27: 215–217 8. Saad AG, Patel S, Mutasim DF (2005) Melanocytic nevi of the auricular region. Histologic characteristics and diagnostic difficulties. Am J Dermatopathol 27: 111–115 9. Stolz W, Braun-Falco O, Bilek P et al (2002) Color atlas of dermatoscopy, 2nd edn. Blackwell, Berlin


Chapter III.10

Halo Nevus Alessandro Di Stefani and Sergio Chimenti


Contents III.10.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 III.10.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . 124 III.10.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . 126 III.10.4 Relevant Clinical Differential Diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 III.10.5 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . 126 III.10.6 Management. . . . . . . . . . . . . . . . . . . . . . . . . . 127

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

III.10.1 Definition Halo nevus (synonyms: Sutton nevus; leukoderma acquisitum centrifugum; albinismus perinaevicus) is a melanocytic nevus surrounded by a rim of depigmentation, resembling a “halo”. The lesion was originally identified as a distinct entity by Sutton in 1916, whereas in 1874 Hebra and Kaposi had described it as vitiligo [1].


III.10.2 Clinical Features Clinically, halo nevus typically appears as a circumscribed, homogeneously coloured, 3–6 mm in size, evenly shaped nevus surrounded by a peripheral sharply defined symmetrical depigmented area. The central nevus usually is a common benign compound nevus [2]. The encircling halo of hypomelanosis has a uniform radial distance from the central nevus and varies in size from a few millimetres up to some centimetres (Fig. III.10.1).

Fig. III.10.1.  Typical clinical presentation of a halo nevus: note the papular, uniformly colored, evenly shaped central nevus with a symmetrical, peripheral rim of ­depigmentation resembling a halo

The incidence of halo nevus in the population is estimated to be around 1%, and a familial occurrence has also been reported [3]. It is more common in children and young adults, with an average age of onset at 15 years, and has no gender or racial predilection. Preferential site of involvement is the trunk, although it may occur anywhere on the body. The presence of two or more halo nevi has been described in 25–50% of affected individuals. Occasionally, a high number of halo nevi may develop simultaneously or sequentially. Over a period of months or years, halo nevi typically show a characteristic clinical course that can be divided into four clinical stages: (a) stage I, in which the white halo around the central nevus appears; (b) stage II, with lightening and reddening of the central nevus; (c) stage III, which is characterized by progressive involution and subsequent complete re­

Halo Nevus

Chapter III.10

Fig. III.10.2.  a Clinical image of the back of a 10-yearold child with a recent history of sunburn. b Three months later, dermoscopic examination of the nevus in the left lumbar region reveals a subtle halo of depigmentation surrounding the central nevus. c Clinical image of

the same patient 12 months later shows a more evident halo nevus. d Dermoscopic examination (at the same time of c) demonstrates involution of the central nevus and a width-surrounding halo

gression of the central nevus, leaving a circular area of non-pigmented skin; and (d) stage IV, in which the depigmentation may persist for years before melanocytes from the surrounding skin eventually re-popularize the area (Fig. III.10.2) [4]; however, unusual clinical evolu­tion of halo nevus has also been reported, with progressive darkening of the nevus component [5]. The coexistence of a halo nevus and vitiligo has been reported in about 20% of cases, although the relationship between these two types of acquired leucoderma has not been fully elucidated [6]. Occasionally, halo nevus is observed in patients with a personal or family

history of melanoma [7]. Association with me­ lanoma has been also supported by detection of circulating antibodies reactive against ne­vus cells as well as melanoma cells in the serum of patients with halo nevus [8]. In addition, the prevalence of halo nevi in patients with Turner’s syndrome has been reported to be higher as compared with the general population [9]. The aetiology of halo depigmentation is unknown: most often it is idiopathic, but sometimes it follows sunburns (Fig. III.10.2). T-lymphocytes are believed to play a key role in the progressive destruction of nevus cells [2].



A. Di Stefani, S. Chimenti

Fig. III.10.3.  Dermoscopy of a halo nevus shows a homogeneous-globular pattern and a whitish, peripheral depigmented area. (Inset: clinical image)

III.10.3 Dermoscopic Criteria


The dermoscopic features that characterize halo nevi have not yet been described in detail. The most frequently observed pattern is the homogeneous-globular pattern, followed by the homogeneous pattern and the globular pattern, while the reticular pattern is uncommon (Fig. III.10.3) [10]. Brown homogeneous pigmentation, brown globules and pigment network are generally associated with benign melanocytic nevi, especially if they are regularly distributed within the lesion [11–10]. The peripheral halo does not display any peculiar dermoscopic criteria, with the exception of a whitish colour. Dermoscopy may reveal the presence of other dermoscopic criteria within the halo lesion in order to establish a definite diagnosis and/or rule out a regressing melanoma [11]. In addition, dermoscopic monitoring of halo nevus allows to better appreciate involution process during follow-up visits [10].

III.10.4 Relevant Clinical Differential Diagnoses Halo nevus usually is a common benign compound or intradermal nevus [2], but an encircling halo is also described in association with congenital nevus, blue nevus, Spitz nevus and, very rarely, with melanoma [7, 12–15]; thus, the

most important differential diagnosis is with a melanoma showing halo-like regression. Clinically, the halo surrounding a regressive melanoma is usually more asymmetrical and, in most cases, the central lesion is more irregular in shape, borders, and coloration [7, 14–15]. In addition, melanoma with halo-like regression may display a dermoscopic multicomponent pattern (i.e. the simultaneous presence of atypical pigment network, blue white veil, irregular dots/globules, regression structures) [10]. Other differential diagnoses include melanocytic lesions such as atypical nevus, recurrent nevus, Meyerson nevus, targetoid hemosiderotic nevus, cockade nevus and melanoma metastases, as well as non-melanocytic lesions as seborrheic keratosis, neurofibroma, and basal cell carcinoma [16]. When the nevus component is completely regressed, halo Nevus must be distinguished from unilesional vitiligo: both disorders present, clinically, a pure white colour of the otherwise unchanged surface of the skin [2, 6].

III.10.5 Histopathology Halo nevus is histopathologically defined by the presence of a striking dense, band-like lymphocytic infiltrate among dermal nevus cells and loss of pigment at the dermo-epidermal junction at the periphery of the nevus [2, 16]. Some nevi with a lymphocytic infiltrate of the type seen in halo nevus (“halo phenomenon”) do not show an obvious clinical depigmented halo; therefore, clinical correlation is important in rendering a diagnosis of halo nevus [16]. The number of remnant nevus cells depend on the stage at which the biopsy is taken. Mitotic figures usually are not present, although occasional apoptotic cells may be identified. Macrophages may be seen within the infiltrate, some of which are loaded with melanin. Immunohistochemical staining for S-100, HMB45 or Melan-A, may be useful to identify residual nevus cells when a dense lymphocytic infiltration obscures surviving melanocytes. Immunohistochemistry shows positivity of lymphocytic cells for CD1a, CD68, CD3 and CD8 [17]. A clonal expansion of T lymphocytes has been demonstrated in cases of halo nevi [17]. There is

Halo Nevus

also evidence of activated lymphocytes in the peripheral blood as well as anti-nevic IgM antibody production in affected individuals [2, 8]. These data suggest that cytotoxic T cells may be involved in the regression of the nevus and that the destruction of melanocytes in the halo phenomenon could be view as the lysis of a distinctive cell type through an autoimmune-like process mediated by an oligoclonal T-cell response [17].

III.10.6 Management Halo nevus is a benign lesion, and no treatment is required. Reassurance of the concerned patient is a relevant issue. If a typical halo lesion is observed in children, no further examinations are needed and it may be of only cosmetic significance. A clinical and dermoscopic follow-up may be performed in order to monitor the characteristic evolution of halo nevi. Despite clinically benign features, the presence of a new halo lesion in an adult individual should be regarded with a high index of suspicion and an excisional biopsy is mandatory. Surgical excision should be performed also in all halo nevi showing clinico-dermoscopic atypical features in order to rule out a regressive melanoma.


Core Messages ■ Halo nevi usually show a characteristic clinical appearance and course. ■ Regression may be explained by direct cytotoxic effects of lymphocytes on melanocytes. ■ The most important differential diagnosis is the rare case of a melanoma revealing a halo-type of regression. ■ Halo nevi are benign lesions and treatment is not necessary in typical lesions in children. ■ Surgical excision and subsequent histopathological examination should be performed in halo nevi showing clinico-dermoscopic atypical features.

Chapter III.10

References   1. Sutton RL (1916) An unusual variety of vitiligo (leucoderma acquisitum centrifugum). J Cut Dis 34:797–800   2. Elder DE, Xu X. Halo naevus (2006). In: Le Boit PE, Burg G, Weedon D et al. (eds) World Health Organization classification of skin tumors. Pathology and genetics of skin tumors. IARC Press, Lyon   3. Herd RM, Hunter JA (1998) Familial halo naevi. Clin Exp Dermatol 23:68–69   4. Barnhill RL, Fitzpatrick TB, Fandrey K et al. (1995) Color atlas and synopsis of pigmented lesions. McGraw-Hill, New York   5. Inamadar AC, Palit A, Athanikar SB et al. (2003) Unusual course of a halo nevus. Pediatr Dermatol 20:542–543   6. Schallreuter KU, Kothari S, Elwary S et al. (2003) Molecular evidence that halo in Sutton’s naevus is not vitiligo. Arch Dermatol Res 295:223–228   7. Fishman HC (1976) Malignant melanoma arising with two halo nevi. Arch Dermatol 112:407–408   8. Tokura Y, Yamanaka K, Wakita H et al. (1994) Halo congenital nevus undergoing spontaneous regression. Involvement of T-cell immunity in involution and presence of circulating anti-nevus cell IgM antibodies. Arch Dermatol 130:1036–1041   9. Brazzelli V, Larizza D, Martinetti M et al. (2004) Halo nevus, rather than vitiligo, is a typical dermatologic finding of Turner’s syndrome: clinical, genetic, and immunogenetic study in 72 patients. J Am Acad Dermatol 51:354–358 10. Kolm I, Di Stefani A, Hofmann-Wellenhof R, et al. (2006) Dermoscopy patterns of halo nevi. Arch Dermatol 142:1627–1632 11. Argenziano G, Soyer HP, Chimenti S et al. (2003) Dermoscopy of pigmented skin lesions: results of a consensus meeting via the Internet. J Am Acad Dermatol 48:679–693 12. Itin PH, Lautenschlager S (2002) Acquired leukoderma in congenital pigmented nevus associated with vitiligo-like depigmentation. Pediatr Dermatol 19:73–75 13. Harvell JD, Meehan SA, LeBoit PE (1997) Spitz’s nevi with halo reaction: a histopathologic study of 17 cases. J Cutan Pathol 24:611–619 14. Saida T, Tsuchiya S (1984) Spontaneous partial regression of primary melanoma with death due to metastases. Arch Dermatol 120:1494–1496 15. Pantoja E, Wendth AJ, Beecher TS (1977) Perilesional vitiligo in melanoma. Cutis 19:51–53 16. Mooney MA, Barr RJ, Buxton MG (1995) Halo nevus or halo phenomenon? A study of 142 cases. J Cutan Pathol 22:342–348



A. Di Stefani, S. Chimenti 17. Musette P, Bachelez H, Flageul B et al. (1999) Immune-mediated destruction of melanocytes in halo nevi is associated with the local expansion of a limited number of T cell clones. J Immunol 162:1789â&#x20AC;&#x201C; 1794


Chapter III.11


Irritated Nevus and Meyerson’s Nevus Regina Fink-Puches, Iris Zalaudek, Rainer Hofmann-Wellenhof


III.11.2 Clinical Features

III.11.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 III.11.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . 129 III.11.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . 130 III.11.4 Relevant Clinical Differential Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 III.11.5 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . 131 III.11.6 Management. . . . . . . . . . . . . . . . . . . . . . . . . . 131 III.11.7 Case Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

III.11.1 Definition Benign melanocytic nevi exhibit a wide spectrum of clinical, dermoscopic, and histopathological appearances. Most of them are histopathologically banal. There is, however, a percentage which show one or more unusual clinical features and require more attention. Included among these are: (a) the irritated melanocytic nevus including the mechanically traumatized nevus with one special recently described variant, namely, the targetoid hemosiderotic nevus [1]; and (b) the UV-irradiated nevus. A special variant is (c) Meyerson’s nevus, which is surrounded by a halo of eczema in the same way that a halo of depigmentation surrounds a Sutton nevus [2].

The occurrence of traumatic changes is frequent in melanocytic nevi, particularly in those that are exophytic. Mechanical irritation by clothing and shaving is probably most often responsible, but other forms of injury, such as scratching and accident, may occur. Traumatized nevi are often found in the beard area of males and axillae of females [3]. Individuals often report a sudden change of pigmentation in the nevus, especially when they did not recognize the injury. Tenderness and itching are common symptoms. In traumatized nevus, a serocrust interspersed with hemorrhage mimicking irregular distribution of pigmentation is present [4]. The surrounding skin usually is erythematous. A variant of traumatized nevus, namely, the targetoid hemosiderotic nevus has recently been described. The main presentation is the sudden development of an asymptomatic halo on a longlasting, acquired nevus. The nevus is always slightly exophytic or papillomatous. The nevus is surrounded by an ecchymotic, violaceous halo causing a target-like phenomenon around the central nevus [1]. The UV-irradiated nevus may exhibit increased pigmentation. The adjacent skin may show an erythema according to the skin type [5, 6]. Meyerson’s nevus is characterized by the development of an eczematous halo around one ore more pigmented nevi [2, 7]. Clinical features are the appearance of an erythematous halo with overlying scales sometimes accentuated at the periphery of the erythematous zone [8]. This process can be confined to one or all nevi of an individual and may be accompanied by similar lesions not associated with nevi [9]. Slight pruri-


R. Fink-Puches, I. Zalaudek et al.

tus is a clinical symptom in most lesions. The eczematous lesions become desquamative and clear spontaneously or resolve under topical therapy with corticosteroids. The nevi persist unchanged once the surrounding lesions have resolved.

III.11.3 Dermoscopic Criteria


In irritated nevus dermoscopy is helpful to differentiate blood and melanin pigmentation. Targetoid hemosiderotic nevi show the typical features of acquired, compound melanocytic nevi with vascular–hemorrhagic changes superimposed on the nevus and particularly surrounding it: especially irregularly sized and shaped, jet-black areas and comma-shaped vessels are notified. The targetoid halo demonstrates a pale, ill-defined inner area surrounded by a homogeneous reddish zone with peripheral jagged margins; however, there are no dermoscopic features specific for a hemangioma [1]. Long-term as well as short-term UV irradiation may induce several changes in the dermoscopic features of melanocytic nevi. Stanganelli et al. found an increase in pigmentation and an increased prevalence of black dots in dermoscopic images of melanocytic nevi taken during the summer months [10]. Furthermore, a higher frequency of broad and prominent pigment network structures was observed. The same authors demonstrated that after 5–13 days of intense natural sun exposure, nevi showed more black dots, brown globules, and pigment network structures [11]. Hofmann-Wellenhof et al. demonstrated that UV-irradiated nevi exhibit significantly darker pigmentation and brown-black globules show an increase in number and intensity, whereas hypopigmented areas decrease. Moreover, the pigment network becomes more faded and less prominent [5]. These changes were already observed 3 days after UV-irradiation with two minimal erythema doses (MED) [12]. Remarkably, Tronnier and colleagues demonstrated that a single erythematogenic UV-irradiation dose induces more effective melanoma-simulating changes than fractionally applied UV doses [13].

In Meyerson’s nevi all dermoscopic criteria of benign compound or junctional melanocytic nevi may be observed.

III.11.4 Relevant Clinical Differential Diagnosis The clinical diagnosis of mechanically irritated nevus might be difficult. An irritated or traumatized nevus is a major simulator of melanoma, because exogenous irritation often results in changes of colors due to the effects of inflammation [14]. Targetoid hemosiderotic nevus should be differentiated from other pigmented lesions clinically with a peripheral halo, namely, a halo nevus, a Meyerson’s nevus, a cockade nevus, a targetoid hemosiderotic hemangioma and, most importantly, a melanoma. A cockade nevus is a very rare variant of a melanocytic nevus characterized by a peripheral pigmented halo with an intervening non-pigmented zone [15]. Targetoid hemosiderotic hemangioma is a benign vascular lesion clinically presenting as a single, small, annular target-like lesion on the trunk or extremity of young adults [16, 17]. The lesion is composed of a brown to violaceous central papule surrounded by a thin, pale area and a peripheral ecchymotic ring, which expands and subsequently disappears, whereas the central papule persists. Targetoid hemosiderotic nevus may clinically simulate melanoma; thus, awareness of it is important to avoid unnecessary management procedures. Ultraviolet irradiation induces transient changes in melanocytic nevi that can be detected dermoscopically, leading in some cases to diagnosis of melanoma; thus, the diagnosis of melanocytic skin lesions in patients after sun exposure should be handled with care [5]. Especially the increase in black-brown globules and darkening of pigmentation are often interpreted as signs of malignancy. [18–20]. In contrast, few hypopigmented areas, a faded border, and regularity of the pigment network are considered to be dermoscopic criteria of benign lesions [19, 21].

Irritated Nevus and Meyerson’s Nevus

III.11.5 Histopathology Histopathological examination of irritated melanocytic nevi reveals findings that depend, in part, on the interval between irritation and excision. Acute changes, such as erosion or superficial ulceration, marked spongiosis, and scale crust, are well-known features of an irritated nevus [22]. The phenomenon of an increase in the number of suprabasal melanocytes after irritation of a nevus has been investigated by Tronnier et al. [14]. These melanocytes above the dermo-epidermal junction, particularly in zones beneath foci of parakeratosis or scale crusts, are mostly arranged in solitary units, but sometimes also in nests. These melanocytic nevi, which exhibit an increased number of suprabasal melanocytes, may be easily confused histopathologically with melanoma [23]; however, the observation of suprabasal melanocytes should not be equated with the diagnosis of melanoma. Excoriated, abraded, or otherwise tormented nevi frequently display features similar to those of a persistent nevus (recurrent nevus or pseudomelanoma) with a scar replacing the upper part of the dermis [22]. The scar is usually smaller and less prominent than in a conventional recurrent nevus. The “scar” or the fibroplasia distorts the architecture of the nevus and is associated with occasional enlargement of melanocytes; therefore, an irritated or traumatized nevus is an important histopathological simulator of a regressive or of a “nevoid” melanoma [22]. Histopathologically, a central, mostly melanocytic component, and a peripheral, mainly hemorrhagic component can be observed in the fully developed stage of targetoid hemosiderotic nevus. No atypia or mitoses are found in the melanocytic component. In the papillary dermis deposits of fibrin, extravasated erythrocytes and a mixed inflammatory infiltrate intermingled with nests of melanocytes are observed. The peripheral violaceous halo is histopathologically characterized by extensive hemorrhage, hemosiderin deposits, and slit-shaped dissecting vascular channels between collagen bundles [1].

Chapter III.11

After exposure to UV irradiation, melanocytic nevi may show intraepidermal features simulating melanoma in situ with solitary melanocytes disposed not only at the dermo-epidermal junction but also in the upper epidermal layers. The dermal component does not reveal any hint for malignancy and, in addition, intraepidermal melanocytes do not show atypical features [24]. The described histopathological features return to normality within a few weeks following UV irradiation. Melanocytic nevi with eczematous halones (Meyerson’s nevi) may be either junctional or compound nevi. The pathognomonic histopathological findings are focal parakeratosis, punctuate crusts, variable amounts of spongiosis with focal microvesiculation, epidermal hyperplasia often of the psoriasiform type, and a moderately dense inflammatory infiltrate in the papillary dermis [8]. This infiltrate is mostly perivascular and composed of lymphocytes, histiocytes, and a few eosinophils; however, there is no evidence of regression in a typical Meyerson’s nevus.

III.11.6 Management Irritated nevi, including targetoid hemosiderotic nevi, return to normal clinical appearance 7–14 days after the initial trauma. A local antiinflammatory therapy or therapy with local heparinoid is recommended. A major pitfall is that melanomas may also show signs of inflammation or irritation; therefore, if there is no change in the clinical appearance after a followup period of 1 month, surgical excision and subsequent histopathological examination is recommended. The dermoscopic diagnosis of melanocytic skin lesions in individuals who present after extensive exposure to sun or after sunburn reaction should also be handled with care. Followup examination of these melanocytic lesions 1 month later to avoid unnecessary surgery should be done. As a rule, in Meyerson’s nevi the inflammatory changes disappear after several months, but the melanocytic nevi persist. No further management is necessary.



R. Fink-Puches, I. Zalaudek et al.

Fig. III.11.1.  Case Study

III.11.7 Case Study


A 44-year-old woman noticed a sudden change of a skin lesion on the right lower abdomen. She was very anxious about this lesion. At her first visit, she presented with a black, well-circumscribed smooth-surfaced papule surrounded by a targetoid violaceous rim (Fig. III.11.1a). Dermoscopically, this lesion revealed a central black area with some brownish coloration at the border of the papule. The papule was surrounded by a targetoid halo with a pale, inner area surrounded by a homogeneous reddish zone with a peripheral jagged margin. Overall the lesion appeared asymmetric in color; also, no dermoscopic structures were visible, despite the central bluish-black blotch (Fig. III.11.1b). Upon questioning concerning a trauma, the patient remembered that one of her children had injured her at that location; thus, the diag-

Fig. III.11.2.  Case Study

nosis of an irritated nevus (targetoid hemosiderotic nevus) was made. Re-examination was recommended. After re-examination 14 days later, clinically a well-shaped papule with a black center and brown periphery were observed. The red halo had disappeared (Fig. III.11.2a). Dermoscopically the periphery of the lesion revealed small globules. The center of the lesion showed a well-demarcated red-black area corresponding to the hemorrhagic crust. The ecchymotic halo had disappeared (Fig. III.11.2b).

Comment The clinical picture of this lesion was difficult to interpret, raising clinical suspicion of melanoma. Using dermoscopy the main structure was the central black-bluish blotch relatively sharply

Irritated Nevus and Meyerson’s Nevus

demarcated at the periphery and surrounded by reddish color indicating hemorrhagia; however, no other dermoscopic structures were visible. Anamnesis was helpful in this case and re-examination was recommended. After 14 days, there was no longer doubt that this was an absolutely benign lesion, showing symmetrical distributed small globules at the periphery of the lesion.


Core Messages ■ Exogeneous irritation of benign melanocytic nevi may often result in clinical changes simulating irregular melanin pigmentation caused by hemorrhagic serocrusts or intralesional dermal hemorrhagia. ■ Clinically, melanoma may be simulated, particularly when injury has not been recognized by the patient and a sudden change of pigmentation appears. ■ In these cases, dermoscopy might be extremely helpful to differentiate between blood and melanin. ■ Targetoid hemosiderotic nevus is a clinicopathological variant of traumatized melanocytic nevus. ■ It might also clinically simulate melanoma; thus, awareness of it is important to avoid unnecessary management procedures. ■ In most UV-irradiated nevi dermoscopic appearance is still suggestive of a nevus, but in some cases the dermoscopic changes may lead to the diagnosis of melanoma. ■ Re-examination of these cases is recommended to avoid unnecessary surgical intervention. ■ Meyerson’s nevus is characterized by a halo of eczema around a nevocellular nevus. In contrast to halo nevus, no zone of depigmentation develops at any time, but the exact nature of the spongiotic process remains obscure.

Chapter III.11

References   1. Tomasini C, Broganelli P, Pippione M (2005) Targetoid hemosiderotic nevus. A trauma-induced simulator of malignant melanoma. Dermatology 210: 200–205   2. Meyerson LB (1971) A peculiar papulosquamous eruption involving pigmented nevi. Arch Dermatol 103: 510–512   3. Blessing K (1999) Benign atypical naevi: diagnostic difficulties and continued controversy. Histopathology 34: 189–198   4. Tronnier M, Alexander M, Neutmann M, Brinckmann J, Wolff HH (2000) Morphologische Veränderungen in melanozytären Nävi durch exogene Faktoren. Hautarzt 51: 561–566   5. Hofmann-Wellenhof R, Soyer H.P, Wolf IH, Smolle J, Reischle S, Rieger E, Kenet RO, Wolf P, Kerl H (1998) Ultraviolet radiation of melanocytic nevi. A dermoscopic study. Arch Dermatol 134: 845–850   6. Pullmann H, Theunissen A, Galosi A, Steigleder GK (1981) Verhalten von Naevuszellnaevi unter PUVAund SUP-Therapie . Z Hautkr 56: 1412–1417   7. Krivanek JFC, Cains GD, Paver K (1977) Halo eczema and junctional naevi: a case report. Austral J Dermatol 18: 81–83   8. Weedon D, Farnsworth J (1984) Spongiotic changes in melanocytic nevi. Am J Dermatopathol 6 (Suppl 1): 257–259   9. Herrera JMF, Montanes MA, Fernandez J.F, Diez G (1988) Halo eczema in melanocytic nevi. Acta Derm Venereol (Stockh) 68: 161–163 10. Stanganelli I, Rafanelli S, Bucchi L (1996) Seasonal prevalence of digital epiluminescence microscopy patterns in acquired melanocytic nevi. J Am Acad Dermatol 34: 460–464 11. Stanganelli I, Bauer P, Bucchi L (1997). Critical effects of intense sun exposure on the expression of epiluminescence microscopy features of acquired melanocytic nevi. Arch Dermatol 133: 979–982 12. Hofmann-Wellenhof R, Wolf P, Smolle J, ReimannWeber A, Soyer HP, Kerl H (1997) Influence of UVB therapy on dermoscopic features of acquired melanocytic nevi. J Am Acad Dermatol 37: 559–563 13. Tronnier M, Rudolph P, Köser T, Raasch B, Brinckman J (1997) One single erythemagenic UV-irradiation is more effective in increasing the proliferative activity of melanocytes in melanocytic nevi compared to fractionally applied high doses. Br J Dermatol 137: 534–539 14. Tronnier M, Hantschke M, Wolff HH (1997) Presence of suprabasal melanocytes in melanocytic nevi after irritation of them by tape stripping. Dermatopathol Pract Concept 3: 6–8



R. Fink-Puches, I. Zalaudek et al. 15. James MP, Wells RS (1980) Cockarde naevus: an unusual variant of the benign cellular naevus. Acta Derm Venereol 60: 360–363 16. Santa Cruz D, Aronberg J (1988) Targetoid hemosiderotic hemangioma. J Am Acad Dermatol 19: 550–558 17. Guillon L, Calonje E, Speight P, Rosai J, Fletcher CDM (1999) Hobnail hemangioma. A pseudomalignant vascular lesion with a reappraisal of targetoid hemosiderotic hemangioma. Am J Surg Pathol 23: 97–105 18. Argenziano G, Fabbrocini G, Carli P, Giorgi V de, Delfino M (1997). Epiluminescence microscopy: criteria of cutaneous melanoma progression. J Am Acad Dermatol 37: 68–74 19. Menzies SW, Ingvar C, Crotty KA, McCarthy WH (1996) Frequency and morphologic characteristics of invasive melanomas lacking specific surface microscopic features. Arch Dermatol 132: 1178–1182


20. Nilles M, Boedeker RH, Schill W-B (1994) Surface microscopy of naevi and melanomas: clues to melanoma. Br J Dermatol 130: 349–355 21. Dummer W, Blaheta HJ, Bastian BC, Schenk T, Brocker EV, Remy W (1995) Preoperative characterization of pigmented skin lesions by epiluminescence microscopy and high-frequency ultrasound. Arch Dermatol 131: 279–285 22. Massi G, Leboit PE (2004) Common nevus. In: Massi G, Leboit PE (eds) Histological diagnosis of nevi and melanoma. Steinkopff Darmstadt, Germany, pp 59–60 23. Ackerman AB, Cerroni L, Kerl H (1994). Pitfalls in histopathologic diagnosis of malignant melanoma. Lea and Febiger, Philadelphia 24. Cerroni L, Kerl H (1998) Simulators of malignant melanoma of the skin. Eur J Dermatol 8: 388–396

Chapter III.12

Melanocytic Lesions in Darker Racial Ethnic Groups


Heather Woolery-Lloyd

Contents III.12.1

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . 135

III.12.2 Clinical Features. . . . . . . . . . . . . . . . . . . . . 135 III.12.2.1 Nevi. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 III.12.2.2 Melanoma. . . . . . . . . . . . . . . . . . . . . . . . . . . 136 III.12.3

Relevant Clinical Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 137


Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . 137

References. . . . . . . . . . . . . . . . . . . . . . . . . . . 138

ally separated melanosomes, whereas keratinocytes from the lighter palmar surfaces of black patients have complexed melanosomes [3]. This finding further supports the theory that skin color correlates with the distribution of melanosomes, since the melanosomes in the light volar skin of black patients closely resemble the melanosomes of white patients.

III.12.2 Clinical Features III.12.2.1 Nevi

III.12.1 Introduction Pigmentation of the skin is determined at a cellular level. Although there may be some variation in the number of melanocytes between races, this difference is not striking. There are approximately 2000 epidermal melanocytes per square millimeter on the head and forearm and 1000 epidermal melanocytes per square millimeter on the rest of the body. These differences are present at birth [1]; thus, all persons have the same total number of melanocytes. It is the distribution of melanosomes in the keratinocytes that correlates with skin color. In white skin, melanosomes are small and aggregated in complexes. In black skin, there are larger melanosomes, which are singly distributed within keratinocytes [2]. Interestingly, the distribution of melanosomes in black patients varies with the location on the body. In white patients, keratinocytes of both the volar and thigh skin demonstrate complexed melanosomes. Keratinocytes from the thighs of black patients demonstrate individu-

There are racial differences in the incidence and distribution of nevi in black and white patients (Table III.12.1). Studies of nevi in white patients range from an average of 14.6 to 61 nevi per patient [4â&#x20AC;&#x201C;6]. Studies of nevi in black patients range from 2.0 to 11 nevi per patient [5â&#x20AC;&#x201C;8]; thus, it appears that nevi in black patients are less common than in white patients. Interestingly, even within the black population, the number of nevi per patient differs. A study of black patients in New Orleans further subdivided the patients into fair, light-brown, and dark-brown groups. The authors reported a greater number of total body nevi in lighter black patients when compared with darker black patients [8]. This finding was different from a prior study which did not demonstrate any variation in number of nevi within the black population [5]. The inconsistency between the two studies may be accounted for by a larger number of subjects in the New Orleans study and also, perhaps, a greater local variation in skin color in the New Orleans population. Another study in the Netherlands also demonstrated a steady decline in the median number of moles from fair


H. Woolery-Lloyd Table III.12.1.  Comparison of study results of distribution of nevi in white and black patients

White patients

Black patients









New York

The Netherlands

New York


New Orleans

The Netherlands








No. of patients







Average nevi per patient







with lighter black patients. Histopathologically, these acral melanocytic lesions were most often lentigo simplex [8]. The average number of nevi on the palms and soles in the New Orleans black patients was 0.3 nevi. A study of 500 Nigerian healthy adults reported an average of one to three nevi per patient on the palms [9]. Acral melanocytic lesions in the black population are of special interest since this is the most common site of melanoma in black patients. In addition, clinical differentiation between acral lentigo and acral lentiginous melanoma can be especially challenging in darkerskinned patients.

III.12.2.2 Melanoma Fig. III.12.1.  This acral melanocytic nevus emphasizes the importance of examining the interdigital space when performing a full skin examination


skin to darker skin complexions [6]. From these data, it appears that as skin color increases, the total number of nevi on the body decreases. The authors of the New Orleans study also examined the location of nevi on the body in the fair, light-brown, and dark-brown groups. This study revealed another interesting variation within the black population: They found a greater number of palmar-plantar nevi in darker black patients compared with lighter black patients (Fig. III.12.1). Similarly, mottled pigmentation of the palms and soles was more frequent in the darker black patients. These data suggest that darker black patients have a greater number of acral melanocytic lesions compared

The annual incidence of melanoma in black patients ranges from 0.5 to 1.1 per 100,000 compared with 2–17 per 100,000 in white patients [10]. Melanomas are divided into four subtypes including nodular, superficial spreading, lentigo maligna, and acral lentiginous melanoma. Acral lentiginous melanoma is the most common subtype of melanoma in black patients [10]. Melanoma can also be categorized by its location on the body. There have been suggestions that plantar melanoma, regardless of subtype, is more common in black patients than in white patients. In fact, the incidence of plantar melanoma is equal among the races [11]; however, in black patients with melanoma, the plantar and palmar surfaces are the most frequent location. In a study of 204 melanomas in black Africans, 86% presented on the palmar or plantar skin [12]. Subungal melanomas also represent a com-

Melanocytic Lesions in Darker Racial Ethnic Groups

mon presentation of melanoma in black patients. Nonacral cutaneous sites for melanoma are less common in black patients making the overall incidence of melanoma in black patients lower than in white patients [13]. Mucosal melanomas are another common presentation of melanoma in black patients. These can occur on mucosal surfaces such as the oral, vulvar, and anorectal mucosa [14]. In contrast to cutaneous melanomas, these melanomas typically present later in life, after 60 years of age [15]. Although the incidence of melanoma is lower in black patients, melanoma is, in fact, a more lethal disease in this population. The California Cancer registry reported a 5-year survival rate for black patients of 70% compared with a survival rate of 87% for white patients [16]. Another study examined melanoma survival rates at Washington Hospital Center. This study found a 5-year survival rate in African Americans of 58.8% compared with 84.8% in white patients [17]. Black patients were less likely to present with in situ/stage-I disease than white patients (39.3% vs 60.4%). Furthermore, black patients were more likely to present with stage-III/IV disease than white patients (32.1% vs 12.7%) [17]. Delayed diagnosis and treatment in black patients may explain the large disparity in survival rates observed between these two groups.

III.12.3 Relevant Clinical Differential Diagnosis Nonmelanoma skin cancers frequently present as pigmented lesion in darker skinned patients. Most black patients with basal cell carcinoma present with hyperpigmented, translucent nodules on the head and neck [18]. Similarly, squamous cell carcinoma can present as a hyperpigmented plaque in black patients. It is commonly described on the legs of elderly black women and can be confused with melanoma (Fig. III.12.2) [19].

Chapter III.12

Fig. III.12.2.  A pigmented squamous cell carcinoma in an elderly African-American woman. This presentation of squamous cell carcinoma can mimic melanoma

III.12.4 Conclusion In conclusion, there are many unique characteristics of melanocytic lesions in skin of color. The number of total body nevi appears to decrease with skin color, whereas the presence of palmar–plantar nevi increases with skin color. The latter observation may explain why the palmar and plantar surfaces are the most frequent location of melanoma in black patients. It is also important to note that other skin neoplasms frequently present as pigmented lesions in darker-skinned patients. Basal cell carcinoma and, especially, squamous cell carcinoma can be confused with melanoma due to their unique presentation in darker skin types. The unique features of pigmented lesions in darker skin types should be considered when examining and treating patients of darker racial ethnic groups.



H. Woolery-Lloyd


Core Messages ■ The total number of melanocytes does not vary greatly with skin color, whereas the distribution of melanosomes within keratinocytes correlates with skin color. ■ The number of total body nevi decreases with increased skin color; the number of palmar–plantar nevi increases with increased skin color. ■ Acral lentiginous melanoma is the most common subtype of melanoma in black patients; however, the incidence of plantar melanoma is equal among the races. ■ Most melanomas in black patients occur on nonglaborous skin (especially in palms and soles, less frequently in subungal skin and mucosa). ■ Melanoma survival rates are significantly lower in black patients, which may be explained by delayed diagnosis and treatment in this patient population. ■ Squamous cell carcinomas and basal cell carcinomas frequently present as pigmented lesions in darker patients and may mimic melanoma.



  1. Jimbow K, Quevedo WC, Prota G, Fitzpatrick TB (1999) Biology of melanocytes. In: Freedberg IM et al. (eds) Dermatology in general medicine, 5th edn. McGraw-Hill, New York, pp 192–220   2. Rosdahl IK, Szabo G (1976) Thymidine labeling of epidermal melanocytes in UV-irradiated skin. Acta Derm Venereol (Stockh) 56:159   3. Milburn PB, Silver DN, Sian CS (1982) The color of the skin of the palms and soles as a possible clue to the pathogenesis of acral-lentiginous melanoma. Am J Dermatopathol 4:429   4. Pack GT, Lenson N, Gerber DM (1952) Regional distribution of moles and melanoma. Arch Surg 65:862–870

  5. Pack GT, Davis J (1963) The relation of race and complexion to the incidence of moles and melanomas. Ann NY Acad Sci 100:719–742   6. Rampen, FH, de Wit PE (1989) Racial differences in mole proneness. Acta Dermatol Venerol 69:234– 236   7. Lewis MG, Johnson K (1968) The incidence and distribution of pigmented naevi in Ugandan Africans. Br J Dermatol 80:362–366   8. Coleman WP, Gately L, Krementz AB, Reed RJ, Krementz ET (1980) Nevi, lentigines, and melanomas in blacks. Arch Dermatol 116: 548–551   8. Crowley NJ, Dodge R, Volmer RT et al. (1991) Malignant melanoma in black Americans: a trend toward improved survival. Arch Surg. 126:1359–1365   9. Otu AA (1990) Incidence of benign pigmented moles (melanocytic naevi) in black Africans: divergent with melanoma. Trop Doctor 20:179–180 10. Coleman WP, Loria PR, Reed RJ et al. (1980) Acral lentiginous melanoma. Arch Dermatol 116:773 11. Stevens NG, Liff JM, Weiss NS (1990) Plantar melanoma: Is the incidence of melanoma of the sole of the foot really higher in blacks than whites? Int J Cancer 45:691–693 12. Giraud RM, Rippey E, Rippey JJ (1975) Malignant melanoma of the skin in black Africans. S Afr Med J 49:665 13. Bartolomei FJ, Dubay GV (1988) Acral lentiginous melanoma pedal lesions in the black population. J Am Podiatr Med Assoc 78:584–589 14. Wu E, Golitz LE (2000) Primary noncutaneous melanoma. Clin Lab Med 20:731–744 15. Tsai T, Vu C, Henson DE (2005) Cutaneous, ocular and visceral melanoma in African Americans and Caucasians. Melanoma Res 15:213–217 16. Cress RD, Holly EA (1997) Incidence of cutaneous melanoma among non-Hispanic whites, Hispanics, Asians, and blacks: an analysis of California cancer registry data, 1988–1993. Cancer Causes Control 8:246–252 17. Byrd KM, Wilson DC, Hoyler SS et al. (2004) Advanced presentation of melanoma in African Americans. J Am Acad Dermatol 50:21–24, 142–143 18. Matsuoka LY, Schauer PK, Sordillo PP (1981) Basal cell carcinoma in black patients. J Am Acad Dermatol 4:670–672 19. McCall CO, Chen SC (2002) Squamous cell carcinoma of the legs in African Americans. J Am Acad Dermatol 47:524–529

Chapter III.13

Miescher Nevus Steven Q. Wang, Harold H. Rabinovitz, Alfred W. Kopf

Contents III.13.1 Definition. . . . . . . . . . . . . . . . . . . . . . . . . . . 139 III.13.2 Clinical Features. . . . . . . . . . . . . . . . . . . . . 139 III.13.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . 139 III.13.4 Relevant Clinical Differential Diagnoses. . . . . . . . . . . . . . . . . . . . . . . . . . . 139


found on the face and neck. Typically, Miescher nevi are seen in people over the age of 30 years. Today, most of the dermatology and dermatopathology textbooks simply refer to them as acquired intradermal nevi. The distinctions between this acquired dermal nevus and other intradermal nevus, such as the Unna nevus, are no longer emphasized.

III.13.5 Histopathology. . . . . . . . . . . . . . . . . . . . . . 140 III.13.6 Management . . . . . . . . . . . . . . . . . . . . . . . . 140 III.13.7 Case Studies. . . . . . . . . . . . . . . . . . . . . . . . . 140 III.13.7.1 Case 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 III.13.7.2 Case 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140

References. . . . . . . . . . . . . . . . . . . . . . . . . . . 141

III.13.1 Definition Miescher nevus is an acquired dermal melanocytic nevus with a smooth, dome shape. This benign nevus is commonly located on the face.

III.13.2 Clinical Features Miescher nevus is named after Guido Miescher [1, 2], who studied 100 melanocytic nevi and classified “nevus cells” into A, B, and C types according to their location within the dermis and their cytological appearance. More than half of the studied nevi were facial, endophytic, dermal lesions. Clinically, this benign intradermal nevus presents as a dome-shaped papule with light brown or skin color. Most Miescher nevi are

III.13.3 Dermoscopic Criteria There are no specific dermoscopic patterns or structures that can differentiate Miescher nevus from other intradermal nevi. The most common dermoscopic pattern associated with the Miescher nevus is the homogeneous globular pattern with focal and symmetric arrangement of dots and globules arranged in cobblestone distribution [3]. The globules can have light to dark brown, and occasionally blue, colors. These lesions often have light-brown or skin-colored homogeneous structureless area. Histologically, the globules correlate with nests of nevus cells. In addition to the globules, Miescher nevus can have “comma-shaped” blood vessels and milia. Pigmented networks, a hallmark structure of melanocytic nevi, are generally not seen in Miescher nevus, because like an intradermal nevus, there is no junctional component.

III.13.4 Relevant Clinical Differential Diagnoses Stereotypical Miescher nevi are relatively easy to diagnose. The differential diagnosis of medium and small intradermal nevus includes a neurofibroma and a fibrous papule of the face.


S.Q. Wang, H.H. Rabinovitz, A.W. Kopf

III.13.5 Histopathology Histopathologically, Miescher nevus is an intradermal nevus with no junctional component. At scanning magnification, Miescher nevus is a symmetrical, dome-shaped papule. The nevus cells are distributed in a wedge shape and arranged deep into the reticular dermis. Because the nevus is commonly located on the face, numerous folliculosebaceous units can be seen on the tissue sections. By and large, the adenxa are avoided by the nevus cells. At a higher magnification, the nevus cells show “maturation” with large and more pigmented nevus cells on top and smaller cells in the deeper dermis.

III.13.6 Management Miescher nevus is benign. It is very rare that these nevi are associated with a melanoma. For cosmetic reasons, most Miescher nevi can be removed with either shave or punch excision. It is unnecessary to remove the entire nevus, and the surgical specimen should be submitted for histopathological examination because rarely incompletely removed intradermal nevi can recur and give rise to lesions which can be easily mistaken for melanoma clinically and histopathologically. Access to the original biopsy sections reveals that the original lesion was completely benign. It is highly unlikely that the recurrence of pigmentation in the residual scar is melanoma.

III.13.7 Case Studies III.13.7.1 Case 1


A 45-year-old Caucasian man presented with more than 5 years history of asymptomatic papule on the left cheek. Clinically, the lesion was soft, exophytic, and about 1 cm in diameter. Dermoscopic examination showed the presence of blood vessels and faint clusters of brown glob-

Fig. III.13.1.  Case Study

ules within a large homogeneous structureless area. The patient was reassured about the benign nature of this lesion, and no treatment was performed.

III.13.7.2 Case 2 A 39-year-old Caucasian man presented with a brown pigmented mole on the left chin within the bearded region. He reported occasional traumas to the area when he shaves. The mole was not painful. Clinically, it was a 1.3-cm brown mole with a mammilated surface. Dermoscopic examination showed clustered light-brown globules with cobblestone arrangement and structureless area. Because of frequent trauma from shaving, the mole was shave removed.

Miescher Nevus

Chapter III.13

Fig. III.13.2.  Case Study


Core Messages ■ Miescher nevus is an intradermal acquired nevus commonly located on the face. ■ As a rule, Miescher nevus is benign but may be uncommonly be associated with a melanoma. ■ Dermoscopically, most Miescher nevi reveal a variation on the theme of a homogeneous globular pattern.

References 1. Ackerman AB, Magana-Garcia M. Naming acquired melanocytic nevi: Unna’s, Miescher’s, Spitz’s, Clark’s. Am J Dermatopathol 1990; 12: 193–209 2. Miescher G, Albertini A von. Histologie de 100 case de naevi pigmentaires d’apres les methods de Masson. Bull Soc Fr Dermatol Syph 1935; 42: 1265–1273 3. Bauer J, Blum A. Dermoscopic features of common melanocytic nevi of the junctional, compound, and dermal type. In: Marghoob AA, Braun RP, Kopf AW (2005) Atlas of dermoscopy. Taylor and Francis, UK, pp 181–188


Chapter III.14

Nevi with Particular Pigmentation: Black, Pink, and White Nevus


Iris Zalaudek, Robert Johr, Bernd Leinweber


III.14.2 Clinical Features


Definition. . . . . . . . . . . . . . . . . . . . . . . . . . . 142

III.14.2 III.14.2.1 III.14.2.2 III.14.2.3

Clinical Features. . . . . . . . . . . . . . . . . . . . . 142 Black Nevus. . . . . . . . . . . . . . . . . . . . . . . . . 142 Pink Nevus. . . . . . . . . . . . . . . . . . . . . . . . . . 142 White Nevus . . . . . . . . . . . . . . . . . . . . . . . . 143

III.14.3 III.14.3.1 III.14.3.2 III.14.3.3

Dermoscopic Criteria. . . . . . . . . . . . . . . . . 143 Black Nevus. . . . . . . . . . . . . . . . . . . . . . . . . 143 Pink Nevus. . . . . . . . . . . . . . . . . . . . . . . . . . 144 White Nevus . . . . . . . . . . . . . . . . . . . . . . . . 144


Relevant Clinical Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 III.14.4.1 Black Nevus. . . . . . . . . . . . . . . . . . . . . . . . . 144 III.14.4.2 Pink Nevus. . . . . . . . . . . . . . . . . . . . . . . . . . 144 III.14.4.3 White Nevus . . . . . . . . . . . . . . . . . . . . . . . . 145 III.14.5 III.14.5.1 III.14.5.2 III.14.5.3

Histopathology. . . . . . . . . . . . . . . . . . . . . . 145 Black Nevus. . . . . . . . . . . . . . . . . . . . . . . . . 145 Pink Nevus. . . . . . . . . . . . . . . . . . . . . . . . . . 145 White Nevus . . . . . . . . . . . . . . . . . . . . . . . . 145

III.14.6 III.14.6.1 III.14.6.2 III.14.6.3

Management . . . . . . . . . . . . . . . . . . . . . . . . 145 Black Nevus. . . . . . . . . . . . . . . . . . . . . . . . . 145 Pink Nevus. . . . . . . . . . . . . . . . . . . . . . . . . . 145 White Nevus . . . . . . . . . . . . . . . . . . . . . . . . 146

References. . . . . . . . . . . . . . . . . . . . . . . . . . . 146

III.14.1 Definition


Nevi with particular pigmentation are defined herein as benign melanocytic nevi that do not contain significant amounts of brown color.

III.14.2.1 Black Nevus This variant of a benign melanocytic nevus is also referred to as a “hypermelanocytic nevus” or “nevus of midlife.” [1] They appear as black macules often with a subtle touch of brown color at the periphery, 5 mm in size or even smaller typically located on the trunk and/or extremities (Fig. III.14.1). Black nevi vary in number from a single lesion to more than 50, typically, but are not seen only in darker-skinned individuals (Fitzpatrick photo-types III and IV) between the ages of 16 and 30 years (“nevus of mid-life”). Because of the intense black color suggestive of melanoma, they are in the group of lesions that are referred to as melanoma simulators. A red flag of concern should always be raised when a black-pigmented lesion is found. A single black nevus is more worrisome than multiple lesions. Concerns about the diagnosis can be easily disarmed by its clinical hallmark, the “black lamella.” This represents a removable pigmented scale located in the center or covering most of the lesion. With tape stripping the black lamella can be removed in most, but not all, lesions displaying local dermoscopic criteria. The pigmented scale often is left on the tape, which confirms the banal nature of the lesion.

III.14.2.2 Pink Nevus The worldwide distribution of this variant of a melanocytic nevus varies from country to country, and even within regions of a single country. Typically seen in individuals with fair skin type

Black, Pink, White Nevi

Fig. III.14.1.  Clinical image of a so-called black nevus shows a symmetric dark-colored plaque with a scaly surface. The surface scale is due to the black lamella, which can be easily removed by tape

Chapter III.14

Fig. III.14.3.  Clinical view of multiple white nevi located on the back. When examined by tangential light, a silvery shiny surface with accentuated skin markings can be seen (left)

III.14.2.3 White Nevus

Fig. III.14.2.  Clinical view of a pink nevus reveals a symmetric pink plaque. Note that on the surrounding skin pigmented nevi are present. Because this was the only pink lesion seen in this patient, excision was performed and histopathology revealed a benign nevus with mild dysplasia

(Fitzpatrick photo-types I and II) of all ages with other pigmented melanocytic nevi, they can be macules and papules (Fig. III.14.2) with varying shades of pink color. The papular lesions are often soft, easily compressible, and at times have a single central hair. The number of pink nevi ranges from single to multiple lesions located on any part of the body including the scalp, where their hidden nature should be uncovered by a complete skin examination [2, 3].

This variant of melanocytic nevus is characterized by white or pale pink macules on papules with accentuated skin markings and a silvery sheen when viewed with tangential lighting (Fig. III.14.3). They are located on the trunk or extremities in adults and vary from a few to hundreds of lesions usually but not always in fair-skinned individuals (Fitzpatrick phototype I). White nevi are rare or under-reported and should be considered possible markers of melanoma development, because they are often found in individuals with a history of melanoma and/or have histopathological characteristics of dysplastic nevi [4].

III.14.3 Dermoscopic Criteria III.14.3.1 Black Nevus Black nevi are characterized by a reticular pattern, typified by a fine brown pigment network with regular holes and meshes. Dots can also be seen; however, most of the criteria are hidden by the black lamella that appears as dark brown or black blotch of featureless color covering most of, if not the entire, lesion (Fig. III.14.4). No high-risk local criteria, such as streaks (typical for spitzoid lesions), are ever seen which ascertains the dermoscopic diagnosis [5].



I. Zalaudek, B. Leinweber, R. Johr

Fig. III.14.4.  Dermoscopic view of the black nevus as shown in Fig. III.14.1. The central lamella appears as a structureless black blotch and covers the underlying regular and fine pigment network, which is seen at the border

III.14.3.2 Pink Nevus Pink nevi can be featureless with only shades of pink color or feature poor with foci of lightbrown color, remnants of fine pigment network, or teleangiectatic vascular structures. The vascular patterns are basically non-specific or may reveal dotted, “comma-shaped,” and larger linear vessels that can be seen alone or in combination (Fig. III.14.5) [6]. The larger arborizing vessels typical of basal cell carcinoma and other high-risk local dermoscopic criteria seen in pigmented melanocytic nevi are absent.

Fig. III.14.5.  Dermoscopy of the pink nevus shown in Fig. III.14.2. There is lack of specific structures which would allow the diagnosis of a benign nevus with extreme confidence. Because this nevus was the only pink lesion in a patient with a fair skin type and numerous nevi, ­excision was performed in order to rule out a malignant tumor

III.14.4 Relevant Clinical Differential Diagnosis III.14.4.1 Black Nevus Melanoma is the most important consideration in this clinical setting. Dysplastic nevi and Spitz nevi should also be included in the differential diagnosis. A single lesion is more worrisome than multiple symmetrical uniformly pigmented round to oval macules or papules with the typical black lamella.

III.14.4.2 Pink Nevus III.14.3.3 White Nevus White nevi are featureless and reveal only teleangiectasias of the dermal plexus shimmering through the epidermis.


A solitary pink macule or papule could be melanocytic or non-melanocytic, benign or malignant. Multiple pink lesions, even in their clinical features, are typically seen in fair skin types. In these cases, regular follow-up should override excision, although they could be a combination of banal and dysplastic nevi. If there is just a single lesion, differentiation from nonmelanoma skin cancer may be difficult, or even impossible, clinically or with dermoscopy. No matter how old or young the patient is, a solitary pink lesion could also be amelanotic melanoma. Pediatric patients have a high per-

Black, Pink, White Nevi

Chapter III.14

centage of amelanotic melanomas that do not fit the criteria of the typical pigmented melanoma [7]. In this clinical setting, “If in doubt, cut it out.”

III.14.4.3 White Nevus The differential diagnosis of white nevus is extensive and depends on the number and distribution of lesions plus the age and history of the patient. When few in number, consider flat warts as well as seborrheic and lichen planuslike keratosis. With multiple lesions consider post-inflammatory hypopigmentation, pityriasis alba, idiopathic guatte hypomelanosis, hypopigmented early vitiligo, morphea, lichen sclerosis et atophicus hypopigmented mycosis fungoides, and leprosy [4]. The silvery sheen seen with tangential lighting will be a clue to the diagnosis, which is finally made when the clinical picture is put together with histopathology.

III.14.5 Histopathology

Fig. III.14.6.  Histopathology of a black nevus reveals an increased number of melanocytes arranged as mainly solitary units at the dermo-epidermal junction. Note the overlying pigmented parakeratosis corresponding to the clinico-dermoscopic feature of the black lamella

changes may show focally lamellar fibrosis, but no evidence of inflammatory infiltrates, accumulation of melanophages, or increase of blood vessels. Staining with Fontana-Masson does not reveal pigmented granules. Immunohistochemical staining for S-100 protein shows strong positivity of all cells, whereas HMB-45 may be positive only in scattered melanocytes.

III.14.5.1 Black Nevus Black nevus is characterized by melanocytes arranged mainly along the basal layer (junctional nevus) and the finding of pigmented parakeratosis in the stratum corneum (Fig. III.14.6).

III.14.5.2 Pink Nevus Histopathologically, melanocytes in pink nevi do not contain pigment and are typically arranged in nests at the dermo-epidermal junction and in the upper dermis (compound nevus).

III.14.5.3 White Nevus Histopathology reveals an increased number of atypical melanocytes with hyperchromatic and pleomorphic nuclei, arranged as solitary units and in nests, mainly at the dermo-epidermal junction and the papillary dermis. Stromal

III.14.6 Management III.14.6.1 Black Nevus The stereotypical black nevus does not need to be excised. Attention should be focused not to miss subtle clues pointing to a more ominous diagnosis. The novice dermoscopist might consider excising a solitary black nevus or one of multiple lesions to confirm the diagnosis. With experience, this will no longer be necessary. Baseline gross and digital dermoscopic images can be used to follow these patients.

III.14.6.2 Pink Nevus The index of suspicion should always be increased for potentially high-risk pathology when a pink lesion is seen. There is no general management rule for these nevi; it depends strongly on the experience of the clinician. In



I. Zalaudek, B. Leinweber, R. Johr

cases of a single lesion and/or history of change, excision to rule out melanoma should be performed.

III.14.6.3 White Nevus The diagnosis of this peculiar nevus is based on its histopathological features, since the clinical diagnosis is often difficult. Patients with this type of nevus seem to be at higher risk for melanoma development and should be managed similar to patients with a dysplastic nevus syndrome (i.e., complete skin examinations and regular follow-up visits every 6–12 months).


Core Messages ■ Black, pink, or white nevi represent a sub-group of melanocytic lesions that differ in color from the ubiquitous brown melanocytic nevus. ■ Their management should be individualized for each patient. ■ A good clinical-dermoscopic correlation is essential and as much of the clinical picture should be put together before deciding on the disposition of a lesion.


References 1. Cohen LM, Bennion SD, Johnson TW, Golitz LE. Hypermelanotic nevus: clinical, histopathologic, and ultrastructural features in 316 cases. Am J Dermatopathol 1997; 19:23–30 2. Friedmann RJ, Heilman ED, Rigel DS, Kopf AW, et al. Clinical features of dysplastic melanocytic nevi. Dermatol Clin 1985; 9:239–249 3. Johr RH. Pink lesions. Clin Dermatol 2002;20:289– 296 4. Zalaudek I, Hofmann-Wellenhof R, Cerroni L, Kerl H. “White” dysplastic melanocytic naevi. Lancet 2002; 359:1999–2000 5. Hofmann-Wellenhof R, Blum A, Wolf IH, Piccolo D, Kerl H, Garbe C, Soyer HP. Dermoscopic classification of atypical melanocytic nevi (Clark nevi). Arch Dermatol 2001;13:1575–1580 6. Argenziano G, Zalaudek I, Corona R, Sera F, Cicale L, Petrillo G, Ruocco E, Hofmann-Wellenhof R, Soyer HP. Vascular structures in skin tumors: a dermoscopy study. Arch Dermatol 2004;140:1485–1489 7. Ferrari A, Bono A, Baldi M, Collini P, Casanova M, Pennacchioli E, Terenziani M, Marcon I, Santinami M, Bartoli C. Does melanoma behave differently in younger children than in adults? A retrospective study of 33 cases of childhood melanoma from a single institution. Pediatrics 2005;115:649–654

Chapter III.15

Recurrent Nevus Andreas Blum

Contents III.15.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 III.15.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . 147

III.15 most important differential diagnosis is recurrent/persistent melanoma and re-evaluation of the original histopathological specimen is mandatory for a definite diagnosis [12].

III.15.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . 147 III.15.3 Relevant Clinical Differential Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 III.15.4 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . 149 III.15.5 Management. . . . . . . . . . . . . . . . . . . . . . . . . . 149

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

III.15.1 Definition Recurrent nevi, also called persistent nevi, are frequently observed following incomplete excision by superficial shaving techniques, an ordinary procedure for the management not only of dermal nevi but also of Clark nevi in the daily routine of a busy dermatological out-patient service. Recurrent nevi are pigmented skin lesions that clinically, dermoscopically, and also histopathologically are commonly interpreted as melanoma in situ or superficial melanoma.

III.15.2 Clinical Features Recurrent nevi usually appear as asymmetric, bizarrely outlined, and poorly circumscribed patches with a dark-brown to black pigmentation resembling a superficial melanoma. As a rule, a scar is present around this pigmented lesion, although in some instances the scar is difficult to detect and only anamnestic data lead to the diagnosis of recurrent nevus. Obviously, the

III.15.3 Dermoscopic Criteria Dermoscopically, recurrent nevi are usually characterized by the presence of a homogeneous or multicomponent pattern with a prominent dark-brown to black coloration. An atypical pigment network, irregular streaks, and black dots are commonly observed in recurrent nevi. Due to this established features, dermoscopy increases the diagnostic accuracy in comparison with the clinical investigation with the naked eye (Fig. III.15.1, III.15.2) [1–3]. However, no study which has described typical dermoscopic features of recurrent nevi has been published thus far; therefore, this chapter describes recurrent nevi in dermoscopy and compares them with the features of melanoma in -situ (Fig. III.15.3, III.15.4). The following features were based on a study of more than 2500 benign and 200 malignant histopathologically proven melanocytic lesions [4]. Six recurrent nevi and 12 melanoma in situ were found in this database [5]. The results of this first observation are given in Table III.15.1. Recurrent nevi showed mostly a symmetric centrifugal pattern from the center of the scar with different dermoscopic structures in one melanocytic lesion. In all 6 cases, a hyperpigmentation at the periphery was not present. Within and in the surroundings of the lesion, reddish areas with vessels could be seen. In our series of melanomas in situ mostly an asymmetric pattern with a hyperpigmentation


A. Blum


Fig. III.15.1.  Recurrent nevus, dermoscopy view. Note an irregular outlined whitish halo representing a superficial scar caused by a shaving biopsy. The centrally situated recurrent nevus is dermoscopically virtually indistinguishable from a melanoma in situ. The patient’s history is crucial for the diagnosis

Fig. III.15.2.  Recurrent nevus, dermoscopy view. The whitish halo here is regular and not so prominent. The recurrent nevus in the center is charaterized by irregular blue blotches

Fig. III.15.3.  Melanoma in situ, dermoscopy view. Besides the lack of a surrounding scar, this melanoma in situ could dermoscopically easily be mixed with a recurrent nevus

Fig. III.15.4.  Melanoma in situ, dermoscopy view. Also this irregularly outlined black lesion shares morphological features with a recurrent nevus

at the periphery was observed. Also, several different dermoscopic structures and colors were present. The pattern of growth was not regular and not centrifugal. Also, no reddish surroundings and vessels could be detected. The dermoscopic pattern of recurrent nevi can be compared with a “bunch of flowers” when the observer is looking at it from the top.

The growth pattern of a melanocytic lesion has an important impact for the benign or malignant potential of the lesion [7]. In the case of a hyperpigmentation at the periphery a precursor of a melanoma or an initial melanoma must be excluded. In contrast, when the pigmentation has a centrifugal pattern, the melanocytic lesion is benign [8].

Recurrent Nevus

Chapter III.15


Table III.15.1.â&#x20AC;&#x201A; Results of study

Recurrent nevus

Melanoma in situ



Not present

Hyperpigmentation at the periphery

Not present


Dermoscopic structures






Pattern of growth


Not regular

Reddish surrounding


Not present





III.15.3 Relevant Clinical Differential Diagnosis Recurrent nevi may simulate melanoma clinically by being asymmetric, poorly circumscribed, and irregularly pigmented. Complete clinical history is crucial for the diagnosis, in order to rule out the possibility of a melanoma recurring after incomplete excision.

III.15.4 Histopathology For a correct histopathological diagnosis of a recurrent nevus, the former report of histopathology must be present. If this report is not available, e.g., due to former laser therapy without any histopathology, the histopathologist may have great difficulties differentiating between a recurrent nevus and melanoma. A particular pitfall is represented by melanocytic tumors recurring after laser vaporization (or other types of surgical treatment without histopathological verification of the clinical diagnosis). In such cases, the diagnosis relies only on the histopathological features. Usually patients give information about former surgery which can support the diagnosis of a possible recurrent nevus. In some cases, how-

ever, the history is not clear or even not given, e.g., in some cases of teledermatology [6]. Recurrent nevi are characterized histopathologically by the proliferation of melanocytes above a scar. Intraepidermal melanocytes are arranged mainly as solitary units disposed in all levels of the epidermis, thus simulating melanoma; however, the atypical growth of melanocytes is strictly confined to the area where scar tissue is present in the dermis (by contrast, melanocytes of recurrent melanoma extend beyond the lateral margins of the scar). Complexes of the pre-existing nevus are often detectable below the scar and/or at the side of the lesion.

III.15.5 Management The clinical and dermoscopic features of recurrent nevus together with the history of removal of a previous nevus at the same site are quite characteristic, still a recurrent melanoma often cannot be ruled out with certainty; therefore, complete surgical excision and subsequent ­histopathological examination of a suspicious recurrent nevus is strongly recommended in order not to overlook a recurrent/persistent melanoma.



A. Blum


Core Messages ■ Recurrent nevi are very frequently observed following incomplete excision by superficial shaving techniques. ■ They usually appear as asymmetric, bizarrely outlined, and poorly circumscribed patches with a dark-brown to black pigmentation. ■ As a recurrent melanoma often cannot be ruled out with certainty, complete surgical excision and subsequent histopathological examination is strongly recommended.

References   1. Mayer J (1997) Systematic review of the diagnostic accuracy of dermatoscopy in detecting malignant melanoma. Med J Aust 167: 206–210   2. Kittler H, Pehamberger H, Wolff K, Binder M (2202) Diagnostic accuracy of dermoscopy. Lancet Oncol 3: 159–165   3. Argenziano G, Soyer HP, Chimenti S et al. (2003) Dermoscopy of pigmented skin lesions: results of a consensus meeting via the Internet. J Am Acad Dermatol 48: 679–693   4. Bauer J, Metzler G, Rassner G, Garbe C, Blum A (2001) Dermatoscopy turns histopathologist’s attention to the suspicious area in melanocytic lesions. Arch Dermatol 137: 1338–1340

  5. Blum A, Luedtke H, Ellwanger U, Schwabe R, Rassner G, Garbe C (2004) Digital image analysis for diagnosis of cutaneous melanoma. Development of a highly effective computer algorithm based on analysis of 837 melanocytic lesions. Br J Dermatol 151: 1029–1038   6. Blum A. Hofmann-Wellenhof R, Luedtke H, Ellwanger U, Steins A, Roehm S, Garbe C, Soyer HP (2004) Value of the clinical history for different users of dermoscopy compared with results of digital analysis. J Eur Acad Dermatol Venereol 18: 665– 669   7. Blum A, Soyer HP, Garbe C, Kerl H, Rassner G, Hofmann-Wellenhof R (2003) The dermoscopic classification of atypical melanocytic nevi (Clark nevi) is useful to discriminate benign from malignant melanocytic lesions. Br J Dermatol 149: 1159–1164   8. Braun RP, Lemonnier E, Guillod J, Skaria A, Salomon D, Saurat J (1998) Two types of pattern modification detected on the follow-up of benign melanocytic skin lesions by digitized epiluminescence microscopy. Melanoma Res 8: 431–435   9. Menzies SW, Gutanev A, Avramidis M, Batrac A, McCarthy WH (2001) Short-term digital surface microscopic monitoring of atypical changing melanocytic lesions. Arch Dermatol 137: 1583–1589 10. Bauer J, Blum A, Strohäcker U, Garbe C (2005) Surveillance of patients at high risk for cutaneous malignant melanoma using digital dermoscopy. Br J Dermatol 152: 87–92 11. Skvara H, Teban L, Fiebiger M, Binder M, Kittler H (2005) Limitation of dermoscopy in the recognition of melanoma. Arch Dermatol 141: 155–160 12. Kornberg R, Ackerman AB (1975) Pseudomelanoma: recurrent melanocytic nevus following partial surgical removal. Arch Dermatol 111:1588–1590

Chapter III.16

Spitz Nevus and Its Variants Gerardo Ferrara, Elvira Moscarella, Caterina M. Giorgio, Giuseppe Argenziano

Contents III.16.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 III.16.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . 152 III.16.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . 153 III.16.4 Relevant Clinical Differential Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 III.16.5 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . 159 III.16.6 Management. . . . . . . . . . . . . . . . . . . . . . . . . . 160

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

III.16.1 Definition The eponymic designation “Spitz nevus” refers to a benign melanocytic proliferation, which was first described in 1948 by Sophie Spitz as “melanoma of the childhood” [1]. Along with this original description, we presently consider as “classical” Spitz nevus a rapidly growing, pink or flesh-colored papule or nodule of the lower extremities or the face in childhood or early adulthood [2–6]. Its histopathological hallmark is the presence of large spindle and/or epithelioid cells, usually in the paucity or absence of melanin. “Reed nevus” is another eponymic designation for a benign melanocytic lesion described by Reed et al. in 1975 as “pigmented spindle cell nevus” [7]. It is mostly found in young adults on the lower extremities as a rapidly growing brownish-black macule or papule [7]. Histopathologically, it is described as made up by interconnecting junctional fascicles of heavily pigmented spindle cells [4, 7]. The nosological


autonomy of Reed nevus from Spitz nevus has been questioned since 1978, when PaniagoPereira et al. [8] underlined the occurrence of cases of spindle and/or epithelioid cell nevi with heavy pigmentation, thereby ascribing Reed nevus to the morphological spectrum of Spitz nevus. At present, some authors still maintain that Reed nevus is an entity that can be clearly differentiated from pigmented spindle cell Spitz nevus [9–15]; however, a clinicopathological evaluation of a large case series has recently shown that the histopathological distinction between these two diagnostic categories is often matter of great debate and has no clinical and dermoscopic relevance [16]. We can therefore refer to Spitz nevus by classifying it into two clinical variants, namely, the classical and the pigmented types (the latter also comprising Reed nevus). Indisputably, some melanomas histopathologically resemble Spitz nevi to various extent [4]. When such similarities are striking from both an architectural and a cytological point of view the term “spitzoid melanoma” is justified [17]. A morphological spectrum of melanomas with “spitzoid” features probably exists, in which one end shows lesions with overtly atypical histopathological features, i.e., lesions which are readily identified as malignant on histopathological examination At the opposite edge of this spectrum, one can conceivably find (rare) cases which can be diagnosed as malignant only retrospectively, i.e., after the development of metastases [17–19]. These lesions have been first referred to as “spindle cell and epithelioid cell nevi with atypia and metastasis” or “malignant (metastasizing) Spitz nevi” [19], and subsequently as “atypical Spitz nevi/tumors” [18]. They could be considered as neoplasms with



G. Ferrara, E. Moscarella, C.M. Giorgio et al.

“bland” histopathological features and metastatic potential limited to the regional lymph nodes [18–20]. The common (although not invariable) absence of further dissemination beyond the regional lymph nodes has even raised the question about the true malignant nature of the lymph node “implants” from spitzoid neoplasms [21]. At present, however, we have no convincing scientific data which can allow to really challenge the dogma of the metastasis as an unequivocal sign of malignancy [22, 23]. The concept of an “intermediate” category of spitzoid lesions placed in between benignity and malignancy does not fit with the traditional dichotomic (“benign vs malignant”) diagnostic approach to histopathology. According to this view, cases of “metastasizing nevi” are simply diagnostic errors, because the distinction between Spitz nevi and melanoma, although sometimes difficult, can – and therefore must – be made [22, 24]. It is obvious, however, that such a “dual” diagnostic approach leads to lowering the diagnostic threshold for melanoma – and therefore to overdiagnosing melanoma – in order not to miss the histopathological recognition of metastasizing lesions with subtle histopathological clues to malignancy. Ongoing molecular genetic studies on spitzoid neoplasms seem to be a promising diagnostic tool. HRAS mutations/amplifications have been detected in 11.8% of Spitz nevi [25]. B-RAF and N-RAS mutations, which are frequently found in melanoma on skin without chronic sun damage [26], are consistently absent in Spitz nevi [27, 28] and probably expressed in a minority of spitzoid melanomas [28]. These data suggest that spitzoid neoplasms probably have a different pathway to tumorigenesis than conventional types of nevi and melanomas.

III.16.2 Clinical Features Spitz nevus is a solitary, round to oval, domeshaped papule, measuring up to 1 cm in diameter. Its surface is smooth or keratotic/verrucous, and occasionally even papillomatous. Although initially described as a non-pigmented lesion [1], recent data underline that Spitz nevi are brown to black in 71.3–92.7% [16, 29] of histologically examined cases. Such a high frequency of pigmented variants in surgical series could be the result of a better clinical recognition due to dermoscopy (see below) coupled with a low excision rate of classical “pink” Spitz nevi in children. As a rule, a rapidly growing, pink or reddish lesion of the head/neck or (lower) limbs is the clinical presentation of classical Spitz nevus in children. A brown/black papule of the trunk or lower extremities is the common clinical picture of pigmented Spitz nevus in young adults [5, 30, 31]; transitional clinical features are also possible. Large (>1 cm) nodular and/or ulcerated lesions must be always regarded as worrisome even in childhood [32, 23]. Rare congenital cases have been reported [33, 34]. A halo phenomenon has also been described [35]. Multiple, and sometimes eruptive [36], Spitz nevi can present in a clustered (agminated) [37] or a disseminated pattern [38]. Agminated Spitz nevi can also occur within a background (diffuse) hyperpigmentation [39] or within a speckled lentiginous nevus [40]. Spitz nevi have a low recurrence rate, even after incomplete excision [41]; however, some cases of satellitosis [42] and giant nodule formation [43] have been reported following surgical procedures. In our opinion, such unusual occurrences could be even in keeping with a low (or very low) malignant potential of some of these lesions.

Spitz Nevus and Its Variants

Fig. III.16.1.  a A pink lesion located on the thigh of a 27-year-old woman. Dermoscopically there is a negative pigment network (reticular depigmentation) with dotted vessels especially visible at the periphery. b A large, sharply circumscribed, plaque-like melanocytic lesion.

III.16.3 Dermoscopic Criteria Six main dermoscopic patterns can be ascribed to Spitz nevus, namely, vascular, globular, starburst, reticular, atypical, and homogeneous [44]. Classical Spitz nevus (Fig. III.16.1) is an amelanotic or hypopigmented lesion with a vascular pattern composed of dotted vessels [45], which are responsible for its “definitional” pink color. Dotted vessels are monomorphic, regularly distributed throughout the lesion, often grouped and surrounded by regularly intersecting white lines, the so-called reticular depigmentation (Fig. III.16.1). A slight pigmentation can be present as a diffuse brownish hue with

Chapter III.16

c A striking epidermal hyperplasia with junctional melanocytic nests demarcated by half-moon peripheral clefts (“capping”). d At a higher magnification large Kamino bodies are seen within the epidermis

widely and regularly spaced gray-brown, smallto medium-sized globules. In frankly pigmented lesions, globules are brown to black, large and regularly distributed at the periphery (Fig. III.16.2). In most cases of pigmented Spitz nevi, peripheral globules are fused with the central body of the lesion; these regular, “on focus” radial projections (so-called streaks) are responsible for a “starburst” appearance (Fig. III.16.3). In a minority of cases, a heavy pigmentation also gives rise to a regular black network, which rests above the lesion and can be removed by tape stripping (“superficial black network”; Fig. III.16.4) [46]. Several of these features can be simultaneously present and/or irregularly distributed within a given le-



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Fig. III.16.2.  a A small pigmented plaque located on the arm of a 23-year-old man. Dermoscopically this is a symmetric lesion with striking brown to black globules especially visible at the periphery and grayish pigmentation in the center. b A medium-sized, well-demarcated, plaque-like melanocytic lesion. c An epidermal hyperplasia with “capping” of junctional nests. d Same features at the opposite side of the lesion. e Periadnexal extension of the melanocytic nests, a microscopic feature which Spitz nevus shares with congenital nevus as well as with melanoma

Spitz Nevus and Its Variants

Chapter III.16

Fig. III.16.3.  a A small hyperpigmented plaque located on the thigh of a 43-year-old man. A starburst pattern is clearly visible by dermoscopy. b A small- to mediumsized, sharply circumscribed, plaque-like melanocytic proliferation with a symmetric distribution of the mela-

nin pigment. c A slight epidermal hyperplasia with junctional nests of melanocytes shows no sharp separation from the nearby keratinocytes. d At a higher magnification, the spindle morphology of junctional melanocytes is evident

sion, thus giving an atypical or “melanoma-like” pattern. Dermoscopic atypia can also be increased by virtue of the presence of a blue-whitish veil as a result of a deep dermal pigmentation with an overlying epidermal hyperplasia (Fig. III.16.5). The “starburst,” the “globular,” and the “atypical” patterns are the most common dermoscopic findings in surgical series of Spitz nevus [16]; however, most of these different dermoscopic patterns simply correspond to different phases of the natural evolution of Spitz nevi. Pizzichetta et al. [47] clearly demonstrated

that a pigmented Spitz nevus can rapidly evolve from a globular pattern to a “starburst” pattern, and finally to a homogeneous pattern; the latter is characterized by a diffuse brown or dark brown color, which resembles a common dermal nevus (Fig. III.16.6). Parenthetically, some “dermal” nevi show that a homogeneous lightbrown pattern could be the end phase of classical Spitz nevi. On the other hand, the final stage in the natural evolution of Spitz nevi might also be represented by a complete involution of the lesion (personal observation).



G. Ferrara, E. Moscarella, C.M. Giorgio et al.


Fig. III.16.4.  a A small black macule dermoscopically typified by a starburst pattern with clearly visible superficial black network. b A small melanocytic proliferation with “skip” pigmented parakeratosis. c A slight epidermal hyperplasia with a “plug” of pigmented parakeratosis

above a junctional nest of melanocytes. d At a higher magnification, junctional melanocytes appear spindleshaped. Some melanophages are intermingled within nests, a microscopic feature which is often observed in Reed nevus

Spitz Nevus and Its Variants

Fig. III.16.5.  a Irregularly pigmented plaque located on the thigh of a 12-year-old girl. Dermoscopically there is asymmetry in color and structure, blue-white veil in the center, and brown globules and dotted vessels at the periphery. b A medium-sized, dome-shaped, and symmetric melanocytic proliferation. c, d The lesion is sharply demarcated at both its edges. e An epidermal hyperplasia with junctional nests of spindle-shaped melanocytes. Some focal “capping” is also evident

Chapter III.16



G. Ferrara, E. Moscarella, C.M. Giorgio et al.


Fig. III.16.6.  a A small black papule located on the arm of a 21-year-old woman. At dermoscopy a homogeneous pattern is seen, with brown to blue-gray structureless pigmentation. b A medium-sized, sharply circumscri bed, and symmetric melanocytic proliferation with dermal melanophages distributed in a band-like fashion.

c A moderate, regular epidermal hyperplasia with regularly distributed junctional nests of melanocytes. d Melanocytes within the junctional nests are spindle-shaped, often with some dendritic processes, a feature which can be observed in early Reed nevus

III.16.4 R  elevant Clinical Differential Diagnosis

dermoscopic criterion can allow such a differential diagnosis with absolute reliability. Differential diagnosis of pigmented Spitz nevus can include “globular” and “hypermelanotic” Clark nevus and melanoma. Brown globules of Clark nevus are usually smaller and regularly distributed throughout the entire surface of the lesion [48, 49]. Hypermelanotic (“black”) nevus is characterized by a central diffuse hyperpigmentation (black lamella) and dark-brown network at the periphery of the lesion. Tape stripping removes the black lamella, but not the pigment network, as observed in rare cases of pigmented Spitz nevus [46]. Atypical pigment network, irregular dots and globules, irregular

Classical Spitz nevus must be differentiated from viral wart, verrucous epidermal nevus, capillary hemangioma, pyogenic granuloma, angiolymphoid hyperplasia with eosinophilia, and lymphoid infiltration of the skin. It has been underlined that dotted vessels seen on dermoscopy are generally predictive for a melanocytic lesion and are especially seen in Spitz nevus [45]. The uniform shape and distribution of dotted vessels can also help in differentiating classical Spitz nevus from amelanotic melanoma. It must be emphasized, however, that no

Spitz Nevus and Its Variants

pigmentation, irregular streaks, and blue whitish veil are specific dermoscopic criteria of melanoma [48, 49]; however, the occurrence of an atypical dermoscopic pattern in Spitz nevus is well recognized [16], as is the occurrence of melanomas showing very few or no dermoscopic features suggestive of malignancy but exhibiting either the globular or the starburst pattern [50]. Remarkably, melanomas with “spitzoid” dermoscopic features do not necessarily show “spitzoid” histopathological features [16]. The substantial lack of reliable differential criteria from melanoma must always be taken into account in the management of Spitz nevus (see below).

III.16.5 Histopathology Spitz nevus is a neoplastic proliferation of melanocytes with large nuclei, prominent nucleoli, and abundant ground-glass cytoplasm with spindle and/or polygonal (epithelioid) outlines. Its early intraepidermal growth phase is characterized by predominance of single melanocytes with some suprabasilar scatter, commonly confined to the lower layers of the epidermis (“pagetoid” Spitz nevus [51] or “baby” Spitz nevus). There can be a slight asymmetry, but some nest formation is evident even in small lesions. Junctional, or predominantly junctional, Spitz nevus is a plaque-shaped, sharply demarcated lesion composed mostly of sharply demarcated melanocytic nests within a hyperplastic epidermis. Nests are equally sized, shaped, and spaced at the junction. Typically, some of them can undergo a transepidermal elimination. A periadnexal junctional component is very common. Melanocytes are arranged perpendicular and parallel to the skin surface. They are highly cohesive and do not destroy the nearby keratinocytes; therefore, a semilunar cleavage is often evident around nests (“capping”) and even around the few single intraepidermal melanocytes (“micro-capping”). Large and coalescent eosinophilic (Kamino) bodies may be found at the dermo-epidermal junction [52] and telangiectatic blood vessels can be seen in the superficial dermis. Melanin pigment is common within spindle cells and dermal melanophages; howev-

Chapter III.16

er, even epithelioid melanocytes [53], as well as single intraepidermal dendritic melanocytes [54], can be pigmented. Finally, pigmented parakeratosis can be present in an ordered “skip” fashion [46]. Neoplasms defined as Reed nevus are composed of heavily pigmented, monomorphic, small- to medium-sized spindle melanocytes, arranged mainly parallel to the skin surface. Junctional nests typically show no sharp demarcation from the overlying epidermis, with the latter showing only little hyperplasia. A bandlike dermal infiltration of melanophages is a common ancillary finding [7–15]. Compound Spitz nevus is a dome-shaped lesion with a dermal component composed of regularly spaced nests and cords of cells. Some maturation is at least focally seen and mitoses may be easily seen, but never as atypical figures and never close to the base of the lesion. Intravascular melanocytes can be detected and are not an ominous sign per se [4]. Dermal Spitz nevus is a dome-shaped or flat lesion which is often characterized by extensive desmoplasia encircling single melanocytes. Its overall picture can closely resemble dermatofibroma [55]. The neoplasm described as “desmoplastic nevus” [56] is probably related to desmoplastic Spitz nevus. A plexiform arrangement of bundles and lobules of melanocytes has been described (plexiform Spitz nevus [4]). A prominent vasculature may also be seen (angiomatoid Spitz nevus [57]). At present, an unequivocal and reproducible definition for “atypical Spitz nevus” and “atypical Spitz(oid) tumor” is probably lacking [22, 24]. In general, these diagnostic categories can be used for lesions showing some distinctly abnormal characteristics commonly absent in “conventional spitzoid” lesions [17]. In a metaanalysis based on 19 papers reporting 62 metastasizing spitzoid neoplasms, an aggressive biological behavior was recorded even for lesions showing only one of the following nine “atypical” features: (a) nodular dermal growth (solid cellular sheets within the dermis); (b) deep extension with absent or impaired maturation; (c) deep dermal mitoses; (d) marked nuclear/nucleolar pleomorphism; (e) heavy melanization in depth; (f) asymmetry; (g) cellular necrosis; (h)




G. Ferrara, E. Moscarella, C.M. Giorgio et al.

epithelioid epidermal melanocytes below parakeratosis and/or epidermal ulceration; and (i) neoplastic cells within the lymph vessels [58]. One can therefore conclude that even the presence of one of the above-listed features is probably enough for ascribing a given spitzoid lesion to an “intermediate” diagnostic category. We prefer to use the term “atypical spitzoid tumor” for lesions which show a large nodular (“tumoral”) dermal component, while leaving the term “atypical Spitz nevus” to the remaining cases.

Every surgical excision must be carried out with a narrow (0.1 cm) margin. Diagnosis of atypical Spitz nevus/tumor requires further surgical procedures as suggested for melanoma [59].

III.16.6 Management The management of Spitz nevus must be decided by considering the following issues: 1. Melanoma in childhood is exceedingly rare [59]; however, amelanotic melanoma surprisingly shows higher prevalence in children than in adults. Moreover, very large (>1 cm) and/or ulcerated spitzoid neoplasms of childhood can show sentinel lymph node metastases [23]. 2. There are no reliable differential criteria between Spitz nevus and melanoma on dermoscopy [49, 50]. Actually, melanomas showing Spitz nevus-like features on dermoscopy are not necessarily “spitzoid” on histopathology [16]. Based on these considerations, a classical or pigmented Spitz nevus appearing up to the age of 12 years [60] can be easily diagnosed and managed conservatively if it is relatively small (up to 1 cm) and shows no atypical clinical and dermoscopic features. Under these circumstances, a follow-up can be scheduled with controls every 6 months [60]. In the absence of dramatic changes in color, shape, or size, such a follow-up protocol can be held until the appearance of a homogeneous pattern. Afterward, a 1-year follow-up can be employed. Large (>1 cm), ulcerated, rapidly changing, or otherwise atypical Spitz nevi of childhood must be excised. Surgical excision is also recommended when Spitz nevi appear in adulthood, regardless of the presence of atypical clinical/ dermoscopic features.

Left: The lesion is mostly nested, mostly at the junction, with some irregular epidermal atrophy. Right: At the center of the lesion the epidermis is atrophic; the melanocytic proliferation becomes more diffuse, with large sheets of cells separated by small amonts of collagen fibers

The lesion is a brownish, dome shaped papule with smooth surface and regular borders. Dermoscopically the lesion shows a central irregular grayish hyperpigmentation, and brown to black globules/dots irregularly distributed throughout the lesion. Histopathogically, a dome-shaped, sharply demarcated and symmetric melanocytic proliferation is seen

Spitz Nevus and Its Variants

Chapter III.16


Core Messages ■ Spitz nevus can clinically present either in the classical (reddish-pink) or in the pigmented (brownish-black) variant. ■ It can show six different dermoscopic patterns – i.e., vascular, globular, starburst, reticular, atypical, and homogeneous – none of which is clearly distinguishable from melanoma. ■ Even histopathologically, a clear-cut differentiation between benign and malignant spitzoid neoplasms is often difficult, so that an “intermediate” diagnostic category is admitted, the socalled atypical Spitz nevus/atypical spitzoid tumor. ■ Because of these difficulties in both clinical and histopathological evaluation, surgical excision is recommended for clinically atypical (large, ulcerated, rapidly changing) spitzoid lesions of childhood and for all the spitzoid lesions of adulthood.

References   1. Spitz S. Melanomas of childhood. Am J Pathol 1948;24:591–609   2. Spatz A, Peterse S, Fletcher CDM, Barnhill RL. Plexiform Spitz nevus. Am J Dermatopathol 1999; 21: 542–546   3. Gartman H, Ganser M. Der Spitz-Nevus, Spindelzellen und/oder Epitheloidzellennevus: eine klinische analyse von 652 tumoren. Z Hautkr 1985;60:22–28   4. Kopf AW, Andrade R. Benign juvenile melanoma. In: Kopf AW, Andrade R, eds. Year book of dermatology. Chicago: Year Book Medical Publisher, 1966;7–52   5. Weedon D. Lentigines, nevi and melanomas. In: Weedon D (ed) Skin pathology, 2nd edn. Edinburgh: Churchill Livingstone, 2002;803–858   6. Weedon D, Little JH. Spindle and epithelioid cell nevi in children and adults: a review of 211 cases of the Spitz nevus. Cancer 1977;40:217–225   7. Reed RJ, Ichinose H, Clark WH, et al. Common and uncommon melanocytic nevi and borderline melanomas. Semin Oncol 1975;2:119–147




G. Ferrara, E. Moscarella, C.M. Giorgio et al.   8. Paniago-Pereira C, Maize JC, Ackerman AB. Nevus of large spindle and/or epithelioid cell (Spitz’s nevus). Arch Dermatol 1978;112:1811–1823   9. 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;22:53–58 10. Barnhill RL, Mihm MC Jr. Pigmented spindle cell nevus and its variants distinction from melanoma. Br J Dermatol 1989;121:717–726 11. Barnhill RL, Mihm MC Jr, Magro CM. Plexiform spindle cell nevus: a distinctive variant of plexiform melanocytic nevus. Histopathology 1991;18:243– 247 12. Gartmann H. Der Pigmentierte Spindelzellentumor. Z Hautkr. 1981;56:862–876 13. Grossin M. Reed’s nevus. Ann Dermatol Venereol 1992;119:145 14. Sau P, Graham JH, Helwig EB. Pigmented spindle cell nevus: a clinicopathologic analysis of ninetyfive cases. J Am Acad Dermatol. 1993;28:565–571 15. Smith NP. The pigmented spindle cell tumor of Reed: an underdiagnosed lesion. Semin Diagn Pathol 1987;4:75–87 16. Ferrara G, Argenziano G, Soyer HP, et al. The spectrum of Spitz nevi: a clinicopathologic study of 83 cases. Arch Dermatol 2005;141:1381–1387 17. Barnhill RL. The spitzoid lesion: the importance of atypical variants and risk assessment. Am J Dermatopathol 2006;28:75–83 18. Barnhill RL, Argenyi ZB, From L, et al. Atypical Spitz nevi/tumor: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. Hum Pathol 1999;30:513–520 10. Smith K, Skelton H, Lupton G, Graham J. Spindle cell and epithelioid cell nevi with atypia and metastasis (malignant Spitz nevus). Am J Surg Pathol 1989;13:931–939 20. Cerroni L. A new perspective for Spitz tumors? Am J Dermatopathol 2005;27:366–367 21. LeBoit PE. What do these cells mean? Am J Dermatopathol 25:355–356 22. Mones JM, Ackerman AB. “Atypical” Spitz’s nevus, “malignant” Spitz’s nevus, and “metastasizing” Spitz’s nevus: a critique in historical perspective of three concepts flawed fatally. Am J Dermatopathol 2004;26:310–333 23. 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 37:816–823 24. Ackerman AB. Garble that derives from lack of definition. Am J Dermatopathol 2005;27:369–370 25. Bastian BC, LeBoit PE, Pinkel D. Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features. Am J Pathol 2000;157:967–972

26. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busan KJ, Kutzner H, Cho KH, Aiba S, Broecker EB, LeBoit PE, Pinkel D, Bastian BC. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353:2135–2147 27. Gill M, Cohen J, Renwick N, et al. Genetic similarities between Spitz nevus and spitzoid melanoma in children. Cancer 2004;101:2636–2640 28. Palmedo G, Hantschke M, Ruetten A, Mentzel T, Huegel H, Flaig MJ, Yazdi AS, Sander CA, Kutzner H. The T1796A mutation of the BRAF gene is absent in Spitz nevi. J Cutan Pathol 2004;31:266 29. Dal Pozzo V, Benelli C, Restano L, Gianotti R, Cesana BM. Clinical review of 247 case records of Spitz nevus (epithelioid cell and/or spinale cell nevus). Dermatology 1997;194:20–25 30. Casso EM, Grin-Jorgensen CM, Grant-Kels JM. Continuating medical education: Spitz nevi. J Am Acad Dermatol 1992;27:901–913 31. Sagebiel RW, Chinn EK, Egbert BM. Pigmented spindle cell nevus: clinical and histologic review of 90 cases. Am J Surg Pathol 1984;8:645–653 32. Spatz A, Calonje E, Handfield-Jones S, Barnhill RL. Spitz nevus in children. A grading system for risk stratification. Arch Dermatol 199;135:282–285 33. Palazzo JP, Duray PH. Congenital agminated Spitz nevi. Immunoreactivity with a melanomaassociated monoclonal antibody. J Cutan Pathol 1988;15:166–170 34. Zaenglein AL, Heintz P, Kamino H, Zisblatt M, Orlow SJ. Congenital Spitz nevus clinically mimicking melanoma. J Am Acad Dermatol 2002;47:441–444 35. Yasaka N, Furue M, Tamaki K. Histopathological evaluation of halo phenomenon in Spitz nevus. Am J Dermatopathol 1995;17:484–486 36. Fass J, Grimwood RE, Kraus E, Hyman J. Adult onset of eruptible widespread Spitz’s nevi. J Am Acad Dermatol 2002;46:S141–S143 37. Lancer HA, Muhlbauer JE, Sober AJ. Multiple agminated spindle cell nevi. Unique clinical presentation and review. J Am Acad Dermatol 1983;8:707–711 38. Smith SA, Day CL. Eruptive widespread Spitz nevi. J Am Acad Dermatol 1986;15:1155–1159 39. Renfro L, Grant-Kels JM, Brown SA. Multiple agminate Spitz nevi. Pediatr Dermatol 1989;6:114–117 40. Aloi F, Tomasini C, Pippione M. Agminated Spitz nevi occurring within a congenital speckled lentiginous nevus. Am J Dermatopathol 1995;17:594–598 41. Kaye VN, Dehner LP. Spindle and epithelioid cell nevus (Spitz nevus). Natural history following biopsy. Arch Dermatol 1990;126:1581–1583 42. Gambini C, Rongioletti F. Recurrent Spitz nevus. Case reoprt and review of the literature. Am J Dermatopathol 1994;16:409–413

Spitz Nevus and Its Variants 43. Krasovec M, Gianadda B, Hohl D. Giant recurrence of an agminated Spitz nevus. J Am Acad Dermatol 1995;33:386–388 44. Peris K, Ferrari A, Argenziano G, et al. Dermoscopic classification of Spitz/Reed nevi. Clin Dermatol 2002;20:259–262 45. Argenziano G, Zalaudek I, Corona R, Sera F, Cicale L, Petrillo G, Ruocco E, Hofmann-Wellenhof R, Soyer HP. Vascular structures in skin tumors: a dermoscopy study. Arch Dermatol 2004;140:1485– 1489 46. Argenziano G, Soyer HP, Ferrara G, et al. Superficial black network: an additional dermoscopic clue for the diagnisis of spindle and/or epithelioid cell nevus. Dermatology 2001;203:333–335 47. Pizzichetta MA, Argenziano G, Grandi G, Giacomi C de, Trevisan G, Soyer HP. Morphologic changes of a pigmented Spitz nevus assesed by dermoscopy. J Am Acad Dermatol.2002;47:137–139 48. Argenziano G, Soyer HP, Giorgi V de, et al. Interactive atlas of dermoscopy (Book and CD-ROM). Milan: Edra Medical Publishing and New Media, 2000 49. Argenziano G, Soyer HP, Chimenti S, et al. Dermoscopy of pigmented skin lesion: results of a cosensus meeting via the Internet. J Am Acad Dermatol 2003;48:679–693 50. Argenziano G, Scalvenzi M, Staibano S, et al. Dermatoscopic pitfalls in differentiating pigmented Spitz nevi from cutaneous melanomas. Br J Dermatol 1999;141:788–793 51. Busam KJ, Barnhill RL. Pagetoid Spitz nevus. Intraepidermal Spitz tumor with prominent pagetoid spread. Am J Surg Pathol 1995;19:1061–1067

Chapter III.16 52. Kamino H, Flotte TJ, Misheloff E. Eosinophilic globules in Spitz’s nevi. New findings and a diagnostic sign. Am J Dermatopathol 1979;1:319–324 53. Choi JH, Sung KJ, Koh JK. Pigmented epithelioid cell naevus: a variant of Spitz naevus? J Am Acad Dermatol 1993;28:497–498 54. Ferrara G, Crisman G, Soyer HP, Zalaudek I, Argenziano G. Intraepidermal dendritic melanocytes in spitzoid neoplasms. Am J Dermatopathol 28:449–450 55. Maize JC, Ackerman AB (eds). Spitz’s nevus. In: Pigmented lesion of the skin. Philadelphia, Lea and Febiger; 1987:228–242 56. Barr RJ, Morales RV, Graham JH. Desmoplastic nevus. A distinct histologic variant of mixed spindle cell and epithelioid cell nevus. Cancer 1980;46:557– 564 57. Diaz-Cascajo C, Borghi S, Weyers W. Angiomatoid Spitz nevus. A distinct variant of desmoplastic Spitz nevus with prominent vasculature. Am J Dermatopathol 2000;22:135–139 58. Urso C. A new perspective for Spitz tumors? Am J Dermatopathol 2005;27:364–365 59. Zalaudek I, Ferrara G, Argenziano G, Ruocco V, Soyer HP. Diagnosis and treatment of cutaneous melanoma: a practical guide. Skin Med 2003;2:20– 31 60. Brunetti B, Nino M, Sammarco E, Scalvenzi M. Spitz naevus: a proposal for management. J Eur Acad Dermatol Venereol 2005;19:391


Chapter III.17

Syndromes Involving Melanocytic Lesions


Cheryl G. Aber, Elizabeth Alvarez Connelly, Lawrence A. Schachner



III.17.1 Introduction

III.17.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . 164 III.17.2 Neurocutaneous Melanosis. . . . . . . . . . . . 164 III.17.2.1 Clinical Features. . . . . . . . . . . . . . . . . . . . . 164 III.17.2.2 Diagnostic Investigation. . . . . . . . . . . . . . 165 III.17.2.3 Management and Prognosis. . . . . . . . . . . 165 III.17.3 Xeroderma Pigmentosum. . . . . . . . . . . . . 166 III.17.3.1 Clinical Features. . . . . . . . . . . . . . . . . . . . . 166 III.17.3.2 Diagnostic Investigation. . . . . . . . . . . . . . 166 III.17.3.3 Management and Prognosis. . . . . . . . . . . 167 III.17.4 Neurofibromatosis Type I. . . . . . . . . . . . . 167 III.17.4.1 Clinical Features. . . . . . . . . . . . . . . . . . . . . 167 III.17.4.2 Diagnostic Investigation. . . . . . . . . . . . . . 168 III.17.4.3 Management and Prognosis. . . . . . . . . . . 168 III.17.5 Familial Atypical Multiple Mole and Melanoma Syndrome. . . . . . . . . . . . . 168 III.17.5.1 Clinical Features. . . . . . . . . . . . . . . . . . . . . 168 III.17.5.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 III.17.5.3 Management and Prognosis. . . . . . . . . . . 169 III.17.6 Carney/LAMB/NAME Syndromes. . . . . 169 III.17.6.1 Clinical Features. . . . . . . . . . . . . . . . . . . . . 169 III.17.6.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 III.17.6.3 Management . . . . . . . . . . . . . . . . . . . . . . . . 170 III.17.7 Occult Spinal Dysraphism/ Tethered Cord. . . . . . . . . . . . . . . . . . . . . . . 170 III.17.7.1 Management . . . . . . . . . . . . . . . . . . . . . . . . 170

References. . . . . . . . . . . . . . . . . . . . . . . . . . . 170

Many congenital syndromes are diagnosed with the aid of cutaneous findings. Certain medical conditions are detected early based on the appearance of premature, numerous, or abnormal skin lesions. The association of melanocytic nevi with specific syndromes is prominent with certain conditions and less consistent with others. Melanocytic nevi are fairly prevalent in the general population and often exhibit familial clustering; therefore, close attention must be paid to all associated findings in order to recognize the pattern of various syndromes and facilitate counseling and timely intervention. This chapter describes syndromes associated with melanocytic nevi.

III.17.2 Neurocutaneous Melanosis Neurocutaneous melanosis is a rare non-hereditary condition characterized by large and or multiple (greater than three) congenital melanocytic nevi associated with melanocytic tumors (benign and/or malignant) of the leptomeninges [39].

III.17.2.1 Clinical Features Main diagnostic features of neurocutaneous melanosis have been reviewed and formulated by Kadonaga and Frieden in 1991 to include melanocytic proliferations of the central nervous system (benign and/or malignant) in association with a large congenital melanocytic nevi (LCMN) or 3 or more smaller melanocytic nevi (satellite nevi) [6]. A LCMN is defined as a ne-

Syndromes Involving Melanocytic Lesions

Chapter III.17

deficits on exam [20]. These symptoms may result from a malignant primary central nervous melanoma or non-malignant proliferation of melanocytes in the CNS (CNS melanocytosis) [41]. Neurological symptoms typically present before 2 years of age, and usually manifest by the first year of life [35]. Although neurological symptoms vary, almost two-thirds of patients with symptomatic neurocutaneous melanosis develop hydrocephalus usually due to obstruction of cerebrospinal fluid flow, decreased absorption by the leptomeninges or associated Dandy–Walker complex (up to 10% of cases) [35]. Neurocutaneous melanosis has been associated with additional neurocutaneous syndromes as well including neurofibromatosis or Sturge–Weber syndrome.

III.17.2.2 Diagnostic Investigation

Fig. III.17.1.  Patients with neurocutaneous melanosis demonstrate large or giant congenital melanocytic nevi often associated with multiple satellite nevi

vus that is or can be expected to measure 20cm in largest diameter in adulthood. This corresponds to a nevi measuring 6cm on an infant‘s body or 9cm on an infant‘s head. Most patients with neurocutaneous melanosis present with nevi on their trunk (typically posterior midline) or head and neck (Fig. III.17.1) [22]. Approximately two-thirds of the patients demonstrate large or giant congenital melanocytic nevi, whereas the remaining third have multiple nevi. These pigmented nevi can be macular or raised and are typically circumscribed with irregular borders. Studies done by Marghoob et al demonstrate that the presence of many satellite nevi (>20) significantly increases the relative risk of NCM. Reference 44. Those affected with neurocutaneous melanosis may be subdivided between symptomatic and asymptomatic depending on the presentation of neurological symptoms such as headaches, seizures, hydrocephalus, tremors, developmental/motor delay, or focal neurological

Brain magnetic resonance imaging (MRI) with gadolinium is the preferred screening modality in potentially affected patients to detect leptomeningeal melanosis, melanomas, and posterior fossa malformations. Ideally, the MRI should be performed between 4 and 6 months of age before normal myelination of the brain.

III.17.2.3 Management and Prognosis Those patients with symptomatic neurocutaneous melanosis carry a poor prognosis irrespective of the presence of a malignancy [30]. No therapy has demonstrated improved clinical outcome in these patients. Patients with truncal large congenital nevi demonstrate a higher incidence of symptomatic neurocutaneous melanosis and mortality vs those with head or extremity large congenital nevi [2]. One large study demonstrated a 34% mortality rate in patients with symptomatic neurocutaneous melanosis and truncal nevi. In contrast, those with a large congenital nevi on the head or neck exhibit a significantly lower rate of symptomatic of neurocutaneous melanosis and death. In addition, the association of neurocutaneous melanosis with Dandy–Walker complex has demonstrated an even poorer prognosis with patients experi-




C.G. Aber, E.A. Connelly, L.A. Schachner

encing neurological decompensation and death by 4 years of age [29]. Any patient with neurological symptoms requires neurosurgical referral. To date, there are no published reports of melanomas arising in satellite nevi associated with a large congenital melanocytic nevi; however, the presence of multiple satellite nevi without a large nevus portends the highest risk of developing symptomatic neurocutaneous melanosis and death [2]. Treatment of cutaneous large melanocytic nevi remains controversial. Given the 5–15% chance of malignant transformation, many dermatologists recommend prophylactic surgical removal [6]; however, removal of cutaneous nevi is a secondary concern in those patients with neurological symptoms.

III.17.3 Xeroderma Pigmentosum Xeroderma pigmentosum is an autosomal-recessive syndrome characterized by a group of degenerative disorders resulting from defective DNA nucleotide excision repair mechanisms. The main features of this disorder include exquisite photosensitivity to UV radiation, early onset of cutaneous malignancies (including melanomas), ocular complications, and in certain subtypes, progressive neurological degeneration.

III.17.3.1 Clinical Features At birth the skin is normal. Cutaneous symptoms typically appear at 1–2 years of age. Initially, patients develop a severe prolonged erythematous reaction to minimal sun exposure (severe abnormal sunburn) and photodistributed solar lentigines that remain. At an early age, signs of premature aging (dermatoheliosis) become apparent such as increased pigmented macules, epidermal thinning, telangiectasias, and patchy hyper/hypopigmentation, collectively termed poikiloderma [16]. Skin malignancies, such as melanomas, basal cell carcinomas, and squamous cell carcinomas, start presenting at an early age primarily in photodistributed areas and often result in significant disfigurement of facial features (Fig. III.17.2). Lentigo maligna

Fig. III.17.2.  Skin malignancies, such as melanomas, present at an early age primarily in photodistributed areas. They often result in significant disfigurement of facial features

melanomas, a common type of cutaneous cancer in xeroderma pigmentosum, develop at a median age of 17.5 years [36]. Compared with age-matched controls, affected xeroderma pigmentosum patients are 2000 times more likely to develop a cutaneous skin malignancy [17]. Patients with xeroderma pigmentosum have a 10–20 times increased risk of developing an internal malignancies compared with agematched controls, with an increased incidence of lung, breast, pancreatic, stomach, brain, and testicular cancer, as well as leukemia. Ocular findings are usually confined to the anterior portion of the eye (eyelids, cornea, conjunctiva), which is vulnerable to greatest exposure of UV radiation. Complications at this site include photophobia, conjunctivitis, keratitis, ectropian, corneal vascularization, basal cell carcinomas, squamous cell carcinomas, and melanomas. In addition, neurological degeneration, including mental deterioration, sensorineural hearing loss, ataxia, and spasticity, occur more frequently in certain complementation groups (group A and group D) [16].

III.17.3.2 Diagnostic Investigation Cell fusion technique has elucidated more than seven different xeroderma pigmentosum complementation groups (A–G) with impaired exci-

Syndromes Involving Melanocytic Lesions

Chapter III.17

sion repair type and one xeroderma pigmentosum variant form with deficient post-replication repair. Each complementation group corresponds to different gene defects which, in turn, codes for different enzymes involved in the DNA nucleotide excision repair process [7]. Specialized laboratories performing UV sensitivity and unscheduled DNA repair testing substantiate the diagnosis. Once the affected xeroderma pigmentosum gene is identified, direct mutation analysis allows for carrier detection and prenatal diagnosis of family members [3].

III.17.3.3 Management and Prognosis Counseling xeroderma pigmentosum patients must include a rigorous protection program against UV light from infancy. Sun avoidance, physical block sunscreens, wide-brimmed hats, appropriate long-sleeved clothing, and UV blocking sunglasses with side shields are some measures that require adherence. Dermatological cancer screenings should occur every 3 months, with prompt removal of suspicious lesions. Pre-malignant lesions can be treated with cryosurgery, topical 5-fluorouracil, or imiquimod. Neoplasms should be removed by excision, chemosurgery, cryosurgery, or intralesional IFN-a. Topical use of a prokaryotic DNA repair enzyme, T4 endonuclease V, has been shown to initiate repair of UV-induced DNA damage, thereby preventing the development of skin cancers [7, 36]. Certain xeroderma pigmentosum patients may benefit from oral isotretinoin, which plays a role in the prevention of new skin cancers. Appropriate referral to ophthalmology and neurology are recommended. Overall the lifespan of those affected with xeroderma pigmentosum is shortened almost 30 years depending on the severity of the genetic defect and lifelong exposure to UV radiation.

III.17.4 Neurofibromatosis Type I Neurofibromatosis type I (NF-1; also known as von Recklinghausen’s disease) is an autosomaldominant syndrome characterized by six or more café-au-lait macules, neurofibromas, axillary/in-

Fig. III.17.3.  Café-au-lait macules and skin fold freckling (axillary/inguinal) are features of NF-1

guinal freckling, and Lisch nodules (Fig. III.17.3). Although controversial, the association between congenital melanocytic nevi and NF-1 has been reported in 1–15% of patients [4, 5, 10]. A mutation in the NF-I gene located in the 17q11.2 gene locus is responsible for the phenotypic features of this disease. NF-1 has an incidence of 1 in 3500 individuals worldwide [9].

III.17.4.1 Clinical Features Diagnostic skin findings include six or more café-au-lait macules measuring at least 5 mm before puberty and 15 mm or more after puberty. Although occasionally seen at birth, café-aulait macules typically appear during the initial weeks to months of life and subsequently darken during the early years of life [36]. The hallmark lesion of this syndrome are neurofibromas which represent nerve sheath growths either at a




C.G. Aber, E.A. Connelly, L.A. Schachner

focal site of the nerve (discrete neurofibroma) or along the nerve length (plexiform neurofibromas). Neurofibromas typically manifest in the preadolescent years and may occur superficially above the skin surface or deeper within the dermal–subdermal layer. Additional features include skin fold freckling (axillary/inguinal) appearing between 3 and 5 years of age. Previous studies have reported an increased incidence of giant congenital melanocytic nevi in patients with NF-1 [12]. A recent study by Ball and Kho analyzed the association of melanocytic nevi and neurofibromas in patients with NF-1 vs patients with sporadic neurofibromas [4]. Melanocytic nevi were identified in 11% of patients with NF-1 compared with none of the patients with sporadic neurofibromas. Neurofibrin, the protein product of the NF-1 gene, affects the ras signal transduction pathway which has been associated with the development of melanocytic nevi [38] and melanomas [24]. Ocular findings associated with NF-1 include Lisch nodules (melanocytic pigmented iris hamartomas), orbital plexiform neurofibromas, and optic gliomas. Skeletal dysplasias, learning disabilities, vascular dysplasias, macrocephaly, short stature, and hypertension are additional features of the syndrome.

III.17.4.2 Diagnostic Investigation The diagnostic criteria are the presence of two of the following features: (a)six or more café-aulait macules; (b) skin fold freckling; (c) two or more neurofibromas or (d) one plexiform neurofibroma; (e) two or more iris Lisch nodules; (f) optic nerve glioma; (g) skeletal dysplasia; or (h) an affected first-degree relative.

ation of learning disabilities, is imperative. Radiological imaging can aid diagnosis of skeletal or vascular dysplasias or central nervous system tumors (astrocytomas). Treatment of NF-1 is symptom driven. Transformation of neurofibromas to malignant peripheral nerve sheath tumors carries a lifetime 10% risk with a poor prognosis [34]. Pain or sudden growth of a neurofibroma may portend malignant transformation and should prompt an excisional biopsy.

III.17.5 Familial Atypical Multiple Mole and Melanoma Syndrome Familial Atypical Multiple Mole and Melanoma syndrome (FAMMM), also known as Dysplastic Nevus syndrome, represents a group of disorders characterized by multiple cutaneous melanomas and atypical melanocytic nevi associated with a probable polygenic inheritance pattern.

III.17.5.1 Clinical Features Hallmark features of FAMMM are early cutaneous melanomas in the setting of multiple atypical melanocytic nevi (often exceeding 100). These nevi are typically greater than 5 mm exhibiting border and pigment irregularities. Individuals with FAMMM develop a higher rate of melanomas at earlier ages of onset with an increased risk of developing multiple primary melanomas compared with the general population [26]. Earlier studies suggest a link between familial melanoma and pancreatic cancer. Goldstein et al. reported a 22-fold increased risk of pancreatic cancer in melanoma-prone families with defective CDKN2A [28]. Some reports of squamous cell carcinomas of the head and neck have also been described in patients with FAMMM.

III.17.4.3 Management and Prognosis The care for an individual with suspected NF-1 requires a multidisciplinary approach involving dermatology, genetics, neurology, and ophthalmology. Given the autosomal-dominant inheritance pattern, genetic and prenatal counseling is highly recommended. Careful neurological and developmental assessment, including evalu-

III.17.5.2 Diagnosis Clinical diagnosis of atypical nevi and melanomas with a family history of melanoma contributes to the diagnosis of FAMMM. Genetic CDKN2A testing, although commercially available, is usually performed in academic settings. In-

Syndromes Involving Melanocytic Lesions

heritance of FAMMM is complex and most likely of polygenic etiology. The prevalence of FAMMM is difficult to assess due to an absence of standardized diagnostic criteria and a lack of a reproducible clinical patterns [43]. Identification of the affected gene loci was localized to chromosome 9p21 [21]. Germline mutations of CDKN2A were demonstrated by Hussussian et al. [27] in 92% of melanoma-prone patients with linkage to the 9p21 chromosome; however, only 30% of persons with dysplastic nevi had mutations in the CDKN2A region, suggesting a related but diverse etiology.

III.17.5.3 Management and Prognosis Regular dermatological screening exams with emphasis on sun avoidance and sunscreen use are fundamental components of care in individuals with FAMMM. Total-body photography using dermoscopy and digital imaging every 6 months is strongly recommended. Using this technology to investigate and follow any new or changing moles is essential in making an early diagnosis of skin cancer. Genetic screening or therapeutic interventions are currently not recommended for relatives of affected family members at this time. Although a lower tolerance for removal of suspicious lesions is warranted. Studies demonstrate approximately a 50% risk of developing a cutaneous melanoma by 50 years of age among individuals with a positive family history of melanoma [23]. Specific therapeutic care of atypical nevi and melanomas are discussed elsewhere in this book.

III.17.6 Carney/LAMB/ NAME Syndromes Carney syndrome is a cardiocutaneous syndrome whose features include: (a) pigmented skin lesions; (b) atrial myxomas; (c) endocrine overactivity; and (d) psammomatous melanotic schwannomas [1]. Linkage analysis has mapped the diseased gene to chromosome 2p16 and 17q2 [31]. Two previously described syndromes that fall under the umbrella of Carney complex [33] are

Chapter III.17

LAMB (lentigines, atrial myxomas, mucocutaneous myxomas, and blue nevi) [32] and NAME (nevi, atrial myxomas, myxoid neurofibromatosis, ephelides, or endocrine overactivity) [11].

III.17.6.1 Clinical Features Cutaneous pigmented lesions typically appear at birth and increase at puberty. These skin findings include congenital melanocytic nevi [13, 14, 15], congenital blue nevi, lentigines [19], perioral/buccal pigmented macules and macular pigmentation of the sclera and conjunctiva. Lentigines, a prominent feature of this syndrome, are scattered throughout the body but appear mostly on the face, specifically the eyelids, conjunctiva, nasal bridge, ears, vermillion lip border, and oral mucosa. Carney syndrome can be distinguished from LEOPARD syndrome (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) by the involvement of the oral mucosa and the absence of dysmorphic features. Cardiac and cutaneous myxomas are another clinically significant feature of this syndrome. Myxomas of the skin manifest as non-tender dermal nodules in the second decade of life. Atrial myxomas, complicated by congestive heart failure, pulmonary edema and emboli, account for up to 20% of deaths in affected patients [33].

III.17.6.2 Diagnosis Diagnostic criteria for Carney syndrome require two or more of the following findings: 1. Spotty skin pigmentation (lentigines, blue nevi) 2. Cutaneous or mucosal myxomas 3. Cardiac myxomas 4. Primary pigmented nodular adrenocortical disease 5. Pituitary adenomas 6. Sertoli cell tumors 7. Thyroid carcinoma 8. Psammomatous melanotic schwannoma



C.G. Aber, E.A. Connelly, L.A. Schachner

III.17.6.3 Management


Dermatological examination with appropriate referral to cardiology, endocrinology, gynecology, and urology.

III.17.7 Occult Spinal Dysraphism/ Tethered Cord Spinal dysraphism describes a spectrum of congenital anomalies characterized by incomplete fusion of the midline vertebral column. Skincovered lesions without exposed neural tissue fall under the heading of spina bifida occulta. Often, congenital midline cutaneous lesions represent the only clues of the diagnosis. Some reports describe midline lumbar–sacral pigmented lesions, including melanocytic nevi,


which are associated with occult spinal dysraphism [25, 40]. Studies demonstrate that a combination of two or more congenital midline lesions is a strong marker of spina bifida occulta.

III.17.7.1 Management Magnetic resonance imaging (MRI) of the lumbar sacral spinal area is a non-invasive optimal choice to detect spinal dysraphism or other intraspinal lesions (lipomas, hemangiomas) [8, 18]; however, MRI requires sedation of a young patient. Although less sensitive, high-resolution spinal ultrasound allows effective, non-invasive screening of spinal dysraphism [18] in a newborn before ages 3–5 months (before the posterior spine ossifies).

Core Messages ■ Melanocytic lesions are associated with a number of syndromes: neurocutaneous melanosis; xeroderma pigmentosum; NF-1; familial atypical multiple mole melanoma syndrome; Carney syndrome; and spina bifida occulta. ■ Skin findings, such as large congenital melanocytic nevi or café-au-lait macules, can provide the outward clue of a systemic disorder.

References   1. Carney JA (1995) The Carney complex (myxomas, spotty pigmentation, endocrine overactivity and schwannomas). Dermatol Clin 13:19–25   2. Bett BJ (2006) Large or multiple congenital melanocytic nevi: occurrence of neurocutaneous melanocytosis in 1008 persons. J Am Acad Dermatol 54:767–777   3. Bale SJ, Digiovanna JJ (2001) Cancer-associated genodermatosis and familial cancer syndromes with cutaneous manifestations. Clin Dermatol 19:284–289

■ Recognizing associated findings is essential to ascertaining a diagnosis. ■ Certain syndromes (neurocutaneous melanosis, NF-1, Carney syndrome) require further diagnostic studies to evaluate and monitor serious associated anomalies.

  4. Ball NJ, Kho GT (2005) Melanocytic nevi are associated with neurofibromas in neurofibromatosis, type I, but not sporadic neurofibromas. A study of 226 cases. J Cutan Pathol 32:523–532   5. Brasfield RD, Das Gupta TK (1972) Von Recklinghausen’s disease: a clinicopathological study. Ann Surg 175:86–104   6. Kadonaga N, Frieden J (1991) Neurocutaneous melanosis. Definition and review of the literature. J Am Acad Dermatol 24:747–755   7. Moriwaki SI, Kraemer KH (2001) Xeroderma pigmentosum: bridging a gap between clinic and laboratory. Photodermatol Photoimmunol Photomed 17:47–54

Syndromes Involving Melanocytic Lesions   8. Perera GK, Atherton D (2006) The value of MRI in a patient with occult spinal dysraphism. Pediatr Dermatol 23:24–26   9. Theos A, Korf B (2006) Pathophysiology of neurofibromatosis type 1. Ann Intern Med 144:842–849 10. Wander JV, Das Gupta TK (1977) Neurofibromatosis. Curr Prob Surg 14:26–73 11. Zahorcsek Z, Schneider I (1996) Generalized lentiginosis manifesting through three generations. Int J Dermatol 35:357–359 12. Crowe FW, Schull WJ, Neel JV (1956) A clinical, pathological and genetic study of multiple neurofibromatosis. Charles C. Thomas, Springfield, Ill., p. 181 13. Atherton DJ, Pitcher DW, Wels RS et al. (1980) A syndrome of various cutaneous pigmented lesions, myxoid neurofibromatoma and atrial myxoma: the NAME syndrome. Br J Dermatol 103:421–429 14. Rhodes AR, Silverman RA, Harrist TJ et al. (1984) Mucocutaneous lentigines, cardiomucocutaneous myxomas, and multiple nlue nevi: the LAMB syndrome. J Am Acad Dermatol 10:72–82 15. Carney JA, Gordon, H, Carpenter PC et al. (1985) The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine 64:270–283 16. Kraemer KH, Lee MM, Scotto J (1987) Xeroderma pigmentosum. Cutaneous, ocular and neurologic abnormalities in 830 published cases. Arch Dermatol 123:241–250 17. Bootsma D, Kraemer KH, Cleaver JE et al. Nucleotide excision repair syndromes: xeroderma pigmentosum, Cocakyne syndrome and trichothiodystrophy. 18. Brophy JD, Sutton LN, Zimmerman RA et al. (1989) Magnetic resonance imaging of lipomyelomeningocele. Neurosurgery 25: 336–340 19. Gorlin RJ, Cohen MN, Levin LS (1990) Syndromes of the head and neck, 3rd edn. New York: Oxford University Press 20. Byrd SE, Darling CF, Tomita T et al. (1991) MR imaging of symptomatic neurocutaneous melanosis in children. Pediatr Radiol 27:39–44 21. Cannon-Albright LA, Goldgar DE, Meyer LJ et al. (1992) Assignment of a locus for familial melanoma, MLM, to chromosome 9p13–p22. Science 258:1148–1152 22. Kadonaga N, Barkovich JA, Edwards MSB, Frieden IJ (1992) Neurocutaneous melanosis in association with the Dandy–Walker complex. Pediatr Dermatol 9:37–43 23. Tucker MA, Fraser MC, Goldstein AM, et al. (1993) Risk of melanoma and other cancers in melanomaprone families. J Invest Dermatol 100 (Suppl):350s– 355s

Chapter III.17 24. Ball NF, John JJ, Morelli JG et al. (1994) Ras mutations in human melanoma: a marker of malignant progression. J Invest Dermatol 102:285s 25. Davis DA, Cohen PR, George RE. (1994) Cutaneous stigmata of occult spinal dysraphism. J Am Acad Dermatol 31:892–896 26. Goldstein AM, Fraser MC, Clark WHJ, Tucker MA (1994) Age at diagnosis and transmission of invasive melanoma in 23 families with cutaneous malignant melanoma/dysplastic nevi. J Natl Cancer Inst 86:1385–1390 27. Hussussian CJ, Struewing JP, Goldstein AM et al. (1994) Germline p16 mutations in familial melanoma. Nat Genet 8:15–21 28. Goldstein AM, Fraser MC, Struewing JP et al. (1995) Increased risk of pancreatic cancer in melanoma-prone kindreds with p16 mutations. N Engl J Med 333:970–974 29. Chaloupka JC, Wolf RJ, Varma PK (1996) Neurocutaneous melanosis with the Dandy–Walker malformation: a possible rare pathoetiologic association. Neuroroadiology 38:486–489 30. De David M, Orlow SJ, Provost N, et al. (1996) Neurocutaneous melanosis: clinical features of large congenital nevi in patients with manifest central nervous system melanosis. J Am Acad Dermatol 35:529–538 31. Casey M, Mah C, Merliss AD et al. (1998) Identification of a novel genetic loci for familial cardiac myxomas and Carney complex. Circulation 98:2560–2566 32. Okulicz JF, Schwartz RA, Jozwiak S (2001) Lentigo. Cutis 67:367–370 33. Abdelmalek NF, Gerber TL, Menter A (2002) Cardiocutaneous syndromes and associations. J Am Acad Dermatol 46:161–183 34. Evans DG, Baser ME, McGaughran J et al. (2002) Malignant peripheral nerve root sheath tumours in neurofibromatosis 1. J Med Genet 39:311–314 35. Mena-Cedillos CA, Valencia-Herrera AM, Arroyo-Pineda AI et al. (2002) Neurocutaneous melanosis in association with the Dandy–Walker complex, complicated by melanoma. Pediatr Dermatol 19:237–242 36. Itin PH, Burgdorf WH, Happle R et al. (2003) Genodermatosis. In: Schachner LA, Hansen RC (2003) Pediatric dermatology. Mosby, Elsevier Limited, Philadelphia 37. Marghoob A, Borrego J, Halpern A (2003) Congential melanocytic nevi: treatment modalities and management options. Semin Cut Med Surg 22:21– 32 38. Pollock PM, Harper UL, Hansen KS et al. (2003) High frequency of BRAF mutations in nevi. Nat Genet 33:19




C.G. Aber, E.A. Connelly, L.A. Schachner 39. Roco F di, Sabatino G, Koutzoglou M (2004) Neurocutaneous melanosis. Childs Nerv Syst 20:23–28 40. Guggisberg D, Hadj-Rabia S, Viney C et al. (2004) Skin markers of occult spinal dysraphism in children: a review of 54 cases. Arch Dermatol 140:1109– 1115 41. Hale EK, Stein J, Ben-Porat L et al. (2005) Association of melanoma and neurocutaneous melanocytosis with large congenital melanocytic naevi: results from the NYU-LCMN registry. Br J Dermatol 152:512–517

42. Robinson AJ, Russell S, Rimmer S (2005) The value of ultrasonic examination of the lumbar spine in infants with specific reference to cutaneous markers of occult spinal dysraphism. Clin Radiol 60:72–77 43. Somoano B, Niendorf KB, Tsao H (2005) Hereditary cancer syndromes of the skin. Clin Dermatol 23:85–106 44. Marghoob AA, Dusza S, Oliveria S (2004) Number of Satellite Nevi as a Correlate for Neurocutaneous Melanocytic Nevi. Arch Dermatol 140:171-175.

Chapter III.18

Nail Apparatus Nevus (Subungual Nevus, Nail Matrix Nevus)


Luc Thomas

Contents III.18.1 Definition. . . . . . . . . . . . . . . . . . . . . . . . . . . 173 III.18.2 Clinical Features. . . . . . . . . . . . . . . . . . . . . 173 III.18.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . 173 III.18.4 Relevant Clinical Differential Diagnoses. . . . . . . . . . . . . . . . . . . . . . . . . . . 175 III.18.5 Histopathology. . . . . . . . . . . . . . . . . . . . . . 175 III.18.6 Management . . . . . . . . . . . . . . . . . . . . . . . . 176 III.18.7 Case Studies. . . . . . . . . . . . . . . . . . . . . . . . . 176 III.18.7.1 Case 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 III.18.7.2 Case 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

References. . . . . . . . . . . . . . . . . . . . . . . . . . . 180

III.18.1 Definition Nail nevus is a benign melanocytic tumor that involves any part of the nail apparatus [1–8]. Most cases involve the nail matrix, and rare cases involve the nail bed and/or the nail lateral folds. Extremely rarely a blue nevus, which corresponds to a heavily pigmented, exclusively dermal melanocytic tumor, involves the nail apparatus.

III.18.2 Clinical Features In most cases, the nail apparatus nevus involves the nail matrix and clinically produces a pigmented longitudinal band on the nail plate. This band is the reflection of the melanin deposit in the nail plate during its early growth in the nail

matrix area and persists in the nail plate toward the distal edge. This clinical presentation is called the melanonychia striata syndrome. Melanonychia striata is also the clinical presentation of early nail apparatus melanoma (see Chap. IV.11); therefore, this syndrome should be regarded cautiously and it is recommended to systematically consider this diagnosis regardless of the other symptoms and regardless of the clinical context. Benign melanonychia striata, however, usually has its onset during childhood, is regular in its coloration, has parallel borders, and does not involve the periungual tissue. Heterochromic melanonychia striata (especially in congenital nevi) and cases with involvement of the periungual tissue, the cuticle and supra-matricial skin (also called Hutchinson’s sign; see Chap. IV.11), or the lateral folds can cause diagnostic difficulties. Blue nevus of the nail apparatus corresponds to a blue spot with a discoid distal edge and a proximal end often hidden from clinical examination by the supra-matricial skin.

III.18.3 Dermoscopic Criteria On the nails, immersion technique should be used for dermoscopy since polarized light appears insufficient to properly illuminate the thick nail plate. We recommend to use gel immersion (uncolored ultrasound gel). In dermoscopy, in case of melanonychia striata syndrome, a nail apparatus nevus has a light- to dark-brown homogeneously colored background overlaid by regular longitudinal lines. These lines are regular in their coloration, spacing, thickness, and do not show areas of parallelism disruption (Figs. III.18.1, III.18.2).




Fig. III.18.1.  Nail apparatus melanocytic nevus of the second right fingernail in a 26-year-old male skin-type-3b patient. Pigmentation has been present since childhood and the patient has observed no enlargement over the years. No other pigmented lesion of the toe and fingernails has been found. The clinical picture corresponds to the classical melanonychia striata syndrome. The lesion is clinically monochromic, and no pigmentation of the peri-

ungual skin is observed. Dermoscopy shows a brown coloration of the background overlaid by longitudinal lines regular in their color, spacing, thickness, and parallelism. In such a case pathological confirmation of the diagnosis is usually not required; however, in this particular case a nail matrix biopsy was performed after the patient’s informed consent was obtained in the setting of a clinical study. It confirmed the diagnosis of junctional melanocytic nevus

Fig. III.18.2.  Nail apparatus melanocytic nevus of the left thumbnail in an 8-year-old skin-type-4 male patient. The lesion has been present since the age of 6 years and was stable in its dimensions and coloration since then. Clinical picture corresponds to the classical melanonychia striata syndrome. By clinical observation we noticed that the lesion was monochromic and its borders were symmetrical. Note that there is a pseudo-Hutchinson’s

sign due to the visibility of the pigmentation through a translucent nail cuticle. This should not be confused with true Hutchinson’s sign, which corresponds to pigmented involvement of the periungual tissue. Dermoscopically, the lesion appears to be composed of regular longitudinal lines overlying a brown background. No biopsy was taken and the lesion remained stable after 4 years of clinicaldermoscopic follow-up

Nail Unit Nevus

Nail apparatus blue nevi display the classical blue homogeneous pattern also observed on non-acral skin in dermoscopy; however, depending on their anatomic location, the proximal edge is often hidden from the dermoscopist.

III.18.4 Relevant Clinical Differential Diagnoses The main differential diagnosis in the melanonychia striata syndrome are the following: 1. Melanoma (see Chap. IV.11), acral lentiginous type, should always be considered in the differential diagnosis of a pigmented longitudinal band on the nail. Clinical criteria for malignancy are: (a) onset during adulthood; (b) polychromic aspect; (c) pigmentation of the periungual tissue (Hutchinson’s sign); (d) enlargement of the band over time; and (e) broader band at the proximal end. Dermoscopy shows an irregular pattern of the lines (irregular in width, color, spacing, and parallelism). 2. Lentigines are often polydactylic and are clinically associated with mucous membrane pigmentation in Laugier– Hutzinger disease. Such lesions occur in adulthood. Dermoscopy reveals a monochrome gray band with thin regular gray lines. 3. Ethnic pigmentation is observed in patients with skin types 5 and 6, the family history reveals similar pigmentation in parents or siblings, and lesions occur in several finger- and toenails. Dermoscopic features are similar to those observed in lentigines. 4. Drug-induced pigmentation is a very frequent phenomenon. Medical history reveals chronic exposure to a pigmentogenic medication (hydroxyurea, chlorpromazine, acyclovir, mynocyclin, etc.). Lesions are polydactylic, and dermoscopic findings are similar to those of lentigines.

Chapter III.18

5. Post-inflammatory reaction (toenail chronic friction with shoes, nail pigmentation after paronychia of any origin) is in most case polydactylic, and often symmetric. Diagnosis is made by recording the patient’s history, observation of the topography of the involvement, and dermoscopic observation of changes similar to those observed in lentigines. 6. In some cases nail apparatus Bowen’s disease is pigmented; however, early periungual involvement and subungual hyperkeratosis is observed. These lesions occur during adulthood. Pathology determines the diagnosis. In case of a blue pigmented spot, the differential diagnosis is subungual hemorrhage; however, these lesions are clinically characterized by their regressive evolution toward the distal edge of the nail plate as opposed to the clinical fixity of the blue nevi. Dermoscopy is extremely useful showing “blood spots” characterized by their round-shape proximal edge and their filamentous distal ending in case of subungual hemorrhage.

III.18.5 Histopathology Histopathological confirmation of the diagnosis of subungual nevus is not mandatory in typical cases; However, in case of doubt a nail matrix biopsy should be taken. This surgical procedure is difficult and often leaves a definitive longitudinal nail plate dystrophy. Moreover the “significant” tissue is very small and any inappropriate management of the specimen could be misleading. Histopathology shows a melanocytic hyperplasia at the basal layer of the matricial epithelium. No cell atypia is found and melanocytes do not exhibit prominent dendrites. The dermal component is composed of nests of small round melanocytes regular in size and shape. Neither mitotic figures nor an inflammatory infiltrate are found.




III.18.6 Management


Treatment of nail apparatus melanocytic nevi is not mandatory. Abstention and follow-up are generally recommended because surgery is difficult and painful and it leaves definitive scars on the nail plate. Treatment of lateral nail apparatus nevi is somewhat easier but scarRing process in the lateral nail fold often causes a lateral deviation of the nail plate. In case of surgical treatment, complete excision of the nevus should be the goal because follow-up of a longitudinal nail pigmentation after partial surgery is extremely difficult since the scarring process causes irregular pigment distribution in the remnant lesion which is extremely difficult to differentiate from melanoma. The surgical excision of a nevus of the nail matrix is conducted after incision of the submatricial skin. A suture of the nail matrix defect should be done with loose stitches. Even in experienced hands this surgery often leaves dystrophic changes of the nail plate. In our opinion, surgery should only be done in case of doubt.

III.18.7 Case Studies III.18.7.1 Case 1 Patient Comment The lesion is observed on the right thumb of a right-handed 11-year-old skin-type-2 female patient. Her parents first noticed the lesion at the age of 4 years. Since then, the lesion has progressively enlarged with the finger, but the proportion of the involved nail plate has remained the same. There is no complaint about this lesion, and the small defect at the distal edge of the nail plate is due to a nail-clipping biopsy performed a few days prior to examination by another dermatologist (pathology found melanin in the nail plate). The parents referred their daughter to obtain a second opinion before potentially scarring surgery of the nail matrix.

Questions Asked By the Physician The interview with the parents and child was quite precise about the age of onset. They provided several family photographs in which the lesion was clearly identifiable. No esthetic complaint was formulated.

Clinical Image Clinical observation disclosed a melanonychia striata syndrome without atypia. The coloration of the band was homogeneous, no Hutchinsonâ&#x20AC;&#x2122;s sign is observed, and edges of the band were regular and parallel.

Dermoscopic Image Dermoscopy showed a typical nevus pattern with regular parallel lines over a light brown background.

Clinical Diagnosis and Relevant Differential Diagnosis The patientâ&#x20AC;&#x2122;s history as well as clinical and dermoscopic findings were highly suggestive of nail matrix melanocytic nevus. Melanoma should always be included in the differential diagnostic discussion of a monodactylic melanonychia striata syndrome; however, in this case the onset during childhood, the absence of band enlargement over time, the regular clinical pattern of the band, and the nevus pattern on dermoscopy were sufficient enough to avoid unnecessary surgery on the thumb of the dominant hand of this young patient. Ethnic-type pigmentation is rarely monodactylic and never occurs in skintype-2 patients.

Performed Management The patient was included in a two-yearly followup program. No change has been observed.

Nail Unit Nevus

Comments Even though melanoma is rare in children, it should systematically be included in the differential diagnosis of a melanonychia striata. In this case the patientâ&#x20AC;&#x2122;s medical history, clinical examination, and dermoscopy, as well as inclusion in a follow-up program, obviated the need for surgery.

Chapter III.18

III.18.7.2 Case 2 Patient Comment This 26-year-old female skin-type-4 patient was referred for nail changes on her second right finger. About 6 years prior to examination, she had noticed for the first time a blue pigmentation of the lunula. The lesion was then attributed to trauma and diagnosed as a subungual hemorrhage; H=however, the pigmentation remained





stable over time and showed no tendency toward regression or distal migration of the pigmentation. An attempt of curettage of the nail plate surface did not permit to eliminate pigmentation but left surface changes observed at the distal part of the plate after nail outgrowth. The lesion was not painful, and X-ray of the distal phalanx was normal.

Questions Asked by the Physician The patientâ&#x20AC;&#x2122;s interview clearly stated that the pigmentation did not enlarge over time and the absence of other symptoms. Examination of the other nails was normal as well as total skin examination. The patient confirmed that changes observed on the distal nail plate were due to an unsuccessful attempt at superficial abrasion of

the plate by a previous examiner performed in order to rule out the diagnosis of subungual hemorrhage.

Clinical Image If we except the artifactual changes of the distal plate, the clinical picture is limited to a hemicircular blue discoloration of the lunula that is also observed through the cuticle (pseudoHutchinsonâ&#x20AC;&#x2122;s sign). No periungual pigmentation was seen.

Dermoscopic Image The dermoscopic examination showed a homogeneous blue pattern limited proximally by the

Nail Unit Nevus

cuticle and with poorly defined distal limit. This image did not show “filamentous” distal aspect observed in subungual hemorrhages.

Clinical Diagnosis with Relevant Differential Diagnosis The dermoscopic image was very similar to the blue homogeneous pattern observed in cutaneous blue nevus. It was similar to the image published by Causeret et al [8]. Accordingly, our dermoscopic diagnosis was blue nevus. The main clinical and dermoscopic differential diagnosis was subungual hemorrhage; however, the absence of distal migration over time and the fixity of the pigmentation despite the absence of repetitive trauma and, moreover, the absence of “filamentous” pattern of the distal part of the pigmentation, were against this hypothesis. Subungual blue nevus is rare, however, and therefore pathological confirmation was preferred.


Chapter III.18

Histopathological Diagnosis and Clinicopathological Correlation Diagnosis of ungual blue nevus (of the cellular subtype) was made. The complete confinement of the pigment deposit to the submatricial dermal tissue explained the blue spot pattern observed on dermoscopy, and absence of involvement of the epithelial tissue explained the absence of longitudinal band.

Comments Facing a well-circumscribed subungual blue pigmentation, clinical diagnosis vacillates between subungual hemorrhage and blue nevus. Clue for the diagnosis in favor of blue nevus are: (a) the absence of distal migration of the pigmentation with the outgrowing nail plate; and (b) the blue homogeneous pattern of the pigmentation with semi-circular shaped distal end without “filamentous” distal pattern.


Core Messages ■ Nail apparatus melanocytic nevus frequently occurs during childhood and its most common presentation is the melanonychia striata syndrome. ■ The main differential diagnosis is nail apparatus melanoma. ■ Dermoscopy shows a regular pattern of pigmentation. ■ In case of doubt surgical biopsy and histopathological examination are required. ■ In typical cases follow-up appears to be the most appropriate management since surgical therapy often leaves definitive nail dystrophy.

Surgical exploration of the nail matrix area disclosed a well-limited discoid blue pigmentation underneath the matricial tissue. Dissection of the submatricial tissue permitted the excision of a charcoal-black piece of dermis, At the end of the surgical procedure reposition of the nail matrix and of the supra-matricial tissue per­ mitted a normal outgrow of an almost normal unpigmented nail plate within 5 months. Follow-up examination after 2 years showed no recurrence.

Histopathological Image Histopathological examination of tissue removed during surgery showed an exclusively dermal proliferation of heavily pigmented cells. Surgical margins were free. Cells were centered by well-nucleolated nucleus. Cytoplasm was filled by granulous or more homogeneous pigment deposits. Neither mitotic figures nor cell atypia were observed.






1. Haneke E, Baran R (2001) Longitudinal melanonychia. Dermatol Surg 27:580–584 2. Hirsch RJ, Weinberg JM (2001) Evaluation of pigmented lesions of the nail unit. Cutis 67:409–411 3. Tosti A, Baran R, Piraccini BM, Cameli N, Fanti PA (1996) Nail matrix nevi: a clinical and histopathologic study of twenty-two patients. J Am Acad Dermatol 34:765–771 4. Goettmann-Bonvallot S, Andre J, Belaich S (1999) Longitudinal melanonychia in children: a clinical and histopathologic study of 40 cases. J Am Acad Dermatol 41:17–22

5. Ronger S, Touzet S, Ligeron C, Balme B, Viallard AM, Thomas L (2002) Dermoscopic examination of nail pigmentation. Arch Dermatol 138:1327–1333 6. Kawabata Y, Ohara K, Hino H, Tamaki K (2001) Two kinds of Hutchinson’s sign, benign and malignant. J Am Acad Dermatol 44:305–307 7. Johr RH, Izakovic J (2001) Dermatoscopy/ELM for the evaluation of nail apparatus pigmentation. Dermatol Surg 27:315–322 8. Causeret A, Skowron F, Viallard A, Balme B, Thomas L (2003) Subungual blue nevus. J Am Acad Dermatol 49:310–312

Chapter III.19

Unna Nevus Susana Puig and Josep Malvehy

Contents III.19.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 III.19.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . 181 III.19.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . 181 III.19.4 Relevant Clinical Differential Diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 III.19.5 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . 183 III.19.6 Management. . . . . . . . . . . . . . . . . . . . . . . . . . 184

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

III.19.1 Definition The term Unna nevus encompasses a clinical, dermoscopic, and histopathological distinctive variant of melanocytic nevus that corresponds to a papillomatous dermal or compound nevus. The other distinct variant of compound or dermal nevus of the face (Miescher nevus) is reviewed Chap. III.13.

III.19.2 Clinical Features Clinically, Unna nevus is a soft polypoid or sessile, usually papillomatous light- to dark-brown lesion frequently located on the trunk, arms, and neck [1, 2]. The clinical features of this common type of benign dermal melanocytic nevus are often quite straightforward, allowing clinical diagnosis at a glance; thus, in many instances dermoscopic examination is superfluous. Nevertheless, the dermoscopic features of Unna

III.19 nevi are very distinctive and in some atypical cases may allow a correct differential diagnosis with other benign and malignant tumors.

III.19.3 Dermoscopic Criteria Dermoscopically, Unna nevi reveal a typical globular pattern composed of numerous tan to dark-brown, round to oval globules distributed regularly throughout the lesion, or a cobblestone pattern consisting of larger, polygonal structures corresponding to big nests of nevus cells (Figs. III.19.1, III.19.2). In addition, Unna nevi in some instances display densely packed exophytic papillary structures (Fig. III.19.3), which are commonly separated by irregular, black comedo-like openings also known as irregular crypts, similar to those found in seborrheic keratosis. These exophytic papillary structures correspond to an exaggeration of the papillomatous surface of an Unna nevus. Sometimes, milialike cysts and comedo-like openings are also detected by dermoscopy. The wobble sign described by Braun et al. [5] is useful to distinguish Unna nevus from seborrheic keratosis, as papillomatous dermal nevi wobble when the dermatoscope is pushed from site to site, whereas seborrheic keratoses do not wobble (see Differential Diagnosis). When appearing as hypopigmented (light brown) or skin-colored nodules, dermal nevi ­reveal numerous vessels that are sometimes polymorphous. Moreover, dermoscopy usually shows, especially at the periphery, the typical “comma-like” vessels [3, 4] which are considered typical of benign dermal nevi and some compound nevi. These types of vessels are different from those seen in seborrheic keratosis.


S. Puig, J. Malvehy Fig. III.19.1.  Typical clinical presentation of Unna nevi on the back of a patient


Fig. III.19.2.  Dermoscopy of Unna’s nevus. A globular pattern with prominent vascularization is seen. “Comma-like” vessels are observed (insets)

Unna Nevus

Fig. III.19.3.  Photomicrograph of an Unna’s dermal nevus exhibits an exophytic structure with a markedly papillated silhouette

III.19.4 Relevant Clinical Differential Diagnoses Seborrheic keratosis may be similar to verrucous dermal nevi and dermoscopy exhibits an overlap of some of the criteria (follicular openings, crypts and fissures, keratin plugs, milialike cysts). The wobble sign has been described to differentiate papillomatous seborrheic keratosis from dermal nevus with similar clinical appearance: In seborrheic keratosis, the tumor follows the movement of the dermoscopic device (contact dermoscopy), leaving back the surrounding skin, but the static image of the tumor does not change, because the stiff papular component cannot be dissociated from the surface of the lesion itself. This sign occurs exclusively in seborrheic keratosis [5]. Vascularization in seborrheic keratosis shows hairpin vessels with a white halo that are prominent if inflammation is present, whereas in dermal nevi the presence of “comma-like” vessels is stereotypical [4]. Basal cell carcinomas may be similar to some dermal nevi. In basal cell carcinoma, the arborizing vessels are characteristic and frequently ulceration or other dermoscopic criteria may be seen. Melanoma sometimes mimicks a dermal nevus, mainly in the case of verrucous or polypoid or nevoid melanomas with poor pigmentation.

Chapter III.19

Since clinical management of Unna nevus is completely different from that of melanoma, a wrong diagnosis may lead to incorrect management (shaving biopsy, electrodissection, cryotherapy, laser treatment) or even to excision without histopathological analyses of the specimen. To avoid misdiagnosis of melanoma resembling Unna nevus, any polypoid tumor with equivocal history of changes and atypical clinical or dermoscopic findings should be considered for biopsy and histopathological examination. A traumatized Unna nevus may resemble a malignant tumor when inflammation or bleeding is observed. In these cases the history of trauma, the observation of typical signs in the examination, and the resolution of inflammation over a short period of time confirms the diagnosis. Other tumors and infectious diseases that could be included in the differential diagnosis of Unna nevus are warts, condilomas, fibromas, and adnexal tumors such as sebaceous epithelioma.

III.19.5 Histopathology Unna nevus is a compound nevus that exhibits an exophytic structure with a markedly papillated silhouette. The epidermis has an epidermal nevus or seborrheic keratosis-like pattern with elongated rete ridges which give a labyrinthine image by merging together. Melanocytic cells are located in the core of the dermal papillae. A few junctional nests can be present, but it seems unlikely that Unna nevi evolves from junctional nevi. They may arise from melanocytes that migrate along neurovascular bundles to barely reach the epidermis. Most of the lesions have a congenital pattern if the base of the lesions is sampled, although they are considered to be acquired lesions. The dermal component of Unna nevus is restricted to the papillary layer, which is greatly expanded, and at the bottom of the tumor a well-demarcated border separates the limit between the papillary and reticular dermis. The general symmetry of the neoplasm should not prevent the need of examination of cellular details of the lesion carefully: a nevoid melanoma can exhibit a similar silhouette.



S. Puig, J. Malvehy

III.19.6 Management Unna nevus is a benign tumor that does not need surgical excision. Nevertheless, in the case of inflammation, or for cosmetic reasons, they are frequently removed.


Core Messages


■ Unna nevus is a compound nevus that exhibits an exophytic structure with a markedly papillated silhouette. ■ Clinically, Unna nevus is a soft, polypoid, or sessile light- to darkbrown lesion frequently located on the trunk, arms, and neck. ■ Clinical differential diagnosis includes seborrheic keratosis, basal cell carcinoma, melanoma, and adnexal tumors of the skin. ■ The general symmetry of the neoplasm should not prevent the need of a careful histopathological examination of cellular details of the lesion: a nevoid melanoma can exhibit a similar silhouette.  

References 1. Unna PG. Naevi und naevocarcinoma. Berl Klin Wochenschr 1893;30:14–16 2. Ackerman AB, Magana-Garcia M. Naming acquired melanocytic nevi. Unna’s, Miescher’s, Spitz’s Clark’s. Am J Dermatopathol 1990;12:193–209 3. Argenziano G, Zalaudek I, Corona R, Sera F, Cicale L, Petrillo G, Ruocco E, Hofmann-Wellenhof R, Soyer HP.Vascular structures in skin tumors: a dermoscopy study. Arch Dermatol 2004;140:1485–1489 4. Kreusch JF. Vascular patterns in skin tumors.Clin Dermatol 2002;20:248–254 5. Braun RP, Krischer J, Saurat JH. The “wobble sign” in epiluminescence microscopy as a novel clue to the differential diagnosis of pigmented skin lesions. Arch Dermatol 2000;136:940–942

Chapter IV.1

Epidemiology of Melanoma Scott Kitchener


IV.1.2 Global Epidemiology

IV.1.1 Epidemiology of Melanoma. . . . . . . . . . . . . 185 IV.1.2 Global Epidemiology. . . . . . . . . . . . . . . . . . . 185 IV.1.3 Real or Apparent Trends in Incidence and Mortality. . . . . . . . . . . . . . . . . . . . . . . . . 186 IV.1.4 Risk Factors. . . . . . . . . . . . . . . . . . . . . . . . . . . 186 IV.1.4.1 Skin Colour. . . . . . . . . . . . . . . . . . . . . . . . . . . 186 IV.4.2 Genetic Factors. . . . . . . . . . . . . . . . . . . . . . . . 187 IV.4.3 Naevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 IV.1.4.4 Latitude. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 IV.1.4.5 Sun Exposure. . . . . . . . . . . . . . . . . . . . . . . . . 188 IV.1.4.6 Migration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 IV.1.4.7 Artificial Light Sources. . . . . . . . . . . . . . . . . 189 IV.1.4.8 Occupation. . . . . . . . . . . . . . . . . . . . . . . . . . . 189 IV.1.5 Prevention of Melanoma . . . . . . . . . . . . . . . 190 IV.1.5.1 Primary Prevention. . . . . . . . . . . . . . . . . . . . 190 IV.1.5.2 Secondary Prevention. . . . . . . . . . . . . . . . . . 190


References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

IV.1.1 Epidemiology of Melanoma Melanoma is a common cancer of humans. Global incidence varies significantly based on a number of risk factors. To a large extent these risk factors have been determined from hypotheses arising from the global distribution, including risk factors such as skin colour and ultraviolet radiation. This chapter discusses the distribution of melanoma, risk factors and preventive measures.

The incidence of melanoma varies by region and is apparently rising in several regions of the world (Table IV.1, IV.2) [1]. Australia has the highest incidence of melanoma, recording 8900 new cases between 1990 and 2000 in a population of nearly 20 million people, making it the fourth most common cancer registered (mandatory reporting of non-melanomatous cancer is not nationwide) [2]. In North America it is now the fifth most common cancer among males and the sixth most common cancer among females in the United States [3]. Several countries in Europe have noted a rising trend and recent stabilization in mela­noma incidence and mortality [3]. Mortality rates are variable, with continuing increases in France, Italy and Czechoslovakia, which seem to be behind a general trend across Europe to decreasing mortality led by the U.K., Scan­dinavian countries and Spain [5–7]. Notably in the UK both stabilization then reductions have been observed in mortality and incidence rates [8, 9]. Table IV.1.  Approximate incidences of melanoma by r­ egion




<10/100,000 [127]

Northern Europe

11/100,000 [128]

South Africa (fair-skinned people)

20/100,000 [129]


30/100,000 [130]

Australia (Queensland)

50/100,000 [131]


S. Kitchener Table IV.2.  Incidence of melanoma in several collocated ethnic groups from surveillance data (U.S.) between 1992 and 2001


Ethnic group (in the U.S.)

Incidence [132]





American Indians


Asian/Pacific Islanders




The first observed flattening in the rise of mortality and then a reduction in mortality rates was observed in Australia [10]. Mortality from melanoma probably peaked in 1985 at approximately 5/100,000, has remained relatively steady for males and has begun to reduce for females. This is believed to be related to early detection, although the full effect of such programs are yet to be seen [11].

IV.1.3 Real or Apparent Trends in Incidence and Mortality While there appears to have been a steady epidemic of melanoma globally followed by early stages of stabilisation of this epidemic, there is some question as to whether these are true variations in the incidence or only apparent variations [12, 13]. An apparent increase in melanoma incidence, rather than a true increase, may be associated with more and closer detection methods in clinics, resulting in more melanoma found [14–16]. The trend in diagnosis of melanoma has been closely shadowed by an increase in biopsy rates [17]. This has led to diagnosis of earlier-stage melanoma and a trend towards thinner, less invasive tumours and perhaps unmasked a form of melanoma that is biologically benign despite appearing malignant on histopathology [18, 19]. As earlier stages of melanoma appear in biopsy and excision specimens presented to histopathologists, the reliability of the histopathology diagnostic process (and incidence data) decreases [20–22], particularly the distinction between severe dysplasia and melanoma in situ [23].

Greater effort and improved sensitivity in detection has resulted in early diagnosis of melanoma, which has probably translated into an apparent stabilization of melanoma mortality [19, 24]. The incidence of melanoma is influenced by several factors and is intimately associated with mortality rates associated with melanoma, not only in the obvious manner, but also through the shifting nature of melanoma being detected and treated. Regions clearly pass through an evolution of incidence and mortality changes. Interpreting these changes must be conducted with caution recognizing multiple and interrelated factors.

IV.1.4 Risk Factors IV.1.4.1 Skin Colour Melanoma incidence is inversely proportional to darkness of skin. Fairer-skinned Singaporeans of Chinese origin have a higher incidence of melanoma (0.5/100,000) than darker-skinned Indian Singaporeans (0.2/100,000) [25], and white South Africans have a greater incidence of melanoma than those with mixed ancestry and then black South Africans [26, 27, 129]; however, the relationship of darkness of skin, ultraviolet light penetration and melanoma incidence is probably complex. Both latitude and the ultraviolet index were associated with significantly greater incidence of melanoma for black men as for white people in the United States, but this was not significant for Hispanic people [28, 29], and unlike Caucasians, the incidence of melanoma among African-Americans, Asians, Indians and Hawaiians has not changed notably over the past three decades [30]. Melanoma in darker-skinned people presents in different anatomic locations than in lightercoloured people with a greater proportion of acral melanoma and melanoma presenting in non-sun-exposed areas [31, 32]. Diagnosis is at a more advanced stage in these groups, and 5-year survival for melanoma is less than for whites in the U.S. (72.2–81.1 vs 89.6% for whites) [33, 132]. This may be an effect of socio-economic status; however, in this study, African-Americans were also found to have a 1.48-fold greater mortality

Epidemiology of Melanoma

risk after adjustment for stage of melanoma at diagnosis, suggesting possible distinct tumour characteristics among this population.

IV.4.2 Genetic Factors Xeroderma pigmentosa is a genetic disorder with a mutation of the XPD gene leading to nucleotide excision repair defects [34]. Patients experience 1000-fold greater risk of melanoma as they are unable to repair UV-induced DNA [35]. This understanding has led to consideration of whether DNA repair capacity may also be a factor in melanoma in the general population. Melanoma cases have been found to have a statistically lesser ability to repair DNA compared with matched controls, and melanoma cases with primary tumours in sun-exposed skin locations have a lower repair capacity than those with primary melanoma on unexposed skin [36]. The relative ability to repair DNA modifies the risk in the presence of other host factors such as age, poor tanning ability and dysplastic naevi [37]. Two pleomorphisms of the XPD gene are associated with a decreased risk of melanoma among women with five or more severe sunburns or high cumulative sun exposure [38]. Mutations of the melanocortin-1 receptor gene variants are more common among fairskinned and red-haired people. Polymorphism of this gene is associated with melanoma (OR=2.43) and, though common, is present in approximately one-third of controls (37.5%) and two-thirds of cases (59.4%) [39]. The risk is additional to the phenotype of pigmentation of the individual atypical naevi, >50 melanocytic naevi, high recreational and occupational sun exposures [39, 40]. The relative risk of melanoma in light of a family history of one or more family members previously with melanoma is approximately two- to threefold based on results from multiple studies across various sun-exposed populations of fair-skinned people [41, 42]. More than three family members with melanoma raises this to over 35, unrelated to other familial traits such as hair and eye colour, naevus count and freckling [41]; nor are sun exposure in childhood and adulthood important determinants of melano-

Chapter IV.1

ma risk in families with a strong history of melanoma [43]. The first familial melanoma-related genetic mutation (in CDKN2A on chromosome 9p21), explaining transmission from one generation to the next, was discovered in 1994 in 13 of 18 kindreds of familial melanoma, followed by another shortly afterwards [44, 45]. A clear association with cell-cycle regulation, cell senescence and apoptosis was demonstrated. Penetrance of the CDKN2A mutation seems to increase with age and vary with population melanoma incidence rates, being greater in Australia (0.91 by 80 years of age) than the U.S. (0.76) and Europe (0.58), leading to the conclusion that the same factors affect melanoma incidence as mediate CDKN2A penetrance [46]. Mutations CDKN2A may account for up to 25% of familial melanoma cases worldwide [47], but the incidence of this mutation, even in Australia, is low (2%) so that only 1 of 200 melanoma cases in Australia probably carry a CDKN2A mutation [48]. As screening has poor predictive value, even in cases of atypical mole syndrome, it is not recommended outside of the research setting at this time [49, 50].

IV.4.3 Naevi Naevi are considered to be harbingers of melanoma, but the number and nature of naevi related to melanoma is complex. Histopathologically dysplastic naevi do not confer an independent risk of melanoma; however, dysplasia is not reliably assessed [51]. Atypical mole syndrome (AMS) is a phenotype characterized by a large number of naevi, both common and atypical. It is more common in families with predisposition to melanoma and more common (OR=10.4) among melanoma cases (16%) than controls (2%) [52]. People with more than 100 common moles (compared with <5; OR=7.7) or more than four atypical naevi (OR=28.7) are also at greater risk of melanoma. The phenotype is more relevant when present in younger people (OR=16.1 if <40 years). The total number of naevi is strongly related to risk of melanoma in Australia – a 12-fold risk




S. Kitchener

with more than 100 naevi compared with less than 10 – and the effect is stronger in younger (<40 years) people [53]. Multiple atypical naevi in either sun-exposed or non-exposed areas carried a fivefold risk in this study. Atypical naevus count is less relevant in higher sun-exposed areas, so that in Australia three or more atypical moles carries less risk of melanoma than in the U.K. (OR=4.6 vs 51.7), as the prevalence of atypical naevi and AMS (6% among control subjects) is greater in Australia [54]. The relationship of naevi count may not be consistent for all melanomas. Cutaneous melanoma may develop along two different paths: associated with naevi in naevi-prone skin on naevi-prone people; and on chronically sun-exposed skin. Those cases of melanoma on the trunk are more likely to have a high naevus count (>60) than cases of melanoma occurring on the head and neck or lentigo maligna melanoma which are more likely to be associated with dermal elastosis or solar keratoses from chronic sun exposure [55, 56]. Not only is naevus count probably related to melanoma arising with melanocyte proliferation, these melanomas are more likely to be identified with histological evidence of having arisen from a naevus [56, 57].

IV.1.4.4 Latitude The negative association of mortality from melanoma with latitude is a long-standing factor in melanoma identified early in Australia asso­ ciated with Caucasians, particularly living in northern, tropical parts of the continent [58, 59]. The relationship also exists for incidence of melanoma among fair-skinned people on other continents [60, 61], and has been demonstrated in some darker-skinned people [28]. The study of populations living closer to the equator has served as a foundation of the argument for sun exposure in the aetiology of melanoma [62, 63].

IV.1.4.5 Sun Exposure While initial clinical investigations suggested a direct association of sunlight in aetiology of melanoma [62], the effect was soon recognized as much less clear than for other skin cancers [64]. Over the past four decades knowledge of this complex relationship still only suggests that the role of sun exposure is possibly primary and probably supportive [62]. As discussed above, lighter-skinned people have a higher risk of melanoma than darker skinned people, those with genetic sensitivity to ultraviolet damage, and proximity to the equator are associated with higher incidence of melanoma, all suggesting the sun exposure is a major risk factor. A purely linear dose response relationship is unlikely to exist between sun exposure and melanoma aetiology. Intermittent sun exposure has been supported as a pattern of exposure more closely related to melanoma incidence, although the retrospective assessment of such an exposure is inaccurate. Nevertheless, recollections of high recreational sun exposure has been associated with an odds ratio for melanoma of 1.71 in a meta-analysis of 23 studies [65]. The nature and measurement of sun exposure varies significantly in these studies. Sunburn is perhaps more objective than quantification of sun exposure; however, it also suffers from recall and measurement bias being variably defined as peeling, blistering or simply erythema. History of sunburn does suggest intermittent very high and damaging sun exposure, and incurs a twofold higher risk of melanoma, approaching a fourfold increased risk following numerous episodes of severe sunburn [65, 66]. More than five severe sunburns recalled before the age of 15 years carried a relative risk of 2.7 for subsequent melanoma [67]. Sunburn at any time in life has often been demonstrated to be associated with increased incidence of melanoma later in life [68, 69]. The effect is most strongly observed in studies of childhood and adolescent exposure; however, adult exposure cannot be excluded in relevance [70]. Chronic high level of sun exposure in adulthood is more associated with melanoma of the head and neck and with lentigo maligna

Epidemiology of Melanoma

melanoma than recreational exposures, whereas intermittent patterns of exposure are more linked to truncal melanoma [71]. A lifelong history of sunburn carries a lesser risk (OR=1.7) than the specific history of sunburn in childhood (OR=5.9) [72], but childhood sunburn is related to the tendency to burn, to skin type and to hair colour which, when controlled, mitigates the association with melanoma development later in life [73, 74]. Thus, sunburns during each of adulthood and childhood are probably interdependent and those people at highest risk are adults who have had intense childhood sun exposure and continue to have burns as adults [75].

IV.1.4.6 Migration Migration studies are often used to investigate the influence of exposures to sun at differing ages. The mortality of native born Australians from melanoma is higher than those coming to Australia [76–79]. As noted above, sun exposure during childhood and adolescence is relevant for later risk of melanoma. When migration towards sunny climates occurs, there is an inverse link between mortality from melanoma and age of migration to the sunnier location [80, 81]. Migration to Australia before the age of 10 years confers a risk similar to locals; however, migrating after 10 and certainly after 15 years of age, is associated with one-third to one-quarter of the local risk [82, 83]. Findings were comparable for European children migrating to the Mediterranean or tropical areas from Belgium, France and Germany before the age of 10 years experiencing a fourfold (OR=4.3; 95% CI: 1.7–11.1) increased risk for melanoma later in life [69]. People migrating to California from more northern areas of North America are also found to be spared risk of melanoma compared with locally born Californians [84]. Duration of residence following emigration from more temperate zones to more sun-exposed areas is probably less relevant than age of migration, but risk for melanoma increases with longer duration in the high sun-exposed climate [69, 80, 82].

Chapter IV.1

IV.1.4.7 Artificial Light Sources Sun beds and sun lamps are an artificial light source used for tanning of skin and treatment of various skin conditions; reduction of UV-B light emission in these occurred during the 1980s. Earlier European studies demonstrated comparable risks for sun bed use beginning before 1980 (OR=2.71) and much higher risk for recreational use for greater than 10 h (OR=8.97) [74, 85]. A later European case-control study did not support an association with sun beds (OR=0.90; 95% CI: 0.71–1.14) despite finding a greater use with more northern locations [86]. A recent systematic review of sun bed use concluded that a history of ever using sun beds was associated with a very mild increased risk of melanoma (summary relative risk=1.15), which increased when first exposure was before the age of 35 years (SRR=1.75) [87]. The known risk factors of number of naevi and skin type were still the strongest indicators for melanoma risk.

IV.1.4.8 Occupation Fritschi and Driscoll recently estimated that in Australia only a small percentage of melanoma (4.3% in males and 0.4% in females) are able to be attributed to occupational exposures [88]. Studies of melanoma in occupations have suggested that occupational sun exposure may be protective [67, 89], or that no association exists between occupation and melanoma incidence, though this is potentially due to inadequate power or misclassification [90]. Considering the more specific classification of melanoma of the head and neck, strong association with high occupational exposure to sun is found [71]. Other studies have found increased incidence assocated with specific occupations including those associated with artificial light exposure, solvent exposure (including polychlorinated biphenyls and polyvinyl chlorides), intermittent high solar ultraviolet light and magnetic fields (arising from electricity transmission) [91–94]. Notably, farmers and other workers in occupations with high ultraviolet light exposure have only a slightly higher incidence of melanoma (odds ratio: 1.07–1.25) independent of other exposures such as solvents and pesticides [95–97].



S. Kitchener

IV.1.5 Prevention of Melanoma IV.1.5.1 Primary Prevention


Environmental alterations, social changes and behavioural modification to reduce ultraviolet exposure have been used for primary prevention of melanoma. The Slip, Slop, Slap program developed and first introduced in Australia to encourage people to slip on a shirt, slop on sunscreen and slap on a hat. Awareness of skin cancer was raised with Skin Cancer Awareness Week [98]. Later the SunSmart program continued these messages with expansion of the program towards environmental interventions. These programs have extended across the country, across social groups and through workplaces, recreation activities and schools. Messages and delivery modes were tailored to focus on children and then adolescents recognizing ultraviolet exposures at these ages as factors in melanoma risk [99, 100]. Have these primary prevention approaches worked? In summary, with regard to international skin cancer primary prevention programs, women are more knowledgeable about sun protection than men, although they are more likely to intentionally sunbathe; children reflect their parentâ&#x20AC;&#x2122;s behaviours; sunscreen is the most commonly used primary (as opposed to adjunct) method of sun protection; and all age groups could improve their use of sun protection [101]. These issues are not addressed in detail here as the most relevant end point for assessment of these programs is incidence and mortality from melanoma in the population. The incidence of melanoma in Australia has been suggested as evidence that programs have not worked [102]. This does not necessarily recognize the complexities of health outcome data in evaluating success of such programs. In fact, as discussed previously, incidence rates have stabilized in Australia, and have even reduced in some age groups, particularly women, supporting efficacy of primary prevention programs which have been running for two decades [103]. In Queensland, with the highest incidence of melanoma recorded in Australia, reduction in incidence attributed to primary prevention has occurred with an age cohort effect (in those less than 35 years of age) [19]. A further generation

will be necessary to realize the full benefit possible. Long-term consistency and continuity of effort at all social levels is necessary for primary prevention programs to be effective [98, 104]. Sunscreens have been a contentious primary prevention approach. Use has been associated with spending longer in the sun with the perception of protection by the sunscreen resulting in more ultraviolet skin damage [105]. The sun protection factor (SPF) of sunscreens has been directly related to increased duration of exposure to the sun by users [106]. An increased risk of melanoma by approximately twofold is related to use, depending upon the nature of the sunscreen [107]. Higher SPF does provide more protection against sunburn, but this may lead to use as a tanning aid rather than protection against exposure [108, 109]. Nevertheless, used correctly as an adjunct to an overall regimen of sun protection including clothing, hats, sun avoidance and shade provision, sunscreens are associated with reducing melanoma incidence on a population level, but the specific contribution can only be determined with a prospective study [101, 110, 111].

IV.1.5.2 Secondary Prevention Screening programs are effective for conditions of high incidence and high mortality for which effective treatment may be initiated. In Australia, incidence is high; however, a national campaign for screening was not instigated following an health economic evaluation finding of AUD5103 as the cost per life saved [112]. Screening for melanoma in selected high-risk groups by dermatologists and plastic surgeons in Western Australia has had disappointing results with a low 1-year sensitivity (63.6%) [113]. Community-based programs of melanoma screening in Queensland are able to attract Queenslanders for skin screening by primary care physicians [114, 115], and these detect melanoma with a reasonable specificity (86.1%) [116] at a rate (1 of 500 patients screened) comparable with other screening programs in Europe and North America [117â&#x20AC;&#x201C;119]. The reluctance of Australian Governments to invest in sustained screening campaigns is partly as the private health market has begun to address the need. Australian primary care phy-

Epidemiology of Melanoma

sicians are familiar with screening and detection of melanoma [120]. Since the start of the randomized community-based trial discussed above, private skin cancer clinics by primary care physicians have begun to expand in number, assuming a significant load of melanoma detection [121]. Evolving technology of dermoscopy and sequential imaging has improved melanoma detection including among primary care physicians [122, 123]. Many primary care skin cancer clinics utilize dermoscopy for detection of melanoma. Further research is required; however, early data from these clinics indicate a rate of melanoma detected comparable to that of screening campaigns employing specialist physicians, with high specificity and moderate to high sensitivity [124–126].


Core Messages ■ For the latter half of the twentieth century, the incidence of melanoma has been recorded and rising. In some countries, incidence and mortality have stabilized and even reduced in some groups. ■ Risk factors known for melanoma are high numbers of (especially atypical) naevi and sun exposure, particularly in childhood and adolescence. ■ Adult and occupational exposures are also important particularly for superficial melanoma of the head and neck. ■ Phenotypic characteristics of fair skin, red hair and the tendency to sunburn are major risk factors, which have been linked to genetic markers. Other genetic markers of DNA repair ability are also relevant. ■ Primary prevention programs have had preliminary success in utilizing knowledge of risk factors. ■ Secondary prevention through early detection has tended to diagnose earlier stages of melanoma, pushing the accuracy of histological diagnosis and consequentially epidemiological data.

Chapter IV.1

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S. Kitchener 77. Dobson AJ, Leeder SR. Mortality from malignant melanoma in Australia: effects due to country of birth. Int J Epidemiol 1982; 11: 207–211 78. McMichael AJ, Giless GG. Cancer in migrants to Australia: extending the descriptive epidemiological data. Cancer Res 1988; 48: 751–756 79. McCredie M, Coates MS, Ford JM. Cancer incidence in migrants to New South Wales from England, Wales, Scotland and Ireland. Br J Cancer 1990; 62: 992–995 80. Khlat M, Vail A, Parkin M, et al. Mortality from melanoma in migrants to Australia: variation by age at arrival and duration of stay. Am J Epidemiol 1992; 135: 1103–1113 81. Cooke KR, Fraser J. Migration and death from malignant melanoma. Int J Cancer 1985; 36: 175–178 82. Holman CD, Armstrong BK. Cutaneous malignant melanoma and indicators of total accumulated exposure to the sun: an analysis separating histogenetic types. J Natl Cancer Inst 1984; 73: 75–82 83. English DR, Armstrong BK. Identifying people at high risk of cutaneous malignant melanoma: results from a case-control study in Western Australia. Br Med J (Clin Res Ed) 1988; 296: 1285–1288 84. Mack TM, Floderus B. Malignant melanoma risk by nativity, place of residence at diagnosis and age at migration. Cancer Causes Control 1991; 2: 401–411 85. Autier P, Dore JF, Lejeune F, et al. Cutaneous malignant melanoma and exposure to sunlamps or sunbeds: an EORTC multicentre case-control study in Belgium, France and Germany. Int J Cancer 1994; 58: 809–813 86. Bataille V, Boniol M, de Vries E, et al. A multicentre epidemiological study on sunbed use and cutaneous melanoma in Europe. Eur J Cancer 2005; 41: 2038–2039 87. The International Agency for Research on Cancer Working Group on artificial ultraviolet (UV) light and skin cancer. The association of use of sunbeds with cutaneous malignanat melanoma and other skin cancers: a systematic review. Int J Cancer 2006 120:1116–1122 88. Fritschi L, Driscoll T. Cancer due to occupation in Australia. Aust NZ J Public Health 2006; 30: 213– 219 89. Kitchener S. Ultraviolet radiation exposure and melanoma in Australian Naval Personnel. Aust Mil Med 2001;10:55–59 90. Fritschi L, Siemiatycki J. Melanoma and occupation: results of a case-control study. Occup Environ Med 1996; 53: 168–173 91. Perez-Gomez B, Polann M, Gustavsson P, et al. Cutaneous melanoma: hints from occupational risks by anatomical site in Swedish men. Occup Environ Med 2004; 61: 117–126

92. Tynes T, Klaeboe T, Haldorsen T. Residential and occupational exposure to 50-Hz magnetic fields and malignant melanoma: a population based study. Occup Environ Med 2003; 60: 343–347 93. Walter SD, King WD, Marrett LD. Association of cutaneous malignant melanoma with intermittent exposure to ultraviolet radiation: results of a casecontrol study in Ontario, Canada. Int J Epidemiol 1999; 28: 418–427 94. Loomis D, Browning SR, Schenck AP, Gregory E, Savitz DA. Cancer mortality among electric utility workers exposed to polychlorinated biphenyls. Occup Environ Med 1997; 54: 720–728 95. Cerhan JR, Cantor KP, Williamson K, et al. Cancer mortality among Iowa farmers: recent results, time trends and lifestyle factors (United States). Cancer Causes Control 1998; 9: 311–319 96. Alavanja MC, Sandler DP, Lynch CF, et al. Cancer incidence in the agricultural health study. Scand J Work Environ Health 2005; 31 (Suppl 1): 39–45 97. Reif J, Pearce N, Fraser J. Cancer risks in New Zealand farmers. Int J Epidemiol 1989; 18: 768–774 98. Montague M, Borland R, Sinclair C. Slip! Slop! Slap! And SunSmart, 1980–2000: Skin cancer control and 20 years of population-based campaigning. Health Educ Behav 2001; 28: 290–305 99. Morris J, McGee R, Bandaranayake M. Sun protection behaviours and the predictors of sunburn in young children. J Paediatr Child Health 1998; 34: 557–562 100. National Health and Medical Research Council. Primary Prevention of Skin Cancer in Australia. Report of the Sun Protection Program Working Party, Centre for Health Promotion and Cancer Prevention Research, University of Queensland, Brisbane, 1996 101. Stanton WR, Janda M, Baade P, et al. Primary prevention of skin cancer: a review of sun protection in Australia and internationally. Health Prom Int 2004; 19: 369–378 102. Weinstock MA. Progress and prospects on melanoma: the way forward for early detection and reduced mortality. Clin Cancer Res 2006; 12 (7 Suppl): 2297–2300 103. McCarthy WH. The Australian experience in sun protection and screening for melanoma. J Surg Oncol 2004; 86: 236–245 104. Marks R. Campaigning for melanoma prevention: a model for a health education program. J Eur Acad Dermatol Venereol 2004; 18: 44–47 105. Westerdahl J, Ingvar C, Masback A, et al. Sunscreen use and malignant melanoma. Int J Cancer 2000; 87: 145–150 106. Autier P, Dore JF, Negrier S, et al. Sunscreen use and duration of sun exposure: a double-blind, randomized trial. J Natl Cancer Inst 1999; 91: 1304– 1309

Epidemiology of Melanoma 107. Autier P, Dore JF, Schifflers E, et al. Melanoma and use of sunscreens: an EORTC case-control study in Germany, Belgium and France. Int J Cancer 1995; 61: 749–755 108. Dupuy A, Dunant A, Grob JJ. Randomized controlled trial testing the impact of high-protection sunscreens on sun-exposure behaviour. Arch Dermatol 2005; 141: 950–956 109. Thieden E, Philipsen PA, Sandby-Moller J, et al. Sunscreen use related to UV exposure, age, sex and occupation based on personal dosimeter readings and sun-exposure behaviour diaries. Arch Dermatol 2005; 141: 967–973 110. McCarthy W. The Australian experience in sun protection and screening in melanoma. J Surg Oncol 2004; 86: 236–245 111. Rigel DS. The effect of sunscreen on melanoma risk. Dermatol Clin 2002; 20: 601–606 112. Carter R, Marks R, Hill D. Could a national skin cancer campaign in Australia be worthwhile? An economic perspective. Health Promotion Int 1999: 14: 73–82 113. Williams HA, Fritschi L, Reid A, et al. Who attends skin cancer screening in Western Australia? Results from the Lions Cancer Institute skin cancer screening program. Aust NZ J Public Health 2006; 30: 75–80 114. Youl PH, Janda M, Elwood M, et al. Who attends skin cancer clinics within a randomized melanoma screening program? Cancer Detect Prev 2006; 30: 44–51 115. Aitken JF, Youl PH, Janda M, et al. Increase in skin cancer screening during a community-based randomized intervention trial. Int J Cancer 2006; 118: 1010–1016 116. Aitken JF, Janda M, Elwood M, et al. Clinical outcomes from skin screening clinics within a community-based melanoma screening program. J Am Acad Dermatol 2006; 54: 105–114 117. Carli P, Giorgi V de, Giannotti B, et al. Skin cancer day in Italy: method of referral to open access clinics and tumor prevalence in the examined population. Eur J Dermatol 2003; 13: 76–79 118. Koh HK, Norton LA, Geller AC, et al. Evaluation of the American Academy of Dermatology’s national skin cancer early detection and screening program. J Am Acad Dermatol 1996; 34:971–978 119. Engelberg D, Gallagher RP, Rivers JK. Follow-up and evaluation of skin cancer screening in British Columbia. J Am Acad Dermatol 1999; 41: 37–42

Chapter IV.1 120. Baade P, Del Mar C, Lowe J et al. Clinical diagnosis and management of suspicious pigmented skin lesions: a survey of GPs. Aust Fam Phys 2005; 34: 79–83 121. Wilkinson D, Bourne P, Dixon A, Kitchener S. Skin cancer medicine in primary care: towards an agenda for quality health outcomes. Med J Aust 2006; 184: 11–12 122. Westerhoff K, McCarthy WH, Menzies SW. Increase in the sensitivity for melanoma diagnosis by primary care physicians using skin surface microscopy. Br J Dermatol 2000; 143: 1016–1020 123. Argenziano G, Puig S, Zalaudek I, et al. Dermoscopy improves accuracy of primary care physicians to triage lesions suggestive of skin tumors. J Clin Oncol 2006; 24: 1877–1882 124. Moffat CRM, Green AC, Whiteman DC. Diagnostic accuracy in skin cancer clinics: the Australian experience. Int J Dermatol 2006; 45: 656–660 125. Wilkinson D, Askew DA, Dixon A. Skin cancer clinics in Australia: workload profile and performance indicators from an analysis of billing data. Med J Aust 2006; 184: 162–164 126. Kitchener SJ, McMaster S, Nasveld P. Who attends skin cancer screening in the suburbs? Aust N Z J Public Health 2006; 30: 290–291 127. Lasithiotakis K, Leiter U, Kruger-Krasaquakis S, et al. Comparative analysis of incidence and clinical features of cutaneous malignant melanoma in Crete (Greece and southern Germany (central Baden-Wurttemberg). Br J Dermatol 2006; 154: 1123–1127 128. Lashithiotakis KG, Leiter U, Gorkievicz R, et al. The incidence and mortality of cutaneous melanoma in southern Germany. Cancer 2006; 107: 1331–1339 129. Saxe N, Hoffman M, Krige JE, et al. Malignant melanoma in Cape Town, South Africa. Br J Dermatol 1998; 138: 998–1002 130. Jelfs PL, Giles G, Shugg D, et al. Cutaneous malignant melanoma in Australia, 1989. Med J Aust 1994: 161: 182–187 131. Buettner PG, Raasch BA. Incidence rates of skin cancer in Townsville, Australia. Int J Cancer 1998; 78: 587–593 132. Cormier JN, Xing Y, Ding M, et al. Ethnic difference among patients with cutaneous melanoma. Arch Intern Med 2006; 166: 1907–1914


Chapter IV.2

Acral Melanoma Toshiaki Saida, Hiroshi Koga, Yoriko Yamazaki, Masaru Tanaka

Contents IV.2.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196


IV.2.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . 197 IV2.3

Dermoscopic Criteria. . . . . . . . . . . . . . . . . . 198

IV.2.4 Relevant Clinical Differential Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 IV.2.5 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . 199 IV.2.6 Management. . . . . . . . . . . . . . . . . . . . . . . . . . 200 IV.2.7 Case Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

IV.2.1 Definition Acral melanoma is a melanoma that affects acral areas of the skin, which is the most prevalent site of melanoma in non-Caucasians [5, 10]. Strictly speaking, acral lentiginous melanoma is not a synonym for acral melanoma. Acral lentiginous melanoma, originally described by Reed in 1976 [21], is one of the four histogenetic types defined by Clark et al. [6]. Almost all acral lentiginous melanomas occur on glabrous (nonhair-bearing) acral skin. Superficial spreading melanomas also occur on acral skin, but they are mostly seen on non-glabrous portions such as dorsal aspects of the hands and feet; however, superficial spreading melanomas can occur also on glabrous skin [12]. Furthermore, nodular melanomas are seen on both glabrous and nonglabrous acral skin. If stratified by the tumor


thickness, biological behavior is not different among the four histogenetic types [16]. Moreover, cutaneous melanomas not infrequently show overlapping histopathological features of the four types [36]. Ackerman repeatedly criticized the validity of the Clarkâ&#x20AC;&#x2122;s classification and proposed the unifying concept of melanoma [1]. Recently, Bastian and co-workers defined acral melanoma as melanoma occurring on the non-hair-bearing skin of the palms or soles or under the nails and found that this type of melanoma was unique in frequent amplifications of chromosomes 5p15, 5p13, 11q13, and 12q14 [4, 7]. Particularly, amplification of 11q13 was detected in ~50% of this type of melanoma. Cyclin D1 is the most important candidate gene located in this chromosome region. It is noteworthy that 5 of 36 acral melanomas defined by Bastian and co-workers were superficial spreading melanoma according to Clarkâ&#x20AC;&#x2122;s classification [7]. Another characteristic of acral melanoma is very low rate of mutation of the BRAF oncogene, which is commonly found in superficial spreading melanoma [8, 18]. These findings suggest that molecular pathogenesis of melanoma is different depending on anatomical locations and/or degrees of sun exposure, irrespective of Clarkâ&#x20AC;&#x2122;s types. In this chapter we use the term acral melanoma according to the definition by Bastian and co-workers [7]. Proportions of acral melanoma in all melanomas are quite different among races [5, 10, 17]: more than 80% in black persons, ~40% in Asians, and ~5% in Caucasian; however, there seems to be no significant difference in absolute incidence of acral melanoma among races [35].

Acral Melanoma


Chapter IV.2

197 Fig. IV.2.1.  Clinical, dermoscopic (a), and histopathological (b) features of acral melanoma. This lesion was from the right heel of an 83year-old Japanese man. Seven years previously, he noticed a small brown macule on his left heel. At his first visit to us, this lesion was 58¥46 mm in size, and irregular and random in shape and color (a, inset), accompanied by ulcerated crusted areas (arrow). Dermoscopically, the parallel ridge pattern was well recognized along with diffuse irregular pigmentation and the fibrillar pattern (circle). Histopathologically, random proliferation of melanocytes is detected in the lower epidermis. It is noteworthy that the degree of proliferation is more prominent in the crista profunda intermedia (arrows) underlying the surface ridge of the skin marking (b)


IV.2.2 Clinical Features Acral melanomas occur in older patients. In a recent study of acral melanoma in Japan, a peak of age distribution was in the seventh decade, and slight male preponderance was recognized [10]. Acral melanomas are most commonly seen on the soles, followed by finger nails and then by toe nails. Palms are least frequently affected. Clinically, most acral melanomas first appear as a brownish macule on glabrous skin. The initial stage may be difficult to recognize clinically because the lesion is small in size and is not so irregular in shape and color [11]. In time, the le-

sion increases in size, and becomes irregular in shape and variegated in color (Fig. IV.2.1a, inset), permitting differentiation from benign melanocytic nevus of the junctional type [23, 25]. Duration of this horizontal growth phase is variable: very long in some cases and transient in others. This macular stage is followed by the vertical growth phase, which is characterized by appearance of indurated portions or elevated nodules. In more advanced lesions, the indurated or nodular portions are partly ulcerated [13]. Even in these advanced stages, macular components are usually detected within or surrounding the lesions. Occasionally, small pale



T. Saida, H. Koga, Y. Yamazaki, M. Tanaka

brownish macules not continuous to the main lesion are detected in the periphery (skip macules), which may be explained by the “field cell” theory by Bastian [3]. Most melanomas affecting nail apparatus are initially seen as longitudinal pigmented bands of the nail plate (see Chap. IV.11) [24, 27]. In time, the pigmented band of the nail plate increases in width and becomes variegated in color from tan to black. Later, pigmented macules on the nail folds (Hutchinson’s sign) may develop [32]. Still later, deformity of the nail plate is recognized, and finally, the nail plate is destroyed, producing nodular lesions often accompanied by ulceration. Acral melanomas are not infrequently hypopigmented; 10~20% of acral melanoma in Japanese was reported to be partly or completely amelanotic [13]. Clinical diagnosis of amelanotic melanoma is difficult and often misdiagnosed as other neoplastic or non-neoplastic lesions (see Chap. IV.3) [34].

IV2.3 Dermoscopic Criteria Dermoscopic features of advanced primary lesions of acral melanoma are common to those affecting other anatomical sites: diffuse pigmentation with variegated shades of brown from tan to black; abrupt edge; blue whitish veil; and regression structures with whitish or grayish color. In addition to irregular streaks found at the periphery, dots/globules of variable sizes are randomly distributed within a lesion [30, 31]. Ulceration is also common in advanced lesions. In macular portions of acral melanoma, a very unique dermoscopic finding, termed the parallel ridge pattern, is frequently detected (Fig. IV.2.1a). This pattern is characterized by band-like pigmentation on the ridges of the skin markings, which run in a parallel fashion on glabrous skin [20, 31]. More importantly, the parallel ridge pattern is also frequently detected in the lesions of melanoma in situ [28]. The sensitivity and specificity of the parallel ridge pattern to acral melanoma are 86 and 99%, respectively [29]. The sensitivity and specificity are almost same between invasive and in-situ mela-

nomas, and thus this pattern is very much helpful in detecting early lesions of acral melanoma [11]. Irregular diffuse pigmentation is another dermoscopic finding of acral melanoma (Fig. IV.2.1a), which is detected in more advanced macular portions [15, 29]. Moreover, dermoscopic patterns observed in melanocytic nevus on acral volar skin, such as the parallel furrow pattern, the lattice-like pattern, or the fibrillar pattern, could be also detected in acral melanoma (see Chap. III.2) [28, 31]; however, they are just focally detected within the lesion of acral melanoma, in contrast to overall regular distribution of the patterns in melanocytic nevus. Characteristic dermoscopic findings of pigmented bands of the nail-apparatus melanoma have not yet been fully clarified [22] (see Chap. IV.11). If hyponychial volar skin is involved by nail apparatus melanoma, the characteristic parallel ridge pattern is detected there, which helps us to determine the diagnosis [14, 28]. In addition, dermoscopy enables us to recognize tiny pigmentation on the cuticle not discernible with the naked eye (micro-Hutchinson sign) [14, 22]. This sign strongly suggests evolving lesions of melanoma of nail apparatus (Fig. IV.2.2); however, even by use of dermoscopy, it is still difficult for us to differentiate pigmented bands of the nail plate caused by early melanoma from those due to benign conditions.

IV.2.4 Relevant Clinical Differential Diagnosis Differentiation of early acral melanoma from melanocytic nevus on glabrous skin is important. Melanocytic nevus is not uncommon on the glabrous skin: about 7% of Japanese general populations have melanocytic nevi on their soles [25]. In general, melanocytic nevus on glabrous skin is regular in shape, usually oval or spindle-shaped, up to 7 mm in maximum diameter, and homogeneous in color. In contrast, most acral melanomas are seen as large, irregular lesions; however, we often encounter difficulties in clinical differentiation of the two biologically distinct entities. Dermoscopy is

Acral Melanoma

Chapter IV.2

Fig. IV.2.2.  Dermoscopic and histopathological features of early melanoma in situ affecting nail apparatus. This lesion was from the right little finger of a 28-year-old Japanese woman. She had noticed the nail pigmentation more than 10 years before. The longitudinal pigmented bands were 4.1 mm in width. Dermoscopically (inset), the pigmented bands were not so irregular, but the nail plate was partly destroyed at the distal tip (arrowhead). Moreover, proximal to the pigmented bands, pigmentation on the

cuticle and proximal nail fold (withe asterisk) was well recognized (Hutchinson’s sign). These findings prompted us to excise this lesion. Histopathologically, random proliferation of solitary arranged atypical melanocytes was detected in the lower epithelium of the nail matrix and nail bed, confirming the diagnosis of melanoma in situ. In addition, solitary melanocytes were detected in the epidermis corresponding to the cuticle (circle)

immensely helpful in this differentiation; the parallel ridge pattern is unique to acral melanoma and the parallel furrow and the latticelike patterns are characteristic of melanocytic nevus (see Chap. III.2) [29]. Regularly distributed fibrillar pattern also strongly suggests melanocytic nevus. Pigmented macules seen in Peutz–Jeghers syndrome and Laugier–Hunziker syndrome show the parallel ridge pattern [28, 31], but these conditions are easily diagnosed clinically: multiple tiny macules on the fingers and toes as well as on the lips. In our evaluation, brown macules induced by cytotoxic drugs such as 5-fluorouracil also show the parallel ridge pattern on dermoscopy. But this condition also can be clinically diagnosable, as multiple lesions on the background of grayish red atrophic skin. Volar melanotic macules commonly seen in black persons may show the parallel ridge pattern. Socalled black heel, i.e., calcaneal petechiae in-

duced by ill-fitted shoes of athletes, is included in clinical differential diagnosis of acral melanoma. This condition is definitely diagnosed by the unique dermoscopic findings termed the reddish black “pebbles on the ridges” [31] and homogeneous pigmentation [38].

IV.2.5 Histopathology Histopathologically, in macular portions of acral melanoma, melanocytes randomly proliferate in the lower epidermis, which shows acanthosis and is often accompanied by elongated rete ridges [23]. Preferential proliferation of melanocytes in the crista profunda intermedia, an epidermal rete ridge underlying the surface ridge, can be recognized (Fig. IV.2.1b). The proliferating melanocytes are usually round or oval in shape but occasionally spindle-shaped or dendritic. The nuclei are often large and hyper-




T. Saida, H. Koga, Y. Yamazaki, M. Tanaka

chromatic. Near the invasive portions, the degrees of melanocytic proliferation become more pronounced: atypical melanocytes are often distributed throughout the entire epidermis [17]. In the invasive areas, growth of atypical melanocytes is seen in the dermis, usually arranged in densely packed nests or in sheets, often accompanied by lymphocytic infiltration. In more advanced lesions, epidermis is destroyed by infiltration of atypical melanocytes, producing necrotic, ulcerated areas. Histopathological features of melanoma in situ affecting glabrous skin are similar to those of macular portion of acral melanoma. It is noteworthy that, corresponding to the dermoscopic parallel ridge pattern, proliferation is prominent in crista profunda intermedia, an epidermal rete ridge underlying the surface ridge [11, 20, 21, 26, 28]. This is in contrast to histopathological findings of melanocytic nevus showing the parallel furrow pattern, in which proliferation of melanocytes (nevus cells) are mostly confined to crista profunda limitans, an epidermal rete ridge underlying the surface sulcus [19]. To recognize these important findings, excised tissues must be cut perpendicularly to the skin markings [9, 11]. If the tissue of melanocytic nevus is cut parallel to the skin markings, continuous, irregular proliferation of melanocytes is seen in the lower epidermis, which mimics the features of melanoma in situ [33]. We occasionally see acral pigmented lesions which exhibit the parallel ridge pattern on dermoscopy, but their histopathological features are too subtle to diagnose as melanoma in situ: only slight increase of melanocytes in the basal layer of the crista profunda intermedia [11]. In about 40% of these subtle lesions, we have found amplification of cyclin D1 by fluorescent in-situ hybridization analysis, which strongly supports that these subtle lesions are evolving melanoma in situ [37].

IV.2.6 Management Primary lesions of acral melanoma without metastatic lesions should be surgically excised with the free margin of 1–2 cm. Acral melanoma in situ is cured by simple excision with only

5 mm free margin. Suspicious lesions whose diagnosis cannot be definitely determined, even with dermoscopy, should be excised and evaluated histopathologically. In this case, the tissue specimen should be cut perpendicularly to the skin markings. If nail-apparatus melanoma is detected early in the in-situ stage, amputation of the digit is not necessary. Such an early nail-apparatus melanoma can be cured with total excision of the nail apparatus, and the tissue defect is easily covered with skin grafting, preserving the function of the digit [27]. In a recent study of a total of 801 acral melanomas in Japan, 5-year survival rates according to the present UICC/AJCC staging were as follows: stage IA, 98.1%; stage IB, 95.8%; stage IIA, 93.8%; stage IIB, 73.4%; stage IIC, 64.2%; stage IIIA, 48.0%; stage IIIB, 39.4%; stage IIIC, 44.1%; and stage IV, 16.0% (unpublished data). The survival rates in stages IIA, IIB, IIC and IIIC seem to be better than those reported by Balch et al. [2], whose patients were mainly Caucasians suffering from superficial spreading melanoma.

IV.2.7 Case Study A 56-year-old Japanese woman noticed a brownish macule on her left sole 6 years previously. At her first visit to us, the pale brown macule was 21¥16 mm in size, and not so irregular in shape and color (Fig. IV.2.3a, inset). These findings suggested benign melanocytic lesions such as lentiginous nevus or volar melanotic macule. Dermoscopically, however, this lesion exhibited the typical features of the parallel ridge pattern (Fig. IV.2.3a), strongly suggesting that this was melanoma in situ, and we excised the lesion totally. Histopathologically, in tissue sections cut perpendicularly to the skin markings, random proliferation of melanocytes was recognized in the lower epidermis, which was more prominent in the crista profunda intermedia under­ lying the surface ridge of the skin marking (Fig. IV.2.3b, arrows).

Acral Melanoma

Chapter IV.2

201 Fig. IV.2.3.  Case Study



Comments C

Using conventional clinical and histopathological criteria, we diagnosed this case as possible lentiginous melanocytic nevus; however, if we consider all the findings, including dermoscopic features of the typical parallel ridge pattern, we could diagnose this lesion as an early lesion of acral melanoma in situ [11, 29, 30]. This case demonstrates that dermoscopy is very helpful in detecting early melanoma on glabrous skin. Preferential proliferation of melanocytes in the epidermal rete ridges underlying the surface ridges, which corresponds to the dermoscopic parallel ridge pattern, strongly suggests the diagnosis of early acral melanoma.

Core Messages ■ The parallel ridge pattern is a highly sensitive and specific dermoscopic pattern of acral melanoma, including early evolving lesions, and thus, using this dermoscopic finding, we can effectively detect acral melanoma in early, curable stages. ■ In addition, recent studies suggest that acral melanoma is unique in molecular pathogenesis, which could be used in developing molecular diagnosis and molecular targeting therapy.


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17. Kuchelmeister C, Schaumburg-Lever G, Garbe C (2000) Acral cutaneous melanoma in Caucasians: clinical features, histopathology and prognosis in 112 patients. Br J Dermatol 143:275–280 18. Maldonado JL, Fridlyand J, Patel H, et al. (2003) Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst 95:1878–1890 19. Miyazaki A, Saida T, Koga H, et al. (2005) Anatomical and histopathological correlates of the dermoscopic patterns seen in melanocytic nevi on the sole: a retrospective study. J Am Acad Dermatol 53:230– 236 20. Oguchi S, Saida T, Koganehira Y, et al. (1998) Characteristic epiluminescent microscopic features of early malignant melanoma on glabrous skin: a videomicroscopic analysis. Arch Dermatol 134:563– 568 21. Reed RJ (1976) Acral lentiginous melanoma. In: Hartmann W, Kay S, Reed RJ (eds) New concepts in surgical pathology of the skin. Wiley, New York, pp 89–90 22. Ronger S, Touzet S, Ligeron C, et al. (2002) Dermoscopic examination of nail pigmentation. Arch Dermatol 138:1327–1333 23. Saida T (1989) Malignant melanoma in situ on the sole of the foot: its clinical and histopathologic characteristics. Am J Dermatopathol 11:124–130 24. Saida T (1992) Heterogeneity of the site of origin of malignant melanoma in ungual areas: “subungual” malignant melanoma may be a misnomer. Br J Dermatol 126:529 25. Saida T (2000) Malignant melanoma on the sole: how to detect the early lesions efficiently. Pigment Cell Res 13 (Suppl 8):135–139 26. Saida T (2005) Lessons learned from studies of the development of early melanoma. Int J Clin Oncol 10:1371–1374 27. Saida T, Oshima Y (1989) Clinical and histopathologic characteristics of early lesions of subungual malignant melanoma. Cancer 63:556–560 28. Saida T, Miyazaki A, Grin CM (2005) Acro-lentiginous melanoma. In: Marghoob A, Braun R, Kopf A (eds) Atlas of dermoscopy. Taylor and Francis, London, pp 221–233 29. Saida T, Miyazaki A, Oguchi S, et al. (2004) Significance of dermoscopic patterns in detecting malignant melanoma on acral volar skin: results of a multi-center study in Japan. Arch Dermatol 140:1233–1238 30. Saida T, Oguchi S, Ishihara Y (1995) In vivo observation of magnified features of pigmented lesions on volar skin using videomicroscope: usefulness of epiluminescence technique in clinical diagnosis. Arch Dermatol 131:298–304

Acral Melanoma 31. Saida T, Oguchi S, Miyazaki A (2002) Dermoscopy for acral pigmented skin lesions. Clin Dermatol 20:279–285 32. Seiji M, Takematsu H, Hosokawa M, et al. (1983) Acral melanoma in Japan. J Invest Dermatol 80 (Suppl):56s–60s 33. Signoretti S, Annessi G, Puddu P, et al. (1999) Melanocytic nevi of palms and soles: a histological study according to the planes of section. Am J Surg Pathol 23:283–287 34. Soon SL, Solomon AR, Papadopoulos D, et al. (2003) Acral lentiginous melanoma mimicking benign diseases: the Emory experience. J Am Acad Dermatol 48:183–188 35. Stevens NG, Liff JM, Weiss NS (1990) Plantar melanoma: Is the incidence of melanoma of the sole of foot really higher in blacks than whites? Int J Cancer 45:691–693

Chapter IV.2 36. Weyers W, Euler M, Diaz-Cascajo C, et al. (1999) Classification of cutaneous malignant melanoma: a reassessment of histopathologic criteria for the distinction of different types. Cancer 86:288–299 37. Yamaura M, Takata M, Miyazaki A, et al. (2005) Specific dermoscopy patterns and amplifications of the cyclin D1 gene to define histopathologically unrecognizable early lesions of acral melanoma in situ. Arch Dermatol 141:1413–1418 38. Zalaudek I, Argenziano G, Soyer P, et al. (2004) Dermoscopy of subcorneal hematoma. Dermatol Surg 30:1229–1232


Chapter IV.3

Amelanotic Melanoma Jürgen Kreusch


Contents IV.3.1 Introduction and Definition. . . . . . . . . . . 204 IV.3.2 Hypomelanotic and Amelanotic Melanoma. . . . . . . . . . . . . . . . . . . . . . . . . . . 204


IV.3.4 Clinical Features. . . . . . . . . . . . . . . . . . . . . 205 IV.3.5 Dermoscopic Criteria. . . . . . . . . . . . . . . . . 207 IV.3.6 Adequate Dermoscopic Inspection of Non-pigmented Lesions . . . . . . . . . . . . 208 IV.3.7 Dermoscopic Features of Amelanotic Melanoma . . . . . . . . . . . . . 208 IV.3.8 Vascular Patterns in Amelanotic Melanoma. . . . . . . . . . . . . 208 IV.3.9 Morphological Changes of Vessels During Tumor Growth . . . . . . 209 IV.3.10 Relevant Clinical Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 IV.3.10.1 The Way to Diagnosis of Amelanotic Melanoma . . . . . . . . . . . . . 210 IV.3.10.2 Strategies for Detecting Amelanotic Melanoma. . . . . . . . . . . . . . . . . . . . . . . . . . . 211

References. . . . . . . . . . . . . . . . . . . . . . . . . . . 212

IV.3.1 Introduction and Definition “Amelanotic melanoma” is a clinical and descriptive term frequently used for any melanoma lacking melanin pigmentation. These tumors represent a large fraction of the so-called “featureless” or “undiagnosable” melanoma [3– 5, 7, 13]. This chapter gives details on the dermoscopic features of amelanotic melanoma which may help to classify the variety of tumors

Fig. IV.3.1.  Amelanotic melanoma (center; SSM, L III, 0.6 mm)

summarized under this general term; however, amelanotic melanoma will not be identified by dermoscopy nor by any other diagnostic method if a lesion is not considered worth inspection with the particular instrument – a screening strategy including knowledge of clinical features, dermoscopic techniques and criteria is ­essential to spot amelanotic melanoma among the variety of non-pigmented lesions of the skin (Figs. IV.3.1, IV.3.5a).

IV.3.2 Hypomelanotic and Amelanotic Melanoma Frequently, melanoma are classified “amelanotic” regardless of the degree and nature of hypopigmentation. One must distinguish two reasons for a melanoma to contain little melanin. There are tumors which produce little or no melanin. On the other hand, there are melanoma which have lost more or less of their melanin

Amelanotic Melanoma

content mostly due to regression. Both phenomena may even occur within the same lesion. The varied reasons for hypopigmentation should find their equivalent in clinical and, more importantly, in dermoscopic terminology.

IV.3.4 Clinical Features Completely amelanotic melanoma are quite rare: estimates between 2 and 8% are given [14]. In general, the descriptive clinical term “amelanotic” melanoma is used imprecisely, as it is frequently attributed to a wide variety of tumors with a broad spectrum of intensity and variable distribution of their pigmentation. Hypopigmentation may refer to the entire lesion or just to a segment of the tumor, and may develop or change with time [8]. One should differentiate between tumors lacking melanin just in circumscribed segments, and other ones which are of homogenous structure and contain little melanin within the entire lesion. The extreme variant of the latter are completely “amelanotic” melanoma. A lesion containing a low amount of

Chapter IV.3


melanin in all segments warrants description as “slightly pigmented melanoma.” Lesions with circumscribed hypopigmentation may be characterized as “partially hypomelanotic” or “partially amelanotic” melanoma (Table IV.3.1). There exist tumors with great differences in melanin content, be it the proportion of the hypopigmented area in partially pigmented melanoma or the intensity of pigmentation within a slightly pigmented melanoma. As a proposal, a melanoma may be considered “partially pigmented” if the section containing melanin is no larger than 30% of the tumoral area. A melanoma should be described as “slightly pigmented” if the intensity of pigmentation is an estimated 30% of a “regular” dark-brown tumor as judged by visual inspection. Colorimetric and quantitative measurements of these details appear desirable for classification of melanoma for scientific purposes. Regressive melanoma may best be spotted by means of grayish or whitish areas, the white areas being whiter than the neighboring skin. Reports of the patient that a dark spot or nodule has become paler may be helpful. Flow-chart IV.3.  For classifying hypopigmented melanoma and diagnosing amelanotic melanoma


J. Kreusch Table IV.3.1.â&#x20AC;&#x201A; Phenotypes of hypomelanotic and amelanotic melanoma

Description of lesion

Category of melanoma

Melanoma not producing any trace of melanin

Amelanotic melanoma (sensu strictu)

Melanoma consisting exclusively of a cell line with low production of melanin

Hypopigmented melanoma

Melanoma consisting of a section (mostly a nodule) with no or little melanin content within a pigmented tumor

Partially pigmented melanoma

Hypomelanotic melanoma with amelanotic components

Partially pigmented melanoma

Amelanotic / hypomelanotic melanoma associated to junctional or compound nevus

Partially pigmented melanoma


Amelanotic Melanoma

Chapter IV.3

Table IV.3.1.  (continued)

Description of lesion

Category of melanoma

Partially regressive melanoma associated to dermal nevus

Partially pigmented melanoma

Amelanotic cell line/metastasis in regressive melanoma

No images available

Collision tumors of amelanotic melanoma and non-pigmented lesions (e.g. BCC, seborrheic keratosis)

No images available

In order to complete the listing of hypopigmented variants of melanoma, collision tumors of a regressive or amelanotic melanoma (or a melanoma metastasis) next to or within a poorly pigmented benign lesion, e.g., a dermal nevus or a seborrheic keratosis, might be taken for an amelanotic melanoma despite the fact that the components are of different origin and biological behavior. Such cases of collision tumors are somewhat hypothetical and certainly very rare. They are not dealt with any further here.

IV.3.5 Dermoscopic Criteria There are few reports in the literature which describe dermoscopic features of truly amelanotic melanoma [1, 2, 6, 12, 14, 15]. The diagnostic importance of vascular structures is stressed in each contribution. In several papers cases of hypomelanotic melanoma due to regression are viewed jointly with completely amelanotic melanoma; however, intermingling melanoma with different origin of hypopigmentation in morphological studies will result in loss of sensitivity and specificity of features.

It is therefore suggested to follow the pathway given in this chapter to distinguish the two basic types of hypomelanotic melanoma before analyzing the morphology any further. Loss of melanin due to regression can be recognized easily in almost any case, as it is indicated by the presence of melanophages visible as tiny grayish granules of approximately 0.01– 0.02 mm diameter (“peppering”), or by the presence of gray-blue veils. Progress of regression results in disappearance of grayish areas and melanophages, leaving behind whitish fibrous tissue resembling a scar. These lesions should be excluded from the suspicion of amelanotic melanoma. They show differences in vascularization as compared with amelanotic melanoma. Truly amelanotic melanoma do not contain any melanin; thus, all features related to details of pigmented lesions must be absent. Size, asymmetry, irregular border, and ulceration are features of secondary diagnostic importance as they are not restricted to melanocytic tumors; however, as vascular structures are easily visible, amelanotic melanoma can be diagnosed with a dermoscope, provided they are inspected properly.



J. Kreusch

Theoretically, there might exist melanoma consisting of a regressive section joint with an amelanotic component (and even in collision with further hypopigmented tumors such as seborrheic keratoses or basal cell carcinoma). They must be identified by stepwise analysis of the various components and certainly are a challenge even for the experienced dermoscopist.

IV.3.6 Adequate Dermoscopic Inspection of Non-pigmented Lesions


Instruments with glass front plate must be set onto the tumoral surface very carefully in order to avoid compression of the soft vascular structures and squeezing out the blood, rendering them invisible. Ultrasound gel is recommended as a contact medium due to its low viscosity and non-volatility. This helps to inspect the vessels with as little pressure as possible. Use of instruments with polarized light may serve better if the light source emits an appropriate spectrum of wavelengths for visualizing reddish structures such as blood vessels and the magnification permits viewing small capillaries of 10 ¾m in diameter; however, most dermoscopes using polarized light operate with low magnification, which is inadequate for analysis of vascularization. If a non-pigmented lesion does not reveal any vessels upon dermoscopic inspection, the first idea should be to control the pressure of the instrument. Any non-pigmented lesion (with the exception of, for example, hyperkeratoses) must present at least some vascular structures upon appropriate examination. In the literature one finds many cases with obvious compression artifacts: no vessels are visible within whitish areas, preferably within the most elevated regions of nodular lesions.

IV.3.7 Dermoscopic Features of Amelanotic Melanoma In truly amelanotic melanoma all features related to pigmentation are absent. Observations of grayish veils, traces of network, etc., refer to regressive, hypomelanotic or partially hypo-/

amelanotic melanoma. If reddish or pink areas are observed, the magnification might be too low to distinguish terminal capillaries, or the vessels might be out of focus; therefore, instruments permitting focus control are quite helpful for better analysis of vascular structures. The only features visible dermoscopically are vessels and whitish structures which resemble pseudohorn cysts (Fig. IV.3.5b); the latter are somewhat misleading, as they might be taken as signs of seborrheic keratoses, basal cell carcinoma, or ordinary nevi. They are present in melanoma of several millimeters in vertical diameter. In histological sections they revealed mucoid degeneration and no keratin (unpublished observations); thus, the remaining features of diagnostic importance are vascular patterns.

IV.3.8 Vascular Patterns in Amelanotic Melanoma The vascular patterns in amelanotic melanoma have been described as pinpoint, point-like, dotted vessels, and as hairpin, loop-like, linear irregular vessels. In principle, all point-like or looped vessels are variants of the basic structure of a vascular loop; however, loop-like terminal capillaries are encountered in melanocytic lesions (Spitz nevi, melanoma) [5] as well as in all keratinizing lesions (vulgar warts, seborrheic keratoses, keratoacanthoma, squamous cell carcinoma, etc.). Of course, vessels encountered in dermal papillae are not to be considered as tumoral vessels. The appearance of vascular loops depends on their length and the angle of viewing them. Upon viewing in axial direction, vertical to the tumoral surface, short loops are visible as tiny red dots. Longer loops resemble hairpins, especially if the direction of view is somewhat oblique. Increasing tumoral thickness requires elongation of the feeding vessels. The longer the vascular loops, the more morphological variations are to be seen. Twisting, splintering, glomerular-like winding of the loops is observed; however, a loop is the basic structure of these peculiarities. There is a tendency to describe too many details within the vascular structures, thus confounding the observers. Another descriptor of vessels is the

Amelanotic Melanoma

Chapter IV.3

mode of their arrangement within the tumor, e. g., regular or irregular, arranged at the periphery or distributed evenly over the tumoral surface, etc. Vascular loops (point-like rather than hairpin-like) in amelanotic melanoma are dispersed quite regularly across the entire area of the tumor; however, this is the case only in early lesions.

IV.3.9 Morphological Changes of Vessels During Tumor Growth The fact that dermoscopic analysis of vessels in melanoma must consider time-dependent changes which occur during tumor growth has attracted too little attention: As horizontal diameter and vertical thickness of melanoma increase with time, vessels in advanced stages will be longer, coarser, and more variable according to the tumoral thickness. Examples for the ­evolution of vascularization of melanoma are given in Figs. IV.3.2–IV.3.5. All thin melanoma (<0.5 mm Breslow thickness) are supplied by point-like vessels in a quite regular arrangement across the entire tumoral area (Figs. IV.3.2, IV.3.3). Tumors of 0.5- to 2-mm thickness reveal vessels of point-like and hairpin appearance, yet the arrangement of vessels is quite regular (Fig. IV.3.4). Beyond 2 mm thickness, the hairpin loops become increasingly more twisted and splintered, and their arrangement is not as regular as in thin tumors; hence, they were described as irregular vessels (Figs. IV.3.3, IV.3.5a,b). Melanoma of more than approximately 3 mm thickness develop a different structure of vascular supply. As vertical growth apparently cannot be maintained by further elongation of the capillary loops, vessels arising from the adjacent dermal plexus appear on the tumoral surface. These vessels resemble arborizing vessels of basal cell carcinoma; however, their winding and branching is less bizarre and irregular as compared with basal cell carcinoma. Reports published on amelanotic melanoma frequently note that tumors were ulcerated [7, 10, 13]. This secondary phenomenon may disturb the morphology of the vessels and make it more difficult to characterize them. Studies frequently report a surprisingly low percentage of

Fig. IV.3.2.  Partially pigmented, hypomelanotic melanoma (SSM in situ). Bar: 5 mm

Fig. IV.3.3.  Amelanotic melanoma (SSM, L III, 0.4 mm)

Fig. IV.3.4.  Amelanotic melanoma (NM, L IV 1.2 mm)

amelanotic melanoma with visible vascularization. This may be ascribed to non-standardized imaging techniques and low magnification, and to mixing truly amelanotic, regressive, and hy-



J. Kreusch

cal” and “irregular.” As a rule – and surprisingly – advanced cases of amelanotic melanoma may be more difficult to identify by dermoscopy than early lesions of low vertical diameter.

IV.3.10 Relevant Clinical Differential Diagnosis


Fig. IV.3.5.  a Amelanotic melanoma (NM, L IV, 2.8 mm). b Amelanotic melanoma (NM, L IV, 2.8 mm): irregular vessels, some of hairpin shape. Note absence of white halo and presence of whitish spots. Histopathology: no pseudo-horn cysts but mucoid degeneration

pomelanotic melanoma. Nevertheless, the importance of vascular structures is underlined. Pizzichetta et al. [14] consider vascular patterns the only relevant ones for diagnostic purposes. The presence of point-like, hairpin-like, linear, and linear-irregular vessels is reported. Diameter, asymmetry, and ulceration are considered less valuable for diagnosis. Few studies separate thin (<1 mm) and thick (>1 mm) melanoma [2, 14]. One of the few papers which deals with amelanotic melanoma of low thickness is that by Bono et al. [2], with the prevailing vascular pattern in accordance with own observations being dotted vessels. This pattern appears to be the most valuable for identification of early amelanotic melanoma. Other studies present cases of considerable thickness, mostly more than 1 mm [15]. As explained above, vessels in these lesions tend to be split, splintered, and twisted, thus appearing “atypi-

Confounding amelanotic melanoma and basal cell carcinoma should not occur if the vascular patterns are viewed correctly – arborizing vessels of basal cell carcinoma can easily be distinguished from point-like or loop-like vessels. The vascularization of dermal nevi consists of coarse and “comma-shaped” vessels in a surprisingly irregular arrangement. The vessels in pyogenic granuloma appear blurred and are of unspecific morphology. In regressive tumors (regressive melanoma as well as in regressive solar keratoses, “lichenoid” keratoses, etc.) the vascular pattern also cannot be ascribed to a certain geometrical structure. Keratinizing tumors represent a large group of non-pigmented lesions and their loop-like vessels may resemble the ones of amelanotic melanoma. Depending on their vertical diameter, flat lesions display point-like vessels, whereas thicker ones are supplied by hairpin-like longer loops. Characteristically, in all keratinizing tumors the vessels are embedded into a whitish halo. The halo represents the vital keratinocytes supplied by the feeding capillary. The whitish zone in most cases merges into a yellowish substance, which is keratin. This observation is most helpful for excluding non-pigmented lesions from suspicion of melanoma. An instrument more powerful than just tenfold magnification is particularly helpful for viewing faint white halos.

IV.3.10.1 The Way to Diagnosis of Amelanotic Melanoma A pathway to diagnosis of amelanotic melanoma based exclusively on analysis of vascular structures was published in 1996 [9, 11]. It is applicable to truly amelanotic melanoma provided the lesions are not ulcerated. Regressive mela-

Amelanotic Melanoma

noma and compression artifacts should be excluded by means of the procedure summarized in the flow chart below. Analysis of vascularized lesions can be summarized in a series of 5 + 2 questions leading directly to diagnosis. This pathway is best applicable to flat lesions. In cases of thick, pink, and nodular tumors one must always consider the morphological changes in vascular patterns, rule out frequently occurring non-pigmented lesions as mentioned above, and treat the remaining ones with special attention. In the list below the presence of a certain type of vessel is asked for – if the answer is “no,” one may proceed to the next question: 1. Presence of arborizing vessels (basal cell carcinoma)? 2. Presence of crown vessels (sebaceous hyperplasia)? 3. Presence of “comma” vessels (dermal nevus)? 4. Presence of unspecific vessels (Kaposi sarcoma, regressive lesions)? 5. Presence of point-like or hairpin vessels? 5.1 Absence of white halos? 5.2 Presence of traces of melanin? If question no. 5 is answered, in the affirmative (i.e., presence of point-like or loop-like vessels), additional questions must ask for the absence of white halos and presence of traces of melanin. If the answer is “yes,” suspicion of melanoma is raised. If traces of brownish melanin, which may not be visible clinically, are present focally within the lesion, they support the diagnosis of melanoma or Spitz nevus, the only other diagnosis, which has to be considered. It is very difficult, often impossible, to discriminate reliably amelanotic melanoma and Spitz nevus by dermoscopy. As histopathological judgment faces the same problem, consequently all lesions with point-like or loop-like vessels without white halo must be considered suspicious and removed.

Chapter IV.3

IV.3.10.2 Strategies for Detecting Amelanotic Melanoma Spotting amelanotic melanoma is one of the challenges for a dermatologist and possibly a life-saving diagnostic procedure if performed early enough. It is not possible to identify these tumors positively by clinical criteria; however, in the present author’s opinion, dermoscopy is effective in diagnosing suspicious lesions in almost all cases of amelanotic melanoma, especially early ones. But dermoscopy is not the first step in diagnosing amelanotic melanoma. The major obstacle in our own strategy in selecting lesions for dermoscopic examination is that we have been trained to consider large and dark tumors as suspicious, and the idea of using a dermoscope arises when we come over such lesions. Small and non-pigmented objects escape our attention and are not considered worthy of further examination. This approach represents a filter mechanism toward large and dark lesions. Small and hypopigmented lesions (“atypical melanoma”) are neglected. “Atypical melanoma” frequently are not examined by dermoscopy and neither photographed nor excised, thus escaping early diagnosis and our visual memory. Most studies are based on cases of melanoma with high thickness, mostly reddish or pink nodules, frequently ulcerated [10, 13], which are eye-catching. The lack of images of early nonpigmented melanoma leads us back to diagnostic recommendations and procedures, and reddish macules too frequently are not inspected dermoscopically. In the working routine of the present author, elimination of the amelanotic melanoma filter mechanism, i.e., not restricting dermoscopy to large and dark tumors (“pigmented lesions of the skin”), has changed the spectrum of melanoma phenotypes. This approach, best described as “non-selective dermoscopy,” has raised the proportion of poorly pigmented melanoma to a constant of 20% of all cases per annum during the past 7 years, among them 6% truly amelanotic melanoma (unpublished observations).



J. Kreusch


Core Messages ■ Do not restrict dermoscopy to large and pigmented lesions. ■ Regressive melanoma present different features as compared with amelanotic melanoma. Rule them out by using flow chart 1. ■ When viewing a non-pigmented lesion make sure the instrument does not exert pressure onto the vessels. ■ Lesions with visible vascularization should be analyzed with the (5 + 2) questions procedure. ■ Lesions with point-like or loop-like vessels lacking a white halo must be considered suspicious for amelanotic melanoma or Spitz nevus. ■ Remember that nodular lesions are particularly difficult to analyze: vessels of pyogenic granuloma are blurred and barely visible, and lesions with vessels characteristic for basal cell carcinoma, dermal nevus, and keratinizing tumors help to rule out these diagnoses. The remaining lesions have to be dealt with carefully, as melanoma cannot be ruled out. ■ There are no “featureless” melanoma: a lesion “without features” must be re-examined, as you have probably missed them.


Acknowledgement: The author gratefully acknowledges Evelyn Kreusch-Shah for carefully reading the manuscript and for valuable advice. Reprint permission for all images was kindly granted by Sur Prise, POB 111107, D-23521 Luebeck, Germany.

References   1. Argenziano A, Zalaudek I, Corona R, Sera F et al. (2004) Vascular structures in skin tumors. A dermoscopy study. Arch Dermatol 140:1485–1489   2. Bono A, Maurichi A, Moglia D, Camerini T et al. (2001) Clinical and dermatoscopic diagnosis of early amelanotic melanoma. Melanoma Res 5:491–494   3. Bowling J, Argenziano G, Azenha A, Bandic J et al. (2007) Dermoscopy key points: recommendations from the International Dermoscopy Society. Dermatology 214:3–5   4. Carli P, Massi D, Giorgi V de et al. (2002) Clinically and dermoscopically featureless melanoma: when prevention fails. J Am Acad Dermatol 46:957–961   5. Cockerell CJ, Sonnier G, Kelly L, Patel S (1994) Comparative analysis of neovascularization in primary cutaneous melanoma and Spitz nevus. Semin Oncol 2:83–103   6. Giorgi V de, Sestini S, Massi D, Maio V, Giannotti B (2006) Dermoscopy for “true” amelanotic melanoma: a clinical dermoscopic–pathologic case study. J Am Acad Dermatol 54:341–344   7. Grant-Kels JM, Bason ET, Grin CM (1999) The misdiagnosis of malignant melanoma. J Am Acad Dermatol 40:539–548   8. Johr RH (2002) Pink lesions. Clin Dermatol 20:289– 296   9. Kreusch JF (2002) Vascular patterns in skin tumors. Clin Dermatol 20:248–254 10. Koch SE, Lange JR (2000) Amelanotic melanoma: the great masquerader. J Am Acad Dermatol 42:731–734 11. Kreusch J, Koch F (1996) Auflichtmikroskopische Charakterisierung von Gefässmustern in Hauttumoren (Characterization of vascular patterns in skin tumors). Hautarzt 47:264–272 12. Menzies SW, Ingvar C, Crotty KA, McCarthy WH (1996) Frequency and morphologic characteristics of invasive melanoma lacking specific surface microscopic features. Arch Dermatol 132:1178–1182 13. Neuber H, Lippold A, Hundeiker M (1991) Nichtdiagnostizierbare maligne Melanome. (Non-diagnosable malignant melanoma) Hautarzt 42:220–222 14. Pizzichetta MA, Talamini R, Stanganelli I, Puddu P et al. (2004) Amelanotic/hypomelanotic melanoma: clinical and dermoscopic features. Br J Dermatol 150:1117–1124 15. Zalaudek I, Argenziano G, Kerl H, Soyer HP, Hofmann-Wellenhof R (2003) Amelanotic/hypomelanotic melanoma: Is dermatoscopy useful for diagnosis? J Dt Dermatol Ges 5: 369–373

Chapter IV.4

Early Evolution of Melanoma (Small-Diameter Melanoma)


Robert J. Friedman, Melanie Warycha, Michele Farber, Dina Gutkowicz-Krusin, Harold Rabinovitz, David Polsky, Margaret Oliviero, Darrell S. Rigel, Lori Kels, Edward R. Heilman

Contents IV.4.1 Introduction and Definition . . . . . . . . . . . . 213 IV.4.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . 214 IV.4.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . 215 IV.4.4 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . 215

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

IV.4.1 Introduction and Definition Detecting melanomas in early stages of development is fundamental for preventing mortality from this disease. Prognosis for patients with melanoma is largely determined by early detection [17, 33], as 10-year survival rates have been reported as high as 99.5% for early melanomas <0.76 mm thick, but are only 48% for lesions >3 mm thick [17]. Early detection followed by appropriate treatment has led to considerable reduction in mortality from melanoma, from 60% for those diagnosed in 1960 to about 11% for those diagnosed in 2005 [39]; however, despite early detection efforts, incidence rates for melanoma have dramatically increased over time both in the United States and worldwide, the etiology of which could be attributed to changes in human behavior, the environment, or increased physician awareness [11, 32, 39]. It is estimated that in 2005 in the U.S. at least 62,000 cases of invasive melanoma will be diagnosed, ranking as the fifth leading cancer in men and the sixth in women [2]. Educational campaigns advocating routine self-examination of the skin have played a significant role in reducing deaths from melanoma

[10, 16]. These efforts, coupled with the advent of novel techniques of melanoma detection, have led to the diagnosis of melanoma at earlier stages of development. Many patients now present to the dermatologist with much earlier lesions than had been encountered in the past [13]; thus, it is no surprise that recent reports have documented the existence of small-diameter melanomas, classified as lesions ≤6 mm [14, 21, 22]. Although there are only a limited number of studies which report on small melanomas of this size, the frequency of small melanomas reported ranges from less than 1% [35] to 17% [14], with the exception of one study conducted in Australia which reported that 31.1% of melanomas were ≤6 mm [36]. A recent survey of available literature on small melanomas estimated their frequency to be between 3 and 14% [1]. The aforementioned frequency of small melanomas is surely a gross underestimation, as most, if not all, melanomas have their origin as tiny, generally clinically unrecognizable pigmented macules of evolving melanoma in situ. Regardless of the true incidence of small-diameter melanomas, a more startling realization is the fact that some of these lesions are already invasive at presentation. Of 47 small-diameter melanomas diagnosed by Bono et al., 14 cutaneous melanomas were in situ, and 33 were invasive [14]. In reviewing published data, small-diameter melanoma tumor thickness has been reported to range from 0.11 to 1.5 mm, with a median thickness of approximately 0.7 mm [9, 21, 22, 36]. Since this thickness range generally corresponds to a favorable prognosis for small melanomas [7], targeting small melanomas for removal could potentially result in a marked reduction in mortality from melanoma.


R.J. Friedman, M. Warycha, M. Farber et al.

IV.4.2 Clinical Features


Small melanomas can be clinically subtle, remaining a diagnostic challenge to even the most astute clinician. In order to promote recognition of early melanomas by both physicians and lay public alike, the ABCD criteria was devised in 1985, emphasizing the clinical features differentiating between thin melanomas and benign pigmented lesions [22]: Asymmetry, Border irregularity, Color variegation, and Diameter >6 mm [17]. This algorithm was later revised to include an “E” criterion for Evolving, which has been demonstrated as another key characteristic of melanoma and as a useful tool for differentiating between melanoma and atypical nevi [1]. Many small melanomas can be identified using the ABCD rule, exhibiting the asymmetry, border irregularity, and color variability characteristics of larger melanomas (Fig. IV.4.1) [19, 22]; however, since all melanomas originate from one or more neoplastic melanocytes, not all of the ABCD criteria will be observable in earlier stages of development [19], but the combination of these criteria have been documented to increase diagnostic accuracy in clinical practice with adequate interobserver concordance [8, 28, 40]. Although no single criterion has been proven to have predictive value in decisions regarding biopsy management, emphasis has recently centered on the element of change in the evaluation of pigmented lesions. The concept of an evolving lesion, whether pertaining to changes in color, size, shape, elevation, surface, surrounding skin, sensation, and consistency [19], has been particularly useful in the identification of melanomas, especially in the subset of “nodular” and small-diameter melanomas (≤6 mm), which frequently fail to satisfy the ABCD rule [16, 23]. Further demonstrating the utility of the “E” criterion for small melanomas, these lesions were often removed because of a change or new discovery of the lesion in adulthood [9, 22] or occurrence of symptoms [9]. Other dermoscopists have also noted that a change of color was more frequently seen in small melanomas than in melanomas >6 mm [20]. Although patient re-

Fig. IV.4.1.  A 4-mm-diameter macular pigmented lesion exhibiting lesion asymmetry, border irregularity, and play in color. The lesion was slowly growing over 9 months. A biopsy revealed melanoma, in situ

call is frequently hampered by subjectivity, its utility in differentiating melanoma from atypical nevi has become increasingly apparent. In addition to aiding physicians in diagnosing melanomas, the dynamic features of a pigmented skin lesion have been the most important indicators of malignancy perceived by the general public [6, 25]. Another important feature of small melanomas is that they tend to be found in patients at younger ages compared with melanomas >6 mm. While the majority of melanomas are found in patients of about 60 years of age or older [18], the average age of patients presenting with small melanomas has been reported to be between 39 and 42 years [9, 21, 22]; however, small melanomas have the same race, sex ratio, and anatomic distribution, including higher frequency on the lower extremity in females, as larger melanomas [22]; thus, the patient’s history and physical examination plays a pivo­tal role in the detection of early melanoma. Change in a melanocytic lesion or development of a new pigmented lesion later in life (after age 40 years) should prompt suspicion for melanoma in physicians and patients alike [19]. Surveillance of high-risk patients using total-body imaging has also proved beneficial in identifying small and early tumors, whether as de-novo lesions or changes in pre-existing melanocytic lesions.

Early Evolution of Melanoma

Chapter IV.4

IV.4.3 Dermoscopic Criteria Dermoscopy has been shown to improve diagnostic accuracy for identifying melanomas [24, 34, 38], although its diagnostic value depends on the experience of the dermoscopist [12]. One of the first dermoscopic features identified in the evolution of early melanoma is the appearance of an irregular and prominent pigment network. Histopathologically this correlates to the proliferation of atypical melanocytes along the dermo-epidermal junction. As these atypical melanocytes extend throughout the thickness of the epidermis, including the granular and cornified layers, the appearance of black dots in irregular distribution is evident. With the formation of confluent junctional nests of melanocytes accentuated toward the periphery of the lesion, irregular streaks appear (previously described as pseudopods and radial streaming). Irregular brown globules, which represent nests of melanocytes irregularly distributed throughout the dermo-epidermal junction and/or papillary dermis, can also be seen. Gray-blue areas are observed once melanocytes extend into the mid- and reticular dermis [3, 4]. Dermoscopic features (Fig. IV.4.2, IV.4.6, IV.4.7) that can help identify early melanomas include: (a) a pigmented network with an abrupt margin [30, 34]; (b) depigmented scar-like areas; (c) a whitish veil; (d) colors of red, blue, gray, or white; (e) four or more colors; (f) border irregularity; and (g) multiple homogenous areas of variable size [34]. Although these features can aid the diagnosis of melanoma, it is important to note that certain characteristics are less frequently observable in earlier melanomas, notably depigmented areas and a whitish veil [34]. Results of a Consensus Net Meeting on Dermoscopy study found that three criteria were especially important in the identification of melanoma from benign pigmented lesions, including: (a) asymmetry; (b) atypical pigment network; and (c) blue-white structures [4]. Since then, this three-point checklist has been shown to be a valid and reproducible algorithm with high sensitivities for the diagnosis of melanoma, even when employed by non-experts [37]; however, it is important to be aware of the limitations of dermoscopy with particular regard to

Fig. IV.4.2.  Dermoscopy image of 5.5-mm-diameter pigmented macule shows a melanocytic lesion with focal structureless areas, a non-uniform network, gray dots and granules, four colors, including light brown, dark brown, gray, and black, and a disorganized, reticular–homogeneous network. These dermoscopy changes are suggestive of either a melanoma or an “atypical melanocytic neoplasm.” A diagnosis of melanoma was favored and a biopsy confirmed melanoma, in situ

identifying smaller melanomas. The ABCD rule of dermoscopy may not be as useful in the identification of small melanomas, as studies have found barely sufficient interobserver agreement in evaluating the presence of each of the criteria in lesions ≤5 mm [31]. Furthermore, others determined that dermoscopy did not improve diagnostic performance for lesions ≤6 mm in diameter, even for those trained in dermoscopy [16]. These observations suggest a need for additional tools to help with the diagnosis of small melanomas. Promising new techniques, include computer-assisted imaging systems, are emerging (Fig.  IV.4.8).

IV.4.4 Histopathology Approximately 75–83% of melanomas arise as de-novo lesions with the remainder developing in continuity with a variety of melanocytic lesions, the majority of which are compound or intradermal in type [18, 26]. Other potential precursor lesions include congenital melanocytic nevi, whose magnitude of risk correlates with increasing size of the nevus [27]. Melanomas have also been shown to originate infre-



R.J. Friedman, M. Warycha, M. Farber et al.


Fig. IV.4.3.  Photomicrograph of a 1.3-mm-diameter tan macule. The patient requested a biopsy because of a prior history of melanoma and due to the fact that this was a “new” lesion. At lower-power magnification, there is a very subtle increase in the number of single melanocytes predominating mostly along the dermo-epidermal junction in a slightly asymmetric array. At higher magnification, a few single melanocytes are present slightly along the dermo-epidermal junction. Diagnosis: early melanoma, in situ, subtle, probable

quently from dysplastic nevi, with higher risks of transformation in those nevi with more severe cytologic atypia [5, 29]. Regardless of subtype, it is hypothesized that melanomas evolve from single collections of melanocytes along the dermo-epidermal junction [18, 19]. Unfortunately, these early changes may not be easily discernible to the pathologist given the lack of reproducible histopathological criteria [19]. Moreover, this small focus of cytologically normal-appearing melanocytes (Fig. IV.4.3) may not yet translate into clinical atypia, thus evading recognition during routine skin examination. At a diameter of only 1–2 mm, early melanoma may present simply as a small

Fig. IV.4.4.  A 3.3-mm-diameter pigmented macule with a subtle play in color centrally. Microscopically, there is a proliferation of mostly single melanocytes at, and somewhat above, the dermo-epidermal junction. Diagnosis: early melanoma, in situ

tan-brown macule, failing to exhibit the distinguishing features of larger melanomas. Over time, a few single atypical melanocytes emerge among the relatively normal-appearing melanocytes, confined initially to the dermoepidermal junction. Clinically this correlates to a slowly growing tan-brown macule which may display subtle abnormalities in symmetry and border. As the stages of melanoma progression advance, atypical melanocytes coalesce to form small nests at the dermo-epidermal junction with a prominent extension of scattered, solitary atypical melanocytes throughout the epidermis (Fig. IV.4.4). At this phase, the melanoma in situ measures approximately 3–4 mm in diameter. As the lesion progresses, nests of atypical melanocytes develop along the lower portion of the epidermis, eventually spreading throughout the entire thickness of the epidermis and involving

Early Evolution of Melanoma

Chapter IV.4

Fig. IV.4.6.  Dermoscopy image of an approximately 5-mm-diameter ill-defined pigmented lesion exhibits the ABCs. Dermoscopy shows a melanocytic lesion exhibiting branched streaks, focal structureless areas, asymmetrically distributed dots and globules, three colors, including light brown, dark brown, and gray, and a reticular–globular–homogeneous disorganized pattern. Overall impression on dermoscopy was melanoma. Diagnosis: melanoma, in situ

Fig. IV.4.5.  A 4.1-mm-diameter pigmented macule with subtle clinical features of the ABCs and a change in D over the past few months (“ABCDE”s). Microscopically, there are single and nested atypical melanocytes at and above the dermo-epidermal junction, including some melanocytes identified in the stratum corneum. Diagnosis: melanoma, in situ

adnexal structures. It is at this stage where variations in color between tan and brown become more apparent, reflective of the presence of melanocytes at higher levels of the epidermis (Figs. IV.4.5). Once they approach the cornified layer, pigment-laden melanocytes may lend to the dark brown or black appearance of some lesions. Melanomas are limited to the epidermis for a variable amount of time, likely contingent upon factors such as host immune response, chemical or humoral growth factors, genetic markers, etc. But for the majority of lesions, atypical melanocytes eventually descend into the papillary dermis. This typically occurs once the proportion of neoplastic melanocytes in nests surmounts those occurring as single atypical melanocytes, which can take months, years, or even decades

Fig. IV.4.7.  Dermoscopy image of a 4.4-mm-diameter pigmented macule with featureless pattern. Ten experienced dermoscopists favored a benign diagnosis. Diagnosis: melanoma, in situ



R.J. Friedman, M. Warycha, M. Farber et al.

IV.4 Fig. IV.4.8.  A 5.4-mm-diameter pigmented macule shows nearly identical dermoscopy pattern with standard dermoscopy and “machine vision” computer-generated dermoscopy image.

in some cases. Although melanocytes can descend from the epidermis into the subjacent dermis while the lesion is only 4–5 mm in diameter, melanomas can remain in situ until they are much larger in size, reaching 16 mm and possibly even 30 mm or more on the head and neck [19]. Once atypical melanocytes have invaded into the papillary dermis, the neoplasm tends to expand three-dimensionally. Neoplasms progress to involve deeper structures, including the reticular dermis and subcutaneous fat, with potential for development of clinically ulcerated and nodular components. The lesion may undergo regression and, in time, may develop multiple colors including red, white, or blue, in addition to those of brown, tan, or black. Presence of the latter features implies a more advanced lesion and as such is associated with a poor prognosis [8]. Eventually many of these neoplasms lead to regional and/or distant metastasis with dismal prognosis for survival. Maize and Ackerman briefly summarized the following histolopathogical features of melanoma regardless of size or anatomic site [26]:

1. Diameter typically >6 mm at time of biopsy 2. Asymmetric growth of atypical melanocytes (correlates to clinical asymmetry) 3. Poor circumscription – atypical melanocytes arranged as solitary units extending above the most peripheral discrete nest of melanocytes within the epidermis 4. Increased number of single atypical melanocytes within the epidermis and epidermal adnexal structures, with single cells often predominating over nests 5. Scattered atypical melanocytes within upper levels of the epidermis (contributing to color variation) 6. Nests of melanocytes within the epidermis not equidistant (contributing to color variation) 7. Irregularity in the shape of nests of melanocytes 8. Confluence of nests of melanocytes (contributes to evolution of color in lesion)

Early Evolution of Melanoma

With regard to early invasive melanomas, they noted the following [26]: 1. Failure of atypical melanocytes to mature with eventual descent into the dermis (contributes to elevation of a lesion) 2. Asymmetrical, patchy distribution of melanin within the neoplasm (contributes to color variation, including blue in more invasive lesions) 3. Extension of atypical melanocytes to epithelial adnexal structures 4. Asymmetrical distribution of inflammatory-cell infiltrates at the base of the neoplasm (contributes to color variation, including red, white, and blue)


Core Messages ■ As the incidence rates for melanoma continue to rise, detection in the earliest phases of tumor progression will become more essential. ■ Regardless of size, melanomas confined entirely within the epidermis are 100% curable once subjected to complete removal. ■ The majority of small-diameter (≤6 mm) melanomas can be identified using the ABCD(E) rule, with emphasis

References   1. Abbasi NR, Shaw HM, Rigel DS, et al (2004) Early diagnosis of cutaneous melanoma: revisiting the ABCD criteria. J Am Med Assoc 292:2771–2776   2. American Cancer Society. Facts and figures 2005. Atlanta, GA: American Cancer Society   3. Argenziano G, Fabbrocini G, Carli P, et al (1997) Epiluminescence microscopy: criteria of cutaneous melanoma progression. J Am Acad Dermatol 37:68–74   4. Argenziano G, Soyer HP, Chimenti S, et al (2003) Dermoscopy of pigmented skin lesions: results of a consensus meeting via the Internet. J Am Acad Dermatol 48:679–693   5. Arumi-Uria M, McNutt S, Finnerty B (2003) Grading of atypia in nevi: correlation with melanoma risk. Mod Pathol 16:764–777

Chapter IV.4

Common cytological features of melanoma also include atypical nuclei, necrosis of melanocytes, a greater number of melanocytes in mitosis, and pagetoid melanocytes within the epidermis. Available evidence indicates that melanomas ≤6 mm display many of these same histopathological atypia as larger melanomas. In a retrospective study of small proliferations <6 mm of atypical melanocytes within the dermis and epidermis, Kamino et al. [22] found that 19 of 30 melanomas showed evidence of all architectural and cytological features described by Maize and Ackerman [26], with the exception of the breadth criterion. Notably, poor circumscription was absent more often than all other criteria, although 87% of cases still evidenced poor circumscription.

on the dynamic features of a lesion over time. ■ Efforts to improve the diagnostic accuracy and sensitivity for melanoma have led to the development of new non-invasive techniques for melanoma detection, including dermoscopy and computerized image analysis systems.

  6. Baade PD, Balanda KP, Stanton WR, et al (1997) Community perceptions about the important signs of early melanoma. J Am Acad Dermatol 36:33–39   7. Balch CM, Soon S, Gershenwald JE, et al (2002) Prognostic factors analysis of 17,600 melanoma patients: validation of the American joint committee on cancer melanoma staging system. J Clin Oncol 19: 3622–3634   8. Barnhill RL, Roush GC (1991) Correlation of clinical and histopathologic features in Clinically atypical melanocytic nevi. Cancer 67:3157–3164   9. Bergman R, Katz I, Lichtig C, et al (1992) Malignant melanomas with histologic diameters less than 6 mm. J Am Acad Dermatol 26:462–466 10. Berwick M, Begg CB, Fine JA, et al (1996) Screening for cutaneous melanoma by skin self-examination. J Natl Cancer Inst 88:17–23




R.J. Friedman, M. Warycha, M. Farber et al. 11. Berwick M, Wiggins C (2006) The current epidemiology of cutaneous malignant melanoma. Front Biosci 11:1244–1254 12. Binder M, Schwartz M, Winkler A, et al (1995) Epiluminescence microscopy: a useful tool for the diagnosis of pigmented skin lesions for formally trained dermatologists. Arch Dermatol 131:286–291 13. Bishop JAN (1997) Molecular pathology of melanoma. Cancer Metastasis Rev 16:141–154 14. Bono A, Bartoli C, Moglia D, et al (1999) Small melanomas: a clinical study on 270 consecutive cases of cutaneous melanoma. Melanoma Res 9:583–586 15. Carli P, Giorgi V de, Palli D, et al (2003) Dermatologist detection and skin self-examination are associated with thinner melanomas. Arch Dermatol 139:607–612 16. Chamberlain AJ, Fritschi L, Kelly JW (2003) Nodular melanoma: patients’ perceptions of presenting features and implications for earlier detection. J Am Acad Dermatol 48:694–701 17. Friedman RJ, Rigel DS, Kopf AW (1985) Early detection of malignant melanoma: the role of physician examination and self-examination of the skin. CA Cancer J Clin 35:130–151 18. Friedman RJ, Heilman ER, Gottlieb GJ, et al (1991) Malignant melanoma: clinicopathologic correlations. In: Friedman RJ, Rigel DS, Kopf AW, et al (eds) Cancer of the skin. Philadelphia: Saunders 19. Friedman RJ (2005) The importance of early detection of melanoma, physician and self-examination. In: Rigel DS, Friedman RJ, Dzubow LM, et al (eds) Cancer of the skin. New York: Saunders 20. Helsing P, Loeb M (2004) Small diameter melanoma: a follow-up of the Norwegian Melanoma Project. Br J Dermatol 151:1081–1083 21. Gonzalez A, West AJ, Pitha JV, et al (1996) Smalldiameter invasive melanomas: clinical and pathologic characteristics. J Cutan Pathol 23:126–132 22. Kamino H, Kiryu H, Ratech H (1990) Small malignant melanomas: clinicopathologic correlation and DNA ploidy analysis. J Am Acad Dermatol 22:1032– 1038 23. Kelly JW (1998) Melanoma in the elderly: a neglected public health challenge. Med J Aust 169:403–404 24. Kopf AW, Elbaum M, Provost N (1997) The use of dermoscopy and digital imaging in the diagnosis of cutaneous melanoma. Skin Res Tech 3:1–7 25. Liu W, Hill D, Gibbs AF, Tempany M, et al (2005) What features do patients notice that help to distinguish between benign pigmented lesions and melanomas? The ABCD(E) rule versus the seven-point checklist. Melanoma Res 15:549–554 26. Maize JC, Ackerman AB (eds) (1987) Malignant melanoma. In: Pigmented lesions of the skin. Philadelphia: Lea and Febiger

27. Marghoob AA (2002) Congenital melanocytic nevi: evaluation and management. Dermatol Clin 20:607–616 28. McGovern TW, Litaker MS (1992) Clinical predictors of malignant pigmented lesions: a comparison of the Glasgow seven-point checklist and the American Cancer Society’s ABCDs of pigmented lesions. J Dermatol Surg Oncol 18:22–26 29. Naeyaert JM, Brochez L (2003) Dysplastic nevi. N Engl J Med 349:2233–2240 30. Pehamberger H, Steiner A, Wolff K (1987) In vivo epiluminescence microscopy of pigmented skin lesions. I. Pattern analysis of pigmented skin lesions. J Am Acad Dermal 17:571–583 31. Pizzichetta MA, Talamini R, Piccolo D et al (2001) The ABCD rule of dermatoscopy does not apply to small melanocytic skin lesions. Arch Dermatol 137:1376–1377 32. Rigel DS, Friedman RJ, Kopf AW (1996) The incidence of malignant melanoma in the United States: issues as we approach the 21st century. J Am Acad Dermatol 34:839–847 33. Rigel DS, Friedman RJ, Kopf AW, et al (2005) ABCDE-An evolving concept in the early detection of melanoma. Arch Dermatol 141:1032–1034 34. Salopek TG, Kopf AW, Stefanato CM, et al (2001) Differentiation of atypical moles (dysplastic nevi) from early melanomas by dermoscopy. Dermosc Clin 19:337–345 35. Schmoeckel C (1991) Small malignant melanomas: clinicopathologic correlation and DNA ploidy analysis. J Am Acad Dermatol 24:1036–1037 36. Shaw HM, McCarthy WH (1992) Small-diameter malignant melanoma: a common diagnosis in New South Wales, Australia. J Am Acad Dermatol 27:679–682 37. Soyer HP, Argenziano G, Zalaudek I et al. (2004) Three-point checklist of dermoscopy. Dermatology 208:27–31 38. Steiner A, Pehamberger H, Wolff K (1987) In vivo epiluminescence microscopy of pigmented skin lesions. 2. Diagnosis of small pigmented skin lesions and early detection of malignant melanoma. J Am Acad Dermatol 17:584–591 39. Thompson JF, Scolyer RA, Kefford RF (2005) Cutaneous melanoma. Lancet 365:687–701 40. Thomas L, Tranchand P, Berard F, et al (1998) Semiological value of the ABCDE criteria in the diagnosis of cutaneous pigmented tumors. Dermatology 197:11–17

Chapter IV.5

False-Negative Melanomas Robert Johr and Giuseppe Argenziano


IV.5.1 Definition

IV.5.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221 IV.5.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . 221 IV.5.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . 222 IV.5.4 Melanoma Simulating Seborrheic Keratosis. . . . . . . . . . . . . . . . . . . 223 IV.5.5 Melanoma Simulating Basal Cell Carcinoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 IV.5.6 Melanoma Simulating Vascular Lesions. . . . . . . . . . . . . . . . . . . . . . . 224 IV.5.7 Melanoma Simulating Dysplastic Nevi. . . . . . . . . . . . . . . . . . . . . . . . 224 IV.5.8 Melanoma Simulating Spitz Nevi. . . . . . . . 224 IV.5.9 Melanoma Simulating Blue Nevi . . . . . . . . 225 IV.5.10 Melanoma Simulating a Combined Nevus. . . . . . . . . . . . . . . . . . . . .225 IV.5.11 Melanoma Simulating a Recurrent Nevus. . . . . . . . . . . . . . . . . . . . . 225 IV.5.12 Melanoma Simulating Ink Spot Lentigo. . 225 IV.5.13 Melanoma Simulating Actinic Lentigo and Pigmented Actinic Keratosis. . . . . . . . 225 IV.5.14 Feature Poor and Featureless Melanomas. . . . . . . . . . . . . . . . . . . . . . . . . . . 225 IV.5.15 Relevant Clinical Differential Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 IV.5.16 Management. . . . . . . . . . . . . . . . . . . . . . . . . . 225


References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

False negative is defined as a negative test result when the attribute for which the subject is being tested actually exists. Clinically, dermoscopically, and/or histopathologically the diagnosis of melanoma is not made, yet, the patient has a melanoma.

IV.5.2 Clinical Features It has been reported that amelanotic melanoma is the great masquerader; however, any melanoma has the potential to fool the most experienced clinician. It is not possible to make the diagnosis 100% of the time no matter what clinical aids one uses. Experienced clinicians can diagnose melanoma clinically 60â&#x20AC;&#x201C;75% of the time. In a metaanalysis it was shown that the diagnostic accuracy can be improved by as much as 49% with dermoscopy. The sensitivity of clinical evaluation plus dermoscopy can be as high as 97%. As many as 15% of melanomas can be false negative, mimicking melanocytic and non-melanocytic lesions or non-melanoma skin cancers. At times, the only way to suspect the diagnosis is by finding clinical and/or dermoscopic changes over time. In general, false-negative melanoma incognito could be a solitary macule, papule, nodule, or plaque that can have a smooth or scaly surface with or without ulceration. Polymorphous lesions can be seen with cutaneous metastatic melanoma. A single relatively innocuous color or multiple colors can be present with various shades of black, brown, gray, or blue. The ABCD clinical


R. Johr, G. Argenziano


Fig. IV5.1.  a A pink plaque resembling a dermal nevus located on the back of a 66-year-old man. b On dermoscopy, instead of the “comma-shaped” vessels expected in a dermal nevus, there are atypical vessels, which increased our index of suspicion to perform a biopsy. Histopathologically, the lesion was diagnosed as a 1-mm-thick amelanotic melanoma

criteria might not be helpful for small-diameter lesions less than 6 mm, desmoplastic, nodular lesions, or patients with multiple dysplastic nevi. Hypomelanotic and amelanotic melanoma can be clear, skin colored, or pinkish red. At times, surface vasculature can be seen with the naked eye or with typical magnification clinicians use. More specifically, melanoma incognito could have the clinical characteristics of a seborrheic keratosis, basal cell carcinoma, hemangioma, pyogenic granuloma, ink spot, or actinic lentigo. They can also be mistaken clinically for dermal, combined, blue, Spitz, recurrent, Unna, Meishner, or dysplastic nevi.

Fig. IV5.2.  a A flat pigmented lesion resembling a common nevus located on the abdomen of a 56-year-old man. b On dermoscopy, there is an atypical pattern composed of a reticular depigmentation and grayish pepper-like pigmentation; thus, the lesion was excised and subsequent histopathological examination revealed a 0.45-mm-thick melanoma

IV.5.3 Dermoscopic Criteria At times, it is not possible to determine if a lesion is melanocytic, non-melanocytic, benign, or malignant. A non-specific dermoscopic pattern should always include melanoma in the differential diagnosis. It is important to not only use dermoscopy for clinically suspicious lesions. Melanoma incognito might not look high risk clinically yet have well-developed melanomaspecific criteria or subtle clues, such as pinpoint telangiectatic blood vessels, that lead to the correct histopathological diagnosis. The most difficult case scenario is a melanoma that has the dermoscopic criteria of non-me-

False-Negative Melanomas

Fig. IV.5.3.  a A small banal pigmented macule located on the lower arm of a 60-year-old woman. b On dermoscopy, the lesion is strikingly asymmetric, with evident regression structures and atypical vessels. The lesion was thus excised and subsequent histopathological examination revealed a melanoma in situ with regression

lanocytic lesions such as seborrheic keratosis, basal cell carcinoma, or hemangioma. The falsenegative criteria can dominate the entire lesion. Foci of melanoma-specific criteria may or may not be present in these lesions. A final group can stimulate the spectrum of benign melanocytic nevi from dermal nevi to Spitzoid lesions (Figs. IV.5.1–IV.5.4).

Chapter V.5

Fig. IV5.4.  a A pigmented lesion clinically diagnosed as nevus on the back of a 29-year-old woman. b On dermoscopy, the lesion is asymmetric with features of regression and irregular dots/globules. The lesion was thus excised and subsequent histopathological examination revealed an in situ melanoma arising within a pre-existing melanocytic nevus

IV.5.4 Melanoma Simulating Seborrheic Keratosis Most melanomas that simulate seborrheic keratosis clinically can be diagnosed with dermoscopy. If criteria used to diagnose both pathologies are present, the clinical decision making will be problematic. In-situ amelanotic pink macular melanoma can be featureless and side by side with what appears to be seborrheic keratosis. A high index of suspicion will lead to the excision and histopathological diagnosis of collision lesions. The most difficult case scenario is a melanoma in which the predominant criteria are milia-



R. Johr, G. Argenziano

like cysts and comedo-like openings. It is not always possible to differentiate pigmented comedo-like openings of a seborrheic keratosis from the dots and globules of a melanocytic lesion. These lesions tend to be uniformly black or grayish. One should always search for foci of melanoma-specific criteria such as irregular dots and globules or streaks. A history of change or the patientâ&#x20AC;&#x2122;s concern for the lesion might be the only reason for an excision. Comedo-like openings and milia-like cysts are not exclusively seen in seborrheic keratosis. They can also be found in banal nevi and in melanomas.

IV.5.5 Melanoma Simulating Basal Cell Carcinoma


Rarely, melanoma can be characterized by the typical in-focus arborizing blood vessels characteristic of basal cell carcinoma. Areas of regression and pigmentation that vary in size, shape, and color may or may not be present. The histopathological surprise could be in-situ or deeply invasive melanoma masquerading as a basal cell carcinoma.

IV.5.6 Melanoma Simulating Vascular Lesions Are the vascular spaces that you see in otherwise typical hemangioma sharply in focus and well demarcated or poorly defined? If they are poorly defined, it could be a melanoma masquerading as a banal hemangioma. Whitish color that is diffuse or localized might represent hyperkeratosis seen in hemangiomas or areas of regression of a hemangioma-like melanoma. The dermoscopic appearance of amelanotic melanoma simulating a pyogenic granuloma is non-specific. They are pinkish or red nodules that are featureless or feature poor with polymorphous vascular pattern with pin-point, irregular linear, and other shaped small telangiectatic vessels with or without ulceration.

IV.5.7 Melanoma Simulating Dysplastic Nevi Patients with multiple dysplastic nevi and a history of melanoma are the number one group in which a dysplastic nevus-like melanoma could be found or missed. They can have a polymorphous dermoscopic appearance usually without well-defined melanoma-specific criteria. One might only find asymmetry of different shades of color with or without barely perceptible foci of regular pigment network or small dots. Various presentations of hyper- and hypopigmentation without true regression can also be present, indistinguishable from the typical benign dysplastic nevus. If pink color is seen, a red flag of concern should be raised that the lesion could be a dysplastic nevus-like melanoma.

IV.5.8 Melanoma Simulating Spitz Nevi Not all melanomas with a Spitzoid dermoscopic pattern turn out to be Spitzoid melanomas histopathologically, and not all Spitzoid melanomas histopathologically have a Spitzoid dermoscopic pattern. A symmetrical starburst pattern with streaks and/or dots and globules at most points along the periphery is the hallmark of a benign Spitz nevus. A small percentage of melanomas can have a symmetrical starburst pattern. Melanoma incognito can also have a globular pattern reminiscent of the globular pattern that can be seen with banal and Spitz nevi. In this case, the dots and globules are irregular in size, shape, and color. Other melanoma-specific criteria, such as blue-white color or foci of irregular pigment network, might also be present. Spitzoid melanomas histopathologically can have a non-specific dermoscopic pattern that can be feature poor with subtle foci of dots, globules, streaks, and pink color.

False-Negative Melanomas

IV.5.9 Melanoma Simulating Blue Nevi Different shades of homogeneous blue and brown color, plus foci of irregular dots and globules, could be seen in this category. The dermoscopic differential diagnosis of a blue nevus includes nodular melanoma and cutaneous metastatic melanoma.

IV.5.10 Melanoma Simulating a Combined Nevus A black or bluish-gray blotch of pigmentation associated with what appears to be banal melanocytic nevus has a dermoscopic differential diagnosis that includes melanocytic atypia or melanoma and could be confused with a combined nevus.

IV.5.11 Melanoma Simulating a Recurrent Nevus Blotches of pigmentation in a surgical scar could represent melanoma masquerading as a recurrent nevus. There is nothing diagnostic about this dermoscopic picture and it is essential to be aware of the histopathological diagnosis of the lesions that was originally excised.

IV.5.12 Melanoma Simulating Ink Spot Lentigo General asymmetry of color and structure plus a prominent dark thickened pigment network with foci of other melanoma specific criteria, such as blue-white color or irregular dots and globules, can be seen.

IV.5.13 Melanoma Simulating Actinic Lentigo and Pigmented Actinic Keratosis Annularâ&#x20AC;&#x201C;granular structures consisting of black, brown, or gray fine dots surrounding appendigeal openings has a dermoscopic differential diagnosis that includes melanoma. Melano-

Chapter V.5

ma could be associated with an actinic lentigo or pigmented actinic keratosis. Multiple skin biopsies might be necessary to make the diagnosis. A feature-poor lesion with moth-eaten borders and asymmetry of various shades of brown color could be a melanoma masquerading as an actinic lentigo.

IV.5.14 Feature Poor and Featureless Melanomas There can be a complete absence of local criteria with different shades of color in featureless melanomas. Feature-poor melanomas do not have well-developed melanoma-specific criteria such as irregular network, dots, globules, or streaks. A polymorphous vascular pattern with pinpoint, linear irregular, and other shaped telangiectatic vessels should raise a red flag of concern, especially if the lesion is pink or red clinically.

IV.5.15 Relevant Clinical Differential Diagnosis For false-negative melanoma incognito the clinical differential diagnosis is extensive. Any solitary pink or red macule, papule, nodule, or plaque with or without scale or skin markings could be melanocytic, non-melanocytic, benign malignant, or inflammatory. Lesions with pigmentation encompass the same clinical differential diagnosis. The patientâ&#x20AC;&#x2122;s personal and family history, plus the history of the lesion as well as the clinical and dermoscopic appearance, should all be taken into consideration when formulating a clinical diagnosis.

IV.5.16 Management Melanoma can be found from head to toe, and comprehensive skin examinations of patients are sometimes essential. A thorough history is also recommended to find out if a lesion is new, changing, or bothersome to the patient, and should never be ignored no matter how banal the lesion might appear. It is not uncommon for




R. Johr, G. Argenziano

a patient with melanoma to seek several dermatologists’ opinions or insist on an excision of a lesion against their physician’s advice. Dermoscopy is a readily available tool that should be used on both clinically suspicious and banal-appearing skin lesions. There should always be a good clinico-dermoscopic correlation and nonspecific dermoscopic patterns could be seen in false-negative melanomas. Total-body photography and/or digital dermoscopy should be used for patients at risk of multiple atypically pigmented skin lesions that are not sufficiently atypical to warrant excision yet cannot be forgotten. Short-term digital dermoscopic monitoring at 3- to 4-month intervals or intervals up to 1 year represents currently the highest level of patient care. Side-by-side comparisons of baseline dermoscopic images that have been mapped out can be performed with the same lesion at follow-up. Even the most insignificant change over time should be taken into consideration and not ignored. Most lesions that change are not melanomas, yet they could be. Melanomas found with digital follow-up tend to be in situ or less invasive than melanomas found at a typical office visit. Digital follow-up for a nodular lesion that raises some sort of suspicion is not recommended. Even with short-term monitoring, waiting a few months with nodular melanoma incognito could worsen the patient’s chances for survival. Any Spitzoid pattern, especially if it is found in an adult, should be excised. If there is any mention of atypicality in the pathology report, more histopathological opinions should be sought and the lesion should be considered melanoma until proven otherwise. Attention should be focused on all aspects of the patient, because melanoma can masquerade as almost anything, and attentive examination will increase the chances of diagnosing false-negative melanomas.

Clinically banal-looking pigmented skin lesion. On dermoscopy there is asymmetry of color and structure, a ­ focus of atypical network on the left side and a small area of blue-white color at the upper pole of the lesion. Despite the banal clinical appearance, the constellation of dermoscopic criteria is strongly suggestive of melanoma

False-Negative Melanomas


Core Messages ■ A high index of suspicion that any skin lesion could be melanoma should always be in the back of one’s mind when performing a skin examination, as the most innocuous-looking lesion could be a melanoma. Clinicians cannot diagnose melanoma 100% of the time. ■ Look for clinical clues that do not fit the typical clinical characteristics of the lesion in question. ■ False-negative melanomas can clinically and/or dermoscopically mimic melanocytic, non-melanocytic, benign, malignant, and inflammatory lesions. ■ The ABCD clinical criteria will be more sensitive to diagnose melanoma if “E” (standing for Evolution) is added to represent evolution or some change in a lesion. ■ Dermoscopy can increase the diagnosis of melanoma and should routinely be used for both suspicious and banalappearing skin lesions. ■ At times it is only possible to diagnose melanoma by finding clinical and/or dermoscopic changes over time. ■ Always look for subtle high-risk criteria before making a dermoscopic diagnosis. ■ Raise a red flag of concern if you do not have a good clinico-dermoscopic correlation. ■ Gut feelings should not be ignored. “If in doubt, cut it out” is an excellent general principle to keep in mind with difficult cases.

Chapter V.5

References   1. Gachon J, Beaulieu P, Sei JF, Gouvernet J, Claudel JP, Lemaitre M, et al. First prospective study of the recognition process of melanoma in dermatological practice. Arch Dermatol 2005;141:434–438   2. Duff CG, Melsom D, Rigby HS, Kenealy JM, Townsend PL. A 6-year prospective analysis of the diagnosis of malignant melanoma in a pigmentedlesion clinic: even the experts miss malignant melanomas, but not often. Br J Plast Surg 2001;54:317– 321   3. Carli P, Nardini P, Crocetti E, Giorgi V de, Giannotti B. Frequency and characteristics of melanomas missed at a pigmented lesion clinic: a registry-based study. Melanoma Res 2004;14:403–407   4. Lindelof B, Hedblad MA, Sigurgeirsson B. Melanocytic naevus or malignant melanoma? A large-scale epidemiological study of diagnostic accuracy. Acta Dermatol Venereol 1998;78:284–288   5. Bafounta ML, Beauchet A, Aegerter P, Saiag P. Is dermoscopy (epiluminescence microscopy) useful for the diagnosis of melanoma? Results of a metaanalysis using techniques adapted to the evaluation of diagnostic tests. Arch Dermatol 2001;137:1343– 1350   6. Kittler H, Pehamberger H, Wolff K, Binder M. Diagnostic accuracy of dermoscopy. Lancet Oncol 2002;3:159–165   7. Soyer HP, Argenziano G, Talamini R, Chimenti S. Is dermoscopy useful for the diagnosis of melanoma? Arch Dermatol 2001;137:1361–1363   8. Soyer HP, Massone C, Ferrara G, Argenziano G. Limitations of histopathologic analysis in the recognition of melanoma: a plea for a combined diagnostic approach of histopathologic and dermoscopic evaluation. Arch Dermatol 2005;141:209–211   9. Argenziano G, Soyer HP. Dermoscopy of pigmented skin lesions: a valuable tool for early diagnosis of melanoma. Lancet Oncol 2001;2:443–449 10. Carli P, Giorgi V de, Crocetti E, Mannone F, Massi D, Chiarugi A, et al. Improvement of malignant/ benign ratio in excised melanocytic lesions in the “dermoscopy era”: a retrospective study 1997–2001. Br J Dermatol 2004;150:687–692 11. Argenziano G, Scalvenzi M, Staibano S, Brunetti B, Piccolo D, Delfino M, et al. Dermatoscopic pitfalls in differentiating pigmented Spitz naevi from cutaneous melanomas. Br J Dermatol 1999;141:788–793 12. Bath-Hextall F, Bong J, Perkins W, Williams H. Interventions for basal cell carcinoma of the skin: systematic review. Br Med J 2004;329:705 13. Zalaudek I, Ferrara G, Stefani A di, Argenziano G. Dermoscopy for challenging melanoma; how to raise the “red flag” when melanoma clinically looks benign. Br J Dermatol 2005;153:200–202



R. Johr, G. Argenziano 14. Steiner A, Pehamberger H, Binder M, Wolff K. Pigmented Spitz nevi: improvement of the diagnostic accuracy by epiluminescence microscopy. J Am Acad Dermatol 1992;27:697–701 15. Ferrara G, Argenziano G, Soyer HP, Chimenti S, Blasi A di, Pellacani G, et al. The spectrum of Spitz nevi: a clinicopathologic study of 83 cases. Arch Dermatol 2005;141:1381–1387 16. Zalaudek I, Argenziano G, Ferrara G, Soyer HP, Corona R, Sera F, et al. Clinically equivocal melanocytic skin lesions with features of regression: a dermoscopic–pathological study. Br J Dermatol 2004;150:64–71 17. Skvara H, Teban L, Fiebiger M, Binder M, Kittler H. Limitations of dermoscopy in the recognition of melanoma. Arch Dermatol 2005;141:155–160


18. Menzies SW, Gutenev A, Avramidis M, Batrac A, McCarthy WH. Short-term digital surface microscopic monitoring of atypical or changing melanocytic lesions. Arch Dermatol 2001;137:1583–1589 19. Argenziano G, Zalaudek I, Corona R, Sera F, Cicale L, Petrillo G, et al. Vascular structures in skin tumors: a dermoscopy study. Arch Dermatol 2004;140:1485–1489 20. Argenziano G, Rossiello L, Scalvenzi M, Staibano S, Ruocco E, Cicale L, et al. Melanoma simulating seborrheic keratosis: a major dermoscopy pitfall. Arch Dermatol 2003;139:389–391

Chapter IV.6

Genital Melanoma Ingrid H. Wolf


Contents IV.6.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 IV.6.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . 229 IV.6.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . 230 IV.6.4 Relevant Clinical Differential Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 IV.6.5 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . 230 IV.6.6 Management. . . . . . . . . . . . . . . . . . . . . . . . . . 231 IV.6.7 Case Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

IV.6.1 Definition Malignant neoplasm of melanocytes, representing a subtype of melanoma which occurs on the mucosal epithelium of vulva and penis.

IV.6.2 Clinical Features Melanoma of the vulva constitutes 2–4% of vulva malignancies and accounts for 1–3% of all melanomas arising in women [9, 10]. It occurs most frequently in patients older than 60 years of age. Common locations are the labia majora and minora, but tumors may also arise on the clitoris or perineum. Clinically, the early stages are characterized by asymmetrical macules with tan-brown to black color variations and irregular notched borders (Fig. IV.6.1a). Sometimes a multifocal origin is observed. More advanced

Fig. IV.6.1.  Melanoma in situ on the vulva. a Asymmetrical, sharply circumscribed black patches. b Increase in number of atypical melanocytes as solitary units at the dermo-epidermal junction and above it

melanomas are characterized by deeply pigmented plaques or ulcerated and bleeding polypoid nodules (Fig. IV.6.2). Frequently, amelanotic tumors are recognized. Male genital melanomas share their clinical (and histopathological) aspects with their female counterpart. Melanomas occur most frequently on the glans penis, sometimes involving the urethral meatus [2].


I.H. Wolf

IV.6.4 Relevant Clinical Differential Diagnosis Vulvar/penile melanosis (melanotic macules) may be indistinguishable from melanoma in situ clinically. Also dermoscopically, melanomas can show overlapping features with vulvar melanosis. A typical parallel pattern with linearly arranged pigmentation (“fingerprint pattern”) or a “structureless pattern” can be found in mucosal melanosis but may sometimes also be present at the periphery of genital melanomas [6].

IV.6.5 Histopathology


Fig. IV.6.2.  Melanoma on the vulva with multifocal appearance

Recently, distinct genetic differences (BRAF, NRAS) could be identified between non UVlight-associated mucosal melanomas and cutaneous melanomas [1].

IV.6.3 Dermoscopic Criteria Melanoma on genital regions show dermoscopically polymorphous features with different colors from red to dark-brown and black. They usually present melanoma criteria, namely irregular streaks and globules, and inhomogeneous pigmentation associated with an atypical vascular pattern. The pigment network may be prominent and irregular. An abrupt cut-off at the periphery, similar to melanomas in other locations, is characteristic [4, 8]. An important indication for the use of dermoscopy in genital locations is to identify atypical areas for biopsy and histopathology to differentiate melanoma from a benign pigmented proliferation.

Genital melanomas reveal the same characteristics as melanomas at other anatomic sites. They are broad lesions, poorly circumscribed, and asymmetric, and have atypical melanocytes arranged as nests and single units at all levels of the epidermis (Fig. IV.6.1b). The growth pattern may be similar to acral melanomas. Demonstration of melanocytes with thick dendrites, found also in the upper part of the epidermis, are a clue for the diagnosis of genital melanoma in situ. Invasive tumors reveal irregular nests and sheets with frequently spindle-shaped melanocytes, looking like sarcomas. Lack of maturation and mitoses in the deeper dermal melanocytic population are other important criteria [7]. Prognostic parameters include tumor thickness and ulceration. A few cases of vulvar melanomas arising in a pre-existing vulvar nevus have been recorded in the literature. Genital melanosis must be differentiated from vulvar and penile melanoma in situ. This is usually not so difficult because melanosis, in contrast to melanoma, reveals no perceptible – or only a slight – increase in the number of melanocytes which are situated as solitary units in the hyperpigmented basal layer. These melanocytes exhibit small and monomorphous nuclei and delicate dendrites [5].

Genital Melanoma

IV.6.6 Management The overall prognosis for genital melanomas is poor, with 5-year survival rates in the 30–50% range. Local excision with adequate margins with or without sentinel node biopsy is the firstchoice therapy [3, 9]. Radical surgery does not improve long-term survival time and should be performed only in larger tumors. For patients who refuse surgery, local radiotherapy is a reasonable option.

IV.6.7 Case Study

Chapter IV.6

Question Asked By the Physician Which symptoms did you recognize?

Differential Diagnosis The differential diagnosis was melanoma, melanosis, and melanocytic nevus.

Management The management was surgical excision.

Patient Comment: A 49-year-old woman presented with a 1.5- to 2-cm long-standing lesion in the genital area/ clitoris.



Fig. IV.6.3.  Malignant melanoma on the vulva. a Asymmetrical poorly delineated patch with shades of dark brown, black, and gray. b Dermoscopy: irregular dots and globules, streaks, and bluish-white structures



I.H. Wolf


Core Messages ■ Genital melanoma is a relatively rare malignancy that occurs especially in patients of older age. ■ It is important to recognize the early in-situ phases because prognosis in invasive melanomas is usually very poor. ■ Any atypical pigmented lesion on the vulva or penis must be biopsied to rule out melanoma. Staging and management follow the treatment guidelines for melanoma of the skin.


References   1. Curtin JA, Fridlyand J, Kageshita T et al ( 2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353: 2135–2147   2. Henderson MA, Thompson JF ( 2004) Melanoma of the urogenital tract. In: Thompson JF, Morton DL, Kroon BB (eds) Textbook of melanoma. Martin Dunitz, London, New York, pp 636–640   3. Hengge UR, Meurer M (2005) Pigmentierte Genitalschleimhautveränderungen. Hautarzt 56: 540– 549   4. Johr R, Soyer HP, Argenziano G et al (2004) Dermoscopy, the Essentials. Mosby, Edingburgh   5. Kerl H, Massi D ( 2006) Melanotic macules, simple lentigo and lentiginous melanocytic naevus. In: Le Boit PE, Burg G, Weedon D, Sarasin A (eds) WHO classification of tumor pathology and genetics of skin tumors. IARC Press, Lyon   6. Mannone F, Giorgi V de, Cattaneo A et al (2004) Dermoscopic features of mucosal melanosis. Dermatol Surg 30: 1119–1123   7. Massi G, LeBoit PE (eds) (2004) Melanoma on genital skin. In: Histological diagnosis of nevi and melanoma. Springer–Steinkopff, Darmstadt, pp 581–590   8. Stolz W, Braun-Falco O, Bilek P et al (2002) Color atlas of dermatoscopy, 2nd edn. Blackwell, Berlin   9. Wechter ME, Gruber SB, Haefner HK et al ( 2004) Vulvar melanoma: a report of 20 cases and review of the literature. J Am Acad Dermatol 50: 554–562 10. Weinstock MA (1994) Malignant melanoma of the vulva and vagina in the United States: patterns of incidence and population-based estimates of survival. Am J Obstet Gynecol 171: 1225–1230

Chapter IV.7


Melanoma of the Face Ulrike Weigert and Wilhelm Stolz


IV.7.2 Clinical Features

IV.7.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 IV.7.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . 233 IV.7.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . 233 IV.7.4 Relevant Clinical Differential Diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 IV.7.5 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . 234 IV.7.6 Management. . . . . . . . . . . . . . . . . . . . . . . . . . 234 IV.7.7 Case Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

Lentigo maligna occurs at an average age of 63 years and lentigo maligna melanoma at 73 years. Lentigo maligna melanomas are more common in women than men, at a ratio of 1.7:1.0. Most lesions develop on the face, frequently on the upper cheek, temple or forehead. About 10% of lentigo maligna melanomas are observed on extrafacial sites such as trunk and limbs [1]. Initially the lentigo maligna is a flat brown or black, irregularly shaped lesion which often gradually thins out toward the periphery. These lesions grow very slowly over months or years and there may be central regression while the peripheral margin continues to extend. In time, a raised nodule will develop indicating transition to the vertical growth phase; therefore, patients usually present with a history of an increase in diameter of the pigmented lesion, and the perception that it has changed in some way.

IV.7.1 Definition Lentigo maligna and lentigo maligna melanoma represent a characteristic, histogenetic subclass of melanocytic malignancies. They are found on chronically light-exposed skin, usually the face of middle-aged and elderly people. During the long preinvasive period, called lentigo maligna, a very slow horizontal growth can be observed. After a variable period of time, invasion into the underlying dermis will occur. Other names for the preceding horizontal or in-situ growth phase are Hutchinson’s melanotic freckle and premalignant melanosis of Dubreuilh. Once obvious dermal invasion is present, the name lentigo maligna melanoma is appropriate.

IV.7.3 Dermoscopic Criteria According to the clinical course of lentigo maligna and lentigo maligna melanoma, Schiffner et al. [2] developed a progression model (Fig. IV.7.1) for lentigo maligna. Slate-grey aggregated dots around the hair follicles are an early feature of lentigo maligna. Then short dark-brown or black streaks can be detected which can progress to very specific dark-brown or black rhomboidal structures around the follicles, resulting in a characteristic annular– granular pattern. Dark-brown or black asymmetrical pigmented follicular openings can also be an early sign of lentigo maligna and represent


U. Weigert, W. Stolz Fig. IV.7.1.  Progression model for lentigo maligna

the irregular proliferation of atypical melanocytes within the follicles. In the final stage, homogeneous areas are present and the hair follicles are now obliterated, and the development of milky red areas correlates with invasive melanoma.


IV.7.4 Relevant Clinical Differential Diagnoses Three relevant differential diagnoses of early lesions are solar (actinic) lentigo (flat seborrheic keratosis), pigmented actinic keratosis and pigmented basal cell carcinoma. Dermoscopically solar lentigines often present with horn pseudocysts, fingerprint-like structures, a moth-eaten border and the jelly sign [3]. Actinic keratoses tend to have more surface scaling and their rough surface often gives a clue to the diagnosis. Dermoscopy also may be helpful in diagnosing a pigmented basal cell carcinoma. Often typical criteria, such as gray-blue ovoid nests and globules, maple leaf-like areas, spoke-wheel structure, ulceration and arborizing vessels, are present.

IV.7.5 Histopathology The histology of lentigo maligna is characterized by an increased number of atypical melanocytes in the basal epidermis, which are arranged as single cells or in small nests. The

lesion is poorly circumscribed and periadnexal extension is common [1]. There is no downward invasion into the underlying dermis. Solar damage is always noted as evidenced by atrophic epidermis, with effacement of rete ridges, and by marked underlying dermal elastosis. In lentigo maligna melanoma an invasion of the underlying dermis can be seen.

IV.7.6 Management Surgical excision is the treatment of choice for lentigo maligna and lentigo maligna melanoma to obtain clinical and histological clearance [4]. There are three surgical options including conventional surgery, staged surgery and Mohs micrographic surgery. In conventional surgery the recommended margins for lentigo maligna are 0.5 cm, the same as for in-situ melanoma [5]. The surgical margins for lentigo maligna melanoma are in principle the same as for invasive melanoma (1 cm for lesions up to 2 mm in thickness, 2 cmmargins for tumor thickness >2 mm) [6], but the margin of excision can be limited on the face to obtain acceptable cosmetic results. Because histological margins can extend beyond the clinically visible lesion, routinely wider margins sometimes might be necessary. Nevertheless, aggressive surgical management is not always considered appropriate on the head and neck, where there may be considerable cosmetic con-

Melanoma of the Face

straints. To ensure complete clearance and best cosmetic results with the smallest margin possible, excision with 3D histology is used. It allows confirmation of negative margins with delayed repair or, in case of Mohs micrographic surgery, completion in a single patient visit. Studies have shown a high cure rate with surgery followed by a careful histological work-up in all directions compared with other treatment modalities [7, 8]. Other treatment options for lentigo maligna include cryotherapy, radiotherapy, azelaic acid, laser therapy or imiquimod. Liquid nitrogen cryotherapy is reported to be as effective as conventional surgery as long as treatment times are sufficiently long [9]. It is recommended for use in elderly or ill patients. A major disadvantage is that is does not allow assessment of whether the lesion has been completely destroyed. Superficial X-ray therapy for lentigo maligna is also convenient and well tolerated, but there are significant time and cost considerations. Clearance rates are comparable to those of conservative surgery and cryotherapy, but possible subclinical disease may be left untreated [10]. The suggested mechanism of action of azelaic acid 20% cream or 15–35% ointment is selective cytotoxicity for abnormal melanocytes by reversible inhibition of tyrosinase and inhibition of mitochondrial enzymes. It has to be applied twice daily for 2 weeks to 12 months, depending on response. Studies on the use of topical azelaic acid have reported variable results [11, 12]. Nevertheless, this convenient and well-tolerated therapy may be worth considering in patients who are unable or unwilling to undergo surgery, or in those with serious coexisting disease. Although there have been some encouraging results with use of various lasers (Argon, CO2, Ruby, Q-switched Neodymium:Yttrium-Aluminium-Garnet) in the treatment of lentigo maligna, there are insufficient data to support the routine use of this approach [13]. The immune response modifier imiquimod is licensed for the treatment of external genital warts and superficial basal cell carcinomas. Successful treatment of lentigo maligna was first reported by Ahmed and Berth-Jones in 2000 [14]. Since then, there have been larger studies

Chapter IV.7

with promising results, although there is confusion about which treatment strategy offers the best results with few complications [15, 16]. Treatment has been used daily for 6 weeks or 3 months, and five times weekly for 9 months. Local effects, such as erythema and crusting, are frequent. Further studies are necessary to identify ideal treatment protocols. The major limitation of all these non-surgical procedures is that the whole specimen is never examined histologically, and so invasive malignancy may be missed. In every case the advantages and disadvantages of various treatment options should be considered and therapy should be tailored to the patient.

IV.7.7 Case Study A 40-year-old woman presented with a brown lesion on the right cheek. The lesion existed for many years and did not change in color or size. The patient has the skin phototype II.



U. Weigert, W. Stolz

The diameter of the lesion was 8 mm. Dermatoscopically, asymmetrical pigmented follicular openings in the upper part of the lesion could be detected. Lentigo senilis and lentigo maligna have to be taken into account as differential diagnoses. The correct diagnosis was lentigo maligna and the management was excision.


Core Messages ■ Lentigo maligna and lentigo maligna melanoma are found on chronically light-exposed skin, mostly on the face of the elderly. ■ Lentigo maligna melanoma is characterized by invasion into the dermis. ■ Dermoscopic criteria for lentigo maligna include asymmetrical pigmented follicular openings, and slategrey aggregated dots around the hair follicles proceeding to dark-brown or black streaks. ■ Differential diagnoses include lentigo senilis (flat seborrhoeic keratosis), pigmented actinic keratosis and pigmented basal cell carcinoma. ■ Surgery is the treatment of choice for lentigo maligna and lentigo maligna melanoma. Other treatment modalities for lentigo maligna include cryotherapy, radiotherapy, azelaic acid and imiquimod.


References   1. Arlette JP, Trotter MJ, Trotter T, Temple CL. Management of lentigo maligna and lentigo maligna melanoma: seminars in surgical oncology. J Surg Oncol 2004; 86:179–186   2. Schiffner R, Schiffner-Rohe J, Vogt T, et al. Improvement of early recognition of lentigo maligna using dermatoscopy. J Am Acad Dermatol 2000; 42:25–32

  3. Stolz W, Braun-Falco O, Bilek P, Burgdorf WHC, Landthaler M. Colour atlas of dermatoscopy, 2nd edn. Blackwell, London, 2002   4. Mahendran R, Newton-Bishop JA. Survey of UK current practice in the treatment of lentigo maligna. Br J Dermatol 2001; 144:71–76   5. National Institute of Health Consensus Conference. Diagnosis and treatment of early melanoma. NIH Consensus development panel on early melanoma. J Am Med Assoc 1992; 268:1314–1319   6. Balch CM, Soong S, Smith T, et al. Long-term results of a prospective surgical trial comparing 2cm vs 4cm excision with margins for intermediate-thickness melanomas. Ann Surg Oncol 2001; 8:101–108   7. Bub JL, Berg D, Slee A, et al. Management of lentigo maligna nd lentigo maligna melanoma with staged excision: a 5-year follow-up. Arch Dermatol 2004; 140:552–558   8. Cohen LM, McCall MW, Zax RH. Mohs micrographic surgery for lentigo maligna melanoma: a follow-up study. Dermatol Surg 1998; 24:673–677   9. Collins P, Rogers S, Goggin M, et al. Cryotherapy of lentigo maligna. Clin Exp Dermatol 1991; 16:433– 435 10. Farshad A, Burg G, Panizzon R, et al. A retrospective study of 150 patients with lentigo maligna and lentigo maligna melanoma and the efficacy of radiotherapy using Grenz or soft X-rays. Br J Dermatol 2002; 146:1042–1046 11. Prieto MAR, Lopez PM, Gonzalez IR, et al. Treatment of lentigo maligna with azelaic acid. Int J Dermatol 1993; 32:353–364 12. Doherty VR. Azelaic acid in lentigo maligna. Br J Dermatol 1987; 116:606 13. Iyer S, Goldman M. Treatment of lentigo maligna with combination laser therapy: recurrence at 8 months after initial resolution. J Cosmet Laser Ther 2003; 5:49–52 14. Ahmed I, Berth-Jones J. Imiquimod: a novel treatment for lentigo maligna. Br J Dermatol 2000; 143:843–845 15. Naylor MF, Crowson N, Kuwahara R, et al. Treatment of lentigo maligna with topical imiquimod. Br J Dermatol 2003; 149 (Suppl):66–70 16. Powell AM, Russell-Jones R, Barlow RJ. Topical imiquimod immunotherapy in the management of lentigo maligna. Clin Exp Dermatol 2004; 29:15–21

Chapter IV.8

Melanoma of the Trunk and Limbs Including Superficial and Nodular Melanoma


Josep Malvehy and Susana Puig

Contents IV.8.1

Definition. . . . . . . . . . . . . . . . . . . . . . . . 238

IV.8.2 IV.8.2.1 IV.8.2.2

Clinical Features. . . . . . . . . . . . . . . . . . 238 Clinical Symptoms. . . . . . . . . . . . . . . . 237 Clinical Signs. . . . . . . . . . . . . . . . . . . . . 238

IV.8.3 IV.8.3.1

Superficial Spreading Melanoma. . . . 239 Borders in Superficial Spreading Melanoma. . . . . . . . . . . . . . . . . . . . . . . . 240


Nodular Melanoma. . . . . . . . . . . . . . . . 243


Dermoscopic Criteria. . . . . . . . . . . . . . 243


Methods for the Dermoscopic Diagnosis of Melanoma. . . . . . . . . . . . 244


Colors in Melanoma by Dermoscopy. . . . . . . . . . . . . . . . . . . . . . 244


Symmetry and Asymmetry in Melanoma by Dermoscopy. . . . . . . 244


Global Patterns in SSM and Nodular Melanoma. . . . . . . . . . . . 244

IV.8.10 IV.8.10.1 IV.8.10.2 IV.8.10.3

Dermoscopic Findings in SSM. . . . . . 244 Pigment Network . . . . . . . . . . . . . . . . . 244 Globules and Dots. . . . . . . . . . . . . . . . . 244 Structureless (Homogeneous) Areas/Blotches. . . . . . . . . . . . . . . . . . . . 245 Blue-White Veil. . . . . . . . . . . . . . . . . . . 245 Streaks. . . . . . . . . . . . . . . . . . . . . . . . . . . 245 Negative Pigment Network. . . . . . . . . 245 Regression Areas. . . . . . . . . . . . . . . . . . 245 Vascular Structures. . . . . . . . . . . . . . . . 245

IV.8.10.4 IV.8.10.5 IV.8.10.6 IV.8.10.7 IV.8.10.8 IV.8.11 IV.8.11.1

Dermoscopic Findings in Nodular Melanoma . . . . . . . . . . . . . 245 Additional Preoperative Information Obtained by Dermoscopy. . . . . . . . . . 246


Relevant Clinical Differential Diagnoses. . . . . . . . . . . . . . . . . . . . . . . . 246

IV.8.13 IV.8.13.1

Differential Diagnosis . . . . . . . . . . . . . 246 Differential Diagnosis in SSM. . . . . . .246

IV. IV. IV. IV. IV. IV.8.13.2

Melanocytic Nevi . . . . . . . . . . . . . . . . . 246 Pigmented Basal Cell Carcinoma. . . . 246 Pigmented Actinic Keratosis/ Bowenâ&#x20AC;&#x2122;s Disease. . . . . . . . . . . . . . . . . . . 246 Seborrheic Keratosis. . . . . . . . . . . . . . . 247 Dermatofibroma. . . . . . . . . . . . . . . . . . 247


Differential Diagnosis in Nodular Melanoma . . . . . . . . . . . . . 247 Spitz Nevus. . . . . . . . . . . . . . . . . . . . . . . 247 Blue Nevus. . . . . . . . . . . . . . . . . . . . . . . 247 Basal Cell Carcinoma. . . . . . . . . . . . . . 247 Clear-Cell Acanthoma. . . . . . . . . . . . . 247 Merkel Cell Carcinoma . . . . . . . . . . . . 247 Bednar Tumor. . . . . . . . . . . . . . . . . . . . 247 Atypical Fibroxantoma . . . . . . . . . . . . 247 Malignant Tumors of the Breast. . . . . 248 Hemangioma. . . . . . . . . . . . . . . . . . . . . 248 Angiokeratoma . . . . . . . . . . . . . . . . . . . 248 Dermatofibroma. . . . . . . . . . . . . . . . . . 248 Seborrheic Keratosis. . . . . . . . . . . . . . . 248 Pyogenic Granuloma . . . . . . . . . . . . . . 248

IV.8.14 IV.8.14.1 IV.8.14.2

Histopathology . . . . . . . . . . . . . . . . . . . 248 Radial Growth Phase. . . . . . . . . . . . . . 248 Vertical Growth Phase. . . . . . . . . . . . . 249

IV.8.15 IV.8.15.1

Management . . . . . . . . . . . . . . . . . . . . . 250 Melanoma Screening and Identification of High-Risk Persons . . . . . . . . . . . . . . . . . . . . . . . . . . 250 Clinical History. . . . . . . . . . . . . . . . . . . 251 Physical Examination. . . . . . . . . . . . . . 251 Examination of Lymph Nodes. . . . . . 251

IV.8.15.2 IV.8.15.3 IV. IV.8.16 IV.8.16.1 IV.8.16.2

Staging and Treatment of Primary Melanoma . . . . . . . . . . . . . 252 Surgical Excision of the Tumor . . . . . 252 Sentinel Node Biopsy. . . . . . . . . . . . . . 252


Treatment of Distant Disease. . . . . . . 253


Case Study . . . . . . . . . . . . . . . . . . . . . . . 254

References. . . . . . . . . . . . . . . . . . . . . . . . 256


J. Malvehy, S. Puig

IV.8.1 Definition


Superficial and nodular melanoma of the trunk and limbs are the most frequent melanoma subtypes in Caucasians, and are largely responsible for the increased incidence of melanoma noted over the past few decades [1, 2]. Superficial spreading melanoma (SSM) is defined as an invasive melanoma that has an in-situ component beyond three rete ridges of its invasive component at the dermal layer. The radial growth phase of SSM is characterized by invasion of tumor cells both singly and in nests upward within the epidermis (pagetoid spread). In the natural progression of the neoplasm the melanoma will progress from the radial growth phase to the vertical growth phase. The SSM may arise in a preexisting nevus or de novo, and although a predilection for the trunk (the back of men) and limbs in women is documented, SSM can certainly develop at any site on the body [3, 4]. Nodular melanoma is the second most common type of melanoma. Epidemiologically it is most commonly seen in elderly men but can occur at any age and in both sexes [1, 2]. By definition, nodular melanoma arises in normal skin or in a precursor lesion, but without an intervening radial growth phase. A widely accepted histopathological definition of nodular melanoma is a melanoma that lacks an in-situ component beyond three rete ridges of the invasive vertical growth phase; thus, nodular melanoma, even in its early stages, has the potential to metastasize [2–4]. While they represent only about 15% of invasive melanomas in Caucasian population, thick melanomas with a poor prognosis are predominantly nodular melanomas [2]. The classification of melanoma by subtype is based primarily on anatomical, epidemiological, and pattern of progression information; however, recent research has shown that there may also be molecular and genetic differences between melanoma subtypes [5, 6]. These differences may explain the difference in the natural evolution of melanoma subtypes. Furthermore, our understanding of this written message in the tumor cell’s DNA may play a principal roll in the therapeutic strategy and prognosis in the near future.

IV.8.2 Clinical Features IV.8.2.1 Clinical Symptoms The mean age at diagnosis of SSM is 51 years, which is one or two decades earlier than that for lentigo maligna melanoma and acral lentiginous melanoma [2]. Patients with SSM often report a pre-existing, relatively stable pigmented lesion at the site which has been present for many years; however, this lesion then undergoes rapid change or develops symptoms, thus prompting the patient to seek medical advice. This pre-existing tumor may correspond to a pre-existing melanocytic nevus or early stages of superficial spreading melanoma. Some SSM can also be symptomatic producing symptoms of itching and pain; however, these symptoms are not specific for melanoma since many benign and malignant skin tumors can present with similar symptoms. In contrast to SSM, nodular melanoma exhibits rapid vertical growth, making it difficult to detect during early phases of tumorigenesis. By the time of presentation many nodular melanoma are deep and ulcerated tumors [7].

IV.8.2.2 Clinical Signs Several mnemonics for the macroscopic findings of melanoma have been developed to help individuals recognize melanoma; these include the ABCD/ABCDE rules [8, 9] (Asymmetry: one half of the lesion does not mirror the other half in shape or in color distribution; Border irregularity: the lesion tends to have an indented and jagged outline; Color variegation: the surface is multicolored and may include shades of tan, brown, blue-black, gray-white, and other variations; Diameter: generally greater than 6 mm, although some melanomas are smaller; Enlargement–Evolution: the tumor changes in morphology and size), the three Cs (color, contour, change) [9], and the Glasgow 7-point checklist (change in size, irregular shape, irregular color, diameter at least 7 mm, inflammation, oozing/bleeding, sensation) [10, 11]. The features described in the above mnemonic apply mainly to superficial spreading melanoma but

Melanoma of the Trunk

can also be seen in benign melanocytic lesions such as atypical nevi. In fact, dysplastic nevi often manifest some or all of the features of SSM, thus making their differentiation from melanoma, on clinical grounds, difficult to impossible. In nodular melanoma most of the criteria of the mnemonics, with the exception of change, fail because these tumors are often small, round shaped, symmetric, and with regular borders [12, 13].

IV.8.3 Superficial Spreading Melanoma The fact that superficial spreading melanomas often manifest the ABCD features can be ex-

Fig. IV.8.1.  Two faces of superficial spreading melanoma. The lesions were detected in the first visit of a 27year-old man consulting for atypical mole syndrome. Clinical examination revealed multiple atypical melanocytic lesions on the trunk and extremities. Two lesions were considered for excision because of the suspicious appearance by clinical and dermoscopic examination (see also Fig. IV.8.2). The lesion on the right side (12¥8 mm) located on the back was slightly palpable with subtle erythema in the center and brown to grayish pigmentation. The shape was rounded and discrete irregularity with indentation in the borders was found. The surface did not exhibit nodules or ulceration. Adnexal appendages were conserved. The histological analyses demonstrated a superficial spreading in-situ melanoma with marked regression. The lesion located on external side of the right

Chapter IV.8

plained by the heterogeneity of different clones of cells, with differences in degree of pigmentation, depth, and inflammatory changes induced by the host. The presence of multiple colors is important in helping clinicians to recognize melanoma, in particular SSM (Fig. IV.8.1, Fig. IV.8.2). While a black or blue/black color is the most well-known color, many shades of brown, blue, red, gray or white can also be seen. A narrow rim of red or white can sometimes be seen around the edge of the lesions caused by lymphangitis or regression, respectively. It is important to note that amelanotic or hypomelanotic melanoma will have little or no distinguishing color. These lesions are often pink in color [14].

thigh was smaller (5 mm) and lightly palpable. The presence of erythema and subtle light brown pigmentation at the periphery with irregular borders that fade were observed. Histopathological examination revealed a superficial spreading melanoma, Clark II, Breslow thickness 0.9 mm, with severe regression. The thicker tumor was the smaller and less pigmented of the lesions. The recognition of “ugly duckling sign” (right lesion) and the “Red Riding Hood sign” (lesions on the left side) may be useful in patients with atypical mole syndrome. Nevertheless, the use of complementary tools, such as dermoscopy or the follow-up with total-body photography and digital dermoscopy (see Fig. IV.8.2), allows the identification of instability in atypical lesions that leads to early detection of melanoma in these patients.



J. Malvehy, S. Puig


Fig. IV.8.2.  Dermoscopy of the lesions of Fig. IV.8.1. Left side: superficial spreading melanoma (Breslow 0.9 mm, Clark II with regression). Dermoscopy reveals asymmetry and remnants of light-brown pigment at the periphery (insets). Signs of melanocytic tumor with a typical pigment network and erythema and atypical vascularization

IV.8.3.1 Borders in Superficial Spreading Melanoma Irregularity of outline is the second most common feature of superficial spreading melanomas. They, in contrast to benign nevi, tend to have an abrupt edge between lesional and surrounding normal skin. If a pre-existing nevus or regression are associated in SSM, then ill-defined borders may be noted. In some SSM, as a result of partial regression of the tumor, normal-appearing skin can be seen between islands of tumor. In these cases a detailed description of the tumor, and perhaps even the provision of drawings or images, will help both the pathologist and surgeon in determining the accurate pathological diagnosis and treatment options. It is important to distinguish regression areas resulting in tumor “islands” from satellitosis, since the prognosis for the latter is completely different. The Wood’s light can often help distinguish between regression and satellite metastasis.

at the center are visible. Right side: superficial melanoma (in situ). Dermoscopy reveals an asymmetric tumor with multiple colors (dark and light brown, red and bluish to gray). Small grayish dots in a pepper-like pattern (inset) suggest intense regression with melanophagia.

Irregularity of the surface is another important sign in melanoma. The texture of the surface of the tumor and the skin marking, mostly in early tumors, may be similar to that of normal skin; however, in advanced melanoma the normal skin markings tend to disappear. Furthermore, the presence of hairs does not exclude melanoma, since in early SSM the follicles and adnexal appendages are still preserved. The characteristics of hair shafts may be similar to the adjacent skin or look like hamartomatous terminal hair seen in congenital nevi. In contrast, in deep tumors the hair follicles tend to be destroyed. A characteristic feature of SSM is a “groundglass” amorphous appearance to part of the lesion. Where the skin lines have been destroyed by the tumor, a shiny, glassy appearance is observed. Many melanomas also have small flakes of keratin on the surface, but it is extremely rare for the lesion to be extensively keratinized such as in the melanomas that resemble seborrheic keratosis.

Melanoma of the Trunk

Chapter IV.8

Fig. IV.8.3.  Superficial spreading melanoma on the back of a 70-year-old patient with severe actinic damaged skin. The tumor (6 mm) located on the upper trunk was slightly palpable with irregular borders and multiple colors: pink; brownish; black; and bluish to whitish. The surface of the tumor was slightly palpable without nodulation, homogeneous in some parts with loss of skin marks, and some follicles were present. Ulceration was not observed. Dermoscopy revealed an asymmetric melanocytic tumor with multicomponent pattern exhibiting multiples colors: white; grayish; blue; red/dark brown; and black. Atypical broadened network, irregular blotches, atypical dots and globules, and streaks (pseudopods) at the periphery were detected. In addition, marked regression is evidenced by homogeneous whitish areas with blue to grayish dots and subtle erythema in the flat part of the lesion.

The surface of SSM can be macular or be macular with areas of elevated papules. In thick tumor, nodules can arise within relatively flat areas corresponding to the superficial spreading part of the tumor. In rare instances SSM presents a verrucous surface, in which case differentiation from seborrheic keratosis may be difficult. Ulceration is commonly seen when the SSM progresses to the vertical growth phase with nodules (Fig. IV.8.3, Fig. IV.8.4). Ulceration of the tumor, a well-recognized prognostic factor, can be seen in the ­ clinical examination as a hemorrhagic crust or eroded area. This important finding is more frequently seen in nodular parts of SSM and this finding is rare in melanomas less that 1 mm of Breslow depth [80]. In tumors that are ulcerated the patient often reports a history of bleeding, although this is not a consistent finding. In addition, the absence of ulceration or bleeding by history or clinical examination does not predict its presence or absence under histopathology.

The phenomenon of regression is commonly seen in SSM and clinically it can be identified as a macule or slightly palpable plaque that shows a spectrum of pigmentation with light brown, pink, and shades of gray due to melanophages. Some SSM can undergo complete regression and culminating in a white patch corresponding to fibrosis. In areas with prominent fibrosis a tone of pink coloration and small vessels may be visible due to the neoangiogenesis associated with regression. If the SSM regresses completely, it can be impossible to identify the site of the primary melanoma. This phenomenon explains, at least for some of the cases, the presence of metastatic melanoma without a known primary. At the time of diagnosis most SSM have a diameter greater than 6 mm. However, it is not uncommon to encounter SSM that have a smaller diameter; thus, it is important to remember the “E” in the ABCDE mnemonic. Any melanocytic lesion, irrespective of its size, that is undergoing change should be viewed with caution.



J. Malvehy, S. Puig


Fig. IV.8.4.  Ulcerated superficial spreading melanoma arising on a congenital nevus (Clark IV, Breslow 2.8 mm) in a 34-year-old man. The lesion was located on the back of the patient. Dermoscopy of the tumor exhibits asymmetry, multiple colors, and two areas with radial growth phase and ulcerated nodule with blue-whitish veil and

atypical vessels. Regression structures (blue-gray dots) were distinguished in combination with atypical pigmented network, atypical dots/globules, and irregular blotches corresponding to the peripheral thinner part of the tumor.

Fig. IV.8.5.  Two faces of nodular melanoma. Left side: amelanotic ulcerated nodular melanoma (Breslow 10 mm, Clark V) on the right groin of a 44-year-old man. The patient referred a rapid increase in size with bleeding of a tumor. On the inguinal fold lymph node multiple metastases were detected by palpation. The clinical examination revealed an ulcerated nodular tumor with

peripheral verrucous expansion (upper side). Right side: pigmented nodular melanoma in a 55-year-old man (Breslow 3.31 mm, Clark IV) located on the trunk. Note the symmetry of the lesion with homogeneous pigmentation. The surface is polylobulated with some follicles. At the periphery a bluish small lesion corresponding to satellite tumor is observed.

Melanoma of the Trunk

Fig. IV.8.6.  Nodular melanoma with histological ulceration on the trunk of a 62-year-old woman (Clark III, Breslow 2.01 mm). The patient reported progressive increase in size over a period of several months without bleeding. Examination revealed a 7-mm symmetric tumor with reddish, pink, and bluish coloration at the center. The surface of the tumor was slightly scaling without

IV.8.4 Nodular Melanoma Nodular melanoma, by definition, arises without an apparent precursor radial growth phase. Indeed, the clinical aspect of this type of melanoma is similar to the tumorigenic areas of other variants including SSM. Nodular melanoma starts with an expanding papule that increases in size quite rapidly and typically the ABCD criteria do not apply to the tumor nodule itself, which is commonly symmetrical with smooth borders [15, 16]. The color is often quite homogeneous compared with SSM and may be pink or reddish rather than black, bluish, or brown, and sometimes the surface of the tumor is shiny (Fig. IV.8.5, Fig. IV.8.6); however, nodular melanoma can be hypochromic or amelanotic. If the tumor is amelanotic, then striking vascularization is usually evident with a red or pink surface. Diameter is usually smaller than SSM and it can be less than 6 mm even in thick tumors. For

Chapter IV.8

adnexal structures. Dermoscopy exhibits an asymmetric tumor with multiple colors (red, pink, blue to grey, and white). A bluish and whitish veil, some remnants of brownish pigment in the center, and atypical vascularization with irregular polymorphous and irregular hairpin vessels are distinguished.

all these reasons, diagnosis of nodular melanoma may be subtle and misdiagnosis or incorrect treatment at the first consultation is not infrequent. Lesional evolution or change has also been demonstrated to be a significant warning sign for nodular melanoma. In a study of 92 patients with nodular melanoma, 71% of patients noted evolution of their lesions [15].

IV.8.5 Dermoscopic Criteria Dermoscopy constitutes a bridge between the clinical examination with naked eye and histopathology [17–22]. In cases in which melanoma is difficult to diagnose, the attention of the histopathologist should be directed to the areas of highest diagnostic relevance based on dermoscopic findings [22–25]. Furthermore, sampling error can be minimized if the step-sectioning of the excised specimen is based on dermoscopic findings.



J. Malvehy, S. Puig

IV.8.6 Methods for the Dermoscopic Diagnosis of Melanoma


In the dermoscopic evaluation of a skin tumor the algorithm of “The two-step method” is utilized [17]. The first step differentiates melanocytic from non-melanocytic tumors. The second step classifies melanocytic lesions into benign and malignant (see also Differential Diagnosis). If a skin tumor is considered melanocytic, then different dermoscopic methods for the classification of benign, suspicious, and malignant tumors are used, including “pattern analyses” [17, 26, 27], “ABCD” [28], ABCDE rule” [29], “Menzies method” [30], “7-point checklist” [31], and ABC-point list [32]. Novice dermoscopists may find the ABCD rule, Menzies method and 7-point checklist most helpful; however, experienced dermoscopists usually rely on pattern recognition to help differentiate between benign nevi and melanoma [17]. For SSM and nodular melanoma we describe the main criteria under dermoscopy as global patterns and local features [17, 26].

IV.8.7 Colors in Melanoma by Dermoscopy With dermoscopy colors are distinguished more accurately. Melanocytic tumors may display one or more of the following colors by dermoscopy: light brown; dark brown; gray; black; red; white; and blue.

IV.8.8 Symmetry and Asymmetry in Melanoma by Dermoscopy In contrast to the clinical definition of asymmetry, which includes the shape/silhouette of the lesion, in dermoscopy the symmetry is determined by the distribution of dermoscopic structures and colors within the lesion, and this is independent of the shape of the tumor. In general, benign lesions have dermoscopic structures and colors distributed symmetrically and melanomas have them distributed asymmetrically.

IV.8.9 Global Patterns in SSM and Nodular Melanoma In superficial spreading melanoma different global patterns can be observed (see Chap. I.3): reticular (a network of pigment); globular (aggregation of globules); and multicomponent (the combination of three or more dermoscopic structures such as pigment network, globules, structureless areas, and streaks, which are ­distributed asymmetrically). Some SSM may exhibit a “starburst pattern” (multiple linear ­ extensions in a radial arrangement at the periphery), but this is considered characteristic of spitzoid lesions [33]. In nodular melanoma reticulation is not seen because they lack an in-situ component. In this type of melanoma the dermoscopic patterns may be globular, homogeneous (structureless bluish to black homogeneous pigment covering the entire lesion), or multicomponent pattern [34]. If a tumor cannot be categorized with the above-mentioned patterns, then the “non-specific pattern” is considered and in this case a clear diagnosis cannot be made. A non-specific pattern can be found in melanoma, and therefore these lesions should be excised [17].

IV.8.10 Dermoscopic Findings in SSM IV.8.10.1 Pigment Network A pigment network is present in over 50% of superficial melanomas. Pigment network tends to be atypical with irregular holes (wide and small), thick lines, and abrupt cut-off at the periphery. The atypical pigment network is not totally specific of melanoma since it can also be seen in atypical nevi, and likewise some early melanomas may exhibit this feature at the beginning. The term “branched streaks” corresponds to network fragments resulting from a broken-up pigment network.

IV.8.10.2 Globules and Dots Globules and dots correspond to nests of melanoma cells with different depths. In melanoma globules tend to be irregular in size, color, and

Melanoma of the Trunk

distribution. Dots may be black, brown, or bluish. Peripheral black dots/globules represent malignant melanocytes found at or near the stratum corneum. The term “multiple brown dots” correlates with suprabasal epidermal malignant melanocytes and represents the pagetoid spread of an SSM. When bluish or grayish dots are seen, they correspond to melanin in the dermis due to regression (melanophages) or tumoral cells.

IV.8.10.3 Structureless (Homogeneous) Areas/Blotches Structureless areas/blotches can be defined as regions devoid of structures and without signs of regression. These areas can be pigmented or hypopigmented; however, if the area is dark brown or black in color, it is called a “blotch.” In melanoma these homogeneous areas are irregularly distributed and variegated in shape and size. A blotch usually does not encompass the entire lesion. (It is noteworthy that all blotches are structureless, but not all structureless areas are blotches.)

Chapter IV.8

the term “starburst pattern” is used. Radial streaming corresponds to linear extensions at the edge of the lesion, whereas pseudopods are brown-black, finger-like projections emanating from the perimeter of the lesion and terminating in knob-like projections.

IV.8.10.6 Negative Pigment Network Negative pigment network represents elongated hypomelanotic rete ridges. It is seen in many Spitz nevi; however, the negative pigment network is also a highly specific feature of invasive melanoma and can be seen in some dysplastic nevi [35].

IV.8.10.7 Regression Areas Regression areas are white, scar-like depigmentation often combined with blue-gray color and/ or peppering (speckled blue-gray granules). Peppering consists of tiny, blue-gray granules of melanin.

IV.8.10.8 Vascular Structures IV.8.10.4 Blue-White Veil Blue-white veil, an important feature, is a highrisk criterion for melanoma. It has been defined as an irregular, structureless area of confluent blue pigmentation with an overlying white “ground-glass” film. The blue-white veil occupies the elevated parts of a nodular melanocytic lesion. Histopathologically this corresponds to compact orthokeratosis, acanthosis, and hypergranulosis of the epidermis, and the presence of a compact aggregation of pigmented malignant cells in the papillary dermis. It is a specific criterion for melanoma; however, a blue-whitish veil can also be observed in Spitz nevi.

IV.8.10.5 Streaks “Streaks” is an alternate term for radial streaming and/or pseudopods. When symmetrically arranged around the entire edge of the lesion,

Vascular structures are seen in melanoma because of the angiogenesis and regression. Some dermoscopic findings caused by vascularization have been described in melanoma such as milky red areas (red-pink whitish veil resulting from increased vascularity), irregular hairpin vessels, dotted vessels, and irregular polymorphous vessels [36, 37].

IV.8.11 D  ermoscopic Findings in Nodular Melanoma Dermoscopy of nodular melanoma is difficult since the asymmetry of pattern is less marked than in SSM [34]. Nevertheless, irregularity in colors is usually present in pigmented nodular melanoma. In nodular melanoma many of the “classic” dermoscopic features of SSM are observed much less commonly. Specifically those dermoscopic structures that correspond to the radial phase or




J. Malvehy, S. Puig

flat parts of the SSM are absent in nodular melanoma: pseudopods; radial streaming; regression structures; and atypical brown dots (see above). Pigment network is absent in nodular melanoma with the exception of the presence of contiguous melanocytic nevus or melanocytic hyperplasia; however, nodular melanomas often display dermoscopic findings associated with deep tumors such as multiple colors, blue-white veil, and atypical vessels due to angiogenesis. In the case of amelanotic or hypopigmented nodular melanoma the vascularization and remnants of pigment are the most important clues (see Chap. IV.3) [14].

IV.8.11.1 Additional Preoperative Information Obtained by Dermoscopy Dermoscopy, due to the fact that it represents a bridge between the clinical examination and pathological examination, can aid in determining tumor thickness, thereby guiding surgery [38, 39]. The presence of pigment network corresponds to melanocytic hyperplasia and represents the radial growth phase. In contrast, bluewhitish veil or atypical vessels in a palpable area of the tumor corresponds to thick tumors with nests in dermis and neoangiogenesis, respectively. Algorithms based on dermoscopy, clinical observation, and/or sonography have been proposed for the preoperative evaluation of melanoma thickness [40]. If these methods are determined to be accurate, they could prove to be very useful in planning surgical treatment.

IV.8.12 Relevant Clinical Differential Diagnoses Superficial spreading melanoma and nodular melanoma may be difficult to differentiate from other melanocytic tumors. During the early stages, SSM may be similar to benign atypical nevi. Moreover, when melanoma is atypical in appearance, even in nodular tumors such as in the case of amelanotic melanoma, the preoperative differential diagnosis can be extremely difficult or even impossible.

IV.8.13 Differential Diagnosis A wide range of tumors may mimic melanoma, and vice versa [41–43].

IV.8.13.1 Differential Diagnosis in SSM IV. Melanocytic Nevi Melanocytic nevi is the most important category since dysplastic nevi are the most important simulators of SSM. Melanocytic nevi may resemble SSM, because they may exhibit asymmetry, irregularity of borders, multiple colors, and a large diameter. In addition, these benign tumors may present some features seen in SSM such as multicomponent pattern, atypical network, regression, or atypical globules. In the case of banal melanocytic tumors, the presence of inflammation, regression, trauma, or surgical scar (recurrent nevus–pseudomelanoma) may modify the lesion and make it look like a melanoma.

IV. Pigmented Basal Cell Carcinoma Pigmented basal cell carcinoma (BCC), due to the presence of melanin, can be pigmented with blue, brown, or black coloration. The intense vascularization and tendency to early ulceration are commonly seen. In these tumors the observation of specific dermoscopic criteria for BCC can help render the correct diagnosis (see Chap. V.1) [44].

IV. Pigmented Actinic Keratosis/ Bowen’s Disease With regard to squamous cell carcinoma, in rare cases the clinical appearance can mimic melanoma. The dermoscopic presence of melanocytic criteria and specific features for melanoma are usually absent (see Chap. V.5) [45– 47].

Melanoma of the Trunk

IV. Seborrheic Keratosis Some seborrheic keratosis may mimic SSM because of their intense pigmentation and red color, as is seen in irritated lesions [48–51]. Dermoscopy, however, usually reveals specific criteria for non-melanocytic tumors such as fissure and crypts, hairpin vessels, follicular openings, and milia-like cysts. Some rare seborrheic keratoses may exhibit a reticulation that may resemble pigmented network in SSM and some cases of melanomas present equivocal features by dermoscopy such as follicular openings, fissures and crypts, or intense hyperkeratosis . In these cases clinical clues, such as intense pigmentation, bluish coloration, or atypical evolution, may give the clue for the diagnosis (see Chap. V.7).

IV. Dermatofibroma Clinically, some dermatofibroma may resemble SSM. The clinical history of the tumor, the presence of the “dimple sign” upon lateral compression, and the observation of the typical dermoscopic central white patch and peripheral delicate reticulation may be useful in difficult cases (see Chap. V.2). Some recent studies have described the dermoscopic findings in atypical dermatofibromas, such as aneurysmatic variants, which can be a diagnostic challenge [52– 53].

IV.8.13.2 Differential Diagnosis in Nodular Melanoma

Chapter IV.8

static melanoma. In these cases the clinical context will provide the correct answer (see Chap. III.4).

IV. Basal Cell Carcinoma In nodular pigmented BCC the differential diagnosis includes nodular melanoma. Dermoscopy of these BCC usually reveals typical arborizing vessels and other criteria that allow for the correct diagnosis (see Chap. V.1).

IV. Clear-Cell Acanthoma This rare tumor may mimic hypopigmented nodular melanoma. In the case of clear-cell acanthoma, dermoscopy shows a characteristic vascular pattern with vessels arranged as a “string of pearls” [54–56].

IV. Merkel Cell Carcinoma Merkel cell carcinoma, a malignant tumor, is seen in elderly patients mainly on the head and neck. Its clinical evolution is similar to an amelanotic nodular melanoma with the rapid growth of a pink to reddish nodule [57].

IV. Bednar Tumor The pigmented dermatofibrosarcoma protuberans is an unusual tumor that presents as a pigmented plaque with progressive development of nodules [58].

IV. Spitz Nevus Pigmented Spitz nevus can mimic nodular melanoma of the amelanotic type. In these cases the excision and histopathological examination of the lesion is mandatory (see Chap. III.16).

IV. Blue Nevus Clinically and dermoscopically a blue nevus may be identical to nodular melanoma or meta-

IV. Atypical Fibroxantoma Atypical fibroxantoma is usually seen in exposed areas of the body, mainly in the head of elderly patients and less frequently in the trunk. With its reddish to brownish coloration and nodular features the atypical fibroxantoma may mimic a thick melanoma [59].



J. Malvehy, S. Puig

IV. Malignant Tumors of the Breast A few cases of malignant tumors of the breast with skin involvement have been reported to mimic superficial melanoma [60–61].


IV. Hemangioma Some hemangiomas, mainly when they are thrombosed, may mimic nodular melanoma. Dermoscopy can readily differentiate between these tumors and correctly identify hemangiomas due to the absence of melanocytic structures and due to the presence of lacunas.

IV. Angiokeratoma Similar to hemangiomas, angiokeratomas may mimic nodular melanoma by clinical examination with the naked eye. The dermoscopic examination is very specific for these tumors, revealing the characteristic red and black lacunas [62].

IV. Pyogenic Granuloma Clinically and dermoscopically a pyogenic granuloma may be identical to the amelanotic variant of nodular melanoma; therefore, biopsy is recommended for these cases [41].

IV.8.14 Histopathology The histopathology of superficial spreading and nodular melanoma can be explained by the “three-step tumor progression model” [63–65]: 1. Radial growth phase exemplified by melanoma in situ when the tumor is confined above the epidermal basement membrane. 2. The microinvasive radial growth phase is when the melanoma penetrates the basement membrane and is present in the superficial papillary dermis. 3. Melanoma that has invaded into the dermis and has acquired the ability to metastasize, known as the vertical growth phase.

IV. Dermatofibroma In some nodular or atypical dermatofibromas the differential diagnosis may be very difficult and a biopsy has to be taken for histopathological diagnosis. The clinical history of the tumor with a long stable evolution in dermatofibroma helps in this discrimination, but in equivocal cases a biopsy is required for the correct diagnosis [41].

IV. Seborrheic Keratosis Similar to SSM, some cases of acanthotic or clonal seborrheic keratosis may mimic nodular melanoma. Dermoscopy in these cases is very helpful, showing typical hairpin vessels associated with other criteria seen in these benign tumors [50–51]. Benign or malignant adnexal tumors may mimic melanoma. Biopsy is required for the correct diagnosis [41].

IV.8.14.1 Radial Growth Phase Superficial spreading melanoma, by definition, must have a radial growth phase component. The presence of the intraepidermal component, extending more than three rete ridges past the confines of the dermal component, has been proposed as the hallmark of SSM. Initially, the radial growth phase is confined to the epidermis with an “in-situ” component. The atypical melanocytes invade the epidermis from the basal layer, and these cells can be epithelioid or spindle-shaped and tend to manifest little cell-to-cell variability. Four basic patterns of intraepidermal growth have been described: 1. Pagetoid pattern with epithelioid melanoma cells. This is the most frequent form of intraepidermal growth and consists of melanoma cells with abundant quantities of eosinophilic or clear

Melanoma of the Trunk

Chapter IV.8

249 Fig. IV.8.7.  Histological view of superficial spreading melanoma with severe regression (Clark II, Breslow 0.50 mm) on the back of a 31-yearold woman with personal background of atypical mole syndrome. The lesion was detected during follow-up due to regression in clinical and dermatoscopic examination and digital follow-up.

cytoplasm containing melanin granules of variable shape and sizes and round or oval nuclei with thick chromatinic rims and macronucleoli. The epidermis is usually hyperplastic and scattered mitotic figures are present. 2. Contiguous proliferation of single melanoma cells along the dermoepidermal junction in a lentiginous pattern associated with obscuration of basal keratinocytes and effacement of rete ridges. In this pattern the tumoral cells exhibit angulated nuclei that exceed the size of adjacent nuclei of keratinocytes. 3. A pattern of confluent oblong nests of hyperchromatic spindle-shaped cells with variable melanization, distinct nuclear grooves, prominent nuclear chromatinic rims, and eosinophilic nucleoli. 4. The fourth pattern comprises the combination of the aforementioned presentations of intraepidermal invasion. In the absence of regression, radial growth phase melanoma is almost never associated with metastases [66–69] (Fig. IV.8.7).

The concept of microinvasive phase has been introduced and widely used to define a intermediate phase in the model of SSM tumor progression [70, 71]. In the microinvasive tumor one observes within the papillary dermis nested cells with a cytomorphology similar to that of the intraepidermal cells, albeit often with more abundant cytoplasm having an eosinophilic hue. Dermal-based mitosis should not be identified, and the size of the dermal nests should not exceed those found along the dermo-epidermal junction. Lymphocytic infiltration of the adjacent papillary dermis may herald the onset of incipient microinvasive melanoma. Other malignant intraepidermal lesions exhibiting pagetoid spread may mimic melanoma in situ. These lesions include epidermotropic neuroendocrine carcinoma, Paget’s disease, or squamous cell carcinoma in situ. Immunohistochemistry can often help differentiate these tumors from each other [71].

IV.8.14.2 Vertical Growth Phase Clark et al. [64] described the early vertical growth phase and distinguished it from the radial growth phase by criteria that included the presence of a dominant nest within the papil-


J. Malvehy, S. Puig Fig. IV.8.8.  Histological view of non-ulcerated nodular melanoma (Clark III, Breslow 1.67 mm) on the trunk of a 49-year-old woman without personal/familial background of melanoma


lary dermis that is larger than any nest within the epidermis or surrounding dermis and forms a small expansible nodule of a shape distinctive from adjacent nests; it may be round or oblong, but it is typically oriented vertically (i.e., perpendicularly to the long axis of the epidermis) w The atypical cells comprising the nodules are cytologically distinct from those of the intraepidermal component. Whereas the intraepidermal cells are usually epithelioid, those in the vertical growth phase may be spindle, small cell, or epitheloid, suggesting a different clonal proliferation. These cells often show greater cytoplasmatic pigmentation than the intraepidermal cells. The cells in the tumorogenic dermal nests invariably show conspicuous nuclei, coarse chromatin, and irregularly thickened and/or notched nuclear membranes.

IV.8.15 Management IV.8.15.1 Melanoma Screening and Identification of High-Risk Persons A favorable prognosis from melanoma depends on early diagnosis. Efforts at improving early

diagnosis have focused on the identification of patients at high risk for developing this tumor [72, 73]. The genetic basis of melanoma risk have been partially elucidated with the identification of loci associated to the susceptibility to develop melanoma [75]. Furthermore, inherited mutations in the melanocortin-1 receptor gene have been linked to people with red hair, to photosensitivity, and to an increased risk of cutaneous melanoma. Having many melanocytic lesions of the common type or atypical moles is also associated with an increased risk of melanoma. Atypical moles can be precursors to melanoma but are also markers that identify a subgroup at high risk for developing melanoma. Intermittent sun exposure and severe sunburns, especially during childhood, and use of tanning beds, have been associated with an increased risk for melanoma [76]. Patients with personal prior melanoma have an increased risk for developing a second primary melanoma [77, 78]. Patients with a strong family history of melanoma and multiple clinically atypical moles are at the greatest risk for cutaneous melanoma. Inherited mutations in the CDKN2A and CDK4 genes, which have been documented in families with hereditary melanoma and in patients with multiple primary melanoma, confer a 60–90%

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lifetime risk of melanoma. Nevertheless, routine genetic testing for these mutations is not widely recommended [75]. The benefit of mass screening campaigns has been studied in Australia, The Netherlands, and the United States. These campaigns allow the detection of high-risk persons and also some early-stage melanomas; however, mass screening campaigns have not yet demonstrated a direct impact on mortality. Although melanomas detected by physicians are thinner than those recognized by patients, it is strongly recommended that patients perform a monthly skin self-examination, in addition to periodic physician-based examinations, to help detect any new or changing lesion. This is the best strategy for the early detection of melanoma in persons at high risk for developing melanoma such as patients with multiple moles [79].

IV.8.15.2 Clinical History In the management of SSM and nodular melanoma patients a complete clinical history at the first visit prior to physical examination is always required. In the clinical history information of personal and familial risk factors for skin cancer, including sun exposure, should be documented. Personal background is also important to detect associated diseases that may impact the prognosis or treatment [72â&#x20AC;&#x201C;74]. Examination of the family members should be recommended especially if the patient has atypical mole syndrome or there is a familial history of melanoma [74]. Relevant information regarding the tumor should also be documented with special emphasis on any pre-existing lesion, time of evolution, time since the patient became suspicious, reason for the consultation, presence of pain, trauma, or bleeding. It is also useful if the patient can describe the colors, diameter, borders, presence of nodules, and other descriptors of the tumor at the time they first became aware of it.

Chapter IV.8

IV.8.15.3 Physical Examination The detailed examination of the tumor includes describing its diameter, shape, presence of nodules, ulceration (bleeding, crusts), colors (number, type and distribution), surface (loss of skin marks and appendages, hyperkeratosis), associated cutaneous tumor (melanocytic nevus, seborrheic keratosis, angiomas and others), surrounding skin (depigmentation halo type, erythema suggesting lymphangiogenesis, other atypical pigmented lesions or satellitosis), and symptoms such as itching or pain. Dermoscopy of the primary tumor will be necessary to study the details of the tumor and detect areas with different components, regression, nodules with ulceration, associated tumors (precursor/collision tumor), and the ability to predict tumor thickness. Photographic documentation is very helpful and should include an image with a perspective showing the tumorâ&#x20AC;&#x2122;s location followed by close-up images. Dermoscopic photography, if possible, is recommended. Since it is not infrequent to detect a second malignant tumor including melanoma or skin carcinomas in patients with melanoma, a complete total-body examination should be performed at the time of the first consultation. The presence of lesions associated with photoaging or sunburns, skin type, number and characteristics of moles (common, atypical, congenital, etc.), or other lesions suggesting satellitosis or cutaneous metastasis (epidermotropic metastasis or palpable subcutaneous nodules) should be documented. Surgical scars, if prior biopsies were performed, should be examined to detect recurrent melanocytic lesions or recurrence of skin carcinomas. Examination should include clinical examination with the naked eye, palpation, and dermoscopy.

IV. Examination of Lymph Nodes Palpation of lymph nodes should be performed and, if possible, sonography of the regional lymph node basins may allow for the early detection of nodal metastasis.



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IV.8.16 Staging and Treatment of Primary Melanoma Staging of the patient is conducted with information obtained from the primary tumor and the study of nodal status and distant metastasis [80].

The most widely accepted surgical margins for melanoma are 1 cm for melanoma with Breslow thickness less than 1.01 mm, 2 cm in melanomas from 1.01 to 4.00 mm and 2–3 cm, in melanomas thicker than 4 mm.

IV.8.16.2 Sentinel Node Biopsy

I.4 IV.8.16.1 Surgical Excision of the Tumor The complete surgical excision of the tumor is preferable to partial incisional biopsies such as punch or shave biopsy [81]. Partial biopsies can be problematic for the pathologist and may not provide the clinician with enough information to make appropriate management decisions. The first excised biopsy should be performed with a narrow excision margin (2–3 mm) and submitted for complete pathological examination. The use of complex closures, such as grafts or skin flaps, should be avoided. In most cases patients with SSM or nodular melanoma on the trunk and extremities can be effectively treated with a simple elliptical excision of the melanoma followed by primary closure. From a technical standpoint, the long axis of the elliptical excision should be designed to maximally utilize the available local skin so as to achieve a relatively tension-free full-thickness primary closure, and the excision should be oriented toward the appropriate draining nodal basin whenever possible. The final surgical margins depend on the tumor thickness. The rationale of the wide-excision margins is based on the risk of local recurrence including in-transit metastasis. Local failure is a function of both biology of the primary tumor and extent of the lesion. In thin melanomas the risk is low and narrower margins are safe. In contrast, thicker tumors and/or ulcerated melanomas are associated with higher rates of local recurrences due to the presence of clinically occult metastasis at the time of initial excision and which were not completely removed. Wide local excision of these high-risk tumors may completely remove these satellite metastases and thereby lower the risk of recurrence.

The most accurate predictor of metastasis is the status of the regional lymph nodes [80, 82]. The current staging system of the AJCC is incorporating the status of the sentinel node. In most centers sentinel node biopsy has been incorporated into the staging protocols. If the sentinel node biopsy is positive, then the patients are offered complete lymph node dissection; however, impact of complete lymph node dissection on overall survival has not been conclusively proven. Sentinel-lymph-node biopsy, a technique developed in the early 1990s by Morton et al., samples selectively the first draining lymph node (or nodes) from a tumor site. A multidisciplinary team is required to successfully perform the procedure including an experienced surgeon, a nuclear medicine radiologist, and a ­pathologist. In skilled hands, the sentinel node is identified in over 95% of cases [81]. The lymph node should be fixed and processed with both hematoxilin and eosin and inmunohistochemical staining (e.g., S-100, HMB-45, and MART-1). With this technique the detection of micrometastasis is possible. Some studies are investigating the impact of testing the sentinel lymph node biopsy by PCR analysis [83]. Since many retrospective studies have shown a strong negative impact on prognosis in the presence of melanoma in the sentinel node, the sentinel node biopsy is currently considered the most powerful technique for staging and prognosis. The proponents of the technique argue that accurate staging allows for the selection of patients that are candidates for further adjuvant treatments such as interferon alpha-2b; however, critics argue that sentinel node biopsy has no proven impact on survival and no adjuvant treatments have proved beneficial for patients with microscopic nodal disease. The Multicenter Selective Lymphadenectomy Trial and the Sunbelt Trial were designed to address these

Melanoma of the Trunk

concerns [84–86]. Sentinel node biopsy is currently recommended in patients at high risk for nodal disease [87]. In most of the centers this includes tumors with a thickness of at least 1 mm or thinner tumors if they also have other poor prognostic factors such as ulceration, Clark level IV, or marked regression >75%. Staging techniques, physical examinations, and the follow-up schedules vary according to the countries and centers, but many include periodic physical examination, blood test (including melanoma blood markers such as S-100, MIA, mRNA tirosinase), chest X-Ray, and imaging techniques (sonography, computed tomography, magnetic resonance imaging, positron emission tomography) [79]. Although an optimal follow-up interval has not been determined, by consensus a minimum of an annual routine physical examination, including full skin assessment and palpation of lymph nodes, is proposed. It is reasonable to state that more frequent follow-up visits will be appropriate for patients with atypical mole syndrome, patients with high-risk tumors, and, of course, if adjuvant treatment is initiated [88]. In the case of patients with susceptibility to multiple melanomas, a short follow-up of 6 months and the use of imaging techniques as dermoscopy, total body photography and digital dermoscopy should be recommended to detect further primary melanomas at early stages [88–90]. Routine laboratory tests, including serum lactate dehydrogenase, albumin, and plasma hemoglobin measurements and chest radiography, have not been conclusively proven be beneficial in screening for recurrence in asymptomatic melanoma patients; therefore, these tests probably should be reserved for patients at moderate to high risk for recurrence [91, 92].

IV.8.16.3 Adjuvant Therapy The most important value of accurate staging of patients with melanoma is the identification of patients that may benefit from adjuvant therapy. In more than 100 randomized, controlled trials attempts to reduce recurrent melanoma with adjuvant therapy have been studied [79]. Recent efforts have been focused on interferon alphal-

Chapter IV.8

pha-2b, vaccination or both. From these trials only interferon alpha-2b has been shown to have a reproducible, albeit small, effect on relapsefree survival [93–95]. Treatment with high-dose interferon alpha-2b was approved by the United States Food and Drug Administration for patients with primary melanomas thicker than 4 mm or melanoma involving regional lymph nodes that have been rendered free of disease after surgery. Since high-dose interferon has different side effects, critics have expressed concern about the toxicity and the lack of consistent impact on overall survival. Since high-dose interferon alpha-2b has toxic effects and prevents recurrence and death in only a minority of patients at risk, it is not currently accepted worldwide and it is unevenly used in the United States and Europe [96–102]. Various efforts to reduce toxicity and improve the efficacy have included low-dosage regimens and the combination with vaccines, but at present such regimens have not provided an overall survival advantage, and therefore such regimens are not be routinely recommended worldwide [101, 103–105]. Since interferon alpha-2b is the only approved therapy in many countries, it is reasonable to inform patients of this treatment. They should be informed of the potential risk and benefits and known adverse effects. Many promising adjuvant regiments with vaccination are being studied in melanoma. Although vaccines are less toxic than some other treatments, their efficacy relative to that of interferon, and their ability to synergize with interferon, remain to be established.

IV.8.17 Treatment of Distant Disease For stage-IV patients, no single randomized, controlled trial has demonstrated an increase in overall median survival, including any combination of drugs and/or interleukin-2. Surgical resection of isolated metastatic foci can result in a 5-year survival rate of up to 25%. These results have been restricted to selected cases when few visceral metastasis could be completely removed [104]. High-dose bolus interleukin-2 was approved by the FDA in 1998, and although tumor responses occurred in only 16% of cases, some cases had complete durable responses lasting for




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more than 30 months [106]. Unfortunately, this regimen is associated with many toxic effects, making it difficult to administer except in specialized centers. Currently, among the cytotoxic agents, dacarbacine remains the key drug, since it produces responses in 15–20% of patients with a mean duration of the response of 4 months. Recently, temozolamide has shown promising results [107]. The future directions in melanoma treatment focus on vaccine-based inmunotherapy and targeted-chemotherapy regimens. These approaches will become ever more utilized as our knowledge of how the genetics, cellular regulatory pathways, tumor profile, and the immune system interact to allow for the growth of melanoma.

IV.8.18 Case Study

brown, bluish, withish, and black. The predominant pattern was reticulated in the peripheral part with atypical network and brown dots. In the center homogeneous with bluish veil correlated with the papular area of the tumor. Irregular black blotch was also seen.

Case Study 1 A 42-year-old woman without personal and familial background of melanoma consulted for a pigmented lesions on her left thigh, detected 18 months previously, with a progressive increase in size and changes in color. Discrete itching during the last months was reported, but bleeding was not detected. Clinical examination revealed skin-type III without elevated number of moles but some lentigo solaris in exposed areas. The tumor was 16¥12 mm in maximal diameter and more palpable in the center. The colors were brown to gray to black and bluish. Signs of ulceration were not detected. Dermoscopy showed a melanocytic tumor with a multicomponent pattern, light and dark

Management A surgical excision of the tumor with 0.5-cm margins with local anesthesia was performed to evaluate histologically the tumor. A superficial spreading melanoma, Breslow 1, 2 mm, Clark III without ulceration was reported (one mitosis per magnification ¥400 and mild lymphocyte inflammatory infiltrate). Wide-margin excision with 1.5 cm around the scar (total 2-cm margins) and sentinel node biopsy revealed a negative sentinel node on the left groin without micrometastasis. Staging of the patient was AJCC IB, and follow-up with clinical examination, including skin and lymph nodes every 6 months during 5 years, was recommended. The patient is free of relapse after 2 years of follow-up.

Case Study 2 Woman of 32 years old with personal history of superficial spreading malignant melanoma (Stage IA) on the trunk excised 3 years before. Severe atypical mole syndrome with more that 200 lesions and multiple biopsies of dysplastic nevi. The patient was included in a follow-up program of total-body photography and digital

Melanoma of the Trunk

Chapter IV.8

Dermoscopy of the lesions detects a predominant reticulated pattern with brown dots and in some of the lesions discrete presence of blue dots. Total body photography do not detects new lesions at the time of the examination. Digital dermoscopy detects a marked change in the coloration of a lesion on the center of the trunk with delicate brownish pigment network and blue dots suggesting regression (figure 2). Clinical examination of the lesion is not suspicious because the similar appearance respect to other lesions of the patient with a irregular brownish with grayish coloration.

Management A surgical excision of the tumor with 0, 3 cm of margins with local anesthesia is performed to evaluate histologically the tumor. A superficial spreading malignant melanoma, Breslow 0,50 mm Clark II with severe regression is reported. No signs of histological ulceration are observed. Wide margins excision with 1 cm around the scar (total 1 cm margins) The patient is free of relapse after 3 years follow-up including total body examination and digital follow-up.


dermoscopy with 3 to 6 months of time between each visit. At the time of the present visit the patient was not aware of any change in any of the lesions. Clinical examination revealed a patient with high number of atypical lesions (Figure 1). Scar of the surgery of the primary melanoma and lymph node areas were normal.

Core Messages ■ Superficial and nodular melanoma of the trunk and limbs are the most frequent melanoma subtypes in Caucasians. ■ A wide range of tumors may mimic melanoma, and vice versa. ■ Experienced dermoscopists usually rely on pattern recognition to help differentiate between benign nevi and melanoma. ■ The histopathology of superficial spreading and nodular melanoma can be explained by the “three-step tumor progression model.”



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Chapter IV.8 42. Cerroni L, Kerl H. Simulators of malignant melanoma of the skin. Eur J Dermatol 1998;8:388–396 43. Zalaudek I, Ferrara G, Stefani A di, Argenziano G. Dermoscopy for challenging melanoma; how to raise the “red flag” when melanoma clinically looks benign. Br J Dermatol 2005;153:200–2002 44. Menzies SW, Westerhoff K, Rabinovitz H, Kopf AW, McCarthy WH, Katz B. Surface microscopy of pigmented basal cell carcinoma. Arch Dermatol 2000;136:1012–1016 45. Malvehy J, Puig S, Marti-Laborda RM. Dermoscopy of skin lesions in two patients with xeroderma pigmentosum. Br J Dermatol 2005;152:271–278 46. Ragi G, Turner MS, Klein LE, Stoll HL Jr. Pigmented Bowen’s disease and review of 420 Bowen’s disease lesions. J Dermatol Surg Oncol 1988;14:765–769 47. Zalaudek I, Argenzia