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Pattern Analysis For Histopathologic Diagnosis of Melanocytic Lesions A Guide To Practical Dermatopathology Complete Chapter Download

The document is a guide on the histopathologic diagnosis of melanocytic lesions using pattern analysis, authored by Almut Böer-Auer, Harald Kittler, and Philipp Tschandl. It emphasizes the importance of recognizing visual patterns in dermatopathology for accurate diagnosis and classification of skin tumors. The book provides a comprehensive overview of various diagnostic patterns, classifications, and practical applications in dermatopathology.
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100% found this document useful (9 votes)
365 views17 pages

Pattern Analysis For Histopathologic Diagnosis of Melanocytic Lesions A Guide To Practical Dermatopathology Complete Chapter Download

The document is a guide on the histopathologic diagnosis of melanocytic lesions using pattern analysis, authored by Almut Böer-Auer, Harald Kittler, and Philipp Tschandl. It emphasizes the importance of recognizing visual patterns in dermatopathology for accurate diagnosis and classification of skin tumors. The book provides a comprehensive overview of various diagnostic patterns, classifications, and practical applications in dermatopathology.
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
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Pattern Analysis for Histopathologic Diagnosis of Melanocytic

Lesions A Guide to Practical Dermatopathology

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Almut Böer-Auer Harald Kittler
Department of Dermatopathology Department of Dermatology
Dermatologikum Hamburg Medical University of Vienna
Hamburg, Germany Vienna, Austria

Department of Dermatology
Münster University
Münster, Germany

Philipp Tschandl
Department of Dermatology
Medical University of Vienna
Vienna, Austria

ISBN 978-3-031-07665-7    ISBN 978-3-031-07666-4 (eBook)


https://doi.org/10.1007/978-3-031-07666-4

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2022
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher,
whether the whole or part of the material is concerned, specifically the rights of translation,
reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any
other physical way, and transmission or information storage and retrieval, electronic adaptation,
computer software, or by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
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The publisher, the authors, and the editors are safe to assume that the advice and information in
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This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
To my teachers and my students, with gratitude
Almut Böer-Auer
To my wife Elisabeth, my greatest mentor
Harald Kittler
To Sophie
Philipp Tschandl
Foreword

Visual patterns can be defined as morphological features that follow a repeat-


able scheme, allowing predictions to be made according to a given pattern. In
dermatology and dermatopathology, the predictions consist of clinical and
histopathological diagnoses. In our approach to patients with pigmented skin
tumors, we constantly use pattern analysis, even when we don’t realize we are
doing so; these patterns reflect our experience, both clinicopathological (i.e.,
experience acquired by working as physicians) and theoretical (i.e., experi-
ence acquired by reading pertinent literature or listening to presentations).
On the other hand, a precise knowledge of various diagnostic patterns is
paramount in order to allow us to recognize them properly. In this book,
Böer-Auer, Kittler, and Tschandl use pattern analysis as the main approach to
histopathological diagnosis of benign and malignant melanocytic tumors,
showing how this method can be effectively used in order to classify cases
correctly. Pattern analysis in dermatopathology is widely used for the classi-
fication of inflammatory dermatoses and was developed mostly by one of the
giants of this field, A. Bernard Ackerman. Ackerman’s book on inflammatory
dermatoses diagnosed by pattern analysis is a masterpiece, and one of the rare
examples of a medical book still useful almost 50 years after its first
publication.
In this volume, Böer-Auer, Kittler, and Tschandl show that the same
method can be successfully applied to the histopathological diagnosis of
melanocytic tumors, allowing to classify cases by an integration of different
patterns and of other histopathological features. This book adds a new dimen-
sion to the histopathological diagnosis of melanocytic tumors, by providing a
detailed and precise analysis of different patterns that can be recognized
under the microscope. As a former student and co-worker of A. Bernard
Ackerman, Almut Böer-Auer very well knows the importance of rational
approach and pattern analysis for dermatopathological diagnosis of skin dis-
eases; Harald Kittler and Philipp Tschandl add their year-long experience in
dermatopathology and in pattern recognition, turning this publication a very
valuable source for all those who are interested in dermatopathological diag-
nosis of melanocytic tumors.

Lorenzo
Graz, Austria Cerroni

vii
Acknowledgments

We especially want to thank Danijela Dobrosavljevic Vukojevic, Gerardo


Ferrara, and Lorenzo Cerroni for providing us with first-rate images, which
are a much valued addition to the contents.

ix
Contents

1 Introduction��������������������������������������������������������������������������������������   1
2 Historical Perspective����������������������������������������������������������������������   7
2.1 Melanoma ��������������������������������������������������������������������������������   8
2.2 Melanocytic Nevi���������������������������������������������������������������������� 10
2.3 The Relationship Between Melanocytic Nevi
and Melanoma�������������������������������������������������������������������������� 11
3 Classifications ���������������������������������������������������������������������������������� 13
3.1 The WHO Classification of Melanocytic Tumors�������������������� 13
3.2 Other Classifications ���������������������������������������������������������������� 17
3.2.1 The MPATH-Dx Reporting Scheme ���������������������������� 17
3.2.2 AJCC and TNM Melanoma Staging���������������������������� 20
3.2.3 ICD-11 and ICD-O Codes�������������������������������������������� 21
3.3 The Relationship Between Pattern Analysis and
Classifications �������������������������������������������������������������������������� 23
4 Pattern Analysis������������������������������������������������������������������������������� 25
4.1 Architecture and Silhouette������������������������������������������������������ 25
4.2 Main Patterns and Their Variations������������������������������������������ 28
4.2.1 Epidermal Patterns�������������������������������������������������������� 28
4.2.2 Dermal Patterns������������������������������������������������������������ 34
4.2.3 Subcutaneous Pattern���������������������������������������������������� 39
4.2.4 Combination of Patterns ���������������������������������������������� 40
4.3 Cytology of Melanocytes���������������������������������������������������������� 41
4.3.1 Shape���������������������������������������������������������������������������� 41
4.3.2 Pleomorphism of Melanocytes ������������������������������������ 46
4.3.3 Crowding���������������������������������������������������������������������� 48
4.3.4 Mitotic Figures�������������������������������������������������������������� 48
4.3.5 Necrosis������������������������������������������������������������������������ 48
4.4 Other Changes�������������������������������������������������������������������������� 50
4.4.1 Epidermis���������������������������������������������������������������������� 50
4.4.2 Collagen������������������������������������������������������������������������ 52
4.4.3 Vessels�������������������������������������������������������������������������� 54
4.4.4 Inflammatory Infiltrates������������������������������������������������ 55

xi
xii Contents

5 Integration of Patterns�������������������������������������������������������������������� 57
5.1 Combination of Patterns and Differential Diagnosis���������������� 57
5.2 The Full Histologic Examination Procedure on the Basis of
Examples���������������������������������������������������������������������������������� 61
5.2.1 Example 1 ��������������������������������������������������������������������   62
5.2.2 Example 2 ��������������������������������������������������������������������   64
5.2.3 Example 3 ��������������������������������������������������������������������   66
5.2.4 Example 4 ��������������������������������������������������������������������   68
5.2.5 Example 5 ��������������������������������������������������������������������   70
5.2.6 Example 6 ��������������������������������������������������������������������   72
5.3 Limitations of Pattern Analysis������������������������������������������������ 74
6 Integration of Context �������������������������������������������������������������������� 79
6.1 Clinical Context������������������������������������������������������������������������ 81
6.2 In Vivo Imaging������������������������������������������������������������������������ 83
6.3 Ex Vivo Dermatoscopy ������������������������������������������������������������ 87
6.4 Immunohistochemistry ������������������������������������������������������������ 88
6.4.1 Use Cases���������������������������������������������������������������������� 90
6.5 Molecular Findings ������������������������������������������������������������������ 96
6.5.1 General Concepts���������������������������������������������������������� 97
6.5.2 Selected Situations�������������������������������������������������������� 97
6.6 Adding It Up: But How?���������������������������������������������������������� 98
7 Pattern Analysis in Practice������������������������������������������������������������ 101
7.1 Patterns�������������������������������������������������������������������������������������� 102
7.1.1 Junctional���������������������������������������������������������������������� 102
7.1.2 Spindled and/or Epithelioid Pigmented, Dermal���������� 128
7.1.3 Epithelioid and/or Spindled Amphophilic�������������������� 144
7.1.4 Nevoid Melanoma and Melanoma Associated
with Nevi���������������������������������������������������������������������� 158
7.1.5 Regression, Sclerosis, Recurrence, and
Inflammation ���������������������������������������������������������������� 169
7.2 Anatomic Sites�������������������������������������������������������������������������� 180
7.2.1 Acral������������������������������������������������������������������������������ 180
7.2.2 Face ������������������������������������������������������������������������������ 188
7.2.3 Nail�������������������������������������������������������������������������������� 200
7.2.4 “Special” Sites (Navel, Mamilla, Genital, Axilla)�������� 212
7.2.5 Conjunctiva ������������������������������������������������������������������ 220
7.3 Clinical Setting������������������������������������������������������������������������� 234
7.3.1 Partial Biopsies ������������������������������������������������������������ 234
7.3.2 Newborns, Babies, and Children���������������������������������� 248
8 Bias,
 Noise, and Error��������������������������������������������������������������������� 257
8.1 Last Words�������������������������������������������������������������������������������� 259

References ������������������������������������������������������������������������������������������������ 261

Index���������������������������������������������������������������������������������������������������������� 269
About the Authors

Almut Böer-Auer is Dermatologist, Dermatopathologist, and Director


of Academics at the Dermatologikum Hamburg, Germany, and Associate
Professor at the Department of Dermatology at Münster University in
Germany. She has been interested in histopathologic pattern diagnosis of skin
diseases for almost two decades. One of her research focuses is identification
and validation of diagnostic patterns by correlation with ancillary methods
like molecular diagnostics. She has authored and co-authored many scientific
articles and textbook chapters and is devoted to teaching dermatopathology
nationally and internationally.

Harald Kittler is Associate Professor of Dermatology at the Department of


Dermatology, Medical University of Vienna, in Vienna/Austria with a sub-
specialization in dermatopathology. His special clinical interest resides in
the diagnosis of melanocytic skin lesions. His main research interest is digital
dermoscopy, follow-up of pigmented skin lesions, computer-assisted digital
dermoscopy, and dermatopathology. Dr. Kittler has been working for over 20
years in the field of dermoscopy and dermatopathology and has been lectur-
ing and publishing a large number of scientific articles.

Philipp Tschandl is Associate Professor of Dermatology with a subspecial-


ization in dermatopathology and managing director of the dermatopathology
laboratory at the Department of Dermatology of the Medical University of
Vienna in Austria. He has published research on growth dynamics of mela-
noma, melanoma association with pre-existing nevi, as well as early detection
of melanoma with dermatoscopy. His work also includes the application of
artificial intelligence alone and in collaboration with physicians for improv-
ing medical diagnoses and decision-making.

xiii
Introduction
1

Why do we need another textbook of dermatopa- ysis, never wrote a book on pattern analysis of
thology dedicated to the diagnosis of melano- melanocytic lesions. It is true that not all of his
cytic lesions? The answer is simple and surprising. ideas and views have withstood the test of time,
Currently, there is no pathology textbook of but pattern analysis certainly has, and so we have
melanocytic lesions rooted in pattern analysis. taken it upon ourselves to fill this gap.
This is surprising because pattern analysis revo- What is pattern analysis? Pattern analysis is
lutionized the way dermatopathologists approach based on deductive reasoning and consists of two
inflammatory and non-melanocytic neoplastic parts, a descriptive and an analytic part. It starts
lesions. When A. Bernard Ackerman introduced with a description and ends with the diagnosis.
pattern analysis in 1970, his ambitions were Because it commences with the description and
higher than the title of the book, “Histologic not with the diagnosis, it is a bottom-up approach.
diagnosis of inflammatory skin diseases”, sug- Top-down approaches, on the other hand, start
gested. His aim was to cover all skin diseases, with the diagnosis. In general, patterns are com-
inflammatory and neoplastic, in a single book, posed of basic elements like mosaics are com-
but he soon realized that this was too large a task posed of individual tiles. The basic element of
to complete in a reasonable timeframe. Holding a pattern analysis for the histopathologic diagnosis
signed publisher contract with an explicit dead- of melanocytic lesions is the neoplastic melano-
line in his hand, he decided to restrict the book to cyte. The morphology, arrangement, and distri-
inflammatory diseases. Later, he and his cowork- bution of melanocytes form the main patterns
ers applied pattern analysis to neoplastic skin that typify nevi and melanoma. Additional crite-
lesions, most notably to adnexal neoplasms with ria, such as stromal or epidermal changes, com-
apocrine, follicular, and sebaceous differentia- plete and refine these patterns.
tion. Together with his co-authors Lorenzo In a first step, pattern analysis provides a tool
Cerroni and Helmut Kerl, he published “Pitfalls that allows the observer to describe melanocytic
in the histopathologic diagnosis of malignant lesions in a meaningful and repeatable fashion. In
melanoma” in 1994, a book which, in his own a second step, pattern analysis offers a rule-based
words, “uses repeatable criteria for the histopath- algorithm to deduce the diagnosis, which, if
ologic diagnosis of melanocytic neoplasms of all applied consistently, should be as robust and
types”. We owe important suggestions and ideas repeatable as the description. We are aware that
to this influential work, which are also reflected morphologic methods such as dermatopathology
in the present book. However, A. Bernard always contain an observer dependent, subjec-
Ackerman, the intellectual father of pattern anal- tive, part, which is one of the main reasons for the

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 1


A. Böer-Auer et al., Pattern Analysis for Histopathologic Diagnosis of Melanocytic Lesions,
https://doi.org/10.1007/978-3-031-07666-4_1
2 1 Introduction

low inter-rater agreement of the pathologic diag- fashion with tables of content that contain lists
nosis of melanocytic skin lesions [1]. Other rea- of diagnoses. To extract specific information,
sons include a confusing multitude of you will have to search for diagnoses. This will
classifications and terms, lack of training or not be helpful if you do not know the diagnosis.
experience, and lack of a structured method. If This book, on the other hand, is organized in a
pattern analysis is applied consistently, the inter-­ bottom-up fashion and the reader can search for
rater agreement will improve, at least with regard patterns and diagnoses alike. With the possibility
to the descriptive part of pattern analysis. The to search for patterns, we want to support the
second, analytic, part of pattern analysis, will reader in classifying unknown cases. Our book is
always be influenced by the personal style and not an atlas of melanocytic proliferations where
the individual threshold of the reporting patholo- you can look up examples for given diagnoses. It
gist. We believe that this subjectivity is not harm- is intended to be more like a map that gives you
ful, provided that the final interpretation is in line directions if you lose your way. If you want to
with the description. acquire a general knowledge of this field, you
Usually, there are two main reasons for con- can read it page by page from the beginning to
sulting a medical textbook. The first is that the the end. If, however, you want to find guidance
reader wants to learn more about the subject at for a specific case you can consult only Chap. 7.
hand, for example, because of a genuine interest. Does this sound too abstract? Let us consider a
The second reason is that the reader seeks advice use case.
on a specific case, for which the diagnosis is not Take, for example, the complex melanocytic
obvious. Traditional textbooks will be perfectly neoplasm shown in Fig. 1.1. The diagnosis is not
suited for those who want to learn but will not be obvious. Which page would you open in a tradi-
exceedingly helpful for those who seek advice tional textbook of dermatopathology? Would you
on a specific case. The reason for this is that look in the chapters of melanoma, combined
most textbooks are organized in a top-down nevi, deep penetrating nevi, Spitz nevus, atypical

a b

c d

Fig. 1.1 (a–l) A complex melanocytic neoplasm of a prepubescent child (see text for a detailed description). (Courtesy
of the Department of Dermatology, Medical University of Vienna)
1 Introduction 3

e f

g h

i j

k l

Fig. 1.1 (continued)

Spitz tumor, congenital nevi, or in all of the men- superficial parts of the subcutis. The melanocytes
tioned chapters? in the epidermis are mainly arranged in nests with
It would be much easier to search by pattern some pagetoid spread. The nests vary in size and
first and not by diagnosis. Studying the pattern, shape and are irregularly distributed. The melano-
you find a fairly asymmetric melanocytic neo- cytes in the dermis are plump, spindle, and epithe-
plasm that involves the epidermis, the dermis, and lioid, and a significant proportion of dermal
4 1 Introduction

melanocytes is heavily pigmented. There are possible to perform molecular studies such as
abundant melanophages and no obvious matura- comparative genomic ­ hybridization (CGH) or
tion. After scanning the lesion in higher magnifica- fluorescence in situ hybridization (FISH) but they
tion for minutes, you find one mitosis in the deeper are not available at your site. You will have to send
portions of the lesion. Given this description, pat- tissue to another laboratory and the results will
tern analysis would lead to two, maximal three dif- not be available within the next 3 weeks. Another
ferential diagnoses, possibly deep penetrating colleague tells you that her experience with CGH
nevus versus Spitz nevus versus melanoma. Next, is that it does not remove doubts, sometimes it
you seek additional information. After contacting even creates new ones. Finally, you will need to
the referring clinician, you learn that this lesion file a report taking everything into account includ-
comes from the cheek of a prepubescent boy ing the consequences the patient and you will
(Fig. 1.2a). You also learn that this boy has have to face if your diagnosis is wrong. You will
Xeroderma pigmentosum, a genetic condition that have to weigh the consequences of calling a nevus
predisposes for UV-induced skin malignancies a melanoma against the consequences of calling a
such as keratinocyte cancer and melanoma. You melanoma a nevus in a 3-year-old. You realize
ask yourself if this information should change that you are not sure what these consequences are
your assessment. The clinician also offers you to either way. Adding everything up, you feel that
have a look at the dermatoscopic image of this you cannot exclude the diagnosis of melanoma in
case (Fig. 1.2b) but you have no experience in der- this context, but you want to convey your uncer-
matoscopy and you decline. tainty in your report, but how?
However, you ask yourself if it would be useful The point is that the answers to most of these
to have some basic knowledge in clinical derma- questions that came up during the study of this
tology and in dermatoscopy, especially for the case will not be found in traditional textbooks.
diagnosis of melanocytic neoplasms. An experi- We do not claim, of course, that you will find all
enced colleague tells you that clinical information the answers in this book, but we are at least aware
is mostly useless and occasionally misleading. of the questions and will not ignore them.
The answer is always in the slide, and if it is not in According to our experience, pattern analysis
the slide, it is nowhere, he says and, having a short will provide you with a framework that will allow
glimpse at your slide, he would call it a mela- you to manage complex and uncertain cases in a
noma. Because you still hesitate to call this lesion repeatable and meaningful fashion. Pattern anal-
a melanoma, you do immunohistochemistry stud- ysis will not resolve uncertainty but it will reduce
ies, which do not help you. You heard that it is confusion.

a b

Fig. 1.2 Close-up clinical image (a; left) and dermatos- hereditary condition that is typified by UV-sensitivity and
copy (b; right) of the lesion on the cheek shown in susceptibility to UV-induced skin neoplasms such as
Fig. 1.1. Although the patient is a prepubescent child, squamous cell carcinoma and basal cell carcinoma but
there is severe chronic sun damage in the surrounding also melanoma. (Courtesy of the Department of
skin. The child suffers from Xeroderma pigmentosum, a Dermatology, Medical University of Vienna)
1 Introduction 5

Diagnostic categories with uncertain progno- expected that a purely morphologic diagnosis
sis such as atypical Spitz tumor (AST), superfi- will be outdated soon and replaced by molecu-
cial atypical melanocytic proliferation of lar methods that categorize and diagnose mela-
uncertain malignant significance (SAMPUS), or nocytic skin lesions more precisely? We do not
melanocytic tumor with uncertain malignant think so. Although we acknowledge that molec-
potential (MELTUMP) represent a constant ular ­methods provide useful additional infor-
source of confusion. There is certainly a need for mation in selected cases, we predict that even
such categories in practice because some mela- 10 years from now the vast majority of melano-
nocytic neoplasms can be diagnosed neither as cytic neoplasms will be diagnosed by micro-
benign (nevus) nor as malignant (melanoma) scopic examination of pieces of tissue stained
with confidence. There are, however, different by hematoxylin and eosin. The reasons for our
points of view about the best way to express this bold claim are manifold but can be condensed
ambiguity. One school of thought will blame the to one single argument. Conventional light
lesion (“the lesion does not know what it is”), the microscopy is a relatively cheap examination
other the ignorance of the reporting pathologist technique that combines high accuracy with
(“I do not know what it is”). The authors of this broad availability. If, however, this textbook is
book are proponents of the latter school of outdated in 10 years and the final diagnosis of
thought, but throughout this book we will try to melanocytic neoplasms is based only on molec-
reconcile both approaches. ular findings, we will happily put our micro-
Is it still appropriate to write a textbook on scopes in the basement and spend our time
the histologic diagnosis of melanocytic skin more wisely.
lesions that is centered on morphology? Is it not
Historical Perspective
2

The following historical summary is not meant to for example is replete with historic ballast. The
be complete. Many important figures and events bulky terminology of nevi, which differs from
are not mentioned. To avoid exhaustion of read- textbook to textbook, is illogical because it grew
ers and authors alike, the summary provides only historically. Nevi have been named according to
as much information as necessary to deliver the different ordering principles, such as anatomic
narrative and to help the interested reader under- site (acral nevus), time of appearance (congenital
stand the big picture. For a more detailed review nevus/acquired nevus), clinical criteria (eclipse
of the history of the clinical and histopathologic nevus, blue nevus), or in an eponymic way (Spitz
diagnosis of melanoma we refer to recent review nevus). The result is an incoherent hodgepodge
articles by Kittler [2] and Weyers [3]. of terms that complicate the study of melanocytic
Although from the current point of view it proliferations. The third and probably most
seems that most of what has been published about important lesson is that evolving concepts in der-
the pathology of melanocytic proliferations pre-­ matopathology are tightly linked to other speci-
1970s is outdated, the study of historic books and alities and influenced by general trends. Changing
manuscripts is not futile. It teaches us three paradigms in the standard of care outside the field
important lessons. First, that scientific knowl- of dermatopathology had a significant impact on
edge is embedded in a specific historic context, the concepts inside the field of dermatopathol-
which shapes the beliefs and concepts of scien- ogy. The shift of focus towards early recognition
tists, who live at that time. If we study medical in the 1980s, the invention of the handheld der-
publications from the past, no matter how bril- matoscope, the increased awareness and
liantly they were written, we cannot help to be melanoma-­related anxiety of the public, and the
amused about the lack of scope and depth, out- increased vulnerability of pathologists to mal-
dated concepts, and primitive techniques. We practice lawsuits created a pull towards lowering
easily feel superior to the physician-scientists of thresholds for the diagnosis of melanoma, espe-
the past but we should not. Looking back should cially for melanoma in situ. In a few decades, the
make us more humble, because most of our cur- landscape shifted from underdiagnosis to overdi-
rent concepts and techniques, no matter how agnosis of melanomas, a development that is now
sophisticated they seem to us today, will be met with increased criticism. By overdiagnosis
equally outdated in the future. Second, we learn we mainly refer to the inflation of the diagnosis
that we cannot easily shake off the past. The cur- of in situ or microinvasive melanomas with
rent classification of nevi and melanoma as set unknown prognostic significance. The undesired
forth by the World Health Organization (WHO) consequences of overdiagnosis are manifold.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 7


A. Böer-Auer et al., Pattern Analysis for Histopathologic Diagnosis of Melanocytic Lesions,
https://doi.org/10.1007/978-3-031-07666-4_2
8 2 Historical Perspective

Apart from putting a significant financial burden which continues to be relevant until today [6–8].
on health care systems, overdiagnosis is associ- In its original form the classification included
ated with increased anxiety and morbidity of three subtypes: nodular melanoma, superficial
affected individuals. All these developments are spreading melanoma, and lentigo maligna mela-
difficult to comprehend without a basic under- noma. Nodular melanoma was typified by pure
standing of their historical evolution. Studying vertical growth, while superficial spreading mel-
the past will also allow us to look into the future. anoma expands along the epidermis (radial or
As of the time of the first edition of this book, the horizontal growth phase). The fourth subtype,
incidence of melanoma seems to have peaked, acral lentiginous melanoma, was added later. In
which might indicate that melanoma overdiagno- the early 1970s, Clark and his coworkers also
sis reached a zenith. It is quite likely that the pen- established the anatomic levels of invasion, and
dulum swings back in the other direction. It is our at the same time Arthur Breslow introduced the
task to make sure that the pendulum levels off at invasion thickness as a prognostic marker for
a desirable position. primary melanoma of the skin [9, 10]. In the
mid-1970s, A. Bernard Ackerman and his
coworkers set forth histopathologic criteria for
2.1 Melanoma the diagnosis of melanoma that are still widely
used by dermatopathologists (Table 2.1) [11].
As pointed out recently in a more comprehensive Ackerman also popularized the concept of mela-
historical outline, a good starting point for a his- noma in situ, clinically and pathologically, and
torical summary on the histopathologic diagnosis negated the concept of precursor lesions such as
of melanoma is the work of L. V. Ackerman in “Allen’s active junctional nevus,” “Hutchinson’s
the late 1940s [2]. He was one of the first to melanotic freckle,” “Kossard’s lentiginous dys-
describe the pathology of “melanocarcinoma,” as plastic nevus of the elderly,” and “precancerous
it was called then, in a systematic way. The clini- melanosis of Dubreuilh,” which, according to his
cal photos and micrographs of his original publi- opinion, were evasions from the correct diagno-
cations demonstrate how advanced typical cases sis of melanoma in situ.
of melanoma were in 1948 [4]. The concept of Pre-1980s, melanoma in situ was not widely
L.V. Ackerman was that melanoma usually starts accepted as authentic melanoma but rather
in a nevus and that “it is most unusual to find the viewed as a precursor. The clinical diagnosis of
changes of malignant melanoma entirely within
the epidermis with no change in the dermis.” This Table 2.1 Significant histopathologic features of superfi-
statement demonstrates that the concept of mela- cial spreading melanoma according to Price, Rywlin, and
noma in situ did not exist in 1948. Ackermann 1976
A few years later in 1953, Arthur Allen and Poor circumscription of the intraepidermal
Sophie Spitz co-authored an article, in which melanocytic component of the lesion with lateral
they set forth their belief that all melanomas start extension of individual melanocytes
Increased number of melanocytes, solitary and in
in a preexisting mole, especially in an “active
nests, within and above the epidermal basal-cell
junctional nevus” [5]. The micrograph of the layer and within adnexal epithelium (Pagetoid
“activated junctional nevus immediately preced- appearance)
ing the development of infiltrating melanocarci- Marked variation in size and shape of the
noma” shown in Fig. 9 of their article of 1953 melanocytic nests
Confluence of melanocytic nests rather than discrete
clearly shows a melanoma in situ. What has been
nests
called a precursor by Allen and Spitz, would be Absence of maturation of melanocytes with descent
called a melanoma today. into the dermis
In the late 1960s and early 1970s, Clark in the Melanocytes with nuclear atypia
USA and McGovern in Australia propagated a Melanocytes in mitosis
“histogenetic” classification of melanoma, Necrosis or degeneration of melanocytes
2.1 Melanoma 9

melanoma was based on gross features such as expressed Antigen in MElanoma), examination
ulceration or bleeding. In the mid-1980s, how- of conventional slides stained with hematoxylin
ever, education campaigns such as the propaga- and eosin still remain the gold standard for the
tion of the ABCD criteria, which addressed diagnosis of melanocytic proliferations. There
health care professionals and the public alike, was, however, a certain hope that these difficul-
shifted the focus towards early recognition. ties in diagnosis will vanish with more sophisti-
Dermatoscopy, which became increasingly pop- cated molecular techniques. In the early 2000s
ular in the 1990s, improved the accuracy for the the molecular revolution in medicine gained
diagnosis of melanoma in comparison to inspec- momentum and new observations challenged our
tion with the unaided eye, especially for flat and concepts of melanoma biology. The first turning
small lesions lacking ABCD criteria. Finally, in point was the discovery of the significance of
January 1992, the National Institutes of Health BRAF mutations in melanoma and in nevi [21],
(NIH) held a consensus conference to discuss which was soon followed by the detection of
the clinical and histological characteristics of other tumorigenic mutations in other oncogenes
early melanoma [12]. The consensus panel [22] and climaxed in the description of the
agreed that melanoma in situ is a distinct entity. genomic landscape of melanoma [23, 24]. While
With this official acceptance of “melanoma in some of these discoveries translated into identifi-
situ” as authentic melanoma, the stage was cation of “druggable” biologic targets [25], the
finally set for early recognition to lift off. new insights into the genetic landscape of mela-
Increased public awareness, the availability of a noma did not translate into reliable diagnostic
new and affordable in vivo examination tech- methods for “borderline lesions.” Although
nique (i.e., dermatoscopy), and the lower hesi- molecular techniques such as fluorescence in situ
tancy of pathologists to diagnose melanoma in hybridization (FISH) [26] or comparative
situ acted in accordance: The incidence for mela- genomic hybridization (CGH) [27, 28] have been
noma skyrocketed and increased more than for used to better classify borderline lesions such as
any other type of cancer. Spitz tumors, they remain auxiliary techniques,
In the following years it was discovered that which need to be integrated with clinical and der-
dermatopathologists tend to disagree, not only matoscopic observations as well as with conven-
on concepts and terminology, but also whether a tional pathology [29]. The importance of genetic
given melanocytic proliferation is benign or alterations for the classification of melanoma has
malignant [1, 13–15]. Problems commonly been increased dramatically by the introduction
occur in lesions that are small or flat or have a of the new WHO classification of melanocytic
spitzoid morphology. For these “borderline” neoplasms in 2018 [30]. The WHO classification
lesions, the community invented terms with tried to integrate the complex and ever evolving
uncertain prognosis such as atypical Spitz tumor genetic landscape of melanoma with the classic
(AST) [16] and superficial atypical melanocytic histogenetic classification and with UVR-­
proliferation of uncertain malignant significance exposure. At present, even with the best will, this
(SAMPUS) [17]. undertaking can only be described as a piecemeal
Since the discovery of the S100 protein in effort, which has a certain theoretical but hardly
melanoma in the 1980s [18–20], a considerable any practical value. Some of the implicit and
number of other immunohistochemical markers explicit hypotheses that form the theoretical
have been used to assist in the differentiation of backbone of the new WHO classification look
melanocytic proliferations from other neoplasms. like ad hoc assumptions invented to save the clas-
Despite initial enthusiasm that some markers sic histogenetic model from falsification.
could also be used in the assessment of challeng- Furthermore, it can be expected that more sophis-
ing melanocytic neoplasms, and despite some ticated genomic analyses such as whole genome
encouraging results with the melanoma-­sequencing, methylation studies, and high resolu-
associated antigen PRAME (PReferentially tion spatial transcriptomics will become more
10 2 Historical Perspective

widely available in the future and will provide refer to nevi with a dermal pattern that differ
new insights into the interaction of germline mainly by anatomic location (Miescher nevus is a
mutations, somatic mutations, and UV-signature dermal nevus on the face and Unna nevus on the
mutations [31]. It is likely that these new insights trunk).
will make it necessary to adjust and revise the Historically, there is a long-lasting controversy
theoretical framework of the current classifica- about the origin of cells that make up a nevus and
tion and add new ad hoc assumptions. whether they should be called nevus cells, nevo-
The recent hype associated with artificial cytes, nevomelanocytes, or melanocytes. In the
intelligence (AI) and deep learning in image-­ 1950s, Arthur Allen still believed that melano-
based diagnostic medicine did not leave dermato- cytes in the epidermis develop from keratinocytes
pathology untouched [32]. It is, however, despite convincing evidence that they derive from
currently unknown how such algorithms will be the neural crest, which was suggested by Masson
used in clinical routine. Beyond fully automatic already in the 1920s [33]. Masson also proposed
diagnosis, which is the least likely use case, that nevi originate in the dendritic melanocytes of
potential roles of AI range from filters for triage, the dermoepidermal junction. The root of this
quality control, predictive models, quality assur- concept can be traced back to Unna, who sug-
ance, and decision support to the discovery of gested that epidermal cells move into the dermis
new knowledge. to give rise to intradermal nevus cells
(“Abtropfung”) in 1893 [34]. Although most stu-
dents of the subject concluded that Unna referred
2.2 Melanocytic Nevi to melanocytes, he did not specify which cells
move into the dermis. It was not possible to dif-
There is no coherent history of the histopathol- ferentiate melanocytes from keratinocytes with
ogy of melanocytic nevi. It is a fragmented land- certainty until Bloch in 1917 was able to localize
scape of individual observations with repeated melanocytes in the epidermis through identifica-
attempts to integrate them into a general classifi- tion of tyrosinase via the DOPA reaction [35]. In
cation of nevi, all of which have failed in one way contrast to Unna’s concept of “Abtropfung,”
or another. If the history of melanocytic nevi Cramer’s concept of “Hochsteigerung” is based
would be a movie, it would have a non-linear nar- on the idea that “nevus cells” ascend from the der-
rative replete with broken up chronologies, spi- mis into the epidermis.
rals, meanders, parallel developments, and story The current concept oof melanocyte precursor
lines that go nowhere. Fascinating and open to migration is based on experimental studies in
interpretation, like David Lynch’s acclaimed zebrafish, mice, and chicken. This work identified
movie “Mulholland Drive,” but difficult to follow two pathways of melanocyte migration, both
and full of riddles. located in the neural crest. One is the dorsolateral
In the past, many nevi were eponymously pathway, in which melanoblasts originating from
named after their first descriptors, such as the neural crest migrate into the epidermis along
Meyerson, Spitz, Reed, Clark, Unna, and the evolving somites and the axons of the spinal
Miescher nevus. We welcome the recent attempts nerves. The other, more recently identified path-
to abolish eponyms in dermatology and restrict way, is the dorsoventral pathway, in which mela-
ourselves to those eponyms that are part of the nocytes derive from Schwann cell precursors.
latest WHO classification. These are mainly the Kinsler et al. recently suggested a third pathway
two terms Spitz and Reed nevus and, with limita- that occurs around the time of gastrulation, pre-
tion, Meyerson nevus. In this book we will not sumably located within the mesoderm [36]. All
use the term “Clark nevus,” which has been used three migration patterns are important to under-
as a synonym for “dysplastic nevus” by those stand the patterns of congenital pigmentary disor-
who reject the term “dysplastic.” We will also not ders including those of congenital nevi. While the
use the terms Miescher and Unna nevus, which first two pathways explain segmental patterns like

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