An Illustrated Guide to Skin Lymphoma 2nd ed - L. Cerroni, et al., (Blackwell, 2004) WW

193 Pages·2004·11.24 MB·English

An illustrated guide to
Skin Lymphoma

To our colleagues, students, teachers and especially our patients

An illustrated guide to
Skin Lymphoma

Lorenzo Cerroni MD

Department of Dermatology
University of Graz, Medical School
Graz
Austria
Kevin Gatter BM, DPhil, MRCPath

Nuffield Department of Clinical Laboratory Sciences
John Radcliffe Hospital
Oxford
UK
Helmut Kerl MD

Department of Dermatology
University of Graz, Medical School
Graz
Austria

Second edition

© 1998, 2004 by Blackwell Publishing Ltd
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First published 1998
Second edition 2004

Library of Congress Cataloging-in-Publication Data
Cerroni, Lorenzo.
An illustrated guide to skin lymphoma / Lorenzo Cerroni, Kevin Gatter, Helmut Kerl.a2nd ed.
p. ;
cm.
Includes bibliographical references and index.
ISBN 1-4051-1376-6 (alk. paper)
1. SkinaCancer.
2. Lymphomas.
[DNLM: 1. Skin Neoplasmsadiagnosis.
2. Skin Neoplasmsatherapy.
3. Lymphomaapathology.
WR 500 C417i 2004]
I. Gatter, Kevin.
II. Kerl, Helmut.
III. Title.

RC280.S5C47 2004
616.99′477adc22
2004000860

ISBN 1-4051-1376-6

A catalogue record for this title is available from the British Library

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Printed and bound in Denmark by Narayana Press, Odder

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Editorial Assistant: Katrina Chandler
Production Editor: Fiona Pattison
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Contents

Preface, vi

1 Introduction, 1

Part 1 Cutaneous T-cell lymphomas, 7

2 Mycosis fungoides, 9
3 Sézary syndrome, 39
4 CD30+ cutaneous lymphoproliferative disorders, 45
5 Subcutaneous T-cell lymphoma, 59
6 Other cutaneous cytotoxic lymphomas, 66
7 Small–medium pleomorphic T-cell lymphoma, 80
8 Other cutaneous T-cell lymphomas, 83

Part 2 Cutaneous B-cell lymphomas, 89

9 Follicle centre cell lymphoma, 91
10 Marginal zone lymphoma and cutaneous
immunocytoma, 100
11 Plasmacytoma, 109
12 Large B-cell lymphoma, leg type, 112
13 B-lymphoblastic lymphoma, 117

14 B-cell chronic lymphocytic leukaemia, 120
15 Other cutaneous B-cell lymphomas, 123

Part 3 Blastic NK-cell lymphoma, 131

16 Blastic NK-cell lymphoma, 133

Part 4 Cutaneous Hodgkin lymphoma, 139

17 Cutaneous Hodgkin lymphoma, 141

Part 5 Other cutaneous lymphomas/leukaemias,
145

18 Cutaneous myelogenous leukaemia, 147
19 Cutaneous lymphomas in immunosuppressed
individuals (post-transplant lymphoproliferative
disorders, HIV-associated cutaneous lymphomas), 151

Part 6 Pseudolymphomas of the skin, 155

20 Pseudolymphomas of the skin, 157

Index, 177

v

Preface

guidelines for the management of patients with cutaneous
lymphomas.
The great strength of the first edition of this book was the
high quality and large number of illustrations. In this second
edition we have increased the number of illustrations by
50%; in addition, many of the figures printed in the first edi-
tion have been replaced by better ones. This was possible due
to the fine efforts of those working at Blackwell Publishing:
we are greatly indebted to Stuart Taylor, Katrina Chandler
and Fiona Pattison for the help and support provided in the
preparation of this second edition.
Of course, the decision as to whether or not our efforts
have produced a valid workaone that can be of help in the
diagnosis and management of patients with cutaneous
lymphomasarests with the readers. We hope that you will
find it helpful and that your patients will profit from it as, in
the end, this is the only consideration that counts in medicine.

Graz and Oxford, January 2004
Lorenzo Cerroni
Helmut Kerl
Kevin Gatter

We would like to thank once again the many clinicians and
patients who provided the essential material and information
necessary to prepare the book.
We would like to express special thanks to Uli
Schmidbauer, who prepared superb histopathological and
immunohistochemical sections, and to Werner Stieber, who
was responsible for the excellent quality of the clinical
pictures.

Acknowledgements

The positive response to the first edition of this book was
most gratifying. However, even as we were completing it, we
knew already that advances in the fields of haematopathology
in general and of cutaneous lymphomas in particular meant
we should need to review many concepts and beliefs in the
light of new discoveries and novel interpretations in the
future. This of course mirrors exactly what is happening daily
in all other fields of medicine. In fact, in the last few years
many entities have been further characterized and some have
been newly described. In addition, the field of cutaneous
lymphomas has been revolutionized by advances in the use of
immunohistological, molecular genetics and in situ hybrid-
ization techniques. In this context, for the second edition of
our book we have completely re-written most of the chapters
rather than just edited them.
Besides updating concepts and interpretation of single dis-
ease entities, we have added completely new chapters such as
those on cutaneous manifestations in myelogenous leukaemia
and on cutaneous lymphoproliferative disorders in immuno-
compromised patients. Some chapters have been deleted and
replaced by new ones that are completely changed (especially
those on cutaneous T-cell lymphomas other than mycosis
fungoides). In addition, several entities that were not
included in the first edition have been added in some of the
chapters. Finally, we have greatly expanded the chapter on
mycosis fungoides, the single disease entity that represents by
itself more than 50% of all cases of cutaneous lymphoma. In
short, this is more a new book than a second edition of the
old one.
One of the criticisms of the first edition was the absence of
in-text citations. We have now added this feature, and in
addition expanded greatly the number of references. The sect-
ions on clinical features, therapy and prognosis have also
been greatly expanded in every chapter in order to provide

vi

It is becoming increasingly evident that primary cutaneous
lymphomas represent distinct clinical and histopathological
subtypes of extranodal lymphomas [1–7]. They can be defined
as neoplasms of the immune system, characterized by a pro-
liferation of either T or B lymphocytes which show a particu-
lar tropism for the skin. Extracutaneous spread with lymph
node involvement can be observed during the course of the
disease.
Primary cutaneous lymphomas should be separated from
secondary skin manifestations of extracutaneous (usually
nodal) lymphomas, which represent metastatic disease and
are characterized by a different prognosis and treatment.
Because the histopathology of primary and secondary cutane-
ous lymphomas may be similar or identical [8], complete
staging investigations are needed to establish this distinction.
The standard definition of primary cutaneous lymphomas
is disease confined solely to the skin for at least 6 months
after complete staging procedures have been performed [4].
Recently, two of the authors (LC, HK) proposed changing
the definition to ‘no extracutaneous manifestations of the
disease at presentation’ [7]. The main reason for adopting
this definition is the need to classify the disease accurately,
and treat patients accordingly, at presentation, without wait-
ing for 6 months.

Clinical and biological differences between nodal and cutane-
ous lymphomas have prompted the development of specialized
classification schemes. In 1997, a European Organization for
Research and Treatment of Cancer (EORTC) Cutaneous
Lymphoma Study Group panel proposed a new classification
of cutaneous lymphomas based on recognized clinicopatho-
logical entities (Table 1.1) [4]. Although this classification is
easily assimilated into the widely accepted general lymphoma
classification (the World Health OrganizationaWHO system;
Table 1.2), as both are based on clinicopathological entities,
some conceptual differences exist [9]. The skin classification

Classification of cutaneous
lymphomas

is obviously expanded in certain areas to allow a detailed
description of individual types of cutaneous lymphoma. At
the time of writing, a combined EORTC/WHO classification
of skin lymphomas is being prepared.
In the following chapters we describe the clinicopatholog-
ical characteristics of lymphomas arising in the skin, with spe-
cial emphasis on primary cutaneous lymphomas. A guideline
for treatment is also included. In addition, a short discus-
sion of the inflammatory diseases that simulate lymphomas
(cutaneous pseudolymphomas) is provided.

Primary cutaneous lymphomas represent an heterogeneous
group of diseases with different clinicopathological presenta-
tions and prognostic features. In order to classify patients cor-
rectly, it is crucial that a complete clinical history is obtained
and integrated with histopathological, immunophenotypical
and molecular data. To take but one example, lesions of type
B lymphomatoid papulosis show histopathological features
that may be indistinguishable from those observed in myco-
sis fungoides, and differentiation in these cases can only be
achieved by correlation with the clinical picture.
As a general rule, complete staging investigations at pre-
sentation include physical examination, laboratory investiga-
tions, chest X-ray, ultrasound of lymph nodes and visceral
organs, computerized tomography (CT) scans and bone
marrow biopsy. Positron emission tomography is also being
increasingly used for staging of patients with cutaneous lym-
phoma. Patients with patch-stage mycosis fungoides or lym-
phomatoid papulosis do not require extensive investigations.
The necessity of bone marrow biopsy in patients with cutane-
ous marginal zone lymphoma is questionable.

Surgical specimens should be carefully removed, paying par-
ticular attention not to crush the tissue. Shave biopsies must

Surgical techniques

Examination of patients

Chapter 1 Introduction

1

2
Chapter 1

be avoided. Punch biopsies, although sometimes insufficient
for a definitive diagnosis, may be performed in special
instances (early lesions of mycosis fungoides).

Histopathology

Sections should be cut with a maximum thickness of 4 µm
and subsequently stained with haematoxylin and eosin
(H&E), periodic acid–Schiff (PAS) and, if possible, Giemsa.
High-quality sections are necessary for a correct diagnosis.

Immunophenotype

Modern immunohistochemical techniques allow the study of
phenotypical patterns on routinely fixed, paraffin-embedded
tissue sections [10–12]. The use of proteolytic enzymes
(trypsin) has been widely replaced by other antigen demask-
ing methods such as microwave heating of sections. In short,
tissue sections are placed in a microwave heater and heated
up to 100°C for 10–15 min, and then slowly cooled off before
application of the first antibody. Microwave heating can be
substituted by pressure cooking or by overnight incubation

Histopathology, immunophenotype
and molecular genetics

of sections at 80°C. A list of antibodies reactive with lym-
phocyte subsets and accessory cells (macrophages, dendritic
reticulum cells and interdigitating cells) in routinely fixed,
paraffin-embedded tissue sections is reported in Table 1.3.

Molecular genetics

Analysis of the T-cell receptor (TCR) and immunoglobulin
heavy-chain (JH) genes has provided a new and important
technique for the study of cutaneous lymphomas. Early in
their differentiation, T and B lymphocytes rearrange their
TCR and JH genes, respectively [13,14]. Analysis of the gene
rearrangement by Southern blot or polymerase chain reac-
tion (PCR) techniques provides clues to the clonality of a
given infiltrate. The PCR technique presents two main
advantages: (i) DNA can be extracted from routinely fixed
tissues; and (ii) the sensitivity is higher (5–10% of clonal cells
within a mixed cell population can be detected by Southern
blot analysis, compared to 1% by PCR). Benign (reactive)
lymphoid proliferations are characterized by a polyclonal
pattern of TCR and/or JH gene rearrangement. In contrast,
malignant lymphomas reveal a monoclonal population of
lymphocytes, identified as an additional band with the
Southern blot method and as a single band with the PCR
technique. Although these methods are effective and reliable,
they have some limitations: benign inflammatory dermatoses

Table 1.1 Classification of cutaneous lymphomas (EORTC Cutaneous Lymphoma Study Group).

T-cell lymphomas
B-cell lymphomas

Indolent behaviour
Indolent behaviour
Mycosis fungoides
Follicle centre lymphoma
Mycosis fungoides with follicular mucinosis
Immunocytoma
Pagetoid reticulosis
(marginal zone B-cell lymphoma)
Large cell cutaneous T-cell lymphoma, CD30+

anaplastic
immunoblastic
pleomorphic
Lymphomatoid papulosis

Aggressive behaviour
Intermediate behaviour
Sézary syndrome
Large B-cell lymphoma of the leg
Large cell T-cell lymphoma, CD30–

immunoblastic
pleomorphic

Provisional entities*
Provisional entities*
Granulomatous slack skin
Intravascular large B-cell lymphoma
CTCL, pleomorphic, small/medium-sized
Plasmacytoma
Subcutaneous panniculitis-like T-cell lymphoma

CTCL, cutaneous T-cell lymphoma.
*This group includes cutaneous lymphomas with insufficient data to delineate clear-cut
clinicopathological entities.

Introduction
3

may rarely present a monoclonal pattern, and a ‘germline’ or
polyclonal pattern may be observed in clear-cut lymphomas.
In addition, lack of sensitivity may give rise to negative results
in many cases of early cutaneous T- or B-cell lymphoma.
A common pitfall in molecular analysis of cutaneous lym-
phoproliferative disorders is the presence of ‘pseudomono-
clonal’ rearrangement of the JH gene in cutaneous lymphoid
infiltrates characterized by the presence of only a few B
lymphocytes. In fact, it is not uncommon to observe this
phenomenon in lesions of cutaneous T-cell lymphoma with
reactive B lymphocytes. A good rule is to perform at least two
(better three) separate extractions of DNA from different
sections of the biopsy tissue, and to run one independent
PCR assay for every extraction. In this way, different ‘pseu-
domonoclonal’ bands will be observed, thus showing overall
a polyclonal pattern.
Molecular analyses are also widely used in haematology to
identify particular genetic aberrations characteristic of a
specific clinicopathological entity, such as the interchro-
mosomal 14;18 translocation typical of nodal follicular lym-
phoma or the t(2;5) of nodal anaplastic large cell lymphoma.
Unfortunately, as yet only a few specific genetic alterations
have been identified in primary cutaneous lymphomas.

Fluorescence in situ hybridization technique

Chromosomal abnormalities are becoming increasingly
important in the study and classification of haematopoietic
neoplasms. In recent years, new methods have been devel-
oped for evaluation of tissue specimens fixed in formalin and
embedded in paraffin, allowing the investigation of routine
biopsy samples and archive material. The fluorescence in situ
hybridization (FISH) technique is based on the same prin-
ciple as the Southern blot method, relying on the annealing
of single-stranded DNA to complementary DNA.
Depending on the probes selected, the FISH method can
be used to detect different types of chromosomal abnormali-
ties, including monosomy, trisomy and other aneuploidies, as
well as translocations and deletions. The use of FISH applied
to routinely processed tissue specimens identified a hitherto
unknown t(14;18)(q32;q21) involving the JH and MALT1
genes in a subset of cases of primary cutaneous marginal zone
B-cell lymphomas [15].

Microarrays

The recent development of techniques of comparative
genomic hybridization, and the identification of over 19 000
human genes by the Human Genome Project, allows one to

Other methods in the study of
cutaneous lymphoid infiltrates

Table 1.2 The WHO classification of tumours of haematopoietic
and lymphoid tissues.

B-cell neoplasms
Precursor B-cell neoplasms
Precursor B-lymphoblastic leukaemia–lymphoma

Mature B-cell neoplasms
Chronic lymphocytic leukaemia/small lymphocytic lymphoma
B-cell prolymphocytic leukaemia
Lymphoplasmacytic lymphoma
Splenic marginal zone lymphoma
Hairy cell leukaemia
Plasma cell myeloma
Solitary plasmacytoma of bone
Extraosseous plasmacytoma
Extranodal marginal zone B-cell lymphoma of mucosa-associated
lymphoid tissue (MALT lymphoma)
Nodal marginal zone B-cell lymphoma
Follicular lymphoma
Mantle cell lymphoma
Diffuse large B-cell lymphoma
Mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
Primary effusion lymphoma
Burkitt lymphoma/leukaemia

B-cell proliferations of uncertain malignant potential
Lymphomatoid granulomatosis
Post-transplant lymphoproliferative disorder, polymorphic

T- and NK-cell neoplasms
Precursor T-cell neoplasms
Precursor T-lymphoblastic leukaemia/lymphoma
Blastic NK-cell lymphoma (neoplasm of uncertain lineage and stage
of differentiation)

Mature T- and NK-cell neoplasms
T-cell prolymphocytic leukaemia
T-cell large granular lymphocytic leukaemia
Aggressive NK-cell leukaemia
Adult T-cell leukaemia/lymphoma
Extranodal NK/T-cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides
Sézary syndrome
Anaplastic large cell lymphoma, primary cutaneous
Peripheral T-cell lymphoma, unspecified
Angioimmunoblastic T-cell lymphoma
Anaplastic large cell lymphoma

T-cell proliferation of uncertain malignant potential
Lymphomatoid papulosis

Hodgkin lymphoma
Nodular lymphocyte-predominant Hodgkin lymphoma
Nodular sclerosis classical Hodgkin lymphoma
Lymphocyte-rich classical Hodgkin lymphoma
Mixed cellularity classical Hodgkin lymphoma
Lymphocyte-depleted classical Hodgkin lymphoma